Corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal axis in psychiatric disease.

Since the 1960s, both corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal (HPA) axis have been studied in detail across a range of psychiatric illnesses, leading to important contributions to our knowledge in this area. This research arose from the conceptualization of depression, in particular, as a stress-related disorder. However, stress is now regarded as an integral component of psychiatric illnesses in general, whether as an environmental trigger or in the initial pathogenesis, and there is evidence of altered HPA axis function across a range of mental disorders. The chapter will cover the extensive literature on HPA axis abnormalities in these disorders with a particular emphasis on the CRH system as it is very evident that this 41-amino acid-containing peptide is not only a major physiologic regulator of HPA axis activity but also important in the pathogenesis of mental disorders. In particular, we discuss the abundant reports pertaining to major depressive disorder, where hyperactivity of the HPA axis, of mild to moderate severity, has been demonstrated in 30-50% of cases. Also under consideration is the less extensively studied, but equally intriguing question of HPA axis integrity in bipolar affective disorder. In addition there will be a concise summary of recent findings in schizophrenia and anxiety disorders, with an emphasis on post-traumatic stress disorder (PTSD) in the latter case. Interestingly, in diametric opposition to the theory of HPA hyperactivity in depression, PTSD has features consistent with hypofunctioning of this system. Advances in animal and human studies have made it possible to synthesize these findings, and while much still remains unknown, we are gradually building up a clearer picture of this very important axis in health, at times of stress, and in chronic enduring mental illness.

The brain-gut axis: a target for treating stress-related disorders.

The brain-gut axis provides a bidirectional means of communication between the microbiota within the gut and the brain. Stress acting via the brain can result in alteration of the microbial composition of the gut, but increasing evidence indicates that bacteria within the gut can influence brain neurochemistry and behaviour. It is clear that post-natal colonisation of the gut plays a key role in regulating the development of the hypothalamic-pituitary-adrenal axis and the development of pivotal neurotransmitter systems. Probiotics are defined as live bacteria which confer a health benefit. Recent studies in rodents have demonstrated the capacity of a probiotic, Lactobacillus rhamnosus, to alter the expression of GABA receptors centrally whilst producing anxiolytic type effects. Preliminary studies in humans are yielding encouraging findings. It may in the future be possible to use probiotic bacteria to treat depression and other stress-related disorder but we await the results of appropriately designed placebo-controlled trials.

Enhanced cholinergic-mediated increase in the pro-inflammatory cytokine IL-6 in irritable bowel syndrome: role of muscarinic receptors.

OBJECTIVES: Irritable bowel syndrome (IBS) is a functional disorder, which has recently been linked to immune activation. We tested the hypothesis that the pro-inflammatory cytokine profile in IBS is driven by the cholinergic system and determined if the responses are mediated by muscarinic receptors. METHODS: Eighty-eight subjects took part in two studies, 37 IBS patients (Rome II), 14 depressed patients, and 37 healthy volunteers. Eighteen IBS patients had diarrhea predominant IBS, 14 were alternators, and 5 were predominantly constipated. In study 1, blood was drawn for baseline measurement of growth hormone (GH) and cytokines IL-6, IL-8, and IL-10. Pyridostigmine 120 mg was administered orally and further blood sampling took place for 180 min. In study 2, patients with IBS, depressed patients, and healthy subjects underwent the pyridostigmine test on two separate occasions with procyclidine (antimuscarinic) pre-treatment on one test occasion. Both GH and IL-6 were monitored. RESULTS: In study 1, baseline IL-6 (P= 0.003) and IL-8 levels (P= 0.001) were higher in IBS than in controls. Pyridostigmine stimulated the release of IL-6 and GH, but not IL-8 or IL-10; these responses were significantly augmented in IBS patients relative to controls. The IL-6 level following pyridostigmine administration correlated significantly with the symptom score (P < 0.01). In study 2, IL-6 rose following pyridostigmine in IBS but not depression and procyclidine blocked the rise. The GH response was abolished by procyclidine in all three groups. CONCLUSIONS: IBS and major depression are characterized by a pro-inflammatory profile, whereas IBS patients alone exhibit an exaggerated muscarinic receptor-mediated IL-6 response.

Impact of gender and menstrual cycle phase on plasma cytokine concentrations.

OBJECTIVE: The lifetime prevalence of major depression is twice as high in females as in males. Depression is known to increase at periods where there are changes in gonadal hormones. We examined pro- and anti-inflammatory cytokine levels during the normal menstrual cycle of healthy females compared to similar time points in healthy males. METHODS: Plasma concentrations of interleukin (IL)-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and soluble IL-6 receptor (sIL-6R) were measured with enzyme-linked immunosorbent assays in healthy females during the normal ovulatory menstrual cycle and also in males at similar time points. RESULTS: The luteal phase of the menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha compared to the early follicular phase. No change was observed in IL-6, IL-8 and IL-10 concentration throughout the menstrual cycle. We found IL-4 positively correlated with oestrogen while TNF-alpha positively correlated with progesterone. Females were found to have significantly higher concentrations of TNF-alpha and sIL-6R across all phases of the menstrual cycle, compared to males across similar time points. CONCLUSION: The normal menstrual cycle is associated with increased production of sIL-6R, IL-4 and TNF-alpha in the luteal phase compared to the early follicular phase. Females have significantly higher concentrations of sIL-6R and TNF-alpha at all time points across the menstrual cycle than males.

Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

Antidepressant therapy and C-reactive protein levels.

BACKGROUND: Major depression is associated with activation of the inflammatory response. AIMS: To examine C-reactive protein levels in depression and to determine the impact of selective serotonin reuptake inhibitor (SSRI) therapy. METHOD: A two-part study. In study 1, which used a between-subjects design, C-reactive protein was measured in 32 patients (20 currently depressed, 12 euthymic) with a history of DSM-IV major depression, all of whom were treated with an SSRI, and in a healthy comparison group (n = 20). Study 2 employed a within-subject design: C-reactive protein was measured in 20 patients with major depression both before and after SSRI treatment. RESULTS: In study 1, C-reactive protein levels did not differ between the group with depressive disorder (either currently depressed or euthymic) treated with SSRIs and the healthy group. In study 2 the protein levels dropped significantly following treatment with antidepressant medication. CONCLUSIONS: Following SSRI treatment for major depression there is a significant drop in C-reactive protein concentrations whether or not the depression resolves. These findings indicate that antidepressants induce an anti-inflammatory response independent of antidepressant action.

Cytokine profiles in bipolar affective disorder: focus on acutely ill patients.

BACKGROUND: The role of the immune system in mood disorders is predominately supported by studies in unipolar major depression. However activation of the immune system has also been demonstrated in bipolar mania. Our study examines pro-inflammatory and anti-inflammatory cytokines in both phases of bipolar affective disorder (BPAD). METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in patients with BPAD who were depressed, or manic and in healthy controls. RESULTS: Bipolar depression had significantly higher production of the pro-inflammatory cytokines, IL-8 (p < 0.001) and TNF-alpha (p < 0.05) compared to healthy subjects. The manic group also had increased production of IL-8 (p < 0.05) and TNF-alpha (p < 0.001) as compared to healthy subjects. Anti-inflammatory cytokine levels did not differ across the 3 groups. LIMITATIONS: A small sample size was studied. All patients remained on medication for this study. CONCLUSIONS: BPAD is associated with increased production of pro-inflammatory cytokines both in the manic and in the depressed phase as compared to healthy subjects. This is the first study, which examined both mania and bipolar depression.

Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression.

BACKGROUND: There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. METHOD: Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). RESULTS: Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-alpha and IL-6. There was a significant inverse correlation between TNF-alpha concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. CONCLUSIONS: These findings suggest that cutaneous GR function is abnormal in antidepressant-resistant depression, that circulating TNF-alpha may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

Anatomy of melancholia: focus on hypothalamic-pituitary-adrenal axis overactivity and the role of vasopressin.

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis characterized by hypercortisolism, adrenal hyperplasia and abnormalities in negative feedback is the most consistently described biological abnormality in melancholic depression. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are the main secretagogues of the HPA/stress system. Produced in the parvicellular division of the hypothalamic paraventricular nucleus the release of these peptides is influenced by inputs from monoaminergic neurones. In depression, anterior pituitary CRH1 receptors are down-regulated and response to CRH infusion is blunted. By contrast, vasopressin V3 receptors on the anterior pituitary show enhanced response to AVP stimulation and this enhancement plays a key role in maintaining HPA overactivity.

Cytokines: abnormalities in major depression and implications for pharmacological treatment.

The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

Vasopressin as a target for antidepressant development: an assessment of the available evidence.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.

Pituitary-adrenal response to naloxone in non-ulcer dyspepsia: preliminary evidence for a reduction in central opioid tone.

BACKGROUND: Non-ulcer dyspepsia (NUD) is one of the core functional bowel disorders. There has been recent emphasis on possible abnormal brain-gut interactions as being central to its pathophysiology. In this preliminary study, we examined central opioid tone in Helicobacter pylori-negative NUD patients using naloxone, an opioid antagonist, which stimulates pituitary-adrenal activity. The opioid system is known to govern nociceptive processing and to play a role in gut motor activity. SUBJECTS: Eight subjects with NUD and 8 age- and sex-matched healthy subjects were examined. METHODS: Naloxone, 0.125 mg/kg, was administered at time 0. Adrenocorticotropin (ACTH) and cortisol responses were measured over a 120-min period. Maximum pituitary-adrenal responses in the 2 groups were compared. RESULTS: The ACTH response was significantly attenuated in the NUD group (p < 0.05). The cortisol response did not differ between the 2 groups (p = 0.7). CONCLUSIONS: Central opioid tone may be reduced in subjects with NUD. Our preliminary findings suggest that altered opioidergic activity may contribute to NUD pathophysiology, influencing the symptom profile through altered gut motor activity or possibly by influencing visceral sensitivity.