Professional Documents
Culture Documents
Robert M. Zacharko
Department of Psychology, Carleton University, Ottawa, Ontario, Canada K1S 586
Abstract: Aversive experiences have been thought to provoke or exacerbate clinical depression. The present review provides a brief survey of the stress-depression literature and suggests that the effects of stressful experiences on affective state may be related to depletion of several neurotransmitters, including norepinephrine, dopamine, and serotonin. A major element in determining the neuroehemical changes is the organism's ability to cope with the aversive stimuli through behavioral means. Aversive experiences give rise to behavioral attempts to cope with the stressor, coupled with increased utilization and synthesis of brain amines to contend with environmental demands. When behavioral coping is possible, neuroehemical systems are not overly taxed, and behavioral pathology will not ensue. However, when there can be no behavioral control over the stressful stimuli, or when the aversive experience is perceived as uncontrollable, increased emphasis is placed on coping through endogenous neuroehemical mechanisms. Amine utilization increases appreciably and may exceed synthesis, resulting in a net reduction of amine stores, which in turn promotes or exacerbates affective disorder. The processes governing the depletions may be subject to sensitization or conditioning, such that exposure to traumatic experiences may have long-term repercussions when the organism subsequently encounters related stressful stimuli. With continued uncontrollable stimulation, adaptation occurs in the form of increased activity of synthetic enzymes, and levels of amines approach basal values. It is suggested that either the initial amine depletion provoked by aversive experiences or a dysfunction of the adaptive processes, resulting in persistent amine depletion, contributes to behavioral depression. Aside from the contribution of behavioral coping, several organismic, experiential, and environmental variables will influence the effects of aversive experiences on neuroehemical activity, and may thus influence vulnerability to depression. Keywords: depression; loss; norepinephrine; separation; serotonin; stress; suicide
Considerable interest has focused on the contribution of aversive life events to both physiological and psychological pathologies (Selye 1973). Indeed, there is good reason to believe that stressful events participate in the induction of pathologies such as ulceration (Weiss 1971a; 1971b; 1971c), heart disease (see Glass 1977), and affective disorders (see reviews in Depue 1979), and may be a salient factor in modifying neoplastic disease (Sklar & Anisman 1981). The finding that stress has such a broad range of effects suggests two possibilities. First, one or more of the physiological changes engendered by stress may represent a common feature for disparate forms of pathology. Second, stress may provoke dysfunction in any number of physiological systems, and the nature of the pathology observed will depend on the particular system adversely influenced by the stress experience. The effectiveness of stressors in provoking pathology is dependent on the organism's ability to cope with these aversive experiences (henceforth "insults"). In this respect a great number of mechanisms are available to the organism in order to diminish the impact of the stressor. Not only will the organism rely on behavioral and psychological responses and on buffering the stress effect using socioenvironmental resources, but several
7982 Cambridge University Press
physiological changes will also occur whose function is primarily one of meeting environmental demands. Some of the physiological changes act to blunt the immediate physical and psychological attributes of the stressor, whereas others will protect the organism from potential health threats. At the same time, the directed mobilization of resources may leave the organism disposed toward, or at least unprotected from, the impact of other physical or psychological insults. Moreover, if the stress is sufficiently protracted, exhaustion of the resources necessary to contend with it may render the organism relatively unable to deal with further environmental insults. Although the term "stress" is widely used, we are not aware of any adequate definition of it (see, for example, the panel discussion on stress theory in Usdin, Kvetnansky, & Kopin 1980). Some investigators have considered stress as the organism's response to aversive events (Rabkin & Streuning 1976). Others have been more concerned with the controllability of the aversive event. For present purposes, stress will be considered the behavioral and physiological response to actual or impending aversive stimuli. In some instances, these responses represent adaptive changes that allow the organism to cope with the events; in others, they are physiological changes (e.g., immunological alterations)
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Anisman & Zacharko: Depression and stress that protect the health of the organism. Stressors include personal life changes and physical or psychological traumas, both actual and threatened. Terms such as "helplessness" will be reserved for hypothetical cognitive changes resulting from uncontrollable aversive events. The present paper will assess the contribution of stress to the precipitation of clinical depression and will evaluate the involvement of stress-related neurochemical changes in affective illness.
Stress as a precipitant of depression
Although stress has been implicated as a factor in the precipitation of depression in a subset of individuals (see review in Akiskal & McKinney 1973; 1975), support for this proposition has not been unanimous. For instance, some theorists have argued that the depressive reaction to stressors may be symptomatic of an already existent depression (Slater & Roth 1969) or that stressors precipitate hospitalization in already depressed individuals (Hudgens, Morrison, & Barchha 1967; Morrison, Hudgens, & Barchha 1968). Still others (e.g., Hinkle 1974) have ascribed a secondary role to stress in the promotion of illness. Unfortunately, disentangling the stress-depression relationship is complicated by the experimental techniques that are available and by the very nature of the illness. Depression is clearly not a unitary illness but appears to be best described in terms of subgroups of affective illnesses differing in symptomatology, therapeutic prognosis, familial history, and so forth (see the descriptions in Depue & Monroe 1979; Fowles & Gersh 1979). Indeed, even within a single "category" of depression interindividual differences in symptomatology are frequent. And, as will be seen later, available evidence points to the possibility that neurochemical substrates for depression are likewise complex and may differ among individuals. The response of individuals to natural or man-made catastrophes provides an opportunity to examine the incidence of affective illness. However, catastrophic events such as war, fire, and earthquake (Eitinger 1964; 1973; Star 1949; Swank 1949) are fortunately not frequent, so detailed analysis is not possible. Besides, many catastrophic events involve a host of variables with stressful components (including anxiety, fear and physical trauma, financial loss etc.) and as a result, their investigation provides little information concerning the potential impact of the more common life stresses. Furthermore, under such drastic conditions many social and cognitive factors, such as reliance on others, shared grief, social pressures, and modelling behaviors, may influence affective outcome. In addition, as will be seen in later sections of this paper, it is important to distinguish between transient and sustained stressors, since these may provoke very different physiological changes and could induce different behavioral outcomes. A second approach is that of retrospective analysis, in which stress history is assessed in depressed and nondepressed populations. It seems, however, that the individual's recollection of past events is not particularly impressive (Jenkins, Hurst, & Rose 1979). Furthermore, the perception of past events in depressed patients may be colored by their current affective state. An event that 90
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might ordinarily be considered a minor inconvenience could assume undue import for the depressed individual, whereas an apparently minor inconvenience from the perspective of the experimental protocol might, in fact, have been a significant event to the individual at the time it occurred. The utility of scaling procedures in the analysis of previous major changes in life-events has been seriously challenged. Rabkin and Streuning (1976) have questioned the reliability and validity of life-event scales, and have indicated that these procedures account for only a small portion of the variance associated with illness. Cross-cultural differences, as well as community lifestyle, also appear to be determinants of the subjective impact of stress. Furthermore, the time between a stressor and the depression may be a major constraint on whether one can conclude that a causal relationship exists between the two (for a detailed discussion of these and other related issues see Dohrenwend & Dohrenwend 1979; Rabkin & Streuning 1976). A third approach is that of the prospective study in which the instances of stress are monitored and related to the occurrence of later psychopathology. Here, as in the case of the retrospective studies, it is difficult to gauge the severity of a given event. The interpretation of an event depends not only on the various variables mentioned earlier, but also on the individual's previous history with similar types of stress. Furthermore, in both the retrospective and prospective analyses it is virtually impossible to assess individually (at least in quantitative terms) the potential impact of a series of apparently inconsequential events. By the same token, the elimination of environmental stimulation, as in the case of the individual who retires from a job or completes a longterm project, might be considered stressful. Finally (and again this applies to the retrospective studies as well), the impact of a stressor must be considered in the context of the various buffers that are available to the individual, such as familial support systems (Brown 1979; Clayton, Halikas, & Maurice 1972; Rabkin & Streuning 1976). A fourth approach has been to simulate "depression" by imposing relatively minor stresses in a laboratory situation (e.g., see reviews in Garber, Miller, & Seaman 1979). As indicated by Costello (1978), this approach is of dubious value. A performance change in a problemsolving task following induction of frustration or failure in college students in a contrived laboratory situation seems far removed from the emotional, motivational, affective, and somatic dysfunctions that characterize depressive syndromes. It should be mentioned, however, that a number of studies have evaluated the response to aversive uncontrollable events among depressed individuals (see review in Abramson, Garber, & Seligman 1980). Such studies have certainly provided essential information concerning attributional style in depressed populations. To analyze stress-depression relations, several additional issues must be considered. Apparently equivalent amounts of stress may have appreciably different affective consequences for different individuals. Likewise, depending on environmental circumstances (including previous history), profound intraindividual differences may occur in response to aversive events (see later discussion). Moreover, other things being equal,
Anisman & Zacharko: Depression and stress the particular pathology engendered by a stressor may also differ from one individual to another. It may be the case that a variety of experiential and environmental factors, acting singly or interacting with genetically based physiological processes, are responsible for the individual differences. In light of these caveats, it should be clear that conclusions concerning the relationship between stressful life events and depression must be considered cautiously. It is not our intention to adopt a narrow position concerning the validity of the conclusions derived from human experiments. However, despite the various shortcomings associated with the approaches described so far, it is significant that most studies have revealed depression to be associated with a high frequency of antecedent stressful life events (Lloyd 1980a; 1980b). Of course, these studies do not in themselves imply that all instances of depression are associated with stressful events, or that the relationship between stress and depression is a causal one. Life changes requiring social adjustment - as measured by the Holmes and Rahe (1967) life-change scale or modifications of this scale - in the 6-month to 1-year period preceding illness have been found to be predictive of depression and of suicide attempts (Briscoe & Smith 1975; Paykel 1979; Paykel, Myers, Dienelt, Klerman, Lindenthal, & Pepper 1969; Paykel, DiMascio, Haskell, & Prusoff 1975; Thomson & Hendrie 1972). In addition, recurrence of depression following remission is more frequent among individuals who have experienced significant life event changes (Paykel & Tanner 1976). Moreover, although stressful experiences were found to precede both depression and schizophrenia, the incidence of undesirable or hazardous events was greater in depressed populations (Beck & Worthen 1972; Jacobs, Prusoff & Paykel 1974). Several experiments (Jacobs et al. 1974; Lewinsohn & Amenson 1978; Paykel 1974; Vinokur & Selzer 1975) have indicated that the "unpleasantness" of the life event, rather than social adjustment per se, was more closely aligned with depression. Significantly, consistent with some of the earlier reports, stress of personal loss (death in the family, divorce, separation) yielded the greatest frequency of depression and attempted suicides (Clayton et al. 1972; Levi, Fales, Stein, & Sharp 1966; Parkes 1964; Paykel et al. 1969; Paykel, Prusoff, & Uhlenhuth 1971; Paykel et al. 1975; Sethi 1964), although other investigators have failed to find such a relationship (Forrest, Fraser, & Priest 1965; Hudgens et al. 1967). One additional factor should be emphasized at this point concerning the contribution of stress to endogenous and reactive types of depression. Thomson and Hendrie (1972) reported that increased life-change scores were associated with both reactive and endogenous depression, although somewhat higher life-change scores were evident in the former condition. In a similar fashion, Goodwin and Bunney (1973) reported that upon hospitalization, endogenously depressed patients did not always disclose stressful events that preceded illness onset; however, in some patients stress experiences that preceded hospitalization by as little as 1-2 months were disclosed after patients had been in hospital for several weeks. Similarly, Leff, Roatch, and Bunney (1970) and Paykel (1974) found a marked incidence of precipitating stress in patients diagnosed as endogenously depressed, although symptom manifestation did not appear to be highly related to their stress experiences. Taken together, these data suggest that despite the differences in symptomatology associated with endogenous and reactive or neurotic depression (Fowles & Gersh 1979), stressful events are not restricted to a single form of affective illness.
Early experience and coping factors
In addition to recent life-event changes precipitating depression, considerable data suggest that early life trauma (e.g., bereavement and separation) may increase vulnerability to later depression (see reviews in Lloyd 1980a; Heinicke 1973). Indeed, several investigators have reported that the death of a parent before a child is seventeen results in a substantial increase in the incidence of adult depression (Beck, Sethi & Tuthill 1963; Brown 1961; Forrest et al. 1965; Greer 1964; Dennehy 1966; Hill 1969; Hill & Price 1967; Caplan & Douglas 1969; Munro 1966; Munro & Griffiths 1969; Roy 1978; see reviews in Brown 1979; Lloyd 1980a). In contrast, bereavement under similar conditions is not associated with increased occurrence of bipolar illness (Hopkinson & Reed 1966). In a particularly interesting series of studies (see Brown 1979) it was reported that women who had lost a parent early in life were more vulnerable to depression as adults. This effect, however, was manifest only if these women encountered a further trauma in adulthood. In effect, the early stress sensitized the subjects to later stress, thereby increasing the probability of affective illness. The second interesting feature reported by Brown was that the presence of a confidant in adulthood counteracted the negative consequences of stressful experience. It seems that the effect of stress on depression may depend on the subject's early life history and on the individual's ability to cope with or buffer the impact of the stress through either behavioral or psychological means. Brown's studies not only underscore some of the salient variables that alter the individual's vulnerability to stress effects, but they also point to the fact that analyses of stress-related pathology should also consider life events beyond those that were immediate antecedents of illness onset. Although most studies have found a relation between early life trauma and vulnerability to depression, Crook and Eliot (1980) have indicated that many of these studies were methodologically flawed (i.e., not controlled for age, sex, and psychiatric history of the deceased parent) and consequently conclusions concerning the early stress-depression relationship should be held in abeyance. On the other hand, Lloyd (1980b) has suggested that despite the procedural weaknesses, the data do, in fact, imply a relationship between early-life stress and depression. Of course, it is not certain that the relationship between bereavement and depression is a causal one. It is possible that repercussions of the early loss, rather than bereavement per se, are actually responsible for the affective illness seen in adulthood. For example, as indicated by Lloyd (1980a), distress on the part of the surviving parent or financial difficulties resulting from the death of a family member may be
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Anisman & Zacharko: Depression and stress responsible for the psychological-behavioral changes. Alternatively, the stressful experience may result in loss of self-esteem or a sense of inability to control events, which in turn may predispose the individual to depression. One final point should be considered. It has been the view of several investigators that early-life trauma increases vulnerability to depression, not that it necessarily provokes depression. Accordingly, it would be expected that variables such as bereavement should increase the probability of depression in the face of a later pathogenic stimulus. Indeed, the literature survey conducted by Lloyd (1980a) reveals that only 20-40% of adult depressives had encountered early parental loss, suggesting that life stress probably interacts with other variables in determining affective changes (see Brown 1979). In effect, it may not be sufficient to consider the contribution of early-life trauma to depression in the absence of data concerning stresses that occur in adulthood (see later discussion concerning stress-induced neurochemical changes).
Cognitive models of stress-induced depression
While most theorists will probably accept the contention that coping factors are fundamental in determining behavioral or emotional consequences of stress, divergent views have been expressed concerning the mechanisms underlying stress-related pathology. One view that has received considerable attention of late deals with the cognitive changes induced by stress. For example, Beck (1976) has indicated that a cognitive triad of negative conceptions (negative perception of the self, negative views of past experiences, and negative expectations of the future) are associated with depression. In a similar fashion, Seligman and his associates (Klein & Seligman 1976; Miller & Seligman 1976; Seligman 1975; Seligman, Klein, & Miller 1976) have proposed that from experiences with uncontrollable events or events perceived as being uncontrollable the individual learns that he is "helpless" in determining outcomes, and consequently stops trying to influence his own destiny. The "helplessness" and the accompanying decline in motivation are responsible for the negative perceptions and negative affect characteristic of depression. Recently, Abramson, Seligman, and Teasdale (1978) have reformulated the "helplessness" hypothesis in terms of attributions formed in the face of uncontrollable events, and expectancies about later performance based on these attributions. The reformulated hypothesis attempts to account both for individual differences in response to uncontrollable events and for the conditions under which helplessness is generalized across environmental situations. According to this hypothesis, the immediate consequence of noncontingency or failure is a tendency to attribute the helplessness to a particular cause. The individual may assume that neither he nor anyone else could have altered the course of events (universal helplessness), or that he alone was unable to alter events (personal helplessness). The former represents an "external" attribution, the latter an "internal" one. The attribution will influence self-perceptions and will also determine expectancies of future performance.
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That is, personal helplessness may be accompanied by a loss of self-esteem, whereas "universal helplessness" may not have the same result. A second important dimension concerns the range of situations covered by attributions. That is, the helplessness may apply to a broad range of conditions (global) or to a narrow range (specific). It may be persistent (chronic) or brief (transient). The attribution may further be stable (recurrent or continuous) or unstable (shortlived or intermittent). In effect, pronounced individual differences may occur in response to a stressor, and variation can be expected in the generality and time course of the helplessness effect. Expectancy of performance is still seen as fundamental to the development of helplessness, but the expectancy is formed on the basis of attributions. Despite the apparent advantages of the reformulated helplessness hypothesis over the initial proposal, it is not without shortcomings. Its suitability as a model of depression has been challenged by several investigators (Costello 1978; Depue & Monroe 1978; Wortman & Dintzer 1978) and consequently these criticisms need not be reiterated. Suffice it to say that although depressed subjects do, in fact, report feelings of helplessness and hopelessness (Beck 1976), it is not clear that these features provoke depression rather than merely constituting symptoms of depressed affect. Moreover, as will be seen in the next section, considerable evidence exists suggesting that depression may result from neurochemical abnormalities, and hence that the feelings of helplessness may simply be a manifestation of these central changes.
