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despnsitisation of Cortisol receptors, increased . activity ofjàiacrophages ind iricieised neiwseof pru-inflmmaLury H cytokines

Cortisol circulation

Figure 18.5. Endocrine-immune relationship following chronic stress. In chronic stress, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback control. Arginine vasopressin (AVP) is secreted from the hypothalamus and induces the release of adrenocorticotrophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands; adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. Unlike in acute stress, the negative feedback of cortisol to the hypothalamus and pituitary is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators.

Cortisol neuropeptides circulation despnsitisation of Cortisol receptors, increased . activity ofjàiacrophages ind iricieised neiwseof pru-inflmmaLury H cytokines

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Figure 18.5. Endocrine-immune relationship following chronic stress. In chronic stress, the hypothalamic-pituitary-adrenal (HPA) axis is up-regulated with a down-regulation of its negative feedback control. Arginine vasopressin (AVP) is secreted from the hypothalamus and induces the release of adrenocorticotrophic hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands; adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. Unlike in acute stress, the negative feedback of cortisol to the hypothalamus and pituitary is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators.

and an insensitivity of Cortisol secretion to suppression by glucocorticoids such as dexamethasone.

The potential association between the immune system and mood disorders has become a major topic of interest in biological psychiatry in the past decade. In general, three immune measures have been examined, namely white blood cell counts, functional measures of cellular immunity such as natural killer cell activity and immune cell markers as exemplified by human lymphoctye antigen (HLA). The cumulative data from these studies suggests that depressed patients have a decreased number of lymphocytes, reduced mitogen-induced lymphocyte proliferation and a reduction in the number of natural killer cells. However, this does not apply to all depressed patients. Furthermore, not all aspects of immune function are decreased despite the presence of hypercortisolaemia. Thus the activity of macrophages (that include the microglia and astrocytes in the brain which are part of the immune system) has been shown to increase in depression. These immune cells release cytokines that not only act as immunoregulators but also as neuromodulators of central neurotransmit-ters. In general, the cytokines are either of the pro-inflammatory type (called Th-1 type, and largely stimulatory in their action) or anti-inflammatory type (called Th-2 type and largely inhibitory in their action). The pro-inflammatory cytokines are exemplified by interleukins (IL-) 1, 6 and tumour necrosis factor (TNF-) alpha while the anti-inflammatory cytokines are IL-4, 10 and 13. The presence of elevated blood concentrations of the pro-inflammatory cytokines, and in the concentration of IL-1 in the CSF, has led to the macrophage hypothesis of depression which suggests that the changes in brain neurotransmitter function are a consequence of the increase in inflammatory changes (involving the inflammatory mediators prostaglandin E2 and nitric oxide which are increased in response to IL-1). The neural damage occurring in cortical and subcortical regions of the brain of depressed patients has been ascribed to the shift in the balance to pro-inflammatory cytokines from anti-inflammatory cytokines. These changes occur both in the brain and in the periphery and, in chronic depression, the brain damage is accentuated by the elevation of glucocorticoids which are hypersecreted due to the desensitization of the glucocorticoid receptors on neurons and on immune cells.

If a malfunctional immune system plays a role in the pathogenesis of depression, it would be anticipated that antidepressants have an immunoregulatory action. Because immune cells express neurotransmitter receptors, mediators such as noradrenaline and serotonin, as well as various neuropeptides, are able to modulate the immune response. Moreover, neurons and glial cells express cytokine receptors and the release and action of neurotransmitters are modulated by cytokines. Antidepressants appear to affect cytokine release from macrophages, monocytes and glial cells in addition to their well-known effects on monoamine synthesis. Antidepressants can also modulate intracellular signals such as cyclic AMP and neurotrophic factors (such as brain derived neurotrophic factor, BDNF) and in this way alter the synthesis of the pro-inflammatory cytokines. The beneficial long-term effects of antidepressant treatments in depression may therefore result from a shift in the balance of the pro-inflammatory to the anti-inflammatory cytokines in addition to improving the brain repair mechanisms (by increasing neurotrophic factor synthesis and reducing the brain concentration of the neurotoxic glucocorticoids).

Clearly, more detailed studies must be undertaken to validate this hypothesis, but these preliminary findings link proven neurotransmitter

Central nervous system

I Noradrenaline release

I Monocytes-*- IL-1 + PGE1 and PGE2—Neutrophils t Figure 18.6. Possible changes in immune function and the brain in depression.

changes in depressed patients with the delays in onset of action of antidepressants and the changes in cellular immunity. Figure 18.6 summarizes the possible links between depression and changes in some aspects of the immune system.

It now seems probable that specific disturbances occur in the immune system in psychiatric illness that are not artefacts of non-specific stress factor, institutionalization or medication. The known effects of the neuroendocrine system on the immune response, and the recent evidence that receptor sites for neurotransmitters and neuroendocrine factors occur on lymphocytes and macrophages, support the hypothesis that immuno-logical abnormalities may assist in precipitating the symptoms of anxiety and depression, commonly symptoms of major affective disorders.

