Eur Arch Psychiatry Clin Neurosci (2001) 251: Suppl.
2, II/47II/52 Steinkopff Verlag 2001
Giovanni A. Fava Lara Mangelli
Assessment of subclinical symptoms and psychological well-being in
depression

Abstract A substantial body of research suggests that
subclinical symptoms characterize the longitudinal
course of major depression and have important patho-
physiological and treatment implications. Specic treat-
ment of residual symptoms may in fact improve long-
term outcome, by acting on those residual symptoms
that progress to become prodromes of relapse. The
assessment of psychological well-being is also important,
since its absence may create conditions of vulnerability
to possible adversities. The route of recovery, thus, lies
not exclusively in alleviating the negative, but in engen-
dering the positive.

Key words Subclinical symptoms Psychological well-
being Depressive disorder Prodromal symptoms
Residual symptoms
Introduction
In the past two decades, mental health research has been
dramatically weighted on the side of psychiatric nosology
and psychological dysfunction. Such emphasis has
resulted in the development of diagnostic criteria (DSM-
IV) aimed at identifying syndromes according to a cut-
off of severity and to disregard subclinical symptoms
(Fava and Kellner 1991). Furthermore, mental health has
been equated with the absence of disease rather than the
presence of psychological wellness (Ryff and Singer
2000).
Prof. G. A. Fava () L. Mangelli
Department of Psychology
University of Bologna
Viale Berti Pichat, 40127 Bologna, Italy
tel. 39-051-2091339
fax. 39-051-243086
E-mail: fava@psibo.unibo.it
Psychometric assessment reected these orientations
and often took a blanket approach. Several instruments
are used, often highly redundant in nature, to differenti-
ate diagnostic groups, violating the psychometric princi-
ple of incremental validity, whereby each distinct aspect
of psychological measurement should deliver a unique
incremental increase in information (Fava 2001).
Per Bech has played a substantial role in shifting gears
in clinical research in psychiatry. In a seminal paper on
measurement of psychological distress and well-being
(Bech 1990), he has anticipated several trends which have
become apparent only today. In particular he has out-
lined:
 The importance of assessing subclinical symptoma-
tology
 The role of psychological well-being in the balance
between health and disease
 The need of developing specic psychometric strate-
gies in assessment, with special reference to the issue
of recovery and to clinimetrics.
We well outline the importance of this approach in the
setting of unipolar depression. Similar considerations,
however, may be formulated in bipolar disorder (Fava
1999; Benazzi 2001), panic disorder (Fava and Mangelli
1999) schizophrenia (Klosterkotter et al. 2001) and eat-
ing disorders (Raf et al. 2000).
Psychopathology of unipolar major depression:
a longitundinal view

Prodromes
Several studies have addressed the issue of symptom
development in unipolar depression. Most of the early
studies are just based on clinical observations.
Hays (1964) examined prodromal symptoms in 81
patients with endogenous depression. Four symptom
II/48
patterns emerged: a) sudden-onset depressions (associ-
ated with melancholic features and bipolar disorder);
b) gradual-onset depressions, where mood disorder
takes months to develop and is related to common stress-
ful life events; c) neurotic-onset depressions, commonly
preceded by anxiety disorders; and d) uctuating onset
depressions, in which symptoms displayed considerable
uctuations in severity before reaching full force. Hop-
kinson (1965) interviewed 43 in patients suffering from
depressive psychosis. About 30% showed a prodromal
phase characterized by tension and vague feelings of
anxiety, and less often other symptoms such as indeci-
sion and impaired concentration. Other studies dealt
with the rapidity of onset of depressive symptoms.
Winokur (1976) found, in a sample of 216 patients, that
depression spectrum disease patients (i.e. patients who
had alcoholism in rst-degree relatives), were much less
likely to have an acute or abrupt onset that were other
depressive patients. Cadoret et al. (1980) found that
somatic complaints and anxiety preceded the onset of
depression in 117 patients in primary care. Young and
Grabler (1985) reported that in 11 depressed patients a
rapid onset of symptoms was associated with the endoge-
nous subtype, the absence of past or current non-affec-
tive disorders, older age and fewer stressful life events.