A number of theorists have argued that depression is associated with dysfunction of neurochemical activity. Since numerous excellent papers are available on this topic (Murphy, Campbell, & Costa 1978; Post & Goodwin 1978; Schildkraut 1978; van Praag 1978a), only a limited review of this literature will be provided here. Two principal hypotheses have been advanced. One of these attributes depression to a functional deficiency in norepinephrine activity (NE) (Schildkraut 1970; 1978), while the other assigns a primary role to serotonin (5-HT deficiency) (Murphy et al. 1978). Mania, in contrast, is thought to be a result of increased amine activity or receptor supersensitivity secondary to a deficiency of central amines (Bunney, van Kammen, Post, & Garland 1979). As indicated by Schildkraut (1978), the NE and 5-HT hypotheses need not be considered mutually exclusive. Moreover, other central transmitters such as acetylcholine (ACh) and dopamine (DA) may also be associated with the depressive symptomatology (Bunney et al. 1979; Janowsky, El-Yousef, Davis, & Sekerke 1972). Several lines of research have supported the basic contention that one or more transmitters underlie the depressive symptomatology. These studies typically include analyzing brain tissue of suicide victims, examining amine and metabolites in blood, urine and cerebrospinal fluid (CSF), and determining the therapeutic effi-
Anisman & Zacharko: Depression and stress cacy of pharmacological treatments with demonstrated effects on central neurotransmission. To be sure, the available data are not conclusive and the experimental procedures are not without shortcomings; nevertheless, these diverse sources of data have converged on NE and 5-HT as two possible candidates prominent in affective illness. Post-mortem studies. The analysis of the biochemical concomitants of depression is hampered (as are other types of research dealing with depression) by the potential for misdiagnosis, and by the fact that the various forms of depression may differ not only in behavioral symptomatology but also with respect to the biochemical mechanisms underlying the illnesses. The analysis of post-mortem brain tissue is further hampered by the fact that the subject population is typically that of suicide victims and it is not clear whether such subjects are representative of the depressed population at large, nor is it clear what effects the cognitive processes preceding suicide have on brain neurochemical activity. Furthermore, the interval between death and tissue extraction varies considerably between subjects, contributing to the variance of the neurochemical levels observed. Finally, the drug history of the individual will alter brain amine levels, adding yet another source of confusion (see review in van Praag 1978a). Inconsistent results have been reported concerning NE concentrations in the brains of depressed subjects. Whereas some investigators (Bourne, Bunney, Colburn, Davis, Davis, Shaw, & Coppen 1968; Pare, Yeung, Price, & Stacey 1969) have found that NE levels do not differ between depressed suicides and controls, others (Birkmayer & Rederer 1975) have found reduced NE concentrations in the brain among depressives who died of causes other than suicide. More consistent results are available concerning 5-HT levels in the brains of depressed suicides. Several investigators, for example, have found decreases of 5-HT (Beskow, Gottfries, Roos, & Winoblad 1976; Bourne et al. 1968; Pare et al. 1969; Shaw, Kemps, & Ecclestone 1967), and analyses of discrete brain regions have revealed that the reductions were localized mainly in the raphe nuclei (Lloyd, Farley, Deck, & Hornykiewicz 1974). Several of these studies also indicated that the reduced 5-HT levels were accompanied by decreases in the concentration of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) (Bourne et al. 1968; Beskow et al. 1976). Cerebrospinal fluid. Consistent with the post-mortem analyses, indications of amine dysfunction have been derived through analyses of cerebrospinal fluid (CSF). It should be noted, however, that since metabolites of 5-HT are determined from CSF taken from the lumbar spinal region, the 5-HT is of mixed spinal and cerebral origin. Thus it is not particularly surprising that some inconsistencies are observed. When the probenecid technique is used to inhibit transport of 5-HIAA from the CNS (central nervous system) the observed results are more uniform. In the absence of probenecid, some investigators report a small decline in 5-HIAA production (Bowers, Heninger, & Gerbode 1969; Papeschi & McLure 1971), whereas others find no appreciable differences (Goodwin & Post 1974). However, Asberg, Thoren, Traskman, Bertilsson., and Ringberger (1976) have found reduced 5-HIAA concentrations in a subgroup of patients with unipolar depression. As indicated earlier, the mixed cerebral and spinal 5-HIAA in these studies may have contributed to the variable results. In addition, it has been reported (see van Praag 1980) that the nature of the depressive symptomatology may also be an essential element in determining whether 5-HIAA changes will be seen in CSF. In studies employing probenecid, the accumulation of 5-HIAA was reduced among individuals who exhibited symptoms characteristic of endogenous depression (Bowers 1969; van Praag, Korf, & Puite 1970). Van Praag and Korf (1971) have suggested that there are two subgroups of depressives, homogenous in symptomatology but biochemically heterogeneous. These investigators observed a bimodal distribution in 5-HIAA accumulation, with about 40% of depressives exhibiting reduced metabolite concentrations. In addition, it was found that the bipolar type of depression was associated with lower metabolite concentrations than the unipolar type (Roos & Sjostrom 1969; van Praag 1978b). It is of interest that van Praag and deHaan (1980) have recently reported that although 5-HTP alleviates depression in a subgroup of patients, the 5-HT deficiency seems to persist. These investigators posit that 5-HT depletion may not cause depression directly but may be a predisposing factor for the illness. Indeed, continued medication with 5-HTP seems to have a prophylactic effect on recurrent depression. With regard to the catecholamines, variable results have been reported concerning NE metabolites in depressed individuals. For example, several investigators found reduced levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) (Gordon & Oliver 1971; Post & Goodwin 1978; Post, Gordon, Goodwin, & Bunney 1973) but others found no such effect (Shopsin, Wilk, Gershon, Davis, & Suhl 1973). The latter investigators, however, did report increased MHPG levels associated with mania. In contrast to NE metabolites, decreased concentrations of the DA metabolite, homovanillic acid (HVA), have been reported in lumbar CSF of depressed patients (Bowers et al. 1969; Brodie, Sack, & Siever 1973; McLure 1973; Mendels, Fraser, Fitzgerald, Ramsay, & Stokes 1972; Nordin, Ottosson, & Roos 1971). These differences in HVA concentrations were most pronounced in retarded forms of depression, that is, where motor deficits were apparent (Mendels et al. 1972). In addition, the reductions in HVA concentration were less pronounced in unipolar than in bipolar depression (Ashcroft, Blackburn, Eccleston, Glen, Hartley, Kinloch, Lonergen, Murray, & Pullar 1973; van Praag & Korf 1975), although such a finding has not been consistently observed (Papeschi & McLure 1971). Using the probenicid technique, Berger, Faull, Davis, and Barchas (1979) found that accumulation of HVA concentrations was decreased in depressed subjects relative to controls, but neither 5-HIAA nor MHPG accumulation differed in these two groups. Likewise, van Praag and Korf (1975) reported reduced HVA concentrations in unipolar "vital" depression, and, as indicated by others, the reduced amine metabolite was accompanied by motor retardaTHE BEHAVIORAL AND BRAIN SCIENCES (1982) 5
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Anisman & Zacharko: Depression and stress tion. Inasmuch as HVA concentrations are not correlated with the severity of the depression, it is possible that the amine metabolite variations were secondary to motor changes associated with the affective state (Goodwin & Post 1975; Post, Kotin, Goodwin, & Gordon 1973; Sachar & Coppen 1975). Urinary metabolites. In contrast to metabolites of 5-HT in CSF, urinary metabolites have not been found to differ between depressed and nondepressed subjects (Fraser, Pandy, & Mendels 1973). With respect to NE, renal excretion of the metabolite normetanephrine was reduced during depressed periods relative to nondepressed periods in these same subjects (Greenspan, Schildkraut, Gordon, Levy, & Durell 1969). However, since normetanephrine reflects peripheral as well as central NE activity, these data must be considered cautiously. In the case of MHPG, it was reported that more than 60% of this urinary metabolite originates in the brain (Maas, Dekirmenjian, Garver, Redman, & Landis 1973), and that this consequently represents an adequate index of central NE activity (Maas, Greene, Hattox, & Landis 1979). In contrast, when MHPG conjugates and vanillylmandelic acid were considered in the analysis of urinary MHPG, it was concluded that only 20% of the metabolite was actually derived from brain norepinephrine (Blomberg, Kopin, Gordon, Markey, & Ebert 1980). Accordingly, it may be premature to accept MHPG concentrations as genuinely reflective of central NE activity. Consistent with a catecholamine hypothesis of depression, it has been reported that MHPG concentrations were lower in depressed than in nondepressed patients (Fawcett, Maas, & Dekirmenjian 1972) and were associated with anxiety in depressed subjects (Beckman & Goodwin 1975). However, other investigations (Coppen, Rama Rao, Ruthven, Goodwin, & Sandier 1979) have been unable to detect differences in urinary excretion of MHPG between depressive and control populations. Furthermore, in a within-subject design, greater MHPG excretion rates have been reported to occur during manic than depressed phases (see review in Goodwin & Potter 1979) although there exist contradictory data in this regard (cf. Bond, Jenner, & Sampson 1972; Bunney, Goodwin, & Murphy 1972; Edwards, Spiker, Kupfer, & Neill 1979; Greenspan, Schildkraut, Gordon, Baer, Aranoff, & Durrell 1970). Several investigators have provided evidence suggesting that there may be biochemically and pharmacologically distinct subgroups of depressives (Goodwin, Cowdry, & Webster 1978; Maas 1975). Specifically, patients with primary affective disorders who excrete relatively small quantities of MHPG respond more favourably to imipramine, desipramine (Maas, Fawcett, & Dekermenjian 1972), and nortriptyline (Hollister, Davis, & Berger 1980) than do patients with high MHPG excretion rates. Conversely, a more favourable therapeutic response to amitriptyline has been observed among patients who exhibit high levels of MHPG excretion (Schildkraut 1973; Beckman & Goodwin 1975). Thus, in cases where depression is associated with reduced NE activity, tricyclic agents that preferentially influence NE uptake are most efficacious, whereas in the presence of adequate NE activity but possibly reduced 5-HT neuronal functioning, drugs with greater effects on 5-HT reuptake are most beneficial. In addition to these subclassifications, lower concentrations of MHPG have been reported in bipolar patients than in other depressions (Goodwin & Potter 1979; Maas, Dekermenjian, & Jones 1973; Schildkraut, Keeler, Grob, Kantrowich, & Hartmann 1973). Moreover, Schildkraut, Orsulak, Schatzberg, Gudeman, Cole, LaBrie, and Rohde (1979) were able to distinguish biochemically among several subgroups of depression. That is, bipolar depression and schizo-affective depression were found to be associated with low urinary MHPG, lowered NE excretion, and low platelet MAO activity. Schizophrenia-related depressions were also characterized by low MHPG excretion, low epinephrine and metanephrine excretion, and high platelet MAO activity. The unipolar nonendogenous depressions were characterized by high MHPG levels, while heterogeneous biochemical results were seen among unipolar endogenous patients. In summary, it appears that the contribution of norepinephrine may vary with different forms of depression. In addition, consistent with the data discussed earlier concerning amine metabolites in CSF, the data derived from studies dealing with urinary amine metabolites suggest that even within a single subtype of depression, heterogeneity may exist with respect to the relative contributions of NE and 5-HT. Therapeutics. Strong evidence supporting the amine hypotheses of depression is derived from clinical studies showing that drugs with known catecholamine or 5-HT action have predictable effects on affective disorders. Before describing these data, however, we must interject one important caveat: In assessing the effects of pharmacological treatments on depression, it should be understood that the drugs may influence the affective symptomatology without necessarily altering the substrate (i.e., the etiology) of depression. The amine uptake inhibitors, imipramine, desmethylimipramine, chlorimipramine, and amitriptyline, have been shown to alleviate depression, although the effects of these agents vary among individuals. For example, as indicated in the preceding section, imipramine and desmethylimipramine, which have strong effects on NE reuptake, are most effective in patients exhibiting low urinary MHPG excretion rates, while amitriptyline is effective in other instances (Beckman & Goodwin 1975; Maas et al. 1972; see the review in Kupfer & Detre 1978, concerning the preferential therapeutic action for different types of depression; Schildkraut 1978). Furthermore, the selective 5-HT reuptake inhibitor, zimelidine, also appears to have potent antidepressant prbperties (Aberg & Holmberg 1979). A number of studies have evaluated the effects of the 5-HT precursors, tryptophan and 5-hydroxytryptophan, alone or in combination with MAO (monoamine oxidase) inhibitors on depression. These studies are based on the proposition that depression is associated with reduced 5-HT at postsynaptic receptor sites, and hence that precursor loading should have a positive therapeutic
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Anisman & Zacharko: Depression and stress effect. It should be understood, however, that the deficiency may reflect a receptor dysfunction, rather than deficits in levels of the monoamine. In the case of tryptophan the data are inconclusive. Coppen, Shaw, Hersberg, and Maggs (1967) have reported that tryptophan alleviates depressive symptoms. However, Dunner and Goodwin (1972) and Bunney, Murphy, and Goodwin (1970) did not observe 1-tryptophan to effectively reduce the depressive symptomatology. As with tryptophan, variable results have been reported with 5-HTP, although precursor loading was found effective in a subgroup of unipolar depressives (Brodie et al. 1973; Takahashi, Gondo, & Keto 1975; van Praag, Korf, Dols, & Shute 1972). Van Praag and Korf (1971) found 5-HTP to be most effective in patients with indications of central 5-HT deficiency, and the therapeutic effectiveness of 5-HTP was not found to differ from that of other antidepressants (Angst, Waggon, & Schopef 1977; van Praag 1978a; 1978b). Finally, when administered in combination with chlorimipramine, 5-HTP was found effective in alleviating depression (van Praag 1978b; van Praag et al. 1972; Walinder, Scott, Nagy, Carlson, and Roos, 1975). In the case of catecholamine precursor loading through tyrosine, only weak evidence has been provided concerning catecholamine involvement in depression. However, it has been reported that in a subgroup of depressives particularly marked elevations of plasma tyrosine levels occurred after oral administration of the compound, possibly suggesting retarded production of NE from its precursor (Takahashi, Utina, Mashiyama, Kurihama, Otsuka, Nakamura, & Konamura 1968). Despite the similarly inconclusive results obtained with tryptophan loading, van Praag (1980) has indicated that the tryptophan studies to date have not been conducted in patients classified on the basis of biochemical dysfunction. Moreover, a critical range of tryptophan concentrations may be necessary in order for any therapeutic efficacy to be evident. It is likewise possible that tyrosine loading will only be effective in a subgroup of depressives, and that studies will require classification of subjects on the basis of biochemical characteristics. Although a number of agents that stimulate catecholamine neurons (e.g., monoamine oxidase [MAOJ inhibitors and tricyclics) alleviate depression, drugs such as 1-dopa, which increase DA levels, are effective exclusively in reducing motor effects associated with retarded depression (Weiss, Kupfer, Foster, & Delgado 1974). More recent experiments, however, have shown that a subgroup of depressives characterized by low levels of homovanillic acid in CSF responded favorably to DA agonists, such as peribedil, nomifensine, and 1-dopa (see Post 1978; Post, Jimersom, Reus, Goodwin, Silberman, & Bunney 1979; van Scheijen, van Praag, & Korf 1977). Such findings led Post (1978) to suggest that DA, possibly in conjunction with several other neurotransmitters, may be fundamental in determining the affective symptomatology, at least in a subgroup of depressives. With regard to the contribution of ACh to affective disorders, it has been suggested that depression and mania may reflect an imbalance in cholinergic and noradrenergic functioning. Depression is thought to result from cholinergic dominance and mania from noradrenergic dominance (Davis & Janowsky 1975; Shopsin, Janowsky, Davis, & Gershon 1975). Indeed, the anticholinesterase, physostigmine, has been shown to reduce mania and elicit depression (Janowsky, ElYousef, Davis, & Sekerke 1972; Janowsky, El-Yousef, Davis, Hubbard, & Sekerke 1972; Janowsky, El-Yousef, Davis, & Sekerke 1973a; 1973b). It is interesting that Shopsin et al. (1975) have found the treatment of manic patients with physostigmine initially to result in attenuation of manic symptoms, followed several hours later by intensification of the manic behavior. It is suggested that a compensatory rebound reflecting noradrenergic dominance may be responsible for the heightened mania. Although the data are intriguing and lend themselves to an interactive chemical model of affective disorder, difficulties in analyzing endogenous ACh activity have prevented a more complete exploration of this proposition. Although the NE and 5-HT hypotheses of depression have received considerable attention, it is important to indicate at this juncture that recent reviews of the NE involvement in depression have taken a different tack. In particular, it has been suggested that depression may not be associated with reduced NE levels, but rather may actually be a reflection of hypersensitive postsynaptic NE receptors (Sulser, Vetulani, & Mobley 1978). The heightened NE receptor activity may, for example, result in exaggeration of a negative affect and may exacerbate the response to environmental stimuli with negative valence. Maas and Huang (1980) have recently reviewed some of the literature in support of such a proposition. Much of the support derives from the finding that the effects of antidepressants, such as desmethylimipramine, are not apparent until 2-4 weeks after commencement of the treatment. Yet the effects of desmethylimipramine on NE reuptake are seen both after acute and chronic treatment with the drug (Schildkraut, Winokur, & Applegate 1970). Moreover, contrary to the view that depression is associated with reduced NE, chronic treatment with desmethylimipramine has been shown to result in decreased brain NE and tyrosine hydroxylase activity (Segal, Kuczenski, & Mandell 1974; Schildkraut et al. 1970), reduced firing rates in cells in the locus coeruleus (Svensson & Usdin 1978) and increased firing rates in hippocampal neurons normally inhibited by NE input from the locus coeruleus (Huang 1979). Finally, chronic treatment with desmethylimipramine has also been shown to decrease the sensitivity of presynaptic autoreceptors (Crews & Smith 1978) and postsynaptic /3-adrenergic receptors (Banerjee, Kung, Riggi, & Chanda 1977; Sulser et al. 1978). On the basis of these findings, Maas and Huang (1980) have suggested that depression is associated with increased postsynaptic NE receptor sensitivity. The heightened postsynaptic receptor sensitivity is accompanied by an increase in the sensitivity of autoreceptors, which in turn decreases impulse flow, thus accounting for the reduced MHPG associated with depression. The efficacy of desmethylimipramine treatment, according to this formulation, is derived from a decrease in postsynaptic receptor sensitivity, which occurs after repeated treatment with the drug.
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We have on several occasions reviewed the neurochemical as well as the hormonal consequences of stress (Anisman 1978; Anisman, Kokkinidis, & Sklar 1981; Sklar & Anisman 1981). Accordingly, only a synopsis of this literature will be presented here, with an emphasis on the relationship between neurochemical consequences of stress and neurochemical concomitants of depression. As indicated earlier, a fundamental feature of our hypothesis is that stress influences neurochemical activity and that the nature and extent of the neurochemical changes are dependent on a series of organismic, environmental, and experiential factors. When an organism encounters aversive stimuli, it adopts defensive behaviors to avoid or terminate these stimuli. Concurrently, several neurochemical changes occur whose function appears to be to facilitate the organism's behavioral response as well as to maintain the biological integrity of the organism. Specifically, soon after stress inception, synthesis and utilization of NE is increased in a wide variety of brain regions (see reviews in Anisman et al. 1981; Stone 1975; Welch & Welch 1970). Such effects are not restricted to any single stressor, but have been shown to occur following a number of physical stressors. When the organism is able to terminate stress through behavioral means, amine utilization is not excessive and synthesis keeps pace with release (see discussion in Anisman et al. 1981). However, when behavioral control over stress is not possible, the utilization of brain amines increases and exceeds synthesis, consequently resulting in reduced levels of NE. Indeed, two groups of investigators (Anisman, Pizzino & Sklar 1980; Weiss, Glazer, & Pohorecky 1976) have shown that depletion of NE will not occur after escapable shock; however, application of an identical amount of uncontrollable shock in a yoked paradigm (i.e., where shock offset is contingent upon the responses of the animal receiving escapable shock), resulted in depletion of NE in the hypothalamus, hippocampus, and cortex. It has similarly been reported that if rats are shocked in pairs and permitted to fight - a response that may serve as a coping response (see Weiss, Pohorecky, Salman, & Gruenthal 1976) - the NE depletion otherwise produced by stress will not occur (Stolk, Conner, Levine, & Barchas 1974). Like NE neurons, DA neurons become more active following stress; however, these variations are restricted to certain specific brain regions, notably the nucleus accumbens (Thierry, Tassin, Blanc and Glowinski, 1976), the mesolimbic frontal cortex (Blanc, Herve, Simon, Lisoprawski, Glowinski, & Tassin 1980), and the arcuate nucleus of the hypothalamus (Kobayashi, Palkovits, Kizer, Jacobowitz, & Kopin 1976; Kvetnansky, Mitro, Palkovits, Brownstein, Torda, Vigas, & Mikulaj 1976). When DA activity is measured in other regions, such as the substantia nigra or the whole hypothalamus, changes in neuronal activity are typically not evident (Thierry et al. 1976; Kobayashi et al. 1976). Although depletion of whole-brain DA is not evident after uncontrollable stress, DA depletions are observed in more discrete brain areas such as the frontal cortex (Blanc et al. 1980) and the arcuate nucleus (Kvetnansky et al. 1976). There are as yet no data directly evaluating the effects of stress 96
THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5
controllability on DA levels in discrete brain regions. However, Cherek, Lane, Freeman, and Smith (1980) have reported that in the frontal mesolimbic cortex, where DA utilization is increased, DA receptor sites are less available in rats that have received uncontrollable shock than rats that have received escapable shock. As in the case of DA and NE, exposure to aversive stimuli was shown to increase the turnover of 5-HT (Thierry, Javoy, Glowinski, & Kety 1968; Thierry, Fekete, & Glowinski 1968). It seems, however, that the stress severity necessary to provoke 5-HT utilization differs from that needed to elicit NE utilization. Specifically, it seems that moderate stress increases the release of NE from the functional storage pools, whereas severe stress results in release from the main storage area. Release of 5-HT from the functional pools, in contrast, requires exposure to a relatively severe stressor (see Thierry 1973). Several investigators have shown that stress of sufficient severity will result in reductions in 5-HT levels (Telegdy & Vermes 1976). However, such an effect is dependent on the brain region examined and the time after aversive stimulation at which tissue is extracted. For example, within 10 min. of stress, 5-HT reductions are seen in the dorsal raphe nucleus, but within 30 min., control levels are attained, and an increase of 5-HT is evident 2 hr. after stress. In the median eminence and forebrain bundle, the depletion at the 10-min. interval is less pronounced, and increased 5-HT concentrations are evident 30 min. after exposure to a stressor (Palkovits, Brownstein, Kizer, Saavedra, & Kopin 1976). Finally, with respect to ACh it has been found that stress will increase levels of this amine, but unlike the rapid catecholamine changes, increased ACh does not occur until about 1 hr after stress termination (Zajaczkowska 1975). Moreover, decreased ACh turnover has been observed in the frontal cortex after 1 hr. of restraint plus cold, but turnover rates approach control values after 4 or 24 hr. of restraint plus cold. In the hypothalamus, the reduced turnover is evident after 1, 4, or 24 hr. of stress (Costa, Tagliamonte, Brunello, & Cheney 1980). These investigators postulate that the ACh changes in the frontal cortex may be secondary to reduced DA levels provoked by stress, while the hypothalamic alterations represent changes in neurons intrinsic to this region. Finally, only limited data are available concerning the effects of stress controllability on ACh levels or turnover. It has been reported that compared to controllable stress, the availability of ACh receptor sites is increased by uncontrollable stress (Cherek et al. 1980) and there are data provisionally suggesting that the changes in ACh levels are dependent on stress controllability (Karczmar, Scudder, & Richardson 1973). It seems that an organism is able to deal with aversive events through both behavioral and neurochemical means. Although neurochemical systems function effectively under most conditions, when the stress is uncontrollable and sufficiently protracted, excessive neurochemical utilization may ensue. Such neurochemical changes may be manifested behaviorally as affective disorders. It should be emphasized that there is no reason to expect that all individuals will respond to a given stressor in a like manner. Experiments with
Anisman & Zacharko: Depression and stress infrahuman animals have shown wide differences in neurochemical change across strains (Ray & Barrett 1975; Winner, Norman, & Eleftheriou 1974). Accordingly, it is theoretically possible that in humans uncontrollable stress will result in an excessive utilization and consequent depletion of NE or 5-HT or both, as well as a depletion of DA and increases in ACh. In effect, a dramatic change in a particular system would represent inadequate ability to adapt to environmental demands. Just as neurochemical variations occur across strains, it has been shown that the depletion of NE in the face of uncontrollable stress is detectably more pronounced in older rats than in younger ones (Ritter & Pelzer 1978). If this were true in humans as well, older people would be more disposed to affective consequences of stress. It should be noted here that in the aged the loss of buffering systems - the result, for instance, of the death of a spouse or of isolation from family members - may not only represent a stressor in its own right, but may also dispose the individual to greater neurochemical lability owing to lesser coping ability. Finally, animal experiments have revealed that social housing conditions influence neurochemical activity and also determine the nature and magnitude of stressrelated neurochemical lability (Blanc et al. 1980). Furthermore, neurochemical lability ordinarily induced by uncontrollable stress are modifiable if animals engage in coping attempts through fighting (Modigh 1976; Stolk et al. 1974; Welch & Welch 1970). Fighting, incidentally, has also been shown to modify the effects of stressors and the development and growth of carcinogen-induced tumors (Sklar & Anisman 1980). In addition to the organismic and environmental variables just discussed, it appears that the neurochemical consequences of stress are dependent in great measure on the organism's prior history. We have shown, for example, that although the NE depletion provoked by uncontrollable stress persists for only a few hours, the amine depletion is reinduced if animals are subsequently exposed to a relatively mild stress that ordinarily has little effect (Anisman & Sklar 1979). Likewise, Cassens, Roffman, Kuruc, Orsulak, and Schildkraut (1980) have reported that a CS (conditioned stimulus) that has previously been paired with shock will increase NE utilization; and Hingtgen, Smith, Shea, Aprison, and Gaff (1976) have found that a CS will increase ACh levels. Exposure to traumatic stress may sensitize the organism to a similar stress or cues associated with the stress. In human studies, it will be recalled that stress applied early in life, particularly in the form of separation, is associated with later depression. As indicated by Brown (1979), these affective changes are most prominent if the individual has suffered parental loss as a child and is subsequently exposed to stress as an adult. In assessing stress-related pathology, it is important to consider that the chronicity of the stress is an important feature in determining neurochemical lability. Although a single session of uncontrollable stress may result in NE depletion, such an effect is absent if animals are exposed to either repeated stress sessions or a single protracted session of uncontrollable stress (Kvetnansky et al. 1976; Weiss et al. 1976). Likewise, the depletion of 5-HT induced by uncontrollable stress will not be evident if the stress session is of protracted duration (Palkovits et al. 1976). It seems that with chronic stress, tyrosine hydroxylase, dopamine-/3-hydroxylase, and tryptophan hydroxylase activity are increased, thereby assuring adequate supplies of brain NE and 5-HT. Such adaptive changes have been seen not only in the central nervous system, but also in peripheral neurotransmitters, and in their synthetic enzymes (Kvetnansky 1980). Moreover, changes in immune functioning, in hormonal activity as well as in the development and growth of transplanted, carcinogen-induced, and spontaneous tumors in animals vary with stress chronicity (see review in Sklar and Anisman 1981). It is conceivable, however, that the neurochemical adaptation that occurs with chronic stress is not equally efficient among all individuals. While adaptive changes in the form of increased enzyme activity may occur in most individuals, thereby preventing psychopathology, a deficit in one or the other of the enzymes may result in insufficient storage of an amine following chronic stress, eventually culminating in affective illness. This proposal, although highly provisional, warrants consideration. The neuronal changes following chronic stress are not restricted to increased activity and levels of brain NE and 5-HT. It will be recognized that equivalent levels of NE in nonstressed and chronically stressed animals do not imply equivalent neuronal activity. On the contrary, the return to normal amine levels in chronically stressed animals is a consequence of a compensatory increase in amine synthesis, but utilization continues at an enhanced rate. In addition, Weiss et al. (1976) have found that NE reuptake diminishes following chronic stress. Thus the increased NE may act at the postsynaptic site for a longer duration. Accordingly, the organism may become over-stimulated, at least in neuronal terms. Stone (1979a) has provided data concerning the presence of yet another adaptive change. Following chronic stress it was found that NE-sensitive cyclic AMP was reduced, possibly suggesting NE receptor subsensitivity. Either as a result of the excessive stimulation or as a direct consequence of the chronic stress the sensitivity of the postsynaptic neuron is reduced, thereby deterring excessive stimulation. As indicated earlier, after treatment with tricyclic antidepressants, receptor subsensitivity ensued. Stone (1979b) is one worker who has suggested that some of the symptoms of depression (e.g., insomnia, anorexia, anxiety) may arise owing to variations in neurochemical activity (e.g., increased sensitivity of NE neurons or changes in a nonnoradrenergic system). It is thought that emotional-laden stimuli may provoke some of the symptoms associated with depression. Depression, according to this view, reflects neurochemical alterations which may heighten the emotional response of depressed individuals to acutely stressful stimuli. Treatment with desmethylimipramine or exposure to chronic stress do not necessarily affect the immediate causal factors in depression, but will result in the blunting of the exaggerated emotional response to incoming stimuli.
