Marie Salomonov, 4163930 ROLE OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN DEPRESSION Introduction Depressed mood, anhedonia, and altered cognitive function

are the main characteristics of a prevalent illness and often disabling condition, major depressive disorder (MDD). MDD has various, often diverse, symptoms and its diagnosis is mostly based on rather subjective assessments. Constant efforts are made to identify the biological bases for the heterogeneity of this condition, since distinct biological markers would not only make the diagnosis of the different MDD subtypes much clearer, but they would also enable new, more direct developments and approaches in the field of treatments (Schmidt et al.; 2011). There are several factors dysregulation of which has been suggested to contribute to MDD symptoms. These include pro-inflammatory cytokines and growth factors, endocrine factors and metabolic dysregulations (Schmidt et al.; 2011). Growth factors, cytokines, hormones and metabolic markers abnormalities are being examined in numerous studies to determine their possible role in the etiology of MDD. This review will provide a brief account of the proposed role of HPA axis in major depressive disorder and present several different recent human subject research studies investigating the pathophysiological mechanisms which are thought to be associated with HPA axis and MDD. Review articles discussing the topic in question will be used to support the analysis and provide a broader insight into the subject. Hypothalamic-pituitary-adrenal Axis (HPA Axis) HPA axis is a major part of the from

neuroendocrine regulates axis

system

that,

apart

many other body processes, controls and stress of reactions, numerous immune types of responses and metabolism. This complex consists interactions among hypothalamus, pituitary gland and the adrenal glands (Pariante et al.; 2008). HPA axis activity is guided by the secretion of corticotrophin-releasing factor (CRF) and vasopressin (AVP) from the paraventricular nucleus of the hypothalamus. Secretion of these
Figure 1 Scheme of HPA axis activity and putative pathways leading to its hyperactivity (Pariante et al.; 2008)

activates

the

release

of

adrenocorticotrophic hormone (ACTH) from

Marie Salomonov, 4163930 the anterior pituitary, and in response glucocorticoids (cortisol in humans) are secreted from the adrenal cortex. Apart from interactions with receptor in multiple target tissues, glucocorticoids also act back at the HPA axis. There they are responsible for the negative feedback (inhibition) of both CRF and AVP release from the hypothalamus, and thus also ACTH from the pituitary corticotropes (Weinstein et al.; 2010). The activated HPA axis regulates peripheral body functions (e.g. metabolism and immunity) and it also has strong effects on the brain - glucocorticoids regulate neurogenesis, acquisition of new memories and the emotional appraisal of events. HPA axis also forms a link between stress and brain functioning. Providing the evidence of the aforementioned physiological interconnections, the abnormalities in HPA axis activity which have been found in many psychiatric disorders, such as MDD, seem justified (Pariante et al.; 2008). HPA Axis Abnormalities in Major Depressive Disorder As many studies over the last 40 years indicated, MDD is associated with up-regulation of the HPA axis that results in increased release CRH and in turn in elevation of cortisol, the so-called stress hormone. There are studies which suggest that elevated cortisol in patients with MDD is a compensatory mechanism developed as a response to decreased glucocorticoid receptor function and expression in the brain which causes malfunction of the negative feedback regulation system. Moreover, some antidepressants, if administered chronically, were shown to up-regulate glucocorticoid receptor expression and function, and thereby down-regulate the HPA axis activity (via negative feedback) (Schmidt et al.; 2011). Apart from response to psychological stress, one of the common experimental measures of HPA axis activity and reactivity includes response to the dexamethasone suppression test (DST). This test measures the levels of cortisol in plasma and/or urine after administration of dexamethasone, a synthetic glucocorticoid imitating the actions of endogenous ACTH. MDD is widely associated with the lack of suppression of plasma cortisol following the administration dexamethasone (Weinstein et al.; 2010). A study conductated by Ising et al. in 2007 tested 50 inpatients diagnosed with severe MDD using the DST. First test was performed after study inclusion and second one in 2 to 3 weeks later while under continuous antidepressant treatment. Increased ACTH and cortisol responses to the first DST were found in comparison with healthy control subjects. The second DST test showed attenuated cortisol respopnse in 36 out of the 50 patients. This response was associated with a positive treatment response after 5 weeks. The 36 subjects also had a higher remission rate at the end of hospitalization. As mentioned before, inflammatory markers, such as pro-inflammatory cytokines, were also found to be abnormal in many MDD patients. Since HPA axis plays a role in immune 2