Fava et al. (1990) investigated prodromal symptoma-
tology occurring in the 6 months prior to the onset of
depressed mood in 15 outpatients at their rst episode of
primary major depressive disorder. A semistructured
interview based on Paykels (1985) Clinical Interview for
Depression was performed 2 to 3 months after the initial
evaluations, when the patients symptoms had improved.
Family members who had observed the patient were
asked to provide additional information. Each of the 15
patients reported having at least one prodromal symp-
tom before the onset of depressed mood. Generalized
anxiety was present in 13 cases and irritability in 9. Other
common symptoms were impaired work and initiative,
fatigue, initial and delayed insomnia. These findings
were independently replicated by Van Praag (1992) and
by Mahnert et al. (1997). These latter authors also used
Paykels Clinical Interview for Depression. These results
support a description in the textbook by Mayer Gross-
Slater-Roth (Mayer Gross et al. 1969, pp. 207208): The
history of change in the patients behavior is characteris-
tic and important; he retires from usual social activities,
avoids his friends in the street, and, if forced into com-
pany, seems bored and inattentive and takes little inter-
est in topics that usually elicit an active response (...). An
initial mood of indifference in depressive states may last
for a considerable time, but sooner or later is replaced by
the one of sadness, .
During a 6 month follow-up, after antidepressant
drugs discontinuation, 4 of the 15 patients relapsed and
required further antidepressant drug treatment (Fava et
al. 1990). In all cases, prodromal symptoms of relapse
closely resembled those of the rst episode. The consis-
tency of symptoms over time in each individual is not
limited to prodromes but applies also to the affective
episode. Paykel et al. (1976) found some similarities in
symptom patterns of 33 depressives between initial rat-
ings at height of a depressive illness and subsequent
relapse several months later, after intervening recovery.
In a study associated with the NIMH Epidemiologic
Catchment Area Program (Dryman & Eaton 1991),
women with sleep disturbances, diminished sexual drive,
feelings of worthlessness and trouble concentrating were
over 5 times more likely to experience an onset of major
depression than those without the specied symptoms.
Using the same database, Judd et al. (1997) found that a
subsyndromal depressive symptoms (dened by two or
more depressive symptoms of at least 2 weeks in dura-
tion) were frequently prodromal to episodes of major
depressive disorder.
Early symptoms of subclinical depression and per-
sistent helplessness were also found by Ernst et al. (1992)
in a longitudinal prospective study on incidence in young
adults.
The results of these studies in unipolar depression
(whether naturalistic or based on rating scales) therefore
suggest that a substantial prodromal symptomatology
exists before the onset of depressed mood. Anxiety and
irritability appear to dominate the clinical picture.

Residual symptoms
In 1973 Paykel and Weissman found social and interper-
sonal maladjustments in fully recovered depressed
patients compared to controls, despite considerable
improvement in social adjustment upon treatment. Sub-
missive dependency and family attachment improved
almost completely, whereas two other personal dysfunc-
tions, interpersonal friction and inhibited communica-
tion, showed little change and greatest residual impair-
ment. Residual social maladjustment was subsequently
reported by other investigators (Goering et al. 1992;
Coryell et al. 1993; Bauwens et al. 1991) and was found to
correlate with long-term outcome (Goering et al. 1992).
Similarly, dysfunctional attitudes and attributions were
found to persist after recovery, despite clinical and cog-
nitive improvement (Eaves & Rush 1984; Williams et al.
1990; Brown et al., 1990). These cognitive patterns were
positively correlated with vulnerability to persistent
depression or relapse (Williams et al. 1990; Brown et al.
