A REVIEW OF THE INVOLVEMENT OF THE HIPOTHALAMIC-PITUITARY AXIS IN DEPRESSION

INTRODUCTION
Depression is a complex disorder, involving all functions of the psyche. It’s devastating effects on the patients, their loved ones and all of society are indisputable. Each year, approximately 20 million people suffer from depression, and it is estimated that by the year
2020, depression will become the second cause of m o r b i d i t y i n t h e a d u l t p o p u l a t i o n . (http://www.who.int/mental_health/management/depres sion/definition/en/). Although by using the treatment available today, around 80% of patients obtain remission, the recurrence rates remain high, adherence to treatment is low and the side effects of the treatment are prevalent. Choosing the right antidepressant still remains somewhat empiric, and therefore the need for the optimization of treatment in depression is evident.
The etiology of depression is complex, involving genes, physiological factors, hormones, stressful life conditions, especially chronic exposure to early life stress as well as other psychological and social factors (1).
As theory states that hormones of the hypothalamus-pituitary-adrenal axis (HPA-axis) are the main mediators of the effects of stress on emotional, cognitive and behavioral responses in humans, they have been intensively researched. A hyperactivity of the HPA axis has been incriminated in the etiology of depression ever since the 1950’s (2), as elevated levels of plasma, salivary and urinary cortisol have been consistently observed in these patients (3, 4).
The question of cause and effect between depression and cortisol remains unanswered, and the need to further understand the mechanisms by which the two interact exists. The decades of research stated different theories as absolute high levels of cortisol(3, 4), negative feedback inhibition(5), high levels of corticotrophin releasing hormone (CRH) in the brain(6), impaired function of the glucocorticoid receptors in certain areas of the brain (7,8), a proinflamatory status created by the stimulated HPA Axis (9, 10), neurotoxicity and the inhibition of neurogenesis in the hippocampus(11,12), interactions with other neuroendocrine systems and neurotransmitters (13), such as a low binding potential of the thalamic serotonin transporter 5-HTT caused by cortisol (14). However it is not yet fully understood if all these alterations are the cause or the effect of the disease, or if they have therapeutic potential, predictive value for response to treatment or risk of recurrence or for the probability of onset of the disease in healthy subjects.

1. THE CIRCADIAN RHYTHM OF CORTISOL SECRETION
Cortisol diurnal rhythms vary according to individual sleep-wake schedules, being high upon waking, increasing to peak levels approximately 30-40 minutes after waking, and declining to a nadir (close to zero) around bedtime (4). Some studies have shown that patients with depression exhibit alterations of this circadian rhythm, such as an elevated nadir with a consecutive blunting of diurnal secretion and an irregular overall secretion (15). An elevated nadir has been significantly correlated with certain subtypes of major depressive disorder, such as the melancholic subtype and psychotic depression (16). Many other alterations of the circadian rhythm of cortisol secretion have been studied such as nocturnal cortisol levels (in urine), mean diurnal cortisol values and the slope of the secretion curve, and alterations have been found in patients already suffering from the disease (17). Some authors recently studied the cortisol awakening response (CAR) as a potential predictor for the onset of the disease in healthy subjects, as there is evidence of both genetic and psychosocial contributions to the size of the CAR, making it a candidate mechanism for both genetic and environmental pathways to the development of depression. In particular, a larger CAR has been associated with higher levels of both acute and chronic life stress (4).

2. THE HPA AXIS
Activation of the HPA axis begins with the release of CRH from the paraventricular nucleus (PVN) of the hypothalamus. CRH neurons of the PVN serve as a final common stress pathway by receiving converging inputs from multiple areas of the brain, allowing CRH to coordinate the behavioral, neuroendocrine, autonomic, and immune responses to stress, as hypothalamic CRH neurons are strategically situated to intercept and disperse signals from and to the body about the internal and external environment (17,18).
CRH-containing neurons in the PVN of the hypothalamus terminate in the median eminence. CRH is then released into the pituitary-portal circulation and acts on CRH-R1 receptors on anterior pituitary corticotrophs stimulating secretion of adrenocorticotropic hormone (ACTH) into the general circulation and promoting s y n t h e s i s o f t h e A C T H p r e c u r s o r p e p t i d e proopiomelanocortin (POMC) in the corticotrophs. Under certain conditions, hypothalamic arginine vasopressin acts in synergy with CRH to stimulate ACTH release. Circulating ACTH then acts on the MC2-R (type 2 melanocortin receptor) in the adrenal cortex, stimulating secretion of glucocorticoids into the bloodstream (17, 18, 19).
In order to maintain appropriate levels of circulating glucocorticoids, these hormones exert negative feedback on the hypothalamus and pituitary to inhibit the synthesis and secretion of CRH and POMC/ACTH, respectively. In addition, they also down regulate the expression of corticotrophic CRH-R1 mRNA, thus decreasing CRH-R1 number, which ultimately diminishes ACTH secretion. Finally, the hippocampus, which expresses a high density of GR, exerts negative feedback control on the PVN, thereby reducing HPA axis activity (17, 18, 19).