Overview
As indicated earlier, there is reason to believe that aversive events may precipitate or exacerbate clinical
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Anisman & Zacharko: Depression and stress depression. To be sure, this view has not been unanimously endorsed, and serious shortcomings in the human experimental data have been documented. However, if there is truth to the contention that stressful events provoke or increase vulnerability to depression, it may be fruitful to consider the neurochemical events induced by stress as a fundamental feature in the stress-depression relationship. It is our view that in the face of aversive experiences, a series of neurochemical changes occur which may be essential in behavioral attempts to cope with stress and instrumental in preventing various forms of pathology (see Sklar and Anisman 1981). When the aversive events are sufficiently severe, and behavioral coping mechanisms fail, depletion of transmitters may culminate in depression. It should be emphasized that we are not proposing that any one neurotransmitter is principally involved in depression, but rather that biochemically distinct subgroups of depression may exist, each involving dysfunction of one or more transmitters. The contribution of stress to these subgroups of depression has yet to be determined; however, as a working hypothesis we have considered that stress may differentially influence neurochemical activity across individuals, possibly reflecting the ability of the synthesis rates of various transmitters to keep pace with utilization. Figure 1 is a schematic representation of the changes in NE that occur under various stress conditions. Following acute uncontrollable stress, NE synthesis and utilization increase to a comparable extent. Welch and Welch (1970) have also suggested that MAO may be transiently inhibited, thereby increasing NE levels and ensuring adequate stores of the transmitter, at least over the short run. Stressors with such an effect would not be expected to lead to depression. Indeed, quite to the contrary, heightened arousal (or vigilance) may ensue. If the stress is uncontrollable, a further increase of NE utilization occurs in order to compensate for the lack of behavioral coping. As a result, synthesis may not keep pace with utilization, and depletion will be observed. Recall that uncontrollable stress will also result in 5-HT depletion, reduction of DA in some brain regions, and an increase of ACh. One, or probably more than one, of these changes may result in behavioral depression. At this point we cannot specify the relationship between the various symptoms of depression and the corresponding neurochemical alterations. For example, as depicted in Figure 1, depression may be a result of brain NE depletion. Alternatively, depression may be a reflection of postsynaptic receptor effects (vis-a-vis excessive stimulation resulting from increased amine release or hypersensitivity owing to the depletion itself). Furthermore, 5-HT, DA, and ACh changes may all provoke different symptomatologies. Indeed, the various subtypes of depression may reflect dysfunction of a single transmitter or the interaction of several neurochemical events. We would expect that individual differences in response to stresses of equivalent severity would reflect the adaptability of the neurochemical system. Those organismic or experiential factors that lend themselves to heightened utilization, together with the rapid and pronounced amine depletion, would likewise render the organism more vulnerable to affective illness. Thus, for
NO STRESS
BRIEF STRESS
Figure 1. A schematic representation of changes in NE levels, synthesis, utilization, and reuptake as well as MAO activity after various stress conditions. In the face of mild, brief stress, NE levels rise, possibly owing to a transient inhibition of MAO activity. If the stress is more prolonged the inhibition is no longer present. In the case of escapable stress, the amine level remains stable since increased utilization is accompanied by increased synthesis. When the stress is uncontrollable, NE utilization rates exceed synthesis, resulting in the reduction of the amine level. Following chronic stress a further increase in synthesis results in adequate levels of NE. In addition, NE reuptake is blocked, and hence the released NE may activate receptors for a longer duration. Not shown in the figure is the finding that chronic stress may reduce NE-sensitive cAMP (cyclic AMP).
example, organismic variables such as age or genetically determined dysfunction of catecholamine turnover would be most likely to provoke stress-induced affective disorders. It should be underscored, however, that the availability of behavioral or social coping mechanisms may reduce demands on neurochemical compensatory systems, thereby minimizing instances of depression. Under normal conditions the NE, DA, and 5-HT depletions which occur after acute uncontrollable stress are not evident following chronic stress exposure. It seems that following chronic stress a compensatory increase in tyrosine hydroxylase and tryptophan hydroxylase reinstates adequate amine levels. In addition, blocked reuptake maximizes the efficiency of released amine substances. The integrity of such adaptive systems may be essential in order to deal with severe, traumatic life events and even with the sustained presence of moderate life stressors. The failure of such an adaptive
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Commentan//Anisman & Zacharko: Depression and stress system and the resultant diminished supply of amines may lead to depression. At the outset of this paper, it was indicated that there were interindividual differences in the affective consequences of a given stressor and in the nature of the pathology engendered by stress. Considering the second of these issues first, it should be recognized that a variety of changes, aside from neurochemical alterations, may be provoked by stress - immunological, hormonal, or steroidal changes, for example. Dysfunction in any one of these adaptive systems could provoke pathology. Furthermore, a change in one system with apparent beneficial consequences for affective processes could have detrimental effects on other attributes of the organism. For example, the excessive utilization of amines to cope with stress may result in ACTH secretion from the pituitary and hence increased release of adrenocorticosteroids. The corticosterone may in turn inhibit /3-lymphocytes, thereby increasing the probability of immunologically-related illness. With respect to the differences in the affective response to a stress of a particular severity, it should be considered that any number of adaptive failures (e.g., rapidity and duration of initial amine depletion, failure of tyrosine hydroxylase or tryptophan hydroxylase activity with chronic stress) would increase the probability of stress-induced depression. Genetic factors could theoretically determine the adaptability of neurochemical systems to stress, as could other organismic variables, such as age. In addition, environmental factors associated with social conditions will affect neurochemical lability. Finally, among individuals that have previously encountered traumatic stress, reexposure to even moderate stress could provoke the amine changes and hence result in the depressive symptomatology. Ultimately, however, the most pragmatic approach to the relation between stress and depression is to consider the organism's ability to cope with acute stress through behavioral means in conjunction with its endogenous adaptability to stress. As indicated earlier, some investigators have assumed that alterations in NE may influence reactivity to environmental events (e.g., Maas & Huang 1980). It is also possible that DA reductions reduce motivation or the rewarding properties of particular stimuli (Wise 1978), or are related to the motor retardation associated with depression. Moreover, cognitive changes (i.e., helplessness) may be associated with alterations of 5-HT or NE (Sherman & Petty 1980; but see Weiss, Glazer, Pohorecky, Bailey, & Schneider 1979). Whatever the correspondence between neurochemical changes and specific behavioral events, it is likely that the composite of symptoms comprising clinical depression involves the direct effects of several neurotransmitters and their interactions.
ACKNOWLEDGMENTS Preparation of this article was supported by Grants A9845 and MA6486 to Hymie Anisman from the Natural Science and Engineering Research Council of Canada and the Medical Research Council. Robert M. Zacharko is an NSERC Research Fellow.
Genuine psychobiologic understanding of psychiatric disorders has been hampered by philosophic dilemmas about the mindbody interface, by professional rivalries among psychoanalysts, behaviorists, and biologically oriented investigators, and by the relative absence of suitable experimental methods. Anisman and Zacharko's (A & Z's) paper is a contribution to the meager literature on attempts to unite insights gained from brain and behavioral sciences in elucidating the pathogenesis of depressive disorders. The authors review animal experimental paradigms developed by themselves and others to shed light on the neurochemical mechanisms linking stressful events to depressive phenomena. Although their approach is not original, it provides a valuable theoretical elaboration of previous work (Goodwin & Bunney 1973; Akiskal & McKinney 1973; 1975; Whybrow & Parlatore 1973; Kraemer & McKinney 1979; Depue 1979). The review's major strength is its discussion of the neurochemical consequences of stressful events in animals. The thrust of the argument is that maladaptive neurotransmitter changes induced by uncontrollable aversive stimulation in animals are similar to those reported in human depressions. A & Z distinguish the impact of acute versus chronic stress and controllable versus uncontrollable stress. They further point to the influence of early stress and of old age in sensitizing the organism to maladaptive neurochemical responses to current stresses. Appropriate parallels are drawn to human depressions, which are more common in the elderly, and which in some studies have been associated with childhood losses. However, other than brief mention of behavioral sensitization by early stress, the focus is primarily on stress as a precipitant of depression, rather than a predisposition, as indicated in the title. A & Z seem to imply that clinical depression is largely the psychobehavioral consequence of stress-induced neurotransmitter dysfunction. Little attention is given to research indicating that psychosocial stress and related mediating mechanisms (e.g., lack of social support) are limited to precipitant roles (Paykel 1976; Warheit 1979). Such studies have suggested that formative (predisposing) influences are to be found in more remote factors, such as developmental experiences and heredity (Akiskal 1979; 1981). There is also limited mention of factors that can increase the depressionengendering influence of current stress (Akiskal 1979) - the nature of the stressful event, concurrent life events, use of depressant antihypertensives, contraceptives, or alcohol, borderline hypothyroidism, and genetic predisposition. Further, there are a host of pharmacologic, hormonal, metabolic, infectious, and neurologic stresses which are established causes of clinical depression (reviewed in Hendrie 1978 and Akiskal 1981). A review of such specific biologic insults as precipitant stresses would have bolstered A & Z's central argument. A & Z pose the question: Since stress appears relevant to a large number of unrelated illnesses, both psychiatric and
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Commentary/Anisman & Zacharko: Depression and stress nonpsychiatric, what determines illness specificity (i.e., the organism's specific response)? Although this question is discussed in terms of individual variation, only brief mention is made of specific genetic factors in depressive illness. Thus, the contribution of heredity in the causation of depressive illness is more firmly established than that of stressful events (Akiskal 1979). Furthermore, the amount of variance contributed by heredity is considerably greater and, at least in recurrent and bipolar forms, appears to be the dominant causative factor (Gershon, Dunner, & Goodwin 1971; Akiskal 1979). A & Z propose that insomnia, anorexia, and anxiety are psychobehavioral consequences of altered central noradrenergic function secondary to stress. However, these symptoms are common to many psychiatric and nonpsychiatric disorders, and it is unclear how the proposed model specifically accounts for such core characteristics of depressive illness as anhedonia, lowered self-esteem, guilty ruminations, and suicidal ideation (DSM-III, 1980). Furthermore, many depressed subjects experience /ii/persomnia and increased food intake. Thus a major shortcoming of A & Z's review is the limited attention given to clinical considerations. The authors do mention the clinical heterogeneity of depressive conditions, citing the largely undemonstrated but plausible hypothesis that differences in neurotransmitter pathologies may account for the heterogeneity. More crucial to their central thesis, however, would be a discussion of the clinical symptoms common to all types of depression, and a demonstration of the relevance of stress-induced synaptic dysfunction to these depressive manifestations. The general tone of the paper is integrative and holistic in that, at various junctures, the joint contribution of experiential and somatic factors in determining depressive behavior is given careful consideration. Yet the paper ends with a reductionistic statement to the effect that depressive experience and behavior are "directly' derived from chemical events. In summary, while they have provided a cogent review of the neurochemical bridge of the stress-depression relationship, A & Z have overlooked major parameters of stress and depression that could have provided the opportunity to build a conceptually sturdier construct. Yet the attempt to construct such a hypothetical bridge is in itself meritorious.
Clinical depression (specify type) Present metabolites or levels ofNE, DA, 5-HT higher cortical functions exposure to, impact of, past stressors Current degree of stress attributional variables Absent Time
High
Low or nil
Figure 1 (Bauer). Multivariate assessment model for research on the stress-depression relationship. It should be noted that "depression" and "stress" are conceived as continuous variables, presented here in binary fashion only for purposes of discussion. Independent variables in the approach are represented by marginal headings; dependent variables are outlined within the upper left cell. Cells A and B are discussed in detail in the text. Dotted arrows representing time emphasize the suitability of the model for use in longitudinal research. a "multilevel" model, encompassing historical (e.g., past learning), neurochemical, "experiential" (e.g., coping) and behavioral components, attempts at validation seem especially prone to tautology (where constructs such as "stress" and "neurotransmitter depletion" are defined in terms of their effects on other systems). In this commentary, I wish to argue that validation must proceed by using dependent measures that are simultaneously (a) reflective of neurotransmitter dysfunction, and (b) correlated with, but not necessarily constitutive of, stress and depression. I will argue for a neuropsychological approach to validation. I begin with the likely assumption that the brain is functionally characterized by neurochemical (transmitter) systems just as it is characterized by neuroanatomical systems (cf. Luria 1973), and that many such systems are localized within specific brain regions. This assumption suggests that specific transmitter dysfunction may lead to localized deficits in higher cortical function. If such deficits can be measured by neuropsychological assessment, and subsequently related to depression or stress in the individual, then strong correlative evidence would exist for the stress-depression model. An example of the application of this approach is sketched below. A & Z suggest that discrete depletion of DA may occur in frontal cortex following uncontrollable stress. If so, individuals exposed to such stress should display convergent evidence of frontal-lobe dysfunction as measured, for example, by formal neuropsychological evaluation. Similarly, if DA deficiency subsequently characterizes some subtypes of depression, these patients should also show maximal neuropsychological impairment localized to brain regions rich in DA neurons (e.g., basal ganglia and frontal cortex). To my knowledge, such predictions have not been systematically tested but would, if confirmed, support the A & Z model. Specific
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Anisman and Zacharko's (A & Z's) paper presents problems and prospects for the interdisciplinary study of the relationship between stress and depression. First, stipulating a stressneurotransmitter relationship as an etiological factor in depressive illness may serve to complicate the already difficult business of constructing causal chains between neurochemistry and behavior. It is clear that specifying the biological effects of stress does not shed light on how specific neurochemical changes lead to the cognitive and behavioral effects constituting depression in the individual. We are still left with the difficult task of understanding the relationship between physical and chemical events on the one hand, and psychological/mental events on the other. In another sense, however, A & Z have created an integrative model that is internally consistent, generates scores of testable hypotheses, and accounts for much extant data. This is all that could be asked of a scientific hypothesis. Attempts to validate their model must verify the stress-depression relationship by using other correlates of behavior in addition to transmitter metabolites or clinical therapeutics. Because their approach is
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Stress, neurochemical substrates, and depression: Concomitants are not necessarily causes
Aaron T. Beck and Raymond P. Harrison
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa. 19104
Anisman and Zacharko (A & Z) have provided a scholarly and wide-ranging review of possible relations between stress responses and depression. The basic thrust of their paper seems to be that when behavioral attempts to cope with stress become inadequate, the increased emphasis on neurochemical coping mechanisms may lead to neurochemical abnormalities that in turn lead to depression. Our own feeling is that the above formulation may be premature, based on the inadequacy of the data currently available. At several points in the paper A & Z acknowledge some of these inadequacies, but they have not emphasized them. Moreover, we believe that it may be counterproductive to speak of the "cause " of depression. There are a multitude of possible predisposing and precipitating factors for depression. What we label as depression is the final common pathway of perhaps many converging variables, and it may be futile to look for an underlying cause. Even the notion that depressed individuals have experienced significantly more stress than others may prove unfounded. Lloyd (1980b) has suggested an alternative explanation based on state-dependent learning. Individuals who are depressed will undoubtedly have a negative set for recollection and will be more likely to recall a preponderance of negative events in their life. Another possibility is that many stressors are a result, rather than a cause, of depression. The lethargy, lack of drive, avoidance, and withdrawal manifested by depressed individuals may often contribute to the creation of additional problems which may then further fuel the depression but not precipitate it. Based on our own research with depressed individuals, we would also say that the reports of stress prior to and during depression may be greatly exaggerated. Magnification, overgeneralization, and selective abstraction are frequently seen in the cognitive processes of depressives. The memories and ongoing reports of depressed individuals must then be suspect. It is interesting to note that despite the voluminous amount of research on stress and its relation to depression, no prospective studies exist that have reliably predicted depression. Early parental loss, for instance, has been proposed as one of the most powerful predisposing factors for depression. However, most depressives have not experienced this kind of early loss, and many individuals who have experienced it never become
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Commentary/Anisman & Zacharko: Depression and stress depressed. The research does seem to indicate a positive correlation, but a direct connection, let alone causality, has not been established. In confining themselves to a restricted definition of stress as a behavioral or physiological event, A & Z have paid scant attention to important data derived from cognitive studies of depression. They have touched only briefly on our work (Beck, Rush, Shaw, & Emery 1979) and have dismissed Seligman's work in favor of a neurochemical explanation. They suggest that the cognitive changes in depression, which are well documented, may simply be the manifestation of more central changes occurring in neurochemical substrates. But why is it any more implausible that neurochemical abnormalities may reflect cognitive changes? There is also a substantial literature that would confirm the latter hypothesis. We will cite only a few studies here. Teasdale and Bancroft (1977) found that instructions to "think sad thoughts" led to increased dysphoric mood and physiological concomitants in subjects. Cognitive inductions appear to be related to physiological changes, which are consistent with the relevant mood state. Changes in physiological process have been found following covert rehearsal of affectively valenced self-referential statements (May & Johnson 1973; Rimm & Litvak 1969; Russell & Brandsma 1974). Even more interesting is a study by Rogers and Craighead (1977) which found that physiological as well as affective measures were associated not only with the specific act of ideating, but the belief in the validity of the thoughts. From studies like this it would not be hard to make the interpretative leap into concluding that depression is caused by cognitions. If one can chart physiological changes so readily in the laboratory, imagine the effect of a lifetime of chronic negative thinking on the neurochemistry of the body. However, we would not make this interpretative leap. We would prefer to think of the cognitive changes, physiological abnormalities, behavioral deficits, and affective symptoms as all part of the whole of depression. To pick out one cluster of factors and posit it as the cause is shortsighted and misguided. positions, coping stategies, and subjective perceptions. In general, stress is the overall transactional process between an organism and a stressor. The stressor is anything that the organism perceives as a threat to self-esteem (Lazarus & Launier 1978). This threat - and possible loss of self-esteem or, at least, of momentary psychological homeostasis - presumably results in the activation of a psychological homeostatic regulatory mechanism (Burchfield 1979; Falek & Britton 1974; Klinger 1975). This mechanism, previously described as the grief cycle (Lindemann 1944), consists of the five stages of denial, anxiety, anger, depression, and acceptance. During the first stage, denial of the threat, homeostasis is maintained. Denial is an adaptive short-term defense, although, if it persists for a long period of time in the face of disconfirming evidence, it is maladaptive. Cognitive awareness of the loss results in fear and anxiety with concomitant attempts to reestablish the status quo. When these efforts fail, the stage of anger begins. In this stage, the psychological integrity of the individual is maintained by externalizing the responsibility for and the source of the threat. When the individual finally achieves both cognitive and emotional recognition of the threat/loss, sadness/depression results because the person realizes that the status quo cannot be regained. At this point the cause of the loss and the associated anger are internalized. As depression subsides, acceptance is initiated as the individual incorporates the meaning of the loss into his self concept. After this growth process is completed, a new level of homeostasis is reached. This entire process may occur within a few minutes, as in the form of thoughts an individual has while waiting for a friend who is late (Breznitz 1971), or it may take several years, as when a family member has died. The psychological homeostatic reaction to stress is one means by which stress is linked to depression. This type of depression, referred to as sadness by Arieti and Bemporad (1978), is normal, although the biochemical process involved is probably similar to that of a depressive disorder. Jacobs and Douglas (1979) have suggested that two antagonistic systems, the ergotropic and the trophotropic, mediate the psychological reaction to a threat/loss. These subcortical systems include the reticular formation, the limbic system, and the hypothalamus (Kiely 1975). The ergotropic system integrates functions that prepare the individual for possible action and, hence, may underlie the stages of denial, anxiety, and anger. The trophotropic system integrates functions that promote withdrawal and energy conservation and may underlie the stage of depression. This activationinactivation sequence is also alluded to by A & Z in their description of biochemical changes after acute stress. Immediately after acute uncontrollable stressor exposure, NE is increased, while after a prolonged period, it is decreased. The time frame within which these alterations occur presumably correlates with changes in the individual's psychological reaction to the stressor. During the inactivation phase, individuals are more susceptible to many health alterations, including depression (Engel 1961; Schmale 1958). Hence, one possible mechanism of stress-induced depression is that the individual does not successfully complete the depressive stage of the psychological regulatory process. Those individuals for whom a normal emotional process precipitates an affective disorder may be identified by their predisposition to depression, their failure to cope adaptively with the stressor, and their lack of social supports. Certain types of reactions to stress - those that result in depletion of NE - are likely to precipitate depression, especially in people whose basal NE level has been lowered by other factors. A & Z briefly review the research on these moderator variables and succinctly show the complexity of the relationship between stress and depression. In their target article, one possible mechanism linking depression with stress was examined. Given that depression/sadness is a normal
Anisman and Zacharko (A & Z) have tied together several disparate lines of research concerning stress and depression. Their premise is that the biochemical changes induced by stress (e.g., norepinephrine and serotonin depletion) are the same as those postulated to underlie depression and, hence, that these changes are one mechanism of stress-induced depression. It is the purpose of this commentary to offer further support for A & Z's thesis by describing mild depression as a homeostatic response to stress and discussing its biological concomitants and relation to depressive illness. Theoretically, stress has been implicated as a predisposing factor in any health alteration, ranging from pregnancy (Schuster & Schuster 1969; Williams, Williams, Griswold, & Holmes 1975) to accidents (Griswold 1970). Given the homeostatic changes that occur when an organism is exposed to a stressor, it is quite reasonable to assume that these biochemical changes could strain the system and result in the activation of other regulatory mechanisms. Together, these alterations could precipitate various health changes depending on the interaction between the organism's past and present biological and psychosocial history. One of the great difficulties of stress research is that the stress construct is broad and encompasses a variety of behaviors that are confounded with individuals' biological predis102
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Does a commonality of neurochemical sequelae imply a relationship between stress and depression?