1990; Power et al. 1995; Bothwell & Scott 1997). These
ndings were consistent with the fact that vulnerable atti-
tudes such as high neuroticism assessed when the
depressed patients are symptomatic predict recovery
(Scott et al. 1992, 1995), but that for the prediction of
relapse, cognitive measures when patients are asympto-
matic need to be used (Williams et al. 1990). Social mal-
adjustment and dysfunctional attitudes may overlap with
characterological traits assessed after clinical recovery
(Fava M et al. 1994, Peselow et al. 1994, Murray & Black-
burn 1974; Perris et al. 1984, Chien & Dunner 1996, Sauer
et al. 1997, Black & Sheline 1997, Enns & Cox 1997) or pre-
morbid personality features (Clayton et al. 1994, Nystrom

& Lindegard 1975). In any case, there appears to be a
residual attributional interpersonal component which is
refractory to otherwise successful treatment of depres-
sion. Such component may entail considerable predictive
value.
The notion that the majority of depressed patients
experience mild but chronic residual symptoms or recur-
rence of symptoms after complete remission, that was
well delineated in the 1970s (Weissman et al. 1976), did
not receive the attention it deserved in subsequent years.
However, the presence of residual symptoms after com-
pletion of drug treatment (Mindham et al. 1973, Faravelli
et al. 1986, Prien & Kupfer 1986, Georgotas & McCue
1989, Maj et al. 1992, Fava et al. 1994, Paykel et al. 1995,
Judd et al. 1997, 2000) or cognitive behavioral therapy
(Simons et al. 1986, Thase et al. 1992) of depression has
been correlated with poor long-term outcome. This
would parallel the fact that patients with so-called dou-
ble depression (major depression overlapping on dys-
thymia) have been shown to be less likely to make a full
recovery and more likely to relapse (Keller et al. 1983).
Methodological problems in assessment of residual
symptoms, however, emerge. There is paucity of psycho-
metric studies addressing the phenomenology of
depressed patients after benefiting from treatment.
Recovered depressed patients displayed significantly
more depression and anxiety than control subjects in one
study (Fava et al. 1986), but not in another (Agosti et al.
1993). Differences in the sensitivity of the rating scales
which were employed may account for such discrepant
results. Using Paykels (1985) Clinical Interview for
Depression, only 6 (12.2 %) of 49 patients with major
depression successfully treated with antidepressant
drugs and judged to be fully remitted had no residual
symptoms (Fava et al. 1994). The majority of residual
symptoms were present also in the prodromal phase of
illness. The most frequently reported symptoms involved
anxiety and irritability. This was consistent with previous
studies on prodromal symptoms of depression (Fava et
al. 1990, Van Praag, 1992) and overlapped with ndings
concerned with interpersonal friction (Paykel & Weiss-
man 1973), irritability (Nystrom & Lindegard 1975) and
anxiety (Murray & Blackburn 1974). Using a similar
methodology, Paykel et al. (1995), found residual symp-
toms to be present in 32% of 60 patients who remitted
from major depression. Previous diagnosis of dysthymia
did not predict residual symptoms. Nierenberg et al.
(1998) found that only 18% of 108 patients who fully
responded to uoxetine had no residual symptoms, and
provided a full replication of the data by Fava et al.
(1994).
In conclusion, substantial residual symptomatology
appears to characterize depressed patients who success-
fully responded to pharmacological or psychological
therapies. Anxiety, irritability and interpersonal friction
appear to be common residual symptoms. Angst, Kupfer
& Rosenbaum (1996) observed that clinical trials overes-
timate the likelihood of full recovery on a single antide-
pressant. The usual response rates of 60 to 70% are typ-
II/49
ically reported when a reduction of 50% or more in the
Hamilton Depression Rating Scale occurs. However,
using a more conservative score for dening response,
only 45 % of approximately 900 depressed patients
achieved a satisfactory response. Similarly, a major nd-
ing of the NIMH Treatment of Depression Collaborative
Program was that 16 weeks of pharmacological or psy-
chotherapeutic treatment were insufficient for most
patients to achieve full recovery and lasting remission
(Shea et al. 1992).