3. CRH AND THE CRH –R1 RECEPTORS
S o m e a u t h o r s h a v e s u g g e s t e d t h a t hypercortisolemia reported in patients with depression may be related to over-secretion of CRH. This evidence is supported by several findings in patients with depression, including increased concentration of CRH in the CSF (cerebrospinal fluid); enlargement of the pituitary gland; blunted ACTH responses to CRH challenge(20, 21); down-regulation of CRH-R1 receptors in frontal brain regions of postmortem suicide patients and increased CRH expression in hypothalamic neurons of postmortem patients (22, 23).CRH has been implicated in stress- induced activation of neurons including hippocampal pyramidal cells. CRH contributes to effects of acute stress on synaptic plasticity and memory. Interneurons expressing CRH are abundant in hippocampus; CRH is released into hippocampal intercellular space during stress; CRH receptor type 1 (CRF1) resides on dendrites of CA1 cells, the same neurons sustaining dendritic atrophy after early-life stress (24); Chronic exposure to CRH provokes dendritic atrophy in a pattern similar to that found after early stress; When administered into brains of immature rats, CRH led to persistent memory impairments reminiscent of those found after chronic early-life stress. Notably, CRH-induced impairments occurred even when glucocorticoid levels were ‘clamped’ at low physiological levels suggesting that they were independent of glucocorticoid receptor activation (1, 25).

4. NEGATIVE FEED-BACK IMPAIRMENT
Elevated levels of cortisol in some patients with depression can also result from a reduced negative feedback response to cortisol that is reflected by a nonsuppression response in the dexamethasone suppression test (DST). Indeed, a large meta-analysis showed that the DST is a potent indicator of a poor prognosis and is also a predictor of suicide in depression. However, due to the fact that dexamethasone has distinct pharmacodynamic and pharmacokinetic profiles from cortisol, and due to the low sensitivity of the DST in detecting patients with depression (26), new tests, such as the DEX/CRH challenge test (27, 28, 29) and the prednisolone test (30), have been developed to evaluate the negative feedback of cortisol.
The DEX/CRH test combines the DST test (oral administration of single dose of dexamethasone at 11 PM) and the CRH stimulation test (intravenous bolus of CRH on the following day at 3 PM). Studies have shown that the DEX/CRH test has a higher specificity than the DST in detecting HPA axis dysfunction in patients with depression compared with the DST alone Patients with depression tend to exhibit a lack of inhibition of ACTH r e s p o n s e s t o C R H f o l l o w i n g d e x a m e t h a s o n e pretreatment, which represents an impaired feedback inhibition at the level of the pituitary.
Recent studies have shown that the test is positive (elevated levels of cortisol) during a major depressive episode, that it tends to normalize after effective antidepressant treatment (clinical remission) and that the initial values of the test (at baseline) could predict the response to treatment (28, 29).

5. THE GLUCOCORTICOID RECEPTORS
A n u m b e r o f s t u d i e s u s i n g d i f f e r e n t methodologies have reported that GR function is impaired in patients with depression. A lack of response of the GR to changes in ligand availability and reduced inhibition of immune function and cytokines production after exposure to dexamethasone, indicating reduced GR sensitivity, have been shown in patients with depression(31). Recently, impaired GR signaling has been proposed as a primary factor that could lead to alterations in HPA axis function, such as hypercortisolism, reduced negative feedback of cortisol, and increased production of CRH, all of which have been described in some patients with depression (17). Interestingly, in patients with depression, GR sensitivity and HPA axis activity tend to return to n o r m a l a f t e r c l i n i c a l r e c o v e r y o f d e p r e s s i v e symptomatology (32, 33).