Douglas L. Chute
Division of Life Sciences, University of Toronto, Scarborough, Ontario, Canada M1C 1A4; Department ot Psychiatry, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
Anisnian and Zacharko (A & Z) present the speculative notion that stress, in particular its neurochemical sequelae, may predispose an individual to depression. The evidence for such a proposition is quite conditional, however, as the authors themselves note appropriately in some circumstances. With the intent of being constructive and not simply critical I would raise additional reservations about the proposition. A & Z point out quite correctly in the initial section the tenuous nature of any conclusion that relates stress to depression either causally or correlationally on the basis of existing studies with human beings. Without putting such differences altogether aside, the A & Z proposal is that stress (neglecting for the moment problems of definition, chronicity, and differences in individual response) causes a measurable change in some CNS neurotransmitters; and, since depression is (arguably) correlated with similar changes in CNS transmitters, this observation may supply new evidence of a relationship between stress and depression. There is no logical reason to assume a relationship, however. If A causes B and C causes B there is not necessarily any causal or even correlational relationship between A and C. For example, if breaking a leg causes you to miss a flight and an air-traffic controllers' strike causes you to miss a flight, not even a correlational relationship need exist between broken legs and controller strikes. The opportunity to demonstrate the presence or absence of a relationship between stress and depression is not readily available. There are no adequate definitions of either concept. There are no suitable animal models of depression. Levels of stress cannot be easily equated without resorting to a circular argument by comparing physiological effects. Individual differences in both stress and depression are such that there is virtually no possibility of predicting whether there is a relationship. Although being depressed may be stressful if such a relationship can be empirically demonstrated, that would in no way logically support a hypothesis that stress may cause depression. For example, "if smoking then cancer' does not necessitate "if cancer then smoking. ' (Not incidentally, suppose depression is a stressor: could this not explain many of the observations without at all implying that stress predisposes one toward depression?) Depression is certainly the "common cold " of psychopathology, as has often been pointed out. Any insight into prevention or treatment that could be gained would be worthwhile. I am unsure, however, about the capacity of the now-traditional neurotransmitter analysis to provide such insight. A & Z's own review illustrates many of the difficulties and contradictory findings relating neurotransmitters and depression. In fact, it seems that the catecholamines and indolamines have been related to just about everything. I suspect that this occurs as much because of their ubiquitous nature as because of their reasonably discrete synthetic pathways and their comparatively old and straightforward methods of assay. The bulk of the evidence suggesting a role for CNS amines in depression comes from the observation that drugs which alter
Anisman and Zacharko's (A & Z's) unique contribution is the juxtaposition of data relating depression and stress, neurochemistry and depression, and the neurochemistry of stress in laboratory animals. I have few quarrels with the main themes of the article, especially the physiological aspects, but I believe that the relationship of stress and depression is better construed as a relationship of biological fitness and affective variation. Constructs such as "stress" seem useful only insofar as they are clearly defined in terms of consistent relationships among concrete, measurable events. A & Z's definition of stress makes reference to "aversive stimuli" and "traumas," which have commonsense meaning but themselves require definition, and to "personal life changes,' which could include almost any environmental or developmental change. Selye (1973) and others have referred to demands upon the organism and stereotyped nonspecific physiological responses accompanying such demands. The term "demand," however, is used only figuratively, except where social demands exist. Also, almost all behavior can be viewed as a response to some environmental "demand," and hence the concept of stress in its broadest sense may have little meaning. We could conceivably define stress in terms of patterns of autonomic or pituitary-adrenal arousal; the question is then whether neurochemical variations and other factors consistently covary with these such that we have a unitary phenomenon. A & Z discuss qualitative differences between acute and chronic stress, and between stress that can and cannot be coped with; these distinctions may help to undermine this unitary notion. The antecedents of depression and various pathologies may be more clearly conceptualized in terms of coping difficulties. Coping status could be defined through parameters of biological fitness relative to the species' behavioral repertoire and ecological history (see de Catanzaro 1981). Any impairment of an organism's capacity to survive, reproduce, and advance the welfare of kin can constitute a coping difficulty. Accordingly, we might define "stressors" or "aversive'stimuli" as events
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Commentary/Anisman & Zacharko: Depression and stress threatening an organism's health and reproduction, and of course organisms tend actively to avoid perceptible events of this sort. In humans, strategies for promoting fitness are complex and structured by culture, and there may exist several alternative strategies for maximizing fitness at various phases in the life cycle. Various threats to an individual's capacity to promote his fitness (i.e., "stressors') differ qualitatively and quantitatively. Acute stressors such as physical insults or especially demanding social situations may be transitory and hence of little consequence for fitness. Such events may recur, however, taxing the resources of the individual and hence diminishing his capacity to promote his fitness. A large variety of chronic situations, such as illness, old age, low social status, unemployment, andfinancialdifficulty, may render effective coping difficult for many individuals. Such situations may impair the ability to develop reproductive relationships, to bear and raise children, to behave toward the welfare of other kin, and so on. A failure in or loss of reproductive relationship (divorce, widowhood, separation) is often very damaging to an individual's residual fitness; some individuals are entirely excluded from reproduction because they fail to compete effectively for mates (Daly & Wilson 1978; Symons 1980). A lack of contact with kin is often especially damaging to fitness, particularly for those that are postreproductive or young but excluded from direct reproductive relationships (see de Catanzaro 1981). Consideration of residual inclusive fitness may allow a relatively objective and conceptually clear scaling of individuals in terms of coping status, clarifying many currently muddled definitions in the area of abnormal psychology. The construct "depression" has also been used with insufficient precision in the literature, being applied to a rather heterogeneous set of phenomena. Much of human affective variation probably derives from variation in fitness, with genetics also involved in individual differences (Gershon 1978). Transitory euphoria in times of success and dysphoria in times of failure are surely normal, universal features of human behavior. Indeed, the pharmacological manipulability of such conditions and other evidence of a neurochemical substrate (see A & Z's target article), taken with ethological evidence on stereotyped facial expressions associated with positive/negative affect in humans and other primates (Ewer 1968; Harlow 1974), suggest that the capacity to vary on this affective dimension is innate. Long-lasting (but usually transitory) states of mourning, bereavement, or dysphoria after a major loss are also surely a normal aspect of human affect. In other cases a dysphoric state may be associated with the cumulation of a large number of experiences that collectively preclude an individual from effectively behaving to promote his inclusive fitness; this may explain many cases of so-called endogenous depression that cannot be attributed to a single adverse event. Where such natural affective variation becomes "pathological" is difficult to define and perhaps is partly a matter of semantics. I do not like the term "depressive illness," because it involves an evaluative rather than a more descriptive and scientific view. Another important distinction is between "depression " and "hopelessness" (see also Beck, Kovacs, & Weissman 1975). A person may experience chronic negative affect due to prolonged adversity but nevertheless anticipate future improvement. Others, due to permanent infirmity, senescence, or a long history of negative experience, may view all conceivable future prospects as negative. The latter condition is the one more commonly associated with suicidal behavior (see Beck et al. 1975; de Catanzaro 1980; 1981; Farber 1968). A breakdown in the life-preserving orientation of behavior with low residual fitness is consistent with evolutionary pressures; there is no conceivable pressure of natural selection supporting lifepreserving behavioral predispositions and gene expression when future reproductive and kin-solicitous behavior are both precluded (see de Catanzaro 1981). It is similarly not surprising that basic patterns of self-maintenance, including eating, sleeping, grooming, and working, break down in some individuals classified as depressed (Beck 1976). Neurochemical and cognitive explanations of these phenomena do not seem entirely contradictory; both involve proximate mechanisms subserving processes attributable to evolutionary pressures. We need to know more about the interaction of cognitive/cortical and neurochemical/hormonal activity accompanying coping difficulty. Perception of social status, achievement or failure in social roles, and many other fitness changes must initially occur on a cognitive level. Such perception may in turn induce affective changes mediated at the physiological level by processes like those discussed in the target article. Much of subsequent behavioral change, for example in general activity level, may indeed be induced more by neurochemistry than by purely cognitive processes. There are limits, however, to analogies between stress-induced behavioral and neurochemical conditions in nonhumans and humans. I doubt that laboratory rats and mice show the richness in affective variation found in humans; the human cognitive structure is undoubtedly much inore developed. Nevertheless, the consistency of the animal data on monoamines and stress with data on monoamines and human depression is notable.
With the advent of highly sensitive neuroscience techniques and a spirit of interdisciplinary collaboration has come a burgeoning literature about the psychobiological concomitants of stress and depression. It is important, however, to emphasize that vastly different explanatory models are being used and that a truly synthetic approach may well be impossible. Can one tie together the following key links? 1. Is there a predisposition to depression? Can one seek this predisposition in genetic terms? Can one seek it in terms of the individual's previous life experience? 2. What is the role of painful life events in precipitating depression? Is there a "threshold" effect, either in terms of immediate difficult events or in terms of an accumulation over time of difficult life events? Can one quantify across all subjects a rating for the severity of difficult events? 3. What are the pathophysiological manifestations of depression? How may these manifestations be studied in humans? 4. What are "depression" and "stress"? There is an immense body of literature on each of the four preceding questions. Investigators have examined meticulously the possible genetic correlates of depression and attempted to tease apart the thorny issue of "nature" versus "nurture" (Allen 1976). Others have developed techniques for monitoring life-change events, examining such issues as the common ranking of distress associated with various life events, the ability of individuals to report accurately in retrospect about the occurrence of life events, and the role of the individual's interpretation of life events as a modifying influence (Dohrenwend & Dowrenwend 1974; Benner, Roskies, & Lazarus 1980). As Anisman and Zacharko (A & Z) have summarized, an impressive literature has accumulated regarding neurochemical concomitants of depression. This literature reflects post-mortem studies in humans, studies of eerebrospinal fluid, blood, and urinary metabolites in humans (Schildkraut 1978) and animals, and studies of brain tissue obtained from animals exposed to various stressful circum-
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Commentary/Anisman & Zacharko: Depression and stress stances. Major strides have also been made regarding the phenomenological description of depressions (Spitzer & Endicott 1978). The attempt to integrate the above divergent research strategies is a laudable one, but it is an attempt that requires restraint because such an integration faces major obstacles. To apply such different investigative approaches to the study of depression is not quite the same as studying tuberculosis in terms of its social setting in poverty, its racial vulnerabilities, or its bacteriology, histology, and clinical signs and symptoms. Would that depression were so homogeneous! Instead, we may ultimately find ourselves with two or more accurate but incompatible theories of depression, similar to theories of light transmission as wave form or particulate. One of the crucial difficulties in studying the psychobiology of depression is the lack of clarity regarding the definition of depression itself. As commonly used, a diagnosis of depression conveys little more information than a diagnosis of fever. We do not know whether a diagnosis of "fever" reflects bacterial or viral infection or pulmonary atalectasis, for example. The physiology and the therapeutics for any of the above causes of fever are quite different. Similarly, for depression, some use the term to reflect a normal continuum of sad feelings, whereas others reserve it for mood states that seem somehow distinct from normal mood states. Phenomenological psychiatry, however, has derived consistent guidelines for reliably diagnosing various forms of depression (Spitzer et al. 1978), guidelines that are crucial for use in psychological studies of depression. As if agreement about depression were not hard enough, agreement about "stress" is more difficult. All investigators are aware of the imprecision of stress. In reaction, some have suggested newer terms such as "negative environmental contingencies" or "aversive events" as an alternative framework; however, it is not clear that such newer terminology helps. It is extraordinarily difficult to find an adequate animal model of depression. The current literature on learned helplessness may be a step in the right direction (Seligman 1975). However, much of the animal literature has assumed that stressing the animal is the same thing as depressing the animal. This is a difficult proposition to defend. To begin with, many of the stresses referred to in this stress-depression neurochemistry literature refer to physical stresses such as imposition of heat or cold. Presumably, the animals are uncomfortable and do not "like" such "stress"; however, I do not believe that anyone has seriously suggested that thermal stress is a good model for depression. The animal studies that have focused on a stress that is more behavioral than environmental would appear to be closer to the mark in terms of modelling depression. However, again, it is not clear whether stressing the animal by the yoked imposition of electrical shock triggers anxiety or rage or frustration or depression. One could perhaps make more progress in the animal modelling of depression if the stresses imposed seemed more consistently related to the stresses associated with human depression. Applying histological and neurochemical analyses to animals that have experienced bereavement or sudden loss of social prestige may be a better long-term strategy for modelling depression (Harlow & Harlow 1965; Henry & Stephens 1977). One way or another, depression must be neurochemically expressed. Research has accumulated regarding the classical neurotransmitters (norepinephrine, dopamine, serotonin, and acetylcholine), but the information is so contradictory that one is hard pressed to accept a paradigmatic view regarding these neurotransmitter abnormalities (Baldessarini 1981). This neurotransmitter-based research may ultimately provide a psychobiological key to understanding this complicated area; in the meantime, replicated studies and studies of some of the newer neurotransmitters' roles in depression would appear to be a profitable research strategy. In recent years, a more modest focus for psychobiological concomitants of depression has been developed. Given that the animal behavioral models of depression are uncertain and that the brain neurochemical changes are also uncertain, some investigators have looked for consistent peripheral biological markers of depression. This research strategy has had a high yield in detecting physiological markers that can be readily studied in a patient population, appearing and disappearing as the depression waxes and wanes. Two promising peripheral biological markers of depression relate to changes in sleep REM activity (Kupfer & Foster 1972; Gillin, Duncan, & Pettigrew 1979) and changes in peripheral cortisol levels. The latter in particular has had wide confirmation. Depressed patients manifest a higher and more frequent pulsatile spiking of cortisol; furthermore, the normal diurnal rhythm with a cortisol nadir in the late afternoon is diminished (Sachar, Hellman, Roflwarg et al. 1973). In normal subjects, a one-time dose of dexamethasone at bedtime is sufficient to inhibit ACTH release for one to two days, and thus the peripheral cortisol levels are diminished. However, in depressed patients, the cortisol is not suppressed. The dexamethasone suppression test has both high sensitivity and specificity (Carroll, Feinberg, Greden et al. 1981). Its ease of administration and its low cost make it a to"ol that will be used increasingly in routine settings. I have highlighted the cortisol changes in depressed patients because there is a consistent literature on this topic, a literature that is soundly grounded in human depression, and a literature with a clearly pathophysiological orientation. Detailed study of the mechanism of these changes may provide vital information about the psychobiology of depression. Human depression has a lifetime prevalence of between 5 and 10 percent. The treatment of depression has made remarkable strides in the past 20 years. The concomitant advances in neurosciences and the willingness of investigators from different areas to collaborate in this complex area offer great promise both for understanding the psychobiological mechanism of depression and for improving the treatment for this major medical problem.
ACKNOWLEDGMENTS This work was supported by a Clinician Scientist Award from the American Heart Association with funds contributed in part by the AHA Massachusetts affiliate.
My comments on this very readable paper are restricted to three questions. (1) What is the conceptual status of the terms "depression" and "stress"? (2) If cognitive events participate in the stress-depression interaction, what form do they take? (3) What is the nature of the dispositions that mediate such interaction? The issues involved here do not appear to be clearly conceptualized by Anisman & Zacharko (A & Z), partly, no doubt, because they reflect our fairly general problems in relating biological and behavioral processes to unobservable cognitive events. Depression is not a unitary category. Apart from differences between the so-called reactive variant without evidence of incongruous (psychotic) thought processes and depressions with evidence of bizarre logic, depression occurs with schizophrenic reactions, in mental retardation, and in combination with severe anxiety. Lader (1975), for example, has demonstrated that so-called agitated depressions are very common.
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Schopenhauer, referring to the question of mind's relationship to matter, called it the "world knot," his wonderfully evocative term for the vortex of philosophical and biological entanglements. In addressing the problem of the effect of stress on the disorder of depression, Anisman and Zacharko (A & Z) have confronted a fundamental issue in the behavioral sciences. The effort of A & Z to provide an integrated framework for psychosocial input (aversive life events) and the physiological correlates of depression focuses on the impact of stress on biogenic amine-level changes. Their main biochemical link to stress effects is the demonstration of a laboratory finding that bodily utilization of biogenic amines is increased under the impact of acute stress. Correlations, however, are not causal relationships. Such a correlation of an external event with a change in brain milieu (and it is often a highly imperfect correlation) does not offer a theoretical framework in which to integrate brain event and environmental influence. I suggest that an approach to integrating the brain and behavioral levels in the condition called depression be approached through a study of the biological aspects of the phenomenology of depression. (My hope would be that the phenomenological study of depression would provide the
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CommentaryVAnisman & Zacharko: Depression and stress necessary links to the psychosocial sphere wherein stress is defined.) The phenomenology of affective disorders has long been studied in terms of three different components. Might these correspond to three different neurophysiological subsystems? Kraepelin, in the last decade of the nineteenth century, delineated in the depressed patient three areas: mood or emotional disorder, motor activity, and cognition. All are altered in depression, or may be so but in varying directions. The depressed patient may manifest motor activity over a range from extreme agitation to catatonia-like stupor. Cognitive changes of a wide range from a minimal apathetic reflection of depression to an elaborate delusional system may occur. These phenomenological changes do not all occur in a uniformly orchestrated fashion. For example, the depressed patient may be agitated or retarded in his motor activity. The development of delusional thinking may accompany a manic mood or a depressed mood. Hallucinations may accompany depression or mania. There are suggestions that these three areas of phenomenology reflect different physiological systems. It is likely that the mood-modulating system is most involved with the biogenic amines discussed by A & Z. Most recently the studies with brain polypeptides have demonstrated their function as neurotransmitters. The threshold for pain, which correlates positively with the level of endorphins generally, is increased in depressed patients. The distress calls of guinea pigs elicited by social isolation have been found to be inhibited by an endorphin-medicated forebrain action (Herman & Panskepp 1981). The inability to experience pleasure, which is an accompaniment of depression, may reflect the malfunctioning of the pain, pleasure, and self-stimulating centers of the hypothalamus and may be related to the diminished ability to experience pleasure which accompanies depression. I would suggest that the mood-change aspect of affective illness is particularly related to this neurophysiological subsystem. Motor disorders are common in affective disorders. In the experimental setting, amphetamines typically produce stereotyped behavior, which may be antagonized by the use of antipsychotic medication. Laboratory studies indicate that the hippocampus and septum are important links in this form of behavior. For example, the stereotyped behavior produced by both amphetamine intoxication and hippocampal damage is antagonized in both cases by use of the antipsychotic haloperidol (Devenport, Devenport, & Holloway 1981). The disorders of volition or motor activity may be related to involvement of the hippocampus and septum, accounting for phenomenological changes which are not always well correlated with mood changes. The third area, cognitive functioning, has in recent years been explored in terms of the characteristic thought structure and content of the depressed patient. The work of A. T. Beck (1967) and others has demonstrated characteristic changes in thinking in depression that may respond to direct treatment (i.e., cognitive therapy), as well as to indirect treatment (biological intervention). The research demonstrating involvement of the nondominant hemisphere of the brain in affective disorders suggests that these higher cortical areas reflect the significant correlates of the cognitive changes in depression (summarized by P. Flor-Henry 1976). In experimental studies with amphetamine intoxication, a dissociation of motor stimulation and delusional thinking has been observed (Angrist & Gershon 1970). When a patient intoxicated with amphetamines is given reserpine, the psychotogenic effect is blocked, whereas behavioral stimulation is retained. There is thus an observable dissociation between these two areas in the phenomenology of affective disorders. The further dissection of brain subsystems along lines suggested by phenomenological findings should lead to a more complete picture of the brain mechanisms underlying the symptomatology. The elucidation of brain mechanisms in relation to the phenomenology of depression should also shed light on the poorly understood area of the relationship of mood, activity, and cognition to each other in affective disorders. Flor-Henry, for example, has tried to explain through lateralization studies why a transition from a chronic manicdepressive psychosis to schizophrenia is possible, but not the reverse. The phenomenological changes of depression are the natural screen on which stressful events are projected. The social and cultural influences on the patient are the sources of the depressive cognitions. The motor activity, agitated or retarded, is gauged by its immediate human environment, which provides the measure for its deviance. If a fully mature brain description of phenomenological changes were to emerge, the aversive life event might be viewed in its phenomenological context and integrated into the physiological understanding of the phenomenological.