Cornwall & Scott (1997) reviewed publications relat-
ing to a precise denition of partial remission (Frank et
al. 1991). Partial remission was found to affect at least one
third of subjects treated for depression, to increase the
risk of further depressive relapse, and to adversely affect
social and work performance.

Rollback phenomena
In a study (Fava et al. 1994), the relationship of residual
symptoms to prodromal symptomatology was speci-
cally addressed. Almost 70% of the residual symptoms
that were found to occur in 40 remitted depressed
patients were present also in the prodromal phase of ill-
ness. This percentage increased to almost 90% of cases
for residual generalized anxiety and irritability. The roll-
back phenomenon (Detre and Jarecki 1971) or, at least,
a strong relationship between prodromal and residual
symptomatology was thus substantiated. These results
achieved independent replication (Mahnert et al. 1997)
and are supported also by two other lines of evidence. In
a prospective study (Shea et al. 1996), that examined the
possibility that episodes of major depression result in
lasting personality changes that persist beyond recovery
(the scar hypothesis), there was no evidence of negative
change from premorbid to postmorbid assessment. This
would suggest continuity whether we rate it in charac-
terological or symptomatological terms between the
prodromal and residual phases. The second line of evi-
dence is based on recognition of specific temporal
courses of change during treatment of depression
(Haskell et al. 1975, Katz et al. 1987, Casper et al. 1994,
Nierenberg et al. 1995). Different types of treatment may
affect the temporal course of change in depression
(Watkins et al. 1993), and the use of pattern analysis may
differentiate true drug and placebo responses early in
treatment (Rotschild & Quitkin 1992). Patients do not
suddenly become well, but tend to gradually lose their
depressive symptoms over the months following treat-
ment (Keller et al. 1992). Stassen and associates (1993)
found that the time course of improvement among
responders to amitriptyline, oxaprotiline and placebo
was independent of the treatment modality, and thus
identical in all three groups. Once triggered, the time
course of recovery from illness became identical to the
spontaneous remissions under placebo. Antidepressant
drugs, therefore, may not change the pattern of the nat-
ural course of recovery from illness, but simply speed the
II/50
recovery and change the boundary between respon-
ders and non-responders (Stassen et al. 1993).

Demoralization
Bech (1990) called attention to the clinical phenomenon
of demoralization. This led to the development of specic
criteria for demoralization (Fava et al. 1995), which iden-
tify a feeling state characterized by the patients con-
sciousness of having failed to meet his or her own expec-
tations (or those of others) or being unable to cope with
some pressing problems. The patient experiences feel-
ings of helplessness, hopelessness or giving-up. Some
preliminary results obtained in the setting of medical
disease (Porcelli et al. 2000, Fava et al. 2001, Grandi et al.
2001) suggest that demoralization is frequently found
and overlaps only to a certain degree with major depres-
sion. Future studies may explore the presence of demor-
alization in the residual phase of major depression.
Psychological well-being
Bech (1990) has emphasized the importance of psycho-
logical well-being whether it is subsumed under Ryffs
(Ryff and Singer 2000) or Antonovskys (Schnyder et al.
2000) conceptualizations as a component of quality of
life. He and Angst (1996) have reviewed the literature on
quality of life in anxiety disorders. Several studies have
shown impaired quality of life and well-being in patients
with major depressive disorders, even in their remitted
status (Schoenfeld et al. 1997, Pyne et al. 1997, Stewart et
al. 1993, Rafanelli et al. 2000). Thunedborg, Black and
Bech (1995) found that quality of life measurements, and
not symptomatic ratings, could predict the recurrence of
depression. In one study, the relationship of psycholog-
ical well-being to distress was investigated in remitted
patients with mood and anxiety disturbances (Rafanelli
et al. 2000). The results suggested that well-being cannot
be equated to lack of distress as implicitly endorsed by
current psychiatric paradigms and the need of a multidi-
mensional assessment in affective disorders. Further, the
hypothesis that the state-trait characteristic of a specic
instrument may be population or stage dependent was
introduced (Rafanelli et al. 2000).