6. THE IMMUNE SYSTEM

Alterations of the HPA axis in psychiatric disorders could also be influenced by activation of the immune system through pro-inflammatory cytokines. Cytokines can stimulate glucocorticoid release and also alter glucocorticoid availability and GR function, which, under certain conditions, may favor a state of glucocorticoid resistance. There is a bidirectional communication between the immune system and the HPA axis, in which cytokines stimulate the HPA axis and the resulting release of glucocorticoids provides negative feedback control of the immune response (8, 31).
Indeed, some patients suffering from depression have been found to exhibit higher levels of proinflamatory cytokines, which produces a resistance to cortisol with secondary hypercortisolism (34). Cytokines have also been shown to induce a constellation of symptoms referred to as “sickness behavior,” which has many overlapping features with depression (lethargy, somnolence, fatigue, anhedonia, decreased appetite and locomotion, and cognitive deficits) (35). Cytokine antagonists on knockout mice have been found to block these behavioral changes in rodents and reduce depression and fatigue in patients with autoimmune or inflammatory disorders (36, 37, 38).
However, conflicting results have been found, as only a certain percentage of depressed patients exhibit a high inflammatory status.

7. INTERACTIONS OF THE HPA AXIS WITH OTHER NEURO-ENDOCRINE SYSTEMS
The HPA axis has interactions with many other systems, and its activity is tightly connected to a number of neurohormones. Increased production of vasopressin (ADH) in depression does not only occur in neurons that colocalize CRH (PVN), but also in neurons of the supraoptic nucleus (SON), which may lead to increased plasma levels of vasopressin, that have been related to an enhanced suicide risk. The increased activity of oxytocin neurons in the paraventricular nucleus (PVN) may be related to the eating disorders in depression. The suprachiasmatic nucleus (SCN), the biological clock of the brain, shows lower vasopressin production and a smaller circadian amplitude in depression, which may explain the sleeping problems in this disorder and may contribute to the strong CRH activation. The hipothalamo-pituitary thyroid (HPT)-axis is inhibited in depression. These hypothalamic peptidergic systems, the HPA-axis, the SCN, the SON and the HPT-axis, have many interactions with aminergic systems that are also implicated in depression (13, 39).
Some studies have shown a connection of relevance between serotonin and the HPA axis. Namely, a significant correlation has been found between a lower binding potential of the thalamic transporter of serotonin –
5-HTT and high levels of cortisol on the Dex/CRH test, suggesting an interaction between the HPA axis and serotonin as a mechanism in depression and other disorders, such as OCD and anxiety disorders (14, 40).
A close interaction between the HPA-axis and the hypothalamic-pituitary-gonadal (HPG)-axis exists. There is a higher prevalence of mood disorders in women as compared to men. In addition, the stress system is affected by changing levels of sex hormones, as found in the premenstrual period, ante- and postpartum, during the transition phase to the menopause and during the use of oral contraceptives (41). In depressed women, plasma levels of estrogen are usually lower and plasma levels of androgens are increased, while testosterone levels are decreased in depressed men (41,42). This is explained by the fact that both in depressed males and females the HPA- axis is increased in activity, parallel to a diminished HPG- axis, while the major source of androgens in women is the adrenal, whereas in men it is the testes. It is speculated, however, that in the etiology of depression the relative levels of sex hormones play a more important role than their absolute levels (13).
NEUROTOXICITYAND NEUROGENESIS
The fact that numerous findings prove a reduced volume and total area of the hippocampus in depression, along with other cortical and subcortical structural alterations in depressed patients, led scientists to believe that glucocorticoids contribute to depression by increasing neurotoxicity in certain areas of the brain. Contradictory results are still being described. A post mortem study on patients suffering from Cushing’s disease and patients being chronically treated with corticosteroids showed no alterations of the structures of the brain involved in the pathophysiology of depression (39).
However, a recent animal study showed an impressive 25 % increase in the number of neurons of the hippocampus, after administration of the antidepressant drug sertraline, effect mediated by glucocorticoid receptors in the hippocampus (12).
Furthermore, other psychotropic drugs, such as the antipsychotics quetiapine and olanzapine, have been shown to induce neurogenesis. Also both drugs have been proven to have an important impact on the HPA axis, by significantly reducing both ACTH and cortisol secretion in healthy subjects. The atypical antipsychotics’ strong influence on HPA-function with pronounced ACTH and cortisol lowering is possibly related to the atypicals’ blockade of serotonergic receptors, but blockade of adrenergic or hystaminergic receptors may play a role as well (11). The role of these antipsychotics in the treatment of depression has been studied, but a further research into the mechanisms of their obvious benefits on affective and also cognitive functioning is needed, in relation to their strong effects on the HPA axis.
The fact that a state of hypercortisolemia does not in itself produce neurotoxicity, as it has been shown in patients suffering from such states but not suffering from depression, but that such a state exists in depressed patients, accompanied by structural changes in various brain structures, does not necessarily prove that neurotoxicity in depression is not related to the HPA axis, but rather that a more complex mechanism for such changes is involved, such as an increased number of GR receptors in the hippocampus of depressed patients as opposed to non-depressed patients. Further research is needed to sustain and fully understand these complex mechanisms.