I would like to compliment Anisman and Zacharko (A & Z) on an interesting and useful presentation and discussion of an important, long-standing problem. It is unfortunate that they revert to unnecessary dualism in their summary when they view behavioral attempts to cope with stress as being coupled in some parallel fashion with alterations in neurochemical activity. The more parsimonious view is that behavior is a consequence of nervous activity; thus, behavioral attempts to cope with stress are only one visible aspect of a large number of adaptive mechanisms occurring in the nervous system in response to stress. Successful behavioral coping would be viewed as an indication that at least some part of the neurochemical system is not overly taxed. There are certainly instances where neurochemical systems decompensate without behavioral decompensation and vice versa. A nondualistic formulation would better focus attention on the critical question -i.e., what are the specific mechanisms involved when the nervous system fails to adapt adequately to stress? A & Z have suggested that one of these mechanisms may be a depletion of the monoamines norepinephrine (NE) and serotonin (5-HT). Neuroactive peptides should also have been considered, since recent evidence indicates that they are at least as important in the regulation of stress reactions as monoamines. Another important mechanism that was not thoroughly discussed involves changes in monoamine-receptor sensitivity. There is considerable evidence that antidepressant treatment (ADT) may act by inducing changes in monoamine-receptor sensitivity independent of changes in synaptic concentrations of monoamines (Charney, Menkes, & Heninger 1981). The "receptor-sensitivity hypothesis," which is an alternative to the "monoamine-deficiency hypothesis," is supported by the evidence that clinically effective antidepressant drugs such as iprindole and mianserin do not inhibit uptake or metabolism (Rosloff & Davis 1974; Goodlet, Mireylees, and Sugrue 1977) and that good uptake inhibitors such as amphetamine, phemoxetine, or cocaine are not effective antidepressant treatments (Post, Kopin, & Goodwin 1974; Overall, Hollister, Pokorny, Casey, & Katz 1962; Ghose, Gupta, Coppen, & Lund 1977). There is the obvious temporal discrepancy between the effects of MAO inhibitors or uptake-blocking drugs on amine concentrations and the delayed clinical response observed when these drugs are used in patients (Oswald, Brezinova, & Dunleavy 1972). Recent research into the mechanism of action
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The hypothesis that stress may provoke psychotic depression through neurotransmitter depletion has been suggested for a number of years. It is gaining even wider acceptance since being coupled with the newer concept of hypersensitive postsynaptic receptors, especially with regard to the serotonergic system (Aprison, Takahashi, & Tachiki 1978; Aprison & Hingtgen 1981). Anisman and Zacharko (A & Z) give an overview of the neurochemical aspects of stress and depression and present a strong case for seriously considering this
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Commentary/Anisman & Zacharko: Depression and stress can compensate for the decreased release of 5-HT, the serotonin synapses in this subgroup of individuals are functioning at close-to-normal levels postsynaptically under most conditions. At some later date, a stress factor causes an increased release of 5-HT, which now interacts with the supersensitive postsynaptic receptors, resulting in behavioral depression. Although there is an excess of 5-HT in the now depressed patients when compared to the previous release, their overall levels of 5-HT are still lower than those of the normal population. Thus, we refer to this hypothesized increased release of 5-HT in the subgroup of depressed patients as a "subjective" excess of free 5-HT acting at postsynaptic receptors. Hence these patients, no doubt, still have lower levels of 5-HIAA, even during the recovery period following treatment (van Praag 1979; 1981). This theory predicts that, in at least one subgroup of human depression, the major action of the clinically effective drugs may be a blocking of the serotonergic receptors in the postsynaptic membrane (although some blockade of the presynaptic uptake of 5-HT may also be involved). One of the critical elements of our theory would necessitate the demonstration that one or more types of stress could produce significant changes in neurotransmitter levels - in the case of our theory, serotonin levels. A & Z cite some studies in which this has been shown. In preliminary studies from our own laboratories we have also found significant depletions of 5-HT in specific brain areas of rats following activity-wheel stress or shock-avoidance stress, sufficient to produce gastric erosions and elevated levels of corticosteroids (Hellhammer, Hingtgen, Wade, Shea & Aprison 1982). The interaction between stress and depression appears to be a fruitful area to search for underlying behavioral and neurochemical mechanisms of depression. As A & Z have noted, physical illness itself could provide sufficient stress for depression to result (see also Hendrie 1981). Perhaps a number of distinct subgroups of depression will be delineated in this way. One or more groups may involve mainly serotonergic mechanisms, whereas others could involve catecholaminergic, cholinergic (Hingtgen, Smith, Shea, Aprison, & Gaff 1976), or ami no acid neurotransmitters (Aprison 1977). Thus, neurotransmitter involvement in the interaction of stress and depression is likely to be extremely complex, but it offers an exciting new approach to the whole field of psychosomatics. helpful, at least briefly? One possible resolution to this confused state of affairs, to which A & Z briefly allude, involves catecholamine autoreceptors, a special class of catecholamine synapse that inhibits catecholamine neurons. If the problem in depression is specifically excess sensitivity of autoreceptors, there could be both a deficit in overall catecholamine release and excess sensitivity of one kind of catecholamine receptor - and both problems might be alleviated by antidepressant drugs. It takes a little handwaving to make this hypothesis seem tofitall the data, but it does gain support from recent evidence that autoreceptors have drug sensitivity different from that of other catecholamine receptors (Skirboll, Grace, & Bunney 1979) and that electroconvulsive shock and the antidepressant drug mianserin both selectively antagonize autoreceptors (Chiodo & Antelman 1980; Dresse & Scuvee-Moreau 1980). At the rate things are going, the autoreceptor hypothesis too may be dead before the ink is dry. A & Z, meanwhile, offer a novel approach to the problem of the biochemistry of depression: Try to make sense out of its relationship to precipitating or predisposing events, such as stress. That is, as when working a complex jigsaw puzzle, it might become easier to deal with one difficult section if we consider its relationship to another section. In a nutshell, A & Z propose that acute, severe, uncontrollable stress depletes amine reserves by utilizing amines faster than they can be resynthesized. Well aware of the complexities of the situation, they add the qualification that a variety of circumstances, including genetics, hormones, previous stress experiences, chronicity of the stressor, and available coping methods, determine which amine transmitter is depleted and to what extent. Further, they do not insist that stress is involved in all cases of depression, but merely that it is involved in some. Their carefully understated proposal does seem to fit a large quantity of data. The question at this point, given the nature of this field, should not be whether A & Z's proposal is right or wrong, but how useful it might be as a working hypothesis to organize future research. Some of the key research questions are obvious: What kinds of stress are effective, what predisposing factors modify this effect, and which types of depressive syndromes are involved? In addition, one could add, what are the differential effects of stress on autoreceptors and conventional synaptic receptors? Another, possibly less obvious, question should be of serious concern: If depression is related to transmitter depletion caused by acute stress, why is depression so persistent? If we deplete a transmitter by reserpine or other drugs, the brain ordinarily resynthesizes the transmitter, and behavior soon returns to normal. But human clinical depression often persists, seriously and unremittingly, for years. There can also be an oscillation between depression and mania that does not relate to anything we can identify in the environment. It is easy to see how stress could precipitate a brief, abating depression. If stress can precipitate persisting or oscillating depressions, however, we will need a concept of "triggering," in which the neurotransmitter abnormality, once triggered, becomes selfperpetuating. Perhaps there is a failure of normal resynthesis processes; perhaps there is a persisting hypersensitivity of autoreceptors; or perhaps other processes are involved. Perhaps depression has something in common with other self-perpetuating processes, such as puberty, or drug addiction, or anorexia nervosa. At any rate, the question of persistence would seem to be critical in the relationship between depression and any precipitating conditions, including stress. The great jigsaw puzzle of depression has seemingly become more complex, the longer we have tried to work it. A & Z, by emphasizing possible links between different parts, may lead us toward a valuable restructuring of the puzzle, and to increased attention to some new questions.
Since Larry Stein's (1962) suggestion that depression was due to a deficit of norepinephrine, a consensus has gradually grown that depression is indeed due to some sort of neurotransmitter abnormality, involving especially the amines. However, hypotheses have proliferated abundantly about the exact nature of that abnormality. As Anisman and Zacharko (A & Z) have amply reviewed, there is evidence suggesting deficits of norepinephrine, dopamine, and serotonin and a possibility that other transmitters are also involved. However, the common therapeutic drugs both increase transmitter levels (rapidly) and decrease receptor sensitivity (slowly). The time course of the drugs' therapeutic value is consistent with an effect primarily on receptor sensitivity. But if the main problem in depression is excess receptor sensitivity to the amines, then why are MAOIs and tricyclics merely neutral at first, instead of harmful? And why are amine depletors, such as reserpine, not
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Commentary/Anisman & Zacharko: Depression and stress Neurochemical correlates of stress and depression: Depletion or disorganization?
Gary W. Kraemer
Department of Psychiatry and Primate Laboratory, University of Wisconsin, Madison, Wis. 53706
Stress may be a predisposing factor in the precipitation of depression. Anisman and Zacharko (A & Z) propose that stressful experiences engage behavioral and neurochemical coping mechanisms. However, if behavioral control of the stress is not achieved then the emphasis on neurochemical coping mechanisms causes the depletion of brain biogenic amines, resulting in affective disorders. The topic of A & Z's paper is relevant because of the intuitive relationship between untoward life events and subsequent depression, and because of the now long-standing hypothesis that affective disorders in humans are somehow related to altered function in brain biogenic amine systems. There may be a link between stress and the function of brain biogenic amine systems. If stress and depression are linked with each other in terms of involvement with the same brain mechanisms, then defining the characteristics of this interaction would be important in understanding the etiology of depression from a neurobiological standpoint. Unfortunately, the premises of this argument are themselves not well established. For both ethical and practical reasons it is either difficult or impossible to test neurobiological-behavioral hypotheses rigorously with human subjects. The role of life events, or "stress," in predisposing humans to depression is not well defined, and this is an area of controversy. Also, the experimental record has not supported the simplistic hypothesis that human depression is the result of depletions of brain biogenic amines; and it is now appreciated that a variety of neurobiological changes probably play a role in affective disorders (Schildkraut 1978). Fortunately, some aspects of hypotheses about life events and the neurobiological basis of depression can be addressed in the context of animal models. A & Z seem to agree, since their review depends heavily on tests conducted in animals. Kraemer and McKinney (1979) examined some of the interrelationships between a psychosocial stressor (social separation) and the response to agents that alter function in biogenic amine systems in the context of a primate model of depression, i.e., the despair response of rhesus monkeys to separation from their peer group. It was found that the severity of the despair response in groups of monkeys was dependent on early rearing conditions and the number of previous separations sustained by the monkeys. Furthermore, the monkeys were differentially susceptible to the depressant effects of catecholamine- (CA) but not indoleamine-depleting drugs, based on these same factors. These results suggest that: (1) social separation early in life, or repeated separations during development, can predispose monkeys to more severe depression-like responses in subsequent tests; and (2) the separation responses are particularly susceptible to alteration by drugs that affect CA metabolism. Viewing social separation as a "stressor" that is unavoidable as long as it persists, the results of this study conform to the analysis presented by A & Z. However, the interaction of the despair response to social separation .with concurrent pharmacological challenges is not a simple one. It was found that extremely low doses of alpha-methyl-para-tyrosine (AMPT, 25 mg/kg/day), known to deplete norepinephrine (NE) and dopamine (DA), exacerbated the despair response. On the other hand, fusaric acid, which depletes NE by inhibition of dopamine-beta-hydroxylase,'ameliorated the despair response and had effects that were opposite to those produced by
AMPT. Ostensibly, it appeared that depletions of both NE and DA augmented the despair response, while depletions of NE alone ameliorated it. However, the results of another study complicate the interpretation of these results. Kraemer et al. (1981) examined the separation response of monkeys following intracerebral administration of 6-hydroxydopamine (neurotoxin) and subsequent reduction of brain NE and DA to about 30% of control values. This treatment had no effect on the separation response in monkeys that had previously been shown to display adverse separation responses when treated with AMPT, although the level of depletion of brain catecholamines produced by 6-hydroxydopamine was much greater. Taken together, these studies indicate that the magnitude of depletion of biogenic amines may not be nearly as important as the particular way in which the functional organization of the system taken as a whole is altered by pharmacological intervention. These findings emphasize the problems with the "overtaxing" or "depletion" neurochemical hypotheses presented as the neurobiological concomitant of the response to stress that leads to depression. Depletions in brain neurotransmitter content, at least as we are able to produce them experimentally, are not necessarily associated with behavioral changes in the predicted direction or of the expected magnitude. Depression, on the other hand, has not been associated with predictable and reliable reductions in neurobiological measures of function. Rather, as A & Z note in their review of the literature, a wide spectrum of changes can be found in depressed patients, there appear to be subgroups, and the sorts of differences found vary from study to study. In humans, and in many cases in animal models, it is not clear that changes in measures of either content or turnover of a given brain neurotransmitter system are interpretable without a further understanding of the dynamic interrelationships that must exist between several of the neurotransmitter systems which we now have the technological capacity to study. While the authors state that a number of systems must be studied, they remain focused only on NE and serotonin and set forth a "bathtub" model of neurotransmitter metabolism to account for behavioral change. However, theories that account for the modulatory influences of one system on another in terms of both excitation and inhibition of function (e.g., that proposed by Antelman & Caggiula 1977) may be more appropriate. The implication that tricyclic antidepressants act by altering postsynaptic-receptor sensitivity is discussed by A & Z. However, this finding points more to the concept of a "mismatch" of interdependent excitation and inhibition in a number of different systems rather than metabolic exhaustion as a neurobiological basis of depression. The "life events" which are thought by some to be possible etiologic factors in depression are not nonspecific "stressors." Rather, they appear to be events that interfere with future performance, or coping, in conceptually similar circumstances. If stressful situations engage a neurochemical coping mechanism, as A & Z suggest, then it may be that this system is organized to mediate complex patterns of coping behavior, and its own organization reflects this. However, repeated or longterm exposure to uncontrollable and inescapable events may leave this mechanism as disorganized as the coping behavior that it is supposed to mediate. Empirically, this could be manifested by a somewhat unitary behavioral syndrome (depression) because the coping mechanism does not work. The associated neurochemical dysfunction might be characterized by a wide spectrum of neurobiological symptoms which are not the primary cause of the disorder, but which are indicative of loss of organized interaction and regulation among a variety of normally interdependent neurochemical systems. This might be true for human depression.
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I would like to thank H. Anisman and R. M. Zacharko (A & Z) for their contribution, including, in their definition, precise details on various senses of the term "stress." I agree to consider it "the organism's response to aversive insults. ' But my own work has convinced me that, except in the case of acute insults and shock, such a response is pathological only if the organism's active behaviour (flight or fight) is unable to bring the situation under control, the situation then becoming chronic. In such a case the peripheral neuroendocrinal response (NE and glucocorticoids) induces an inhibition of immunological defenses with consequent susceptibility to infectious or tumoral disease. Along with this goes hydrosaline retention, which, combined with vasoconstriction, provokes both a hypertensive syndrome and a perturbation of protein synthesis and catabolism; these last participate strongly in many disorders, including sleep dysfunctions. I regret that the authors did not indicate some of the relations between depressive states and the hypercortisolemia, which very frequently accompanies them and seems to be an important factor in all so-called psychosomatic pathology (Laborit 1974; 1979). For us, depression appears to be the syndrome that accompanies "inhibition of action" (Laborit 1974; 1979). But A & Z are right to insist that there is no "single" isolated cause of this syndrome; every subject possesses the memory of his experiences since birth, conscious and, especially, unconscious. The "vecu" of each individual is practically impenetrable to everyone, beginning with the individual himself. Action inhibition appears at a moment of one's life when memorized automatisms prohibit gratifying action; that is, a stimulus may be aversive for one individual but gratifying for another. One of my criticisms of this work is that it leaves out one whole level of organisation - the neurophysiological - and passes directly from the event level to the behavioural to the biochemical. For us, however, there is a relation on the level of cerebral organisation between that area which controls consummatory reinforced behaviour (MFB), fight or flight behaviour (PVS), and inhibitory behaviour (action inhibitory system - AIS). Most authors consider the first to use catecholaminergic neuromediators (NE, DA) and the latter cholinergic and serotonergic neuromediators. We believe that it is these same mediators which control the appearance of the depressive state. A molecule, minaprine, synthesized and studied by our group (Laborit et al. 1972; Laborit 1981) and recently available on the market, gives some indirect pharmacological and therapeutic evidence for this. It does not belong to any known antidepressant family. It limits ACh (Garattini 1981) and 5-HT release without influencing the concentration and turnover of CA. It increases brain protein synthesis and memory retention. In short, this pyridazine acts as an "inhibitor of behavioural inhibition." We greatly appreciate the care with which A & Z interpret the published results of their studies of the biochemical basis of depression. The level of neuromediators in the whole brain compared to that in specific areas, the difficulty in determining their turnover, the variable sensitivity of postsynaptic and autoreceptors, the as yet unclear role of brain neuropeptides, the feedback action of various hormones on the brain - all these are difficult to interpret. Nevertheless, it seems to us that, roughly and globally speaking, an increase in the level of neuromediator will generally favor a decrease in its release and vice versa (Laborit et al. 1980). If such were the case we would
expect to find, and indeed do find, that after daily, inescapable electric shock, rats show an increase in the level of CA and a decrease in the level of 5-HT in the brain. This fact suggests that in an inhibitory state (depression), the central catecholaminergic system is inhibited while the serotonergic system is stimulated (Laborit 1981). In conclusion, when we observe a depressive state, it might be interesting not to think solely of the exhaustion of one activational system (the catecholaminergic) but rather to consider that the environment is activating an inhibitory system (cholinergic and serotonergic) in the organism. Many experimental facts show that when this system's activity is long and repeated it triggers the set of biological and physiological perturbations which accompany depressive and chronic states of stress.
This very interesting article by Anisman and Zacharko (A & Z) introduces a new twist into traditional theories of the biochemistry of depression. The more traditional views have argued that depression is the result of some biochemical abnormality in the central nervous system; A & Z's article proposes that reaction to stress, and perhaps hyperreactivity to it, can be one of the sources of that biochemical abnormality. However, both this new hypothesis and the more traditional theories that preceded it posit a particular series of events in depression that, I shall argue here, is not necessarily supported by the extant data. I propose here an alternative sequence to account for the role of biochemical alterations in depressive states. The A & Z hypothesis is that certain individuals respond to stressful events with a particular biochemical alteration that then leads to the onset of depression. Thus, the sequence they propose is: environmental stressor-* biochemical stress response - depression. Most of the data called upon in support of this hypothesis are the same as those used to argue for one or another of the more traditional views: (1) Depressed individuals have certain biochemical traits that are different from those of nondepressed individuals. (2) "Reversing" those biochemical abnormalities via pharmacological interventions results in a decrease in the depressive symptoms. The data reviewed by A & Z, then, are consistent with the view that stress exposure can lead to the biochemical abnormalities associated with depression. The data called upon to support this view, as well as to support more traditional theories, however, are all either correlational or post hoc, and where this theory and those which have come before it break down is in their inability to account fully for the facts that (1) individuals prone to depression but not actively depressed have perfectly normal biochemical characteristics, and (2) inducing the biochemical abnormality in the absence of depression-causing events or stimuli has never been shown to result in true depression. In the first case, A & Z argue that it is the stress response of the depressive that is critical, rather than its baseline biochemical state. Thus, within the A & Z framework, in nondepressed states the depressive would appear normal but would become biochemically abnormal when exposed to stress. This is an advance over earlier theories, which could not account for the normal biochemical profiles of nondepressed depressives. However, neither the A & Z hypothesis nor the older ones
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The argument proposed by Anisman and Zacharko (A & Z) may be summarized as follows: (1) stress is a precipitant of depression, (2) depression has particular neurochemical concomitants, (3) stress has similar neurochemical concomitants, and (4) therefore, stress provokes depression by means of these neurochemical mechanisms. Stress as a precipitant of depression. A & Z note that stress has been shown to lead to ulceration, heart disease, affective disorders, the development of neoplastic diseases, and other disorders. They note that life-stress events, in particular, have been found to precede both depression and schizophrenia (though the incidence of such events was higher in depressed persons), and that life-stress events precede both reactive and endogenous depressions. It becomes critical, therefore, to ascertain the conditions under which stress leads to each kind of disorder. A & Z mention in passing several explanations of this plethora of stress-related disorders. First, these different disorders may be related physiologically. Second, individual responses to stress may differ depending upon previous experiences or present environment. But a passing reference is hardly sufficient. It is critical to identify which stresses lead to which disorders in which individuals in which circumstances. It is critical to do this, for unless we do so, stress loses its explanatory power. We are left with statements of the form "Stress precedes disorders," which by itself is not a very powerful proposition. We might well replace the word "stress" by a word like "experience," particularly since Selye has distinguished between good stresses (eustress) and bad stresses (distress), leaving only neutral stresses unmentioned. All events are stressful. It is interesting to rephrase several well-known theories using the concept of stress. Henry and Short's (1954) proposition that experience of physical punishment leads to assaultive life-styles whereas experience of love-oriented punishment leads to self-destructive life-styles could be rephrased as: Stress leads to assaultive life-styles and stress leads to self-destructive life-styles - a rephrasing that loses most of the original theory. Or the double-bind theory of schizophrenia may be rephrased as: Stress leads to schizophrenia. This comment becomes more pointed since A & Z state that stress of separation is most salient for depression. We can question the usefulness of the word "stress" here. What does its use add to the conclusion? A statement that experience of separation is found more often in depressed people than in nondepressed people says as much, and avoids the use of the word "stress." Since the different disorders may be caused by different stresses, one way out of this dilemma may be to define which experiences lead to which disorders, and, when we do so, we can clearly dispense with the word "stress."