Therapeutic implications
There has been increasing awareness of the bleak long-
term outcome of depression as to relapse and recurrence
(Piccinelli & Wilkinson 1994). Ramana et al. (1995)
reported on the course of depression with respect to
remission and relapse in a two-year prospective follow-
up. Remission was rapid with 70% of subjects remitting
within 6 months and only 6 % failing to do so by 15
months. However, 40 % relapsed over the subsequent
months, with all relapses occurring during the rst 10
months. This unfavorable outcome seems to parallel the
presence of substantial residual symptomatology in
patients judged to be remitted and no longer in need of
active treatment. Indeed, residual symptoms, as well as
persistence of altered biological markers such as the dex-
amethasone suppression test, are probably the most con-
sistent predictors of relapse. In a large cohort study,
asymptomatic recoverers relapsed in 157 weeks, com-
pared to residual recoverers who relapsed in about 28
weeks (Judd et al. 1997).
However, the challenge of treatment of depression
today appears the prevention of relapse more than
attainment of recovery. And the question arises as to
whether reduction or disappearance of residual sympto-
matology may entail a more favorable long-term out-
come of depression. A preliminary answer to this ques-
tion was provided by a controlled therapeutic trial (Fava
et al. 1994, 1996). Forty patients with major depressive
disorder who had been successfully treated with antide-
pressant were randomly assigned to either cognitive
behavioral treatment or clinical management of residual
symptoms. In both groups, antidepressant drugs were
tapered and discontinued. The group that received cog-
nitive behavioral treatment had a signicantly lower level
of residual symptoms after drug discontinuation in com-
parison with the clinical management group. Cognitive
behavioral treatment also resulted in a lower rate of
relapse, which achievement of statistical signicance at a
4 year follow-up (Fava et al. 1996). The rationale of this
approach was to spend cognitive behavioral treatment
resources when they are most likely to make a unique and
separate contribution to patient well-being and to
achieve a more pervasive recovery. It was fully validated
in a large controlled trial where cognitive therapy of
residual symptoms was found to improve long-term out-
come of major depression compared to clinical manage-
ment (Paykel et al. 1999). The sequential, stage oriented
approach was applied to 40 patients with recurrent major
depression, who had been successfully treated with anti-
depressant drugs, using the same criteria that had been
outlined by Frank et al. (1990), that is 3 or more episodes
of unipolar depression (with the immediately preceding
episode being no more than 2.5 years before the onset of
the present episode). Patients were randomly assigned to
either cognitive behavioral treatment of residual symp-
toms supplemented by lifestyle modication and well-
being therapy (Fava et al. 1998a) or clinical manage-
ment. In both groups, antidepressant drugs were tapered
and discontinued. At 2-year follow-up, cognitive behav-
ioral treatment resulted in a signicantly lower relapse
rate (25%) than did clinical management (80%) (Fava et
al. 1998b). These results challenge the assumption that
long-term drug treatment is the only tool to prevent
relapse in patients with recurrent depression. Although
maintenance pharmacotherapy seems to be necessary in
some patients, a 2-stage, sequential, intensive approach
(pharmacotherapy for acute treatment of depression,

followed by cognitive behavioral treatment for its resid-
ual phase) appears to be a viable alternative for other
patients (Fava et al. 1998b). Amelioration of residual
symptomatology may reduce the risk of relapse in
depressed patients by affecting the progression of resid-
ual symptoms to prodromes of relapse.
Acknowledgment This paper was supported in part by a grant Outcome
evaluation in mental health from the Istituto Superiore di Sanit
(Rome), from a grant from the Ministero dellUniversit e della Ricerca
Scientica e Tecnologica (MURST, Rome), and from a grant from Con-
siglio Nazionale delle Ricerche (CNR, Rome) to Professor Fava.
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