DISCUSSIONS
Although the involvement of the HPA axis in depression is very likely and numerous studies have been conducted over the years, conflicting results are described, and the full extent of the part played by the axis in the pathogeny of the disorder is not yet fully understood.
Only a number of patients suffering from depression exhibits alterations of the HPA axis activity. A number of factors could be incriminated as the source of these discrepancies, such as the presence of anxiety, personal history of early life stress and other psychosocial factors, certain subtypes of depression and the severity of the disease, inflammatory status and gender differences (17).
In regard to subtypes of depression, severe forms, namely the psychotic and melancholic subtypes, have a much stronger association with elevated cortisol levels, especially an elevated nadir value (43, 44). Negative feed-back impairment has been associated with anxiety by some authors, while others have found only a poor correlation between anxiety and an elevated cortisol value at the Dex/CRH test (14). Also, low levels of cortisol have been proven in patients suffering from other psychiatric disorders, such as PTSD (45, 46).
Further research is needed to better understand the causality relationship and the mechanisms linking depression to the activity of the HPA axis, as many variables should be taken into account.
Once this understanding has been obtained, the benefits to the patient could prove to be very significant. Screening methods and vulnerability markers, prediction markers for the response to treatment and the rate of recurrence could be used in clinical trials and clinical practice. New medication compounds are already being studied for the treatment of psychotic and melancholic depression, such as the cortisol secretion inhibitor mifepristone (43) and metirapone (49), a glucocorticoid receptor antagonist. As CRH is believed to play a very important role in the mechanisms of depression, CRH-R1 receptor antagonists (48) are also under research, and are believed to be of great promise.
At present, no viable means of treatment have yet been implemented regarding this strong association between depression and the HPA axis. However, the extended research that is being done in this direction shoes great promise, and hopefully the near future will bring therapeutic solutions which will help the millions of people suffering from this debilitating, horrible disease.

REFERENCES
1.Autumn SI, Rex CS et al. Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 2010;1784-10. PubMed
2.Michael RP, Gibbons JL. Interrelationships between the Endocrine
System Neuropsychiatry. Int Rev Neurobiol 1963;5: 243–302. PubMed
3.Holsboer F. The corticosteroid receptor hypothesis of depression.
Neuropsychopharmacology 2000;23: 477–501. PubMed
4.Adam EK, Doane LD, Zinbarg RE et al. Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence. Psychoneuroendocrinology 2010;35(6): 921–931. PubMed.
5.Juruena MF, Cleare AJ, Pariante CM. The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression. Rev Bras Psiquiatr 2004;26: 189–201. PubMed
6.Roy A et al. CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 1987;144: 641–645.
7.Pariante CM. Glucocorticoid receptor function in vitro in patients with major depression. Stress 2004;7: 209–219. PubMed
8.Pariante CM. Risk factors for development of depression and psychosis: glucocorticoid receptors and pituitary implications for treatment with antidepressant and glucocorticoids. Ann NY Acad Sci.
2009 Glucocorticoids and Mood: Clinical Manifestations, Risk Factors, and Molecular Mechanisms. In press 9.Dantzer R et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;