Marie Salomonov, 4163930 responses, inflammatory markers are likely to have an impact on its function (Weinstein et al.; 2010). Increased release of CRH, ACTH and cortisol has been observed after acute cytokine administration and it has been inferred that the neuroendocrine function impairment in MDD may be partly due to cytokine interference with the negative feedback regulatory system of the HPA axis. There is a very fine balance between HPA axis sensitivity to glucocorticoids and the innate immune system, which has been often reported as dysregulated in MDD patients. Recent studies indicate that the relationship between immune system responses and neuroendocrine activation is most likely bidirectional (Miller et al.; 2009). HPA axis hyperactivity as a MDD predictor? The relationship between HPA axis dysregulation and MDD is being explored from a variety of different perspectives. Most models of developmental psychopatology generally hypothesize that HPA axis dysregulation can be considered a MDD biomarker, regarding that atypical HPA axis functioning precedes the emergence of depressive symptoms and its dysregulation can therefore be considered a risk factor for MDD (Guerry et al.; 2011). In other words, HPA axis hyperactivity that has been consistently described in depressed individuals, may merely be a manifestation of neurobiological abnormalities that predispose to MDD, rather than a consequence of depression (Pariante et al.; 2008). One of the studies which support the hypothesis that HPA axis dysregulation can indicate susceptibility do MDD was conducted in 2010 by Adam et al. This study measured cortisol awakening response (CAR - salivary cortisol levels at 30-40 min after awakening) in 230 17-year-olds that were evaluated as at high risk for developing MDD. S ymptoms of depression in these subjects were then measured one year later. Results of the research suggest that, compared to average, young adults who had highly elevated CAR a year earlier were three times more likely to have developed MDD. Hyper-responsiveness to Acute Mental Stress in Depression A 2010 study by Weinstein et al. investigated neurohormonal and inflammatory hyperresponses to acute mental stress in 14 individuals diagnosed with MDD (diagnosed according to DSM-IV) and 14 non-depressed controls (matched on gender, age and body mass index). Considering mood measures and blood samples for neurohormonal and immunological analysis it was determined heightened acute mental stress reactivity in depressed participants, as the changes in their ACTH and cortisol levels as well as inflammation markers were significantly higher than in the control participants. Immediate and steeper increase in ACTH following mental stress was observed in depressed participants and their cortisol response (measured 30 min post-mental stress)