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A & Z note that depression has been associated with a norepinephrine deficiency, a serotonin deficiency, and deficiencies in other central neurotransmitters such as acetylcholine and dopamine. Similarly, uncontrollable acute stress has been found to lead to deficiencies in norepinephrine, dopamine (in some regions of the brain), and serotonin, but to increases in the levels of acetylcholine. This proposed physiological basis for the stress-depression relationship raises several problems. First, some biochemical theories of schizophrenia (for example, Snyder 1974) are based on the neurochemical concomitants of increased levels of norepinephrine and dopamine. Thus, schizophrenia and depression are contrasting behaviors. It would be difficult (neurochemically) for both to occur at the same time in the same individual. However, diagnoses of schizoaffective disorders imply an inability to distinguish between the two major syndromes of schizophrenia and psychotic depression. Furthermore, surveys of untreated psychotic depressed patients often report a high incidence of typically schizophrenic symptoms (for example, Rennie 1942). However, leaving this problem aside, if life-stress events are found to precede both depression and schizophrenia (Beck & Worthen 1972; Jacobs, Prusoff, & Paykel 1974), how do we explain the stressschizophrenia association neurochemically? Finally, the neurochemical concomitants of stress that are necessary for the stress-neurotransmitter-depression association to be supported are found only for acute uncontrollable stress. At this stage of research, can it be demonstrated that the stresses found to precede depression are acute and uncontrollable? For example, experience of early separation is found to be frequent in depressed patients. Is early separation an acute uncontrollable stress? Possibly yes. Could the reason that double-bind communications may precede schizophrenia but not depression be that double-bind messages are chronic stresses rather than acute stresses? Stress as a distal variable. Stress is an easy variable to measure at a distal level of analysis. That is to say, we can subject a laboratory organism to an objectively defined stress, such as electric shock of a given duration and intensity. We can quantify the recent life-event stresses with a scale. But the intensity of a stress is clearly subject to individual perceptions and evaluation. The death of a spouse is not 100 points of stress for all widows and widowers. To measure the subjective level of stress (a proximal variable) is more difficult, but it would be more meaningful. At this proximal level of analysis, the intensity of the stress and the type of stress as well as a knowledge of the type of individual, are critical. The stress of a promotion, for example, will be different in intensity and type for a person low in self-confidence than for a person high in self-confidence. As long as research into stress stays at a distal level of analysis, it is likely that its incorporation into propositions will remain less than fully informative.
Anisman and Zacharko (A & Z) suggest that stress may challenge brain norepinephrine (NE) systems to the point that they fail, causing what Ritter, Pelzer, & Ritter (1978) have elsewhere termed a "functional lesion." The question then is what sort of mental pathology would result. A & Z suggest that "depression may be a result of brain NE depletion." I have elsewhere suggested that a more likely result is a subset of some of the symptoms seen in schizophrenia (Mason 1979a; 1981).
One way to decide what mental pathology would occur after loss of brain NE function is to examine the behavioral effects of NE depletion caused in experimental animals by the neurotoxin 6-hydroxydopamine (6-OHDA). Rats injected bilaterally in the dorsal NE bundle with 4 fig of 6-OHDA dissolved in 2 /ul of saline-ascorbate solution show depletions of more than 95% in the NE content of the cortex, hippocampus, and other forebrain areas (see Mason & Iversen 1979). These animals, when examined behaviorally, show unimpaired learning of many simple tasks (Mason 1979b) but are resistant to extinction (Mason & Iversen 1975) so that they continue responding in the face of contrary environmental influences. Such NEdepleted rats are only impaired in learning complex tasks, such as a multiple choice-point maze (Leconte & Hennevin 1981) or visual-discrimination tasks and their reversals (Mason & Iversen 1977). Similar alterations in complex cognitive processing without global learning deficit have also been seen in primates following alpha-receptor blockade with aceperone (Ridley, Haystead, Baker, & Crow 1981). One analysis which accounts for these behavioral deficits suggests that NE depleted rats are deficient in filtering out irrelevant environmental stimuli. This is the attentional model (Mason 1980) based on the notions of a Broadbent selective attention filter (Broadbent 1958) and its detailed application to rodent discrimination behavior (Mackintosh 1965; Sutherland 1964). Rather than attempt to review here the extensive evidence implicating NE in selective attention, I refer the reader to Mason (1980; 1981) for a rigorous treatment. A pathology of attentional processes has often been suggested in the history of theory of schizophrenia. Kraepelin (1923) noted that patients "let their thoughts wander without voluntary control in the most varied directions" and showed "an irresistible attraction of the attention to casual external impressions." Failure to filter out irrelevant stimuli leads schizophrenics to show overinclusive thinking and an inability to preserve the conceptual boundaries which normally act to exclude distantly related material (Cameron, 1938a; 1938b; 1939a; 1939b). On object-sorting tasks schizophrenics include more attributes of the objects than normals (Payne & Friedlander 1962; Payne, Ancevich, & Laverty 1963). NE-depleted rats are more distractable by external stimuli than normals (Roberts, Price, & Fibiger 1976; Mason & Fibiger 1978a), and this parallels similar reports on enhanced distractability in human schizophrenic patients (Chapman 1956; Salzinger, Portnoy, & Feldman 1966). NE systems project to many sensory relay stations and play a direct role in reducing transmission along these pathways. Thus, NE projections to, and alteration in transmission across, the lateral geniculate nucleus in the visual system (Nakai & Takaori 1974), the dorsal cochlear nucleus in the auditory system (Chikamori, Sasa, Fujimoto, Takaori, & Matsuoka 1980) and the trigeminal nucleus in the somatosensory system (Sasa & Takaori 1973) have been reported, as well as changes in olfactory (Sobrian & Cornwell-Jones 1977) and pain processing (Segal & Sandberg 1977). This raises the possibility that the hallucinations of schizophrenics may be due to the penetration into sensory systems of random noise which would normally have been filtered out by NE systems. The resistance to extinction seen in rats after forebrain NE depletion (Mason & Iversen 1975) parallels the behavioral inflexibility of schizophrenic patients and is truly a cardinal feature of the NE-depleted rat (as shown by Thornton, Goudie, & Bithell 1975; Tremmel, Morris, & Gebhart 1977; Owens, Boader, & Gray 1977; Plaznik & Kostowski 1980; and Ashford & Jones 1976). This generally consists of continued responding when reward is withdrawn (but see Mason & Fibiger 1978b; 1979). While the analogy with schizophrenia is clear, such inappropriate overresponding would not be thought to be a sign of depression.
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In their target article, Anisman and Zacharko (A & Z) attempt to review the stress-depression literature in humans, the learned-helplessness controversies, the neurochemical concomitants of depression in humans, and the neurochemical concomitants of stress in animals. As they state in their abstract, they are proposing that stress, especially uncontrollable stress, increases the demand on coping mechanisms and specifically leads to depletion of norepinephrine and serotonin and that these changes may be the mechanism whereby stress provokes depression in humans. Each of these represents large and complex research areas, and it would be impossible in one article comprehensively to review any one of them, let alone all of them. A & Z's attempt is to bridge research areas. I consider this a worthy goal and a particularly important one with illnesses as complex as depressive illnesses. The task of bridging these areas is particularly difficult because of the shifting foundations available for the bridges. Each of the basic areas is still in considerable flux. It is, therefore, not surprising that there are omissions, and I will mention only those I consider 114
Stress as activation
Robert Murison and Holger Ursin
Institute of Physiological Psychology, University of Bergen, 5000 Bergen, Norway
Anisman and Zacharko (A & Z) have provided us with a useful and long overdue review of the putative relationship between changes in brain chemistry and clinical depression, and also with a comprehensive summary of the animal literature on the neurochemical effects of aversive stimulation. In bringing these two areas together, they have also emphasized the importance of the subject's previous history and experiences as factors which may determine the response to later aversive situations. This seems to us to be a praiseworthy extension of a basic psychosomatic concept into the field of neurochemistry. With regard to the definition and use of the term "stress," however, A & Z seem to have added to the general confusion rather than resolving the issue. In their definition, they state
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Commentary/Anisman & Zacharko: Depression and stress by the stress response, or affected by earlier stressful experiences. Stress-induced disease will occur when the activation is sustained, i.e., when activation-dampening mechanisms fail to come into play. We believe that sustained activation is also the important variable for the A & Z model of depression, and we also agree with them that coping is one way to avoid the pathological effects of stressful situations. The question is why coping should protect the individual. Coping may be operationally defined in terms of the subject's endocrine response (activation) to repeated exposure to the stress stimulus. It is important, therefore, that the individual not only master the situation, but that he also perceive his own mastery. When animals or humans have learned that they have mastered the situation, they exhibit a decline in their endocrine response to subsequent exposure, this decline being not necessarily correlated with improved performance (Coover, Ursin, & Levine 1973; Berger, Starzec, & Mason 1981: Ursin 1978). On the other hand, if an animal learns that there is no way to control aversive stimulation, subsequent exposures lead to sensitization of the adrenocortical response, not only to the aversive stimulus but also to novel environments (Levine, Madden, Conner, Moskal, & Anderson 1973). This may have consequences for the somatic effects of later stress stimuli (Murison & Isaksen 1980). As an alternative to coping, the human subject may employ psychological defense mechanisms. Whereas coping occurs over several trials, defense mechanisms operate at first exposure to the stress stimulus and involve perceptual distortion of the situation. Whereas coping leads to stable performance with minimal activation, the operation of psychological defenses has its own hazards in terms of reliability and safety. High scores on defense tests (Kragh 1960) are predictive of poor and unsafe performance in parachutists (Ursin, Baade, & Levine 1978) and divers (Vaernes 1981). High scores on the Kragh test also correlate with the cortisol factor in the subjects' endocrine activation response to stress stimuli (Ellertsen, Johnsen, & Ursin 1978). Other studies have suggested a relationship between cortisol and depression (Carrol, Curtis, & Mendels 1976). There is therefore some evidence for a connection between psychological defense and depression via the cortisol response. However, the widespread use of one-hormone/onesymptom studies should make us proceed with caution. The sustained-activation hypothesis for psychosomatic disease (Ursin 1980) and the model for depression described by A & Z are clear in their predictions of no pathology when the stress stimulus either is short-lasting or can be coped with. Danger occurs when the aversive situation is chronic and no coping occurs. The symptoms displayed will be a function of the predominant factor in the individual's activation pattern. If the predominant factor in the individual's activation response is catecholamine as measured in urine, one might expect the main effect to be on the cardiovascular system. If, on the other hand, the main factor is that of NE (norepinephrine) utilization in the brain, one might expect the main effect to be one of clinical depression. The important point is that the common process for depression and psychosomatic diseases is sustained activation, and it is this process which needs to be described and used instead of the misleading and unclear "stress." factors for illness, and with the biology of psychiatric disorders, often make merely token gestures toward a synthesis of research findings from these three fields. Confronted with the wealth of publications in each area, this course is only prudent. Consequently, Anisman and Zacharko's (A & Z's) attempt to link stress with depressive illness by means of catecholamine hypotheses of depression is laudable for its courage and is a most welcome stimulus to debate and future research. Unfortunately, the authors' daring is not always matched by their rigor. Their exposition suffers, at times, from ambiguous and inconsistent terminology and from incompletely elaborated causal sequences. In addition, they never satisfactorily argue that stress is strongly implicated as a risk factor for clinical depression. The causal sequence proposed by A & Z begins with stress and concludes with depression. But what is "stress"? A & Z's definition advises us that "stress" represents "the behavioral and physiological response to actual or impending aversive stimuli, ' whereas "stressors" refer to "personal life changes." In other words, "stressors" constitute phenomena occurring outside the organism; "stresses" constitute internal organismic changes. While this distinction seems serviceable enough, it is promptly ignored in the text proper. Thus, retrospective life-event studies in which depressed patients and nondepressed controls are interviewed regarding stressful occurrences in the period preceding the onset of the illness or the date of interview are said to assess "stress history" in the two groups of subjects. No. They measure "stressor history." A similar misnomer appears in the remarks on prospective studies. Implicitly equating stressors with stress while explicitly distinguishing between them misrepresents the true causal mechanisms examined in these studies and thereby obscures their potential contribution to an understanding of the psychosocial origins of psychiatric illness. In general, these nonexperimental investigations look for an association between recent routine life events and depression. Let's assume for the moment that their findings of a direct association are valid. Then, if A & Z elect to enlist these studies in the service of their argument, they must first address the question of how stressors, such as life events, are related to stress. Do stressors produce stress always, usually, or only sometimes? If only sometimes, the authors' model, to be compelling, should include personality or social characteristics that attenuate or augment the ability of given stressors to provoke stress. A & Z aim at a behavioral and neurochemical model that explains the demonstrated association between stress (or stressors) and depressive illness. Readers are left in grave doubt, however, as to where, when, and by whom this relationship has been demonstrated. A & Z assemble some supportive citations, only to demolish them with considerable acumen. Four types of studies are noted: (1) reports on the incidence of affective states in the aftermath of catastrophic occurrences; (2) studies of exposure to stressful life events among depressed patients and nondepressed controls, with data on patient exposure obtained after illness onset; (3) prospective studies of illness experience among previously depressed patients experiencing varying levels of stress (really stressors); (4) experimental work involving the administration of minor contrived stressors in an effort to simulate depression. No sooner are these studies summoned than they are dismissed for conceptual or methodological shortcomings. The value of the first and fourth types of studies is properly challenged because they provide only meagre information on the possible impact of mundane stressors experienced in normal nonlaboratory settings. The validity of retrospective studies is sensibly questioned because of the inadequacies and possible distortions in life-event recall; a caution about prospective investigations is also introduced. Given these shortcomings, A & Z fail to clarify why their synthesis and model-building efforts have been launched at this time. Invoking a familiar arithmetic, they
Investigators concerned with physiological (and, specifically, neurochemical) consequences of stress, with psychosocial risk 116
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Before the advent of somatic treatments for depression and mania in the 1940s and 1950s, the vast majority of theoretical approaches to the etiology of the affective disorders involved the individual's psychological reaction to various kinds of stressors. The success of somatic treatments, however, led to the postulation of biological factors in these disorders. The simultaneous elucidation of the catecholamine hypothesis of depression by Bunney and Davis (1965) and by Schildkraut (1965) was followed by the indoleamine hypothesis (Lapin & Oxenkrug 1969), and later by substantial evidence for the involvement of ACh (Janowsky, El-Yousef, Davis, & Sekerke 1972). As implied by Anisman and Zacharko (A & Z), these approaches have been seen as being in conflict with each other, and the recent contributions of the behavioral and cognitive theorists (Abramson, Seligman, & Teasdale 1978; Beck, Rush, Shaw, & Emery
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Figure 1 (Noll and Davis). Neurotransmitter relationships in the brain motivational systems.
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CAs
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Figure 4 (Noll and Davis). Patterns of altered transmitter functioning in Bipolar II affective disorder. \ = Functionally elevated; | = Functionally reduced; = Functionally unchanged. sion (Carlton 1963). Cholinergic agonists produce crying spells in affective patients (Janowsky & Davis 1979). Changes in these behaviors and functions in patients might be expected to parallel the particular neurochemical changes that underlie these patients' depression and could even be used diagnostically. The particular patterns of transmitter alterations, and their relation to various diagnostic subgroups, are proposed in Figures 2, 3, and 4. Thus, in all depressed groups, patients would be experiencing an excess of aversive experience over pleasurable experience, and thus would probably experience a great deal of stress even if there were not a large number of stressful events happening to them. Furthermore, these individuals would (correctly) perceive that these changes in their experience were internal, global, and stable, the characteristics of the learned-helplessness-generating cognitions proposed by Abramson et al. (1978). Their reward-maintained behaviors would extinguish (as noted by Ferster 1973; and Lewinsohn et al. 1979). Patients in the Bipolar II group, whose transmitter profile is postulated to be the most abnormal, have been observed by Dunner, Gershon, & Goodwin (1976) to have the highest probability of attempting suicide; this may be the same apparently unipolar, low-5-HIAA group observed by Asberg, Traskman, & Thoren (1976) to have a higher risk of attempted and completed suicide than other depressed patients. This paradigm shows how preexisting changes in nervoussystem chemistry might lead to a patient's experiencing of excessive levels of stress even in the absence of clearly stressful environmental events; combined with stress-induced further alterations in transmitters such as those proposed by A & Z, symptoms would be expected to grow progressively worse, and this is in fact what is frequently observed. A & Z have mentioned several possibilities for how an individual might be genetically predisposed to these neurohumoral disruptions, but have been vague as to what specific enzymes might be involved, or how these changes might produce the transmitter alterations. One possibility is a change in the calcium- and magnesium-dependent contractile protein responsible for the exocytosis of vesicles containing certain of the neurotransmitters. While NE, DA, and ACh are released by this calcium-dependent process (Berl, Puszkin, & Nicklas 1973), 5-HT and GABA are not (Katz, Chase, & Kopin 1969); and GABA and 5-HT have been found to be deficient in depressed patients (Gold, Bowers, Roth, & Sweeney, 1980). This might be the site of action of lithium ion; Birch (1973) observed that lithium binds to many calcium and magnesium binding sites in various enzymes, and has varying effects on their function. Another likely candidate is the enzyme choline acetyltransferase (choline acetylase), the activity of which is the rate-limiting step in the production of ACh. An individual who had more of this enzyme available (perhaps by inheriting more gene segments containing the DNA sequence for the enzyme) might show more elevated cholinergic function in response to
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Unipolar III Figure 2 (Noll and Davis). Three patterns of altered neurotransmitter functioning in unipolar affective disorders, t = Functionally elevated; j = Functionally reduced; = Functionally unchanged. This also shows how changes in the functional activity of these neurotransmitters could lead to symptoms that in some cases differ between patients and in some cases are puzzlingly similar. For example, either depletion of catecholamines or an excess of ACh would lead to aversive events' becoming more salient to the individual than pleasurable events, while at the same time other functions controlled by these transmitters would show differences; a reduction in 5-HT in the absence of changes in the others might produce an individual generally more emotionally responsive (or labile, to use the clinical term) under normal circumstances and much more affected by stress-induced alterations in catecholamines or ACh. Alterations in various behaviors related to transmitter changes have been reported in the literature; for example, catecholamines appear to affect activity level (Seiden 1976), eating behavior (Booth 1968; Ungerstedt 1971), and sexual behavior (Brown, Brown, Kofman, & Quarrington 1978), among other things. Serotonin affects arousal (Hollister, Breese, Kuhn, Cooper, & Schanberg 1976), sleep (Koella 1974), and pain sensitivity (Lints & Harvey 1969; Lytle, Messing, Fisher & Phebus, 1975); ACh is significantly involved in memory (Davis, Mohs, & Tinklenberg 1979; Davis, Mohs, Tinklenberg, Pfefferbaum, Hollister, & Kopell 1978; Sitaram, Weingartner, & Gillin 1978), dreaming (Sitaram et al. 1980), and behavioral suppresReward citatory CAs| Punishment Reward Punishment ACh
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Figure 3 (Noll and Davis). Patterns of altered transmitter functioning in Bipolar I affective disorder (the "Permissive Hypothesis"). | = Functionally elevated; I = Functionally reduced; = Functionally unchanged.
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Anisman and Zacharko (A & Z) present a good review of the growing knowledge and remaining ambiguities concerning the relations between stress and depression. Let me say at the outset that some major role for neurochemical (see Akiskal 1979) and genetic (e.g., Akiskal, Rosenthal, Haykal,.Lemmi, Rosenthal, & Scott-Strauss 1980; Rosenthal, Akiskal, ScottStrauss, Rosenthal, & David 1981) determination now appears beyond dispute in both the full syndromal and subsyndromal forms of affective disease. Likewise, the role of stress as at least a modulator and perhaps a cause of depression keeps gaining plausibility. Given such substantial agreement with A & Z's key views, I shall confine further comment to issues left unraised, and I shall examine them from the standpoint of a working clinician (with a few technical citations given to the scientific literature). In our experience at the University of Tennessee Department of Psychiatry's Stress Management Clinic, extant lifeevent scales do not allow sufficiently for the role of personal perceptions and values in assigning subjective weights to a (potential) stressor. For this reason, we are collaborating with Professor Albert Bandura to develop self-efficacy scales that can better index common sources of stress as subjectively weighted by the patient. Our reasoning is based on social learning theory (Bandura 1981; Rosenthal, in press) plus considerable clinical exposure, and it leads me to raise three matters from that vantage point which are ignored in A & Z's discussion. First, the effective impact of a stressor will hinge heavily on how well or poorly the patient deploys attention. For instance, endorphins may enter into somatosensory (and perhaps also visual and auditory) attentional mechanisms (see Davis, Buchsbaum, & Bunney, in press), likewise, clinically, when under duress and time pressures, patients typically surrender the leisure interests and other distracting activities, which they misperceive as "low-priority." These life events serve essential buffer functions and, when deleted, can hasten the development of an exacerbation cycle which may result in an affective episode, in cardiovascular strain, in gastrointestinal illness, etc. (For a discussion of attention, distraction, and depression see Rosenthal 1980.) Second, once the person's attention becomes "stuck" on stressful cues, a pattern of self-referent brooding, worrying, and negative self-evaluation is often observed clinically.