Changes in the immune system in schizophrenia

Evidence suggesting an abnormality in immune function in those subject to severe stress or suffering from depression largely relates to an abnormality in function. Such abnormalities do not appear to occur in schizophrenia. Possibly because of its well-established genetic component, many aspects of the immune system would appear to be deranged in schizophrenic patients. Thus abnormalities in the concentration of serum immunoglobulins and deficiencies in immune responsiveness have been reported to occur in such patients.

Several investigators have reported a generalized increase in the immunoglobulins in both acute and chronic stages of schizophrenia, although not all investigators have been able to confirm this. There is some evidence that antibrain antibodies which could selectively destroy specific types of brain cells have been detected in schizophrenic patients. Some years ago, a factor was isolated from the serum of schizophrenic patients that produced catatonia and an abnormal electroencephalographic pattern when injected intravenously into monkeys or human volunteers; the electroencephalogram changes were similar to those seen in schizophrenic patients. The serum protein causing these abnormalities was termed taraxein. These findings were confimed by some researchers but not by those who used a more reliable radioimmunoassay method. However, in an extensive study of antibrain antibodies in 69 schizophrenics and 58 controls, it has been shown that if antibrain antibodies play any role in psychiatric disorders they are nonspecific and only present in a small percentage of patients.

Allergic reactions entail disordered immune functioning, and controversy exists regarding allergies to various food substances and the incidence of schizophrenia. Some studies have suggested that schizophrenics have an increased incidence of allergies in childhood, especially involving an intolerance to wheat gluten. However, there are few adequately controlled studies to show that food allergies play any role in the aetiology of schizophrenia and, to date, there is little unequivocal evidence to support the view that allergies play a causal role in this illness.

There is evidence to suggest that there are at least two genetically determined components in those at risk from schizophrenia. One of these components facilitates a decrease in suppressor cells, while the other promotes the accumulation of antithymic immunoglobulins. The consequences of the resultant imbalance between the helper and suppressor mechanism which arises from these immune malfunctions are the occurrence of specific antitissue antibodies, the formation of which is normally controlled by a balance between helper and suppressor T cell mechanisms.

There have been several suggestions whereby the negative symptoms of schizophrenia could represent an autoimmune encephalitis-like syndrome in which a viral infection, for example, could initiate an autoimmune response against dopaminergic pathways. One possibility is that dopamine receptor stimulating antibodies could be produced as part of the pathological processes that have a high affinity for the dopamine autoreceptors and thereby decrease the release of the neurotransmitter in specific dopaminergic pathways. However, it must be emphasized that the clinical data upon which many of these speculations are based have been obtained from patients on prolonged treatment with neuroleptics. These drugs are known to modify the immune system which could increase the subsequent vulnerability of the patient to viral infections.

It may be speculated that an inherited primary defect in the immune system could initiate schizophrenia by stimulating the production of antibrain antibodies or by increasing the vulnerability of the patient to a viral infection. Alternatively, a primary defect in central neurotransmitter metabolism, possibly involving dopamine, may cause the immune abnormalities which have been described. In this case it may be argued that the immune changes are an epiphenomenon of the disease and not necessarily the primary cause.

Although there has been considerable interest in investigating the changes in the immune system of patients with depression, it is only more recently that researchers have turned their attention to the possible involvement of the immune system in the pathogenesis of schizophrenia. As has already been mentioned, antibrain antibodies have been detected in the CSF of chronic schizophrenic patients while the presence of an increase in the concentration of immunoglobulin G in the CSF, which correlates with the presence of negative symptoms, is a further suggestion that an inflammatory process is operational in the brain of the schizophrenic patient. With regard to the pro-inflammatory cytokines, IL-6 is increased in both the CSF and serum from medicated and unmedicated patients; this is reduced by effective antipsychotic drug treatment. Studies in children with schizophrenia have shown that interferon alpha is raised in the CSF and that this cytokine correlates both with the severity of the symptoms and in their refractoriness to drug treatment. It is of interest to note that the secretion of interferon is an important component of the antiviral immune response that may provide further evidence in favour of the viral hypothesis of schizophrenia. Unlike depression, IL-2 concentrations have been found to increase in the CSF of schizophrenic patients. As there is some evidence that this cytokine can increase the release of dopamine from central neurons, it is possible that IL-2 could contribute to the hyperdopaminergic state which characterizes the acute form of the disease. Support for a central inflammatory process being involved in the pathology of schizophrenia comes from the recent report that cyclo-oxygenase 2 inhibitors, such as celecoxib, potentiate the action of atypical antipsychotics such as clozapine in schizophrenic patients who appear to be resistant to the therapeutic effects of atypical antipsychotics.

In CONCLUSION, it seems probable that some disturbances in immune function do occur in mental illness and are not artefacts of medication or the effects of institutionalization. The known effects of the neuroendocrine system on the immune response and the recent evidence that receptor sites for neurotransmitters and neuroendocrine factor occur on lymphocytes and macrophages, support the hypothesis that immunological abnormalities may assist in precipitating the symptoms of anxiety, depression and schizophrenia. Nevertheless, the nature of specific immunological disturbances which underlie these diseases remains elusive.

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Anxiety and Depression 101

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