Marie Salomonov, 4163930 was also elevated compared to controls. Same effect was seen examining the inflammatory measures. Weinsteins study also further discusses the various reasons for hyper-reactivity to stress in depressed individuals. Apart from the previously mentioned malfunction of negative feedback response and dysregulation of HPA system, the study also proposes that the prolonged involuntary processing of emotional information, which has been observed in depressed individuals, could play a role in the exaggerated reactivity to acute mental stress. Differential Role of HPA axis in Distinct Subtypes of MDD Reviewing the research executed in the discussed field, the great variations between the reported effect sizes among individual studies of HPA axis role in MDD have to be considered. Lamers et al. argue that one of the important factors which may potentially explain the variability of different studies results could be the heterogeneity of MDD. In 2012 Lamers et al. conducted a study of significantly larger scale than Weinstein et al. Their study involved data from 776 subjects, from which 111 subjects were suffering from chronic melancholic depression, 122 were diagnosed with atypical depression and rest of the sample were controls. Inflammatory markers and saliva cortisol levels were analysed and compared. And although significantly higher levels of cortisol were measured in the melancholic MDD diagnosed subjects, this was not true for the subjects diagnosed with atypical depression. However, atypical MDD diagnosed subjects had been measured to have significantly higher levels of inflammatory markers, which were not found in the melancholic MDD subjects. Problems & Limitations of Current Research of HPA Axis Pathophysiology in MDD The above described study highlights the fact that, as in most scientific disciplines, individual differences play an important role in evaluating the extent to which the results of a research can be generalised. The next part of this review will therefore concentrate not only on the heterogeneity of MDD and its subtypes, but it will also consider variation in diagnostic methods used for subject selection in different studies. Considering the two aforementioned studies, it is important to note that each used a slightly different diagnostic method to assess the subjects entering their research. Whereas the study conducted by Lamers et al. in 2012 used Composite International Diagnostic Interview (CIDI) for confirmation of MDD diagnosis and latent transition analysis (LTA) to further identify the MDD subtype of the participants, Weinstein et al. used Structured Clinical Interview for DSM-IV (SCID) to select MDD subjects. Since there is about 15 internationally recognised diagnostic questionnaires for MDD alone that are being frequently used in research studies, not including the numerous different methods 4

Marie Salomonov, 4163930 used to distinguish between depressive disorder subtypes, an argument can be made about comparability of the studies outcomes (van Loo et al.; 2012). There are 5 subtypes of MDD recognised by the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders). These are melancholic depression, atypical depression, catatonic depression, postpartum depression and seasonal affective disorder. Each of the subtypes presents with slightly different symptoms and usually reacts to a slightly different treatment, which leads to a reasonable assumption about possible differences in biological markers among these subtypes. The discrepancies and variations between different studies may therefore not only be caused by different methodology, but also by the heterogeneity of MDD (Lamers et al.; 2012). Conclusion To conclude, it is important to mention that even though there are many inconsistencies and variations among the studies concerning HPA axis role in MDD, HPA axis dysregulation is by far one of the most commonly found biological abnormalities consistently observed in human subjects diagnosed with MDD. It is therefore considered to be one of the potential biomarkers of this mental disorder. Nevertheless, HPA axis function abnormalities are most likely not the only biomarkers of MDD, especially taking into account the wide heterogeneity of the disorder in question. As any mental disorder, MDD also presents with great individual variations which make it very hard to generalize the results of any research studies concerned with this topic. From the point of view of future research and development of more precisely targeted medications, the great variations among individual studies of HPA axis role in MDD have to be considered. As there are, without any doubt, numerous diagnostic subtypes of depressive disorder as well as great individual variations between patients, future research into biological markers should be more specific and account for the diversity of MDD subtypes.

Marie Salomonov, 4163930 References Adam et al.; Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence; Psychoneuroendocrinology, 2010; 35:921931. Guerry et al.; In search of HPA axis dysregulation in child and adolescent depression; Clinical Child and Family Psychology Review, 2011; 14(2):135-160. Ising et al.; Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker?; Biological Psychiatry, 2007; 62(1):47-54. Lamers et al.; Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression; Molecular Psychiatry, 2012; advance online publication. Miller et al.; Inflammation and its discontents: the role of cytokines in pathophysiology of major depression; Biological Psychiatry, 2009; 64(9):732-741. the

Pariante et al.; The HPA axis in major depression: classical theories and new developments; Trends in Neuroscience, 2008; 31(9):464-468. Schmidt et al.; Functional biomarkers if depression: diagnosis, treatment, pathophysiology; Neuropsychopharmacology, 2011; 36(12):2375-2394. and

Van Loo et al.; Data-driven subtypes of major depressive disorder: a systematic review; BMC Medicine, 2012; 10:156. Weinstein et al.; Neurohormonal and inflammatory hyper-responsiveness to acute mental stress in depression; Biological Psychology, 2010; 84(2):228-234.