In the first and second parts of their article, Anisman and Zarchako (A & Z) present evidence that (1) stress is a predisposing factor in the development of at least some cases of depressive illness and (2) depression is characterized by dysfunction of neurotransmitter systems. In developing an integrated position relating stress, depression, and neurotransmitter dysfunction in humans, A & Z in a third section examine studies of stress-induced neurochemical changes in animals. Their review indicates that acute uncontrollable stress (e.g., one hour of cold swimming or footshock) often results in maladaptive behavior, such as failure to escape from shock, whereas chronic stress (e.g., several hours of stress in a single session or several days of one-hour sessions) does not have this effect. Likewise, acute-stress treatment has been shown to result in depletions of NE, DA, and 5-HT and an increase in ACh, whereas changes in the levels of neurotransmitters are no longer observed following chronic treatment. Rather, an increase in synthesis and a reduction of reuptake occurs, changes which apparently act to normalize both escape/avoidance behavior and the levels of transmitters available at the synapse. Presumably because of the differential effects of acute and chronic stress on behavior and neurotransmitter levels, A & Z rely on the effects of acute uncontrollable stress to provide an
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CommentaryI'Anisman & Zacharko: Depression and stress appropriate model for understanding the changes in neurotransmitter functioning that occur in human depression. An animal model based on chronic-stress effects is seen as less appropriate, although A & Z do suggest that some individuals may be unable, due to constitutional, environmental, or experiential factors, to compensate for the increased utilization of transmitters via increased synthesis, etc., and may thus show a depressive reaction when chronically stressed. An emphasis on the effects of acute stress as a model implies that less stress (acute) is more likely to result in the neurochemical changes leading to depression than is more (chronic) stress. In fact, at the end of the section on neurochemical concomitants of stress, A & Z suggest that chronic stress may reduce the symptoms of depression in the same way that certain tricyclic antidepressants do. Should one conclude that chronic stress might be an effective treatment for depression? An emphasis on the effects of acute stress as a model is at variance with the evidence that stressful life events are a precipitating factor in the development of depression. Such evidence implies that depression is more likely to occur with increasing stress - i.e., more likely with chronic than with acute stress. Experimental treatments and their effects in an animal model should reflect as closely as possible the etiological factors and symptomatology of the human psychopathology being modelled. Although presumed behavioral analogues of the symptoms of human depression in animals, such as impaired escape/avoidance, are not always found following chronic stress (Weiss, Glazer, & Pohorecky 1976 vs. Seligman & Groves 1970), few studies comparing the behavioral effects of acute and chronic stress have been conducted, and there is no clear consensus as to what forms of stress leading to behavioral impairment likewise induce changes in neurotransmitter systems (for a discussion of these issues, see Seligman, Weiss, Weinraub, & Schulman 1980). In terms of neurochemical disturbances in human depression, the physiological effects of chronic stress in animals may provide a better model than the effects of acute stress. For example, the study of the effects of chronic stress on neurotransmitter function could aid the search for variables predicting which individuals are predisposed to depression. A & Z suggested that not all humans suffering chronic stress may be able to compensate for increased utilization of neurotransmitters, and that those who cannot consequently become depressed. If there were a greater emphasis in animal studies on the effects of chronic stress, attention could be focused on those animal subjects who do not show the compensatory changes. A search for variables that predicted which subjects do not show these adaptive changes might also have some import for understanding which humans are unable to adapt neurochemically to stressful life events. (Such an approach would assume, of course, that it is changes in neurotransmitter levels that are responsible for depression.) In depressed humans, the only direct evidence for changes in the levels of neurotransmitters comes from post-mortem analysis of brain tissue. The only consistent result, according to A & Z, is that the level of 5-HT is reduced in depressed suicides. Most of the evidence indicating dysfunction of neurotransmitter systems in depressed humans stems from the analysis of metabolites in cerebrospinal fluid and urine and from knowledge of the biochemical effects of antidepressant drugs. Neither area provides unequivocal evidence for changes in transmitter levels. The failure to find changes in levels following chronic stress in animals should thus not rule out the possibility that chronic-stress effects may aid our understanding of human depression. Two areas of human depression research reviewed by A & Z suggest that more than changes in levels are involved. The first concerns the subpopulations of depressives who differ both in 3-methoxy-4-hydroxy-phenylglycol (MHPG) excretion rate and in which drug treatment has the best therapeutic effect. The second area of research centers on the effects of desmethylimipramine. Based in part on the finding that this antidepressant may exert its therapeutic effect by reducing NE, both Sulser, Vetulani, and Mobley (1978) and Maas and Huang (1980) have suggested that depression might be the result of postsynaptic receptor hypersensitivity. We can no longer rely on the notion that only changes in levels of neurotransmitters are correlated with or cause depression. Changes can occur in synthesis, reuptake, and degradation rates, in receptor sensitivity, and probably in other processes not yet understood. After having reviewed both human and animal studies, A & Z present an integrated theory relating depression, stress, and neurotransmitters. They conclude that depletion of amines under acute uncontrollable stress and the failure of adaptive compensatory mechanisms to maintain normal levels under chronic stress conditions may lead to depression. Certainly such a viewpoint is an advance in conceptualizing the relationships between stress, neurotransmitters, and depression. With increasing knowledge of the complexity of changes occurring in human depressive illness, a further extension of the theory proposed by A & Z is warranted. A more thorough examination of the neurochemical effects of chronic stress in animals may aid this extension.
Anisman and Zacharko (A & Z) have presented a comprehensive review and integration of findings in the area of stress and depression with special attention to neurochemical mediators. They have delineated some problems faced by a stressdepression model. However, the shortcomings of a view that focuses on the role of stress in causing depression warrant further attention. Specifically, the utility of such an approach is limited by problems of inconsistent use of terms, lack of consensus regarding measurement and quantification, and weak empirical relationships between life events and depression or other pathological states. Though in the abstract stress would seem to be related to depression, the relationship appears extremely complex and mediated by such a large number of variables as to render it a construct of limited explanatory value. A & Z indicate that they are not aware of any adequate definition of the term "stress." They define "stress" and "stressor"; yet their use of these and other terms (e.g., "aversive experiences," "aversive events," "stresses") is often far from distinct, and it is often difficult to discern conceptual and operational differences among terms. Take, for example, their statement that "aversive experiences give rise to behavioral attempts to cope with stress." Their definition of stress as "the behavioral and physiological response to actual or impending aversive stimuli" suggests that aversive experiences lead to behavioral attempts to cope with the response to the aversive stimuli rather than to attempts to cope with the aversive stimuli itself. A & Z's reference to uncontrollable stress is similarly confusing. Do they mean to refer to an uncontrollable response or an uncontrollable aversive event or are the terms meant to be interchangeable? "Uncontrollability" is another term that plays an important role in A & Z's conceptualization. They imply that uncontrollability is a function of the severity of the aversive insult and the success of behavioral coping mechanisms, terms that resemble Lazarus's concepts of primary and secondary appraisal (Lazarus & Launier 1978). But is severity and success at coping determined subjectively by the victim or by more objective means?
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In attempting to assess the relationship between stress and depression, the commentator is invariably faced with one monumental problem - that the effects of stress on neurotransmitter systems in the human brain are essentially undefined. This problem can be circumvented by relying on studies of the neurochemical effects of well-defined stressors in animals. If the rat brain can be taken as an acceptable model for the human, one wonders why studies of the effects of chronic stress on rat behavior have been omitted from Anisman 6c Zacharko's (A & Z's) review, especially considering the substantial contribution that Dr. Anisman s lab has made to this area. Exposure to aversive stimulation does produce a transient escape deficit in rats which is not evident after chronic exposure to stress. Chronic stress, in the form of 20 days of alternating shock, food deprivation, swimming in cold water, water deprivation, tail pinches, being shaken, switching of cage mates, increased housing density, or isolation (Katz, Roth, & Carroll 1981) also produces only transient behavioral changes. In addition, nonbehavioral stressors (i.e., ether anesthesia) which result in a hypothalmic norepinephrine depletion which outlasts the anesthesia (Vellucci 1977) are without behavioral consequences. In light of this, one must conclude either that the rat is an unacceptable model for studies on stress and depression or that during some "stressful" situations some other factor is also present, and that this second factor may, in fact, be the one related to the precipitation of depression. Another indication that a second factor, actually related to depression, may be involved can be obtained from literature reviews. For example, at one point A & Z propose that sufficiently protracted and uncontrollable stress may result in neurochemical changes which are manifested as affective disorders. Later, they note that chronic stress has actions similar to those produced by antidepressants, and thus would eliminate some depressive symptoms. Thus, unless stress is both the cause and the cure of depression, a second factor might be present. Some of the reluctance to admit the possibility of a second factor's being present in some stress situations may derive from the assumption that "controllable stress" is really not very stressful, while "uncontrollable stress" is. Just the opposite is the case. More of the classical signs of the general adaptation syndrome (i.e., gastric lesions, changes in adrenal weight, thymus involution, and elevated 17-hydroxy-corticosteroids) were observed in the 1950s in the animals performing an avoidance task than in their yoked counterparts, who received identical shock that was uncontrollable by them. We performed a neurochemical study which differentiates between these two factors (Petty & Sherman 1980b). Animals were either stressed by being forced to acquire and perform an escape response ("executives") or received an equal amount of shock in a "yoked" paradigm. The "yoked" animals are thus exposed to equivalent shock, but a much reduced level of stress. In assaying the crude synaptosomal pellets derived from several brain regions for serotonin, two distinct patterns were clear. "Executive" (stressed) animals showed a slight elevation of serotonin similar to that seen after restraint stress (Curzon and Green, 1971). These changes dissipated in 24 hours. "Yoked" animals had decreased levels of serotonin in pellets derived from the septum and anterior neocortex. These decreases were returning to normal in five days, but were still significantly lower when compared either to unshocked controls or to "executives." Since no other neurotransmitter systems were measured, there is no evidence that this effect was specific to serotonin. This "second factor," neurochemically and behaviorally differentiated from "stress," was suggested almost 15 years ago
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CommentaryVAnisman & Zacharko: Depression and stress (Seligman & Maier 1967). It is the separation of reinforcement from behavior leading to "helplessness." This state, although dismissed by A & Z as a "hypothetical cognitive change," is easily defined and measured in animals, who are the source of all of the neurochemical data on stress. Animals exposed to "uncontrollable stress" have a long-lasting behavioral deficit which can be reversed by chronic treatment with tricyclic antidepressants (Petty & Sherman 1980a), atypical antidepressants, or MAO inhibitors, but not major or minor tranquilizers or stimulants. Although one may argue about the cognitive aspects of helplessness in humans, failing to include this important theory (which has immense predictive utility) in a review involving studies on animals represents a considerable oversight. 1978). We observed no effect of chronic footshock on the concentration of NE required to elicit a half-maximal cAMP response (EC5o) in the cortex or hypothalamus; it is known that a reduced reuptake will markedly shift the NE-cAMP doseresponse curve to the left to produce a smaller EC30 (Kalisker, Rutledge, & Perkins 1973). The above findings have led us to conceptualize stress, depression, and central neurochemical changes in the following way (Stone, 1979b): When animals are first exposed to stress there is an excessive release of catecholamines as well as of other neurotransmitters and hormones. The release of these substances causes a variety of behavioral, emotional, and physiological reactions. A subset of these responses, involving changes in motivation and mood, comprises the phenomenon that we call depression. It should be noted that in this scheme NE depletion is held to be an index of high release and not, as A & Z propose, a deficit leading to impaired transmission. As animals are subjected to repeated stress a number of adaptive changes occur which reduce the impact of stress. One of these changes is a reduction in the function of adrenergic receptors. Others may include subsensitivity to endorphins and alterations in responsiveness to brain dopamine and serotonin. As these receptor changes develop, the animals show fewer adverse reactions to stress, and there is a corresponding reduction of depressive symptoms. We think that our theory has a number of advantages over the one presented by A & Z. First, our hypothesis offers a unified conceptual framework which fits together many diverse findings on stress, adaptation, depression, and antidepressant therapy. According to our view the various antidepressant agents, all of which are known to induce subsensitivity to NE in the brain, work by mimicking the biochemical effects of adaptation to stress at brain NE (and possibly other) receptors. By inducing subsensitivity, these agents may increase resistance to emotional stress in patients, and this process may facilitate recovery from depression. Antidepressant therapy can therefore be viewed as a unique form of adaptation to stress in which adaptive changes are produced without actually subjecting patients to stress. Second, our theory appears to agree more closely with the physiological actions of catecholamines. These substances are extremely potent, they are generally liberated in emergency situations, and when released excessively or for prolonged periods they are known to produce deleterious effects. Subsensitivity to catecholamines would therefore be expected to reduce adverse consequences of stress. Third, our view, like A & Z's, is in accordance with the time course of the relationship between stress and depression and also agrees with the time course of antidepressant therapy. When there is clear evidence of precipitation by stress - e.g., after object loss or loss of function - depression is usually an acute reaction which gradually diminishes with time. Although many cases of depression coexist with chronic stress, this may reflect a failure of adaptive processes rather than an etiological effect of the chronicity of the stress. Likewise, antidepressant therapy is generally effective only after several weeks of treatment, an interval similar to the time needed for adaptation and receptor changes to occur. Finally, our hypothesis is unique in that it predicts the effectiveness of antidepressants in a nondepressive disorder involving a high degree of stress - i.e., panic and phobic states such as agoraphobia.
Anisman and Zacharko (A & Z) attempt a major synthesis of stress and depression based on central neurochemical changes known to occur after stress. Although they consider a number of mechanisms involving multiple transmitters, it appears that the central aspect of their argument concerns changes in brain noradrenergic function. Specifically, the depletion of brain norepinephrine (NE) after acute stress is held to be a sign of impaired neurotransmission that contributes to the etiology of depression, while adaptive changes of enhanced noradrenergic function after chronic stress are held to be restitutive processes leading to remission. We think that a good case can be made for the reverse series of changes - i.e., an excessive noradrenergic activity after acute stress followed by an adaptive decrease after chronic exposure. First, in the acute situation, the evidence indicates that the depletion of brain NE by stress does not lead to a decrease of NE release but rather to an increase. We have demonstrated this point in studies with forced running stress in rats involving measures of hypothalamic NE turnover based on the utilization of tritiated NE and the decline of endogenous NE after synthesis blockade (Stone 1971; 1973). The same effect (increased release during depletion) was found by Weiss, Glazer, and Pohorecky (1976) in the hypothalamus, brain stem, and telencephalon of rats subjected to uncontrollable shock stress. Similar findings were also reported in the rat brain stem during acute hindlimb ischemia (Stoner & Elson 1971; Stoner & Hunt 1976). Second, in the chronic-stress situation our evidence supports the occurrence of decreased noradrenergic function. We and others have found that chronic footshock or restraint stress leads to reduced postsynaptic sensitivity to NE in the rat cortex, hypothalamus, and brain stem (Stone 1978; 1979a; U'Prichard & Kvetnansky 1980; Torda, Yamaguchi, Hirata, Kopin, & Axelrod 1981). The chronic situation is made more complex because changes indicative of increased presynaptic function (elevated tyrosine hydroxylase [TH] activity and reduced reuptake) are known to occur. Our data suggest that these changes may be misleading, however. The increase in brain TH should lead to an increase in the amount of NE released by stress. We have not found this to be the case (unpublished experiments). Rats subjected to chronic footshock and having a higher brain TH activity do show increased resting-brain NE release but do not show augmented stressinduced release. If anything, these animals show diminished NE release in the brain stem and possibly the hypothalamus. The other presynaptic change, a decrease in reuptake, should prolong and enhance the action of NE at receptors. However, this action was not evident in our studies of the cAMP (cyclic AMP) response to NE in brain slices from stressed rats (Stone
The terminology in the Stress field is enough to cause depression. That which we are sure is stress (e.g., personal life
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interactions contributing to symptom profiles, it is not surprising that disentangling the relationship between stressful life events, neurochemical lability, and depression would not be simple. It is even less surprising that considerable disagreement and different focuses of attention would exist between the views we expressed and those of several commentators. Despite the shortcomings and inconsistencies in the stress-depression literature there is reason to believe that stressors contribute to depression through their actions on neurochemical processes. Although one might choose to offer alternatives or elaborations of our working hypothesis (Beck & Harrison, Hingtgen & Aprison, Stone), it is inappropriate to assume that provisional working models cannot be derived on the basis of available data (Usdin). Many of the commentators provided insightful and provocative suggestions that required modifying our working model and that certainly point to the need for multidisciplinary research. We have directed our response primarily to those issues which either appeared most frequently in the commentaries or appeared to us as most challenging. Limitations of space and time prevented a detailed discussion of several other issues. Stress as an elusive concept. The intention of our definition of stress was twofold. First, we wished to indicate that the concept is a vague one and that it is understandably difficult to provide a definition to which some investigators will not take exception. Second, we wanted to emphasize that stressful experiences should be considered, inter alia, in terms of the organism's ability to cope with those experiences. That an aversive event can be coped with through behavioral means does not rule out the fact that it is a stressor. An individual can certainly consider an aversive experience stressful regardless of whether or not control over that stimulus is possible. Likewise if one chooses to consider stress a physiological response to aversive stimulation then either controllable or uncontrollable stressors can be assumed to produce stress, even though these treatments may induce quantitatively (and perhaps qualitatively) different physiological effects. We had hoped that we could bypass semantic arguments and get to the gist of the problem, namely, the conditions that provoke or exacerbate clinical depression. If our expectation was not met, we suppose this might be considered a stressor hopefully depression will not ensue. Several commentators (de Catanzaro, Hamilton, Lester, Murison & Ursin, Neugebauer, Rosenthal, Sacco) took exception to our definition of stress and offered alternatives. De Catanzaro, for example, finds the term "stress" vague, and chooses instead to define "stressors" as "events threatening an organism's health and reproduction." Murison & Ursin suggest that the simplest operational definition of stress would be "the process which produces a change in your own [the experimenter's] favorite physiological parameter." Hamilton differentiates between stress as an agent and stress as an effect and suggests that agents be termed stressors and effects be termed strain. The combination of stressor and strain represents the load on an adaptive system. Sacco correctly indicates that stress should be considered in terms of subjective appraisal of environmental events.
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Authors' Response
Stressing our points
Hymie Anisman and Robert M. Zacharko
Department of Psychology, Carleton University, Ottawa, Ontario, Canada K1S 586
The purpose of our target article was to sketch a mechanism whereby aversive events might increase vulnerability to clinical depression. As indicated by several commentators (Akiskal, Dimsdale, Lester, McKinney, Noll & Davis), the symptoms that characterize depression vary widely among individuals, and it might be more appropriate to consider the illness in terms of subtypes with some common underlying features. The pharmacological and biochemical evidence lends support to the contention that different neurochemical and hormonal factors subserve or are associated with these different subtypes of depression. In view of the diversity of symptoms which characterize depression and the potential for complex neurochemical
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Response/Anisman & Zacharko: Depression and stress He also notes that we frequently interchange the terms stress and stressor, while Neugebauer appears to delight in this revelation again (and again). It is certainly essential to define operationally what is meant by stress; however, it appears that Neugebauer had little difficulty in recognizing those occasions in which we inappropriately used the term stress (or stressor). We were sorry that Usdin found the stress terminology depressing. He no doubt recalls the "Panel Discussion on Stress Theory" in the volume edited by Usdin, Kvetnansky, and Kopin (1980), in which the participants of the symposium were apparently likewise unable to reach agreement on an appropriate definition. Indeed, the proposal was made there that "we be as specific as we can when we use the word and that the definition of stress awaits the next Symposium on Catecholamines and Stress" (p. 586) (whatever that is). In general, it seems that some researchers prefer to consider stress in terms of physiological responses whereas others consider it in terms of subjective appraisal. Evidently, we all have an intuitive appreciation for the term stress although formulating a precise definition is difficult. Most investigators appreciate that by stress or stress reaction we mean the response to aversive events or stimuli associated with those events. To be sure, as indicated by Sacco, Rosenthal, and Lester, what is perceived as stressful by one individual may not be perceived as stressful by another. For instance, divorce or marital separation, which rate highly on most lifechange scales, may be viewed as aversive by some individuals but as a blessing by others. By the same token, occupational disengagement or, for that matter, dramatic changes in life style may be differentially construed by individuals. The experimental analysis of the contribution of stressors to pathology must consider the context in which the stressor occurs as well as the subjective response to it (Sacco, Rosenthal, Lester, Murison & Ursin). In this respect, it is significant that Seligman and his associates (e.g. Abramson, Seligman & Teasdale) have proposed several variables which may govern the cognitive changes brought about by aversive events and have emphasized that an individual's performance expectancy is an essential element in determining behavioral outcome. We are not in disagreement with this view and are surprised that several of the commentators perceived our view of stressors as being a narrow one (e.g., Rosenthal). Omission of potential stressors such as perfectionism (Rosenthal) and daily hassles (Sacco) stemmed from our reluctance to attempt an exhaustive list. Coping processes. In the study of coping processes, animal experimentation has chiefly involved comparing the behavioral and neurochemical consequences of controllable and uncontrollable stressors. In their discussion, Sherman and Petty reported that escapable shock produced an increase in 5-HT whereas yoked, inescapable shock produced a relatively persistent reduction in the concentration of this amine. This finding is reminiscent of the differential effects of escapable and yoked inescapable shock on central NE levels reported by Anisman, Pizzino & Sklar (1980) and by Weiss, Glazer & Pohorecky (1976). Sherman and Petty suggested that the independence of reinforcement from outcomes lead to a 124
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state of "helplessness" that characterized or provoked the alterations of 5-HT levels. We have consistently maintained, as have Weiss et al. (1976), that control over aversive stimuli is an essential factor in determining neurochemical lability and behavioral outcome. However, we question whether it is necessary to invoke a concept such as "helplessness" to account for the differential outcomes induced by the two stress paradigms. It should be added that Sherman and Petty have provided impressive data showing that repeated treatment with tricyclic antidepressants eliminates the escape deficits ordinarily introduced by prior exposure to uncontrollable shock. However, such data can neither be taken to indicate that uncontrollable shock induces "helplessness" nor that the behavior of rats in a shuttle-box after exposure to uncontrollable shock represents a valid animal analogue of human depression. As with tricyclic antidepressants, L-dopa treatment, which is relatively ineffective in combating depression, has also been shown to counteract the performance deficits engendered by uncontrollable shock (Anisman, Remington & Sklar 1979; Anisman & Sklar 1979). We would like to believe that the behavior of rats or mice in a shuttle-box could be taken as representative of clinical depression in humans. Indeed, we have expended considerable effort in the past assessing the effects of controllable and uncontrollable events on neurochemical functioning and its relation to escape behavior. It seems, however, that, without resorting to cognitive interpretations, one can interpret the data derived from infrahuman studies comfortably on the basis of changes in response initiation and maintenance induced by uncontrollable shock (Anisman, Kokkinidis & Sklar 1981; Weiss et al. 1976). Moreover, as indicated by Dimsdale and by de Catanzaro, it is difficult to equate the consequences of shock applied to rats or mice with the complex stressors (including the antecedent events and subjective interpretations) encountered by humans. In considering coping styles, much of our discussion centered around the effects of controllable and uncontrollable shock in infrahuman subjects, with occasional reference to aggressive behavior as a means of coping. Of course, a great number of coping strategies are possible in humans. As we indicated in the target article, prior history in dealing with stressors will determine coping style; the availability of a buffer such as a close friend or confidant may diminish the impact of a stressor; even belief in God may represent a coping strategy. One of us, being airplane-phobic, makes (financial) deals with God before every flight. Thus far, God has religiously kept His side of the bargain, while the phobic renegotiates the terms of the contract at the termination of each flight (double or nothing?). Just as a given stressor may be variously perceived by different individuals, surely coping strategies are equally individualistic. Accordingly, it is commendable to develop a scale that allows one to assign subjective weights to a (potential) stressor and that considers whether behavioral coping methods are available to the individual (see Rosenthal). In their discussion, Murison & Ursin indicate that aversive stimulation increases endocrine secretion, but that once the animal learns (perceives) its mastery over the situation, the endocrine response declines. If animals learn they cannot control aversive stimulation,
Response/Anisman & Zacharko: Depression and stress further increases occur in the endocrine response. This raises an interesting issue bearing on the relationship between coping factors and amine depletion. (We have discussed this point elsewhere [Anisman & Lapierre 1981] but it warrants repeating.) What, specifically, provokes the catecholamine depletion provoked by an uncontrollable stressor? On the one hand, it can be argued that depletion only occurs when animals perceive that they have no control over environmental events. Alternatively, it may be argued that any aversive stimuli, if sufficiently severe and protracted, will provoke amine depletion, but that learning that behavioral control over the stressor is possible reduces the burden on neurochemical systems, thereby reducing the likelihood of depletion. The fact that Anisman et al. (1980) and Weiss et al. (1976) found that only uncontrollable shock provoked NE depletion does not imply that controllable shock will not produce such an effect, only that it is less likely to do so. Similarly, escape deficits are more pronounced after uncontrollable shock than controllable shock; but among some naive animals and some animals that received controllable shock, performance deficits may nonetheless be observed. The parameters of the test task, of course, determine to a great extent the frequency of escape failures. The point is that control over a given stressor does not assure that amine depletion and behavioral deficits will not occur. In a similar fashion, one can imagine that sustained aversive stimulation, or a series of "minor" stressors, whether controllable or not, could potentially influence affective state. Cognitive aspects of depression. If it appeared to the commentators that we overstated the case for neurochemical contributions to affective illnesses this stems from the fact that the major thrust of the target article was to describe the course of neurochemical changes provoked by stressors and some of the conditions that maximize these neurochemical events. Obviously any multidisciplinary approach to the analysis of conditions leading to depression should not ignore the potential contribution of cognitive processes to depression. In fact, we have indicated in several papers (Anisman 1978, 1982; Anisman & Sklar 1979) that cognitive processes or stimuli associated with a stressor may influence neurochemical state. There seems to be a belief (de Catanzaro, Beck & Harrison, Leshner) that we have adopted the view that neurochemical lability - and only neurochemical lability - determines whether or not depression will occur. This is simply not the case. Leshner proposes that stressors cause neurochemical depletions, which provoke depression. Therefore, it follows that drug-induced neurochemical depletion should provoke a similar depression. In effect, the equation here is that a stressor plus the ensuing neurochemical depletion should have effects comparable to that of neurochemical depletion alone (e.g. as induced by drug treatment). Although this may be applicable to the effects seen in a shuttle-box using rats or mice, it can also be argued that the neurochemical events associated with the stressor may provoke emotional repercussions that sustain or enhance neurochemical lability, which ultimately leads to depression. Certainly, the effects of the neurochemical depletion must be considered with respect to the background conditions in which they occur. For example, one could imagine that a catecholamine-depleting agent would have somewhat different quantitative and qualitative consequences under ideal versus unattractive environmental conditions. Both Burchfield and Rosentha! comment that the impact of a stressor not only involves an immediate cognitive reaction, but also the rumination and selfreferential brooding that may continue for some time after termination of the stressor. We have no quarrel with such an hypothesis. On the contrary, Anisman (1978, 1982) indicated that cognitive consequences associated with a stressful experience may exacerbate or invite further alteration of brain NE activity. As Bauer suggests, the alterations in neurochemical lability could create difficulties in initiating or executing a plan that is effective in dealing with environmental demands. Furthermore, it is conceivable that neurochemical status at any given time may also determine the individual's behavioral coping ability or perception of stressful events
(Kalat, McKinney, Noll & Davis, Sacco).