9: 46–56. PubMed
10.Ehlert U et al. Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: The role of the hypothalamus-pituitary-adrenal axis. Biological Psychology 2001;57: 141–152. PubMed
11.Cohrs S, Röher C, Jordan W et al. The atypical antipsychotics Quetiapine and Olanzapine, but not Haloperidol, reduce ACTH abd cortisol secretion in healthy subjects. Psychopharmacology 2006;185(1): 11-8.
12.New scientist: Formarea noilor neuroni in hipocampus este facilitata de utilizarea antidepresivelor; Aprilie 2001.
13.Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration.
14.Reimold M, Knobel A, Rapp MA et al. Central serotonin transporter levels are associated with stress hormone response and anxiety. Psychopharmacology 2011;213(2-3): 563–572. PubMed.
15.Deuschle M et al. Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. J Clin Endocrinol Metab 1997;82: 234–238. PubMed
16.Schatzberg AF et al. Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry 2000;157: 1095–1100. PubMed
17.Marques AH, Silverman MN, Sternberg EM. Glucocorticoid Dysregulations and Their Clinical Correlates.From Receptors to Therapeutics. Ann N Y Acad Sci 2009, October. PubMed
18.Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation.
Endocrinol Metab Clin North Am 2005;34: 271–292. vii. PubMed
19.Herman JP et al. Evidence for hippocampal regulation of neuroendocrine neurons of the hypothalamopituitary-adrenocortical axis. J Neurosci 1989;9: 3072–3082. PubMed
20.Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001;62: 77–91. PubMed
21.Young AH. Cortisol in mood disorders. Stress 2004;7: 205–208. PubMed
22.Merali Z et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004;24: 1478–1485. PubMed
23.Raadsheer FC et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60: 436–444. PubMed
24.Chen Y, Brunson KL, Adelmann G, Bender RA, Frotscher M, Baram TZ. Hippocampal corticotropin releasing hormone: pre- and postsynaptic location and release by stress. Neuroscience 2004a;126: 533–540. PubMed
25.Brunson KL, Eghbal-Ahmadi M, Bender R, Chen Y, Baram TZ. Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc Natl Acad Sci USA
2001b;98: 8856–8861. PubMed.
26.Ribeiro SC et al. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry 1993;150: 1618–1629. PubMed
27.Hatzinger M et al. The combined DEX-CRH test in treatment course and long-term outcome of major depression. J Psychiatr Res 2002;36: 287–297. PubMed
28.Watson S et al. The dex/CRH test—is it better than the DST?
Psychoneuroendocrinology 2006;31: 889–894. PubMed
29.Ising M, Künzel HE, Binder EB, Nickel T, Modell S, Holsboer F. The combined Dex/CRH test as a potential surrogate marker in depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(6): 1085-93.
30.Pariante CM et al. A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis. Biol Psychiatry 2002;51: 922–930. PubMed
31.Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun
2007;21: 9–19. PubMed.
32.Calfa G et al. Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment. Psychoneuroendocrinology 2003;28:
687–701. PubMed
33. Linkowski P et al. 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. J Clin Endocrinol Metab 1987;65: 141–152. PubMed
34.Pace TW et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 2006;163: 1630–1633. PubMed
35.Dantzer R et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:
46–56.PubMed.
36.Capuron L et al. Treatment of cytokine-induced depression. Brain
Behav Immun 2002;16: 575–580. PubMed
37. Maddock C et al. Psychopathological symptoms during interferon- alpha and ribavirin treatment: effects on virologic response. Mol Psychiatry 2005;10: 332–333. PubMed
38.Raison CL et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005;66: 41–48. PubMed
39.Linkowski P et al. 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. J Clin Endocrinol Metab 1987;65: 141–152. PubMed
40.Gunthert KC et al. Serotonin Transporter Gene Polymorphism (5- HTTLPR) and Anxiety Reactivity in Daily Life: A Daily Process Approach to Gene-Environment Interaction. Psychosomatic Medicine 2007; 69(8): 762-768.
41.Schmidt PJ, Rubinow DR. Sex hormones and mood in the perimenopause. Ann N Y Acad Sci. 2009 Glucocorticoids and Mood: Clinical Manifestations, Risk Factors, and Molecular Mechanisms. In press.
42.Daly RC et al. Concordant restoration of ovarian function and mood in peri-menopausal depression. Am J Psychiatry 2003;160: 1842–1846. PubMed
43.Belanoff JK et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002;52: 386–392. PubMed
44.Schatzberg AF et al. Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry 2000;157: 1095–1100. PubMed
45.Young EA, Breslau N. Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study. Biol Psychiatry 2004;56: 205–209. PubMed
46.Yehuda R. Status of glucocorticoid alterations in Post-traumatic stress disorder. Ann N Y Acad Sci. 2009 Glucocorticoids and Mood: Clinical Manifestations, Risk Factors, and Molecular Mechanisms. In press.
47.Bremmer MA et al. Major depression in late life is associated with both hypo- and hypercortisolemia. Biol Psychiatry 2007;62: 479–486. PubMed
48.Künzel HE, Zobel AW, Nickel T et al. Treatment of depression with the CRH-1-receptor antagonist R121919: endocrine changes and side effects.
49.Tudose F, Tamasan S. Sindromul anxietate-depresie. In : Tudose F, Tudose C, Vasilescu A, Tamasan S. Sindroame ratacitoare. Bucuresti: Ed. Info Medica, 2005, 119-141.

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