Although we assume interplay between neurochemical and cognitive events, caution must be exercised in describing the dynamics of such interactions. Leshner, for example, feels that our approach is too restricted. Rather than supposing that environmental stimuli biochemical change > depression, he suggests that environmental stimuli emotional state * biochemical response prolonging of the emotional state. But surely some neuronal events must have occurred when the environmental stimuli initially provoked the emotional state. As indicated earlier, we accept that an emotional state can exacerbate extant neurochemical aberrations. Perhaps the initial emotional state would not be clinically diagnosed as depression, and that only once rumination and its associated neurochemical states come into play would the full-blown depressive symptomatology be exhibited. Any way one looks at it, though, the initial stressor must be viewed as having neuronal consequences (whatever they may be) that ultimately lead to depression (Kalat). In addition to cognitive appraisal of stressful stimuli there exists a host of other factors that probably governs vulnerability to affective illnesses. Characteristics of the individual such as those described by Abramson, Seligman & Teasdale (1978) may be one set of factors that determine the way individuals perceive aversive experiences; and they may be determinants of the emotional state as well as the neurochemical consequences of an aversive experience. As we indicated in the target article, a great number of variables, including social factors, early life events, age of the individual and so forth, may all determine vulnerability to illness. Akiskal notes several additional factors which may act similarly. Moreover, as briefly indicated in the target article, and emphasized further by both McKinney and Akiskal, genetic factors should be considered when one assesses the contribution of stressors to the induction of depression. From our perspective, genetic predispositions might be viewed as greater vulnerability to neurochemical dysfunction given an appropriate set of environmental events. That is, inherited characteristics, including nongenetic factors such as in utero environment (see
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Response/Anisman & Zacharko: Depression and stress Wahlsten, 1979), while not necessarily influencing basal neurochemical levels and activity, may under some circumstances affect the course of the neurochemical alterations that follow aversive experiences. Dimsdale, Laborit, and Noll & Davis suggest that the rate of cortisol secretion and the activity of enzymes involved in synthesis and degradation of transmitters are associated with depression and may serve as genetic markers for such illnesses. At any rate, as indicated by McKinney and explicitly stated in the target article, there is no reason to assume that stressful experiences will always lead to depression, nor that depression is in all individuals necessarily a consequence of the stressful experience. Contrary to the assertion of Beck & Harrison, we argued that stressful life experience in some individuals may represent a predisposing factor for the illness, but certainly not the sole factor. One final remark concerning the stress-depression relationship seems appropriate. If the cycle of neurochemical dysfunction and cognitive disturbance is self-perpetuating, adaptation might be expected to occur, as it does in infrahuman animals that receive repeated exposures to shock. Our model predicts that considerable interindividual variability should exist with respect to the adaptability of neurochemical systems. This is not to imply that chronic physical or psychological insults act as antidepressants, but that depression following chronic stressors occurs because of failure of neurochemical adaptation (see Rush). Wide-ranging differences in neurochemical activity occur in different strains of mice exposed to stressors of equivalent severity. We are unaware whether differential rates of adaptation occur with repeated exposure to a stressor. It would be difficult to assess the contribution of rumination to changes in catecholamine activity in humans, much less to determine when rats or mice are ruminating over stressful experiences. Perhaps some indication can be derived from the "despair response" of rhesus monkeys (Kraemer), although the validity of this procedure would be questionable. Life stressors and relation to depression. The validity of studies showing a relationship between life stressors and depression was questioned by several commentators
(Beck & Harrison, Chute, Neugebauer, Sacco). We
Although not indicated in the target article, it has been our feeling that most life-event inventories may not be tapping essential life stressors. The procedure described by Rosenthal considers important issues in this respect, and we look forward to hearing the results of his work. Subgroupings of depression. There is a good deal of data indicating a relationship between NE activity and depression, but there is equally good evidence pointing to a role for 5-HT. Furthermore, DA and ACh have also been implicated in affective illness. On the one hand, one can conclude that all of this is just too complex to disentangle and that we are not yet ready to reach definitive conclusions (Usdin). A more optimistic view, on the other hand, is that at least we are rid of a monistic approach to the analysis of depression. As Akiskal indicates, the questions that the optimistic view now encounters are, among others: What forms do these complex interactions take? Do some neurotransmitters play a permissive role in the induction of depression, while others are responsible for expression of the symptomatology? What is the correspondence between specific neurochemical changes and specific symptoms characterizing depression? How do stressors come to provoke particular symptoms? We would like to be able to make definitive statements concerning these questions. Unfortunately, the data are still too sparse, the techniques too limited, and the research approaches too restrictive to permit valid conclusions to be drawn. The very fact that depression is characterized by dramatic individual differences in symptom profile tells us, as indicated by Dimsdale, that analysis of the illness will not be simple. It also raises the possibility that depression may represent several illnesses characterized not only by different experiential and environmental premorbid factors, but also by different neurochemical substrates. Studies of oncology indicate that the cancer process should not be considered a singular illness: tumors can either be spontaneous or induced by carcinogens or viruses; they may be hormonally dependent or independent; immune factors may or may not play a role; treatments that are effective for one form of cancer may be ineffective for another form. Does this mean that no definitive conclusions can be reached? Clearly not! It means that therapies must consider the nature of the processes subserving the particular form of cancer and the factors that lead initially to the presence of those particular neoplastic cells. So, too, in the case of depression. Acknowledging the importance of subtypes of depression has not only been instrumental in determining more effective choice of treatment, but it seems to have been beneficial in discerning, at least to some extent, neurochemical correlates of depression that might otherwise have been obscured.
Correspondence between neurochemical lability and
presented a brief overview of this literature followed by a series of caveats questioning the conclusions derived from these experiments. Moreover, we stated explicitly that relationship between these variables may not be causal but secondary to the initial life stressors encountered by the individual (e.g., the financial difficulty which may follow parental loss). Neugebauer actually wonders why we bothered reviewing this literature when immediately afterward we called its value into question. This particular literature is so fraught with problems one would be foolhardy to accept it uncritically; yet its pervasiveness makes it equally foolhardy to dismiss it entirely. McKinney addressed this issue exceptionally well, and we refer the reader to his commentary. We agree with Beck & Harrison that there is a need for prospective studies evaluating whether a relationship exists between life stressors and depression, although such studies may not be without their own shortcomings.
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behavior. The problem of the relation between specific neurochemical dysfunctions and corresponding behavioral pathologies is brought up by both Lester and Murison & Ursin. Sklar and Anisman (1981) suggest that aversive stimuli not only influence the activity of central neurotransmitters, but also affect hormonal secretion and peripheral transmitters release and influence immune functioning. The way in which a particular
Response/Anisman & Zacharko: Depression and stress stressor provokes a specific pathology would depend, according to Murison and Ursin, on the specific process (e.g., central or peripheral) activated by the physical or psychological insult. Yet the fact that such insults may have parallel and serial effects on numerous endogenous substrates makes it difficult to discern which of these is primarily involved in the emergence of the pathology. It has been our contention that many of the endogenous chemical actions induced by stressors serve in an adaptive capacity, and the specific pathology witnessed reflects the weak link among these systems (e.g., reduced central NE may increase vulnerability to depression; altered epinephrine functioning could lead to cardiovascular problems). In addition, as indicated in the target article and emphasized by Laborit, endogenous chemical change induced by a stressor with assumed positive affects may also have secondary consequences which are detrimental to the organism's welfare (e.g. the immunosuppressive effects of corticoid release). Noll & Davis describe several of the neurochemical factors that are associated with depression and suggest several symptoms of the illness that may correspond to variations in these endogenous substrates. As we indicated in the target article, and as is further emphasized by Noll & Davis, DA depletion may be responsible for the anhedonia frequently seen in depression. While this is certainly a viable hypothesis (see Wise 1978), it has been our contention that the available data are not sufficiently compelling to permit such a conclusion (see the accompanying target article by Wise and commentary by Anisman, this issue). In the case of 5-HT, Noll and Davis suggest that reduction of this amine may be responsible for heightened emotional responsiveness. Indeed, in their review of the literature Peters, Anisman, and Pappas (1978) indicated that considerable data point to 5-HT involvement in reactivity to environmental stimuli. Mason suggests that reductions in forebrain NE may provoke attentional deficits, while Kokkinidis and Anisman (1980) expressed the view that reduced NE coupled with increased DA neuronal activity provoke disorganized patterns of responding. Although both explanations merit consideration, they may be overstating the case. The difficulty in specifying a one-to-one correspondence between a neurochemical event and a particular behavior is revealed in a statement made by Karczmar (1975) in his review of cholinergic influence on behavior. He states "I do not know of any behavioral paradigm which is not affected by the cholinergic agonists and antagonists or which does not affect acetylcholine (ACh), cholinesterase (ChE) or their turnover" (p. 501). To a great extent, a similar statement could also be applicable when one is considering the catecholamines. The problem, as we see it, is specifying the conditions that lead to particular neurochemical events in specialized brain regions and then determining the precise behavioral expression induced by a restricted neurochemical effect. A phenomenological approach, as suggested by Hankoff, or a longitudinal-multivariate approach, as described by Bauer, represent potentially useful strategies in determining the relation between life stressors, neurochemical activity, and depression. At this time, however, any attempt on our part to provide anything more than a rudimentary analysis could be counterproductive and misleading. Neurochemical interactions. As if determining the relationship between neurochemical events and behavior were not sufficiently difficult, we are also faced with the problem of deciphering the contribution of fairly complex neurochemical interactions to behavioral output. Moreover, the joint effects of two or more neurotransmitters in one brain region may not be the same as in another brain region. In the case of some behaviors, (e.g., stereotypy, locomotor activity) considerable information is available pointing to dopaminergic-cholinergic interactions (see Butcher 1978), as well as noradrenergic-dopaminergic interactions (Antelman & Caggiula 1977). Analyzing such interactions has not been easy, and it will be considerably more difficult to determine the nature of the interactions that govern more complex behaviors such as avoidance-escape performance, let alone syndromes such as human depression. Kraemer, for example, documents work conducted in his own laboratory demonstrating the complexity encountered in attempting to decipher the effects of reductions of DA and NE on depression-like behaviors in monkeys. In our studies of escape performance in mice, we have likewise found several complex interactions between these transmitters (Anisman, Irwin & Sklar 1979; Anisman, Ritch & Sklar 1981). Kraemer suggests that stressors may result in the disorganization, as opposed to the depletion, of interdependent neurochemical systems, which in turn results in coping failure and the emergence of a behavioral syndrome that can be characterized as depression. This view is not inconsistent with our hypothesis and differs only in that we assert neurochemical depletion to be fundamental to the disorganization. We make our arguments simply on the basis that in several species uncontrollable shock has reliably been shown to result in reductions of NE as well as region-specific changes of DA. We should add that we are in total agreement with the comments made by Laborit. One should not only consider inhibition of an activating system, but also excitation of an inhibitory system. We also note that our failure to discuss peripheral neuroendocrine responses should not be taken to imply that we view these substrates as unimportant in depressive symptomatology. Rather, it reflects our limited familiarity with this line of research. Alternative neurochemical models. The argument presented by Stone and by Heninger (see also Rush and Mason) is intriguing and certainly accounts for a great deal of data. In fact, this position is not one which we would wish to dismiss. Accordingly, the ensuing remarks should only be considered as cautionary notes. While the proposition advanced by Stone would appear to be in direct opposition to our hypothesis, there does appear to be common ground. For example, Stone suggests that depression may result from the increased release and postsynaptic..receptor stimulation that occur following exposure to a stressor. We suggest that depression is associated with the reduced amine levels and release after the initial amine efflux. Perhaps depression will only occur if amine release is sufficiently great for the depletion to occur. It is even conceivable that the initial amine release sets the stage for the adverse consequences that occur once amine levels and activity are reduced. Increased amine activity may be essential for behavioral
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Response/Anisman & Zacharko: Depression and stress coping responses to be manifested or may be involved in the subjective appraisal of the stressor's impact (see discussion in Redmond & Huang 1979; see also Burchfield). So long as heightened amine activity persists, the organism is prepared to engage in coping attempts. Only when levels of the amine are reduced will depression be manifested. (A cognitively oriented theorist might wish to rephrase this description to read that the initial amine release is responsible for cognitive coping strategies, but continued failure to gain control over the stressor results in amine depletion and hence the cognitive changes associated with depression.) Upon exposure to chronic shock, tyrosine-hydroxylase activity increases and amine concentrations return to control levels. We have assumed that the resultant increased postsynaptic NE activity should counteract the depressive symptomatology or lead to further behavioral-cognitive coping attempts. In contrast, Stone posits that receptor subsensitivity is responsible for the reduction of the depressive symptoms. We accept that the subsensitivity reflects an essential adaptive change, but suggest that it represents a compensatory response to deal with the sustained increase of amine utilization. Stone reports that rats subjected to chronic foot-shock show increased levels of NE and tyrosine hydroxylase activity, but not augmented release of the amine. As yet unpublished data collected in our laboratory indicate similar effects 24 hours after fourteen sessions of stress applied on consecutive days. Measurements taken immediately after the last stress session, however, revealed increased utilization of NE in the hypothalamus, cortex, hippocampus, and locus coeruleus. A major source of support for Stone's position comes from the fact that antidepressant therapy requires several weeks of administration before it is effective. As indicated by Huang (1979) and Maas and Huang (1980), there is good reason to believe that the beneficial effects of this drug treatment are derived from the receptor subsensitivity following repeated drug treatment. It is unclear, however, whether the subsensitivity is responsible for the antidepressant effects of the chronic drug treatment or the subsensitivity simply follows, and is an index of, the sustained NE postsynaptic stimulation (Tang, Seeman & Kwan 1981; Crews, Paul & Goodwin 1981) that might be necessary to antagonize the depressed symptomatology. Furthermore, the fact that the receptor subsensitivity and therapeutic effects of desmethylimipramine are not evident for several days following drug administration may be due to the passage of time rather than repeated treatment with the drug (Chiodo & Antelman 1980). Alternatively, repeated drug treatments may be necessary for sufficient drug to accumulate in some brain regions before the treatment is therapeutically efficacious. Finally, it should be noted that if /3-NE receptor subsensitivity alone is responsible for the therapeutic effects of chronic desmethyiimipramine treatment, then any direct-acting /3-NE antagonists should have a beneficial effect on the depressive symptomatology. One final note should be added before concluding this section. Although several investigators have reported decreased NE postsynaptic receptor activity (Huang 1979; Olpe & Schellenberg 1980; Korf, Sebens, & Postema 1979; Sulser 1978; Sulser, Vetulani & Mobley 128
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1978) or decreased sensitivity of DA autoreceptor (Serra, Argiolas, Fadda & Gessa, 1980) after repeated treatment with tricyclics, others have reported either no effect or apparent increases in NE postsynaptic receptor activity (Wang & Aghajanian 1980; DeMontigny & Aghajanian 1978). As indicated by Wang and Aghajanian (1980), the discrepant results following repeated treatment with tricyclic antidepressants may reflect differential action of the drug on different types of receptors in various brain regions. It should also be noted, as discussed by Korf et al. (1979), that the dosage of tricyclic antidepressants employed in rat studies considerably exceeds the therapeutic dose used in humans. Thus, caution must be exercised in extrapolating the data from infrahuman experiments to the clinical setting. Finally, in the rat studies, the effects of tricyclic antidepressants are presumably evaluated under conditions in which the interplay between neurons is functionally undisturbed, whereas the therapeutic effectiveness of such drugs in humans is examined in a system that may already be out of kilter. Somewhat related to the NE receptor subsensitivity model is the view of Hingtgen & Aprison. They suggest that reductions of 5-HT may result in supersensitive 5-HT receptors (see, for example, Wang & Aghajanian 1980), such that environmental stimuli that provoke 5-HT release produce exaggerated postsynaptic receptor activity. Antidepressants, according to this view, might be clinically effective because of a blocking action (or reduced sensitivity) at receptor sites. As suggested by Olpe and Schellenberg (1980), depression may in fact reflect the joint effects of hypersensitive 5-HT receptors and hyposensitive NE receptors. The beneficial effect of antidepressants results from alterations in the imbalance between these systems. The view expressed by Hingtgen and Aprison is not inconsistent with our proposition, and raises the possibility that stressors could provoke different subtypes of depression depending on the relative adaptability of NE and 5-HT systems in response to environmental stimuli (see Laborit). Mason raises the possibility that reductions of NE may result in schizophrenic-like symptoms, rather than symptoms associated with depression (see also Lester). Specifically, he indicates that depletion of forebrain NE by 95% in 6-hydroxydopamine-treated rats results in behavioral changes reminiscent of the inability to filter irrelevant environmental stimuli. Although schizophrenia has been associated with apparent deficits in filtering environmental stimuli, or stimulus "overload" (see Hamilton), the reductions of NE necessary to induce the assumed attentional deficit in rats (95%) is probably considerably greater than the NE reductions that are actually present in schizophrenic brains. Moreover, it remains to be determined whether reductions of NE actually do affect attentional processes (Pisa & Fibiger 1980). These caveats notwithstanding, Kokkinidis and Anisman (1980) proposed that some schizophrenic-like symptoms, at least those related to chronic amphetamine abuse, may be due to reduced NE activity coupled with hypersensitive DA receptors. The heightened motor activity associated with increased DA receptor activity may not be sufficient to provoke schizophrenic-like behavior. When accompanied by deficits in stimulus filtering, presumably related to NE reductions induced by
References/Anisman & Zacharko: Depression and stress chronic amphetamine treatment, the nondirected, hyperactive responding may be more closely related to the schizophrenic symptomatology. It should be noted, however, that in Kokkinidis and Anisman's model, chronic amphetamine treatment no doubt produced wide-spread neurochemical alterations beyond that of modifying NE and DA activity. Concluding remarks. Even a cursory overview of the various commentaries reveals a broad spectrum of opinions concerning both the target article and the strategies that should be employed in assessing the processes responsible for depression. Some investigators have placed greater emphasis on cognitive processes and the effects of stressors on these, while others have been more concerned with neurochemical mechanisms (and interactions) and their relation to the various symptoms and subtypes of depression. It will be clear from our response that each of these issues is considered essential for a comprehensive understanding of depression. Our contention that neurochemical lability induced by stressful experiences is one factor determining vulnerability to depression does not exclude the possibility that cognitive changes are essential in sustaining the affective state. Together, neurochemical and cognitive factors may be part of a dynamic process which culminates in the progressive exacerbation of the depressive symptomatology. The nature of the neurochemical events associated with depression has yet to be fully elucidated. The diverse symptomatology which characterizes the illness suggests the involvement of more than a single neurotransmitter. Even when one considers the involvement of any given transmitter, it remains to be demonstrated whether it is dysfunction of this substrate directly that influences the illness or whether serial effects associated with the dysfunction are more closely related to the depressive symptomatology. In addition, it seems that dysfunction of a given neurotransmitter system may consist of reduced levels or activity, or it may reflect alterations of pre- and postsynaptic receptors. Stressful experiences may influence vulnerability to affective illnesses by altering the unique balance that exists within a neurochemical system as well as between several such systems.
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