Gunter Kenis

The environment and schizophrenia

Psychotic syndromes can be understood as disorders of adaptation to social context. Although heritability is often emphasized, onset is associated with environmental factors such as early life adversity, growing up in an urban environment, minority group position and cannabis use, suggesting that exposure may have an impact on the developing ‘social’ brain during sensitive periods. Therefore heritability, as an index of genetic influence, may be of limited explanatory power unless viewed in the context of interaction with social effects. Longitudinal research is needed to uncover gene–environment interplay that determines how expression of vulnerability in the general population may give rise to more severe psychopathology.

Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events

BACKGROUND Recently, it has been reported that serum interleukin-1 beta (IL-1 beta), but not soluble IL-2 receptor (sIL-2R), concentrations were significantly higher in patients with posttraumatic stress disorder (PTSD) than in normal volunteers, and that psychological stress in humans is associated with increased secretion of proinflammatory cytokines, such as IL-6. METHODS The aim of the present study was to examine the inflammatory response system in patients with PTSD through measurements of serum IL-6, sIL-6R, sgp130 (the IL-6 signal transducing protein), sIL-1R antagonist (sIL-1RA; an endogenous IL-1 receptor antagonist), CC16 (an endogenous anticytokine), and sCD8 (the T suppressor-cytotoxic antigen). RESULTS Serum IL-6 and sIL-6R, but not sgp130, sIL-RA, CC16, or sCD8, concentrations were significantly higher in PTSD patients than in normal volunteers. Serum sIL-6R concentrations were significantly higher in PTSD patients with concurrent major depression than in PTSD patients without major depression and normal volunteers. There were no significant relationships between serum IL-6 or sIL-6R and severity measures of PTSD. CONCLUSIONS The results suggest that PTSD is associated with increased IL-6 signaling. It is hypothesized that stress-induced secretion of proinflammatory cytokines is involved in the catecholaminergic modulation of anxiety reactions.

Negative Immunoregulatory Effects of Antidepressants: Inhibition of Interferon-γ and Stimulation of Interleukin-10 Secretion

There is now some evidence that major depression is accompanied by activation of the inflammatory response system. There is also some evidence that antidepressants may suppress the release of cytokines, such as interleukin-1β (IL-1β) and IL-6 by activated monocytes and IL-2 and interferon-γ (IFNγ) by activated T cells. This study was carried out to examine the effects of clomipramine, sertraline, and trazodone on the stimulated production of IFNγ, a pro-inflammatory cytokine, and IL-10, a negative immunoregulatory cytokine. Whole blood of nine healthy volunteers was stimulated with PHA, 5 μg/mL and LPS, 25 μg/mL for 72 hr with and without incubation with clomipramine, 10−6 and 10−9 M, sertraline, 10−6 and 10−8 M, and trazodone, 10−6 and 10−8 M. All three antidepressants significantly reduced IFNγ secretion, whereas clomipramine and sertraline significantly increased IL-10 secretion in culture supernatant. All three antidepressants significantly reduced the IFNγ/IL-10 ratio. The results suggest that antidepressants, at concentrations in the therapeutical range, have negative immunoregulatory effects through inhibition of IFNγ and stimulation of IL-10 release.

Effects of antidepressants on the production of cytokines

There is now evidence that major depression is associated with an up-regulation of the inflammatory response system (IRS). One of the major factors in this IRS activation is the hyperproduction of pro-inflammatory cytokines. Recently, a number of studies examined whether there is a causative role of these inflammatory mediators in the aetiology of major depression. Studies with animal models and cytokine immune therapy in humans suggest that pro-inflammatory cytokines induce depressive symptomatology. Moreover, these depressive symptoms can be effectively reversed by antidepressant treatment. Thus, it may be suggested that antidepressants suppress pro-inflammatory cytokine production and/or action, resulting in improvement of depressive symptoms. The influence of antidepressants on cytokine production has been examined in culture systems in vitro, and in animal models of depression - in which cytokine production is induced by endotoxin administration. Results suggest that antidepressants of several classes decrease the production of pro-inflammatory cytokines such as interferon-gamma and tumour necrosis factor-alpha, and increase that of interleukin-10, an anti-inflammatory cytokine. Further, the effect of antidepressive treatment on cytokine secretion and on plasma levels of cytokines in depressed patients has been studied. Unfortunately, different approaches to examine cytokine production and different techniques to measure cytokines in plasma are used in these studies. Despite this, current data indicate a normalization of cytokine plasma levels and cytokine production after antidepressant treatment. It is clear, however, that more research is warranted and we strongly argue the need for higher standardization in the methodology used to examine the cytokine network in depressed patients.

Anti-inflammatory Effects of Antidepressants Through Suppression of the Interferon-γ/interleukin-10 Production Ratio

There is some evidence that major depression-in particular, treatment-resistant depression (TRD)-is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-γ (IFN-γ), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6 ± 3.9 years) and age-matched healthy controls (mean age, 51.6 ± 1.7 years) and younger healthy volunteers (mean age, 35.4 ± 9.6 years) was stimulated with phytohemagglutinin (1 μg/mL) and lipopolysaccharide (5 μg/mL) for 48 hours with and without incubation with the antidepressants at 10−6 M and 10−5 M. IFN-γ and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-γ to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-γ. All four antidepressants significantly reduced the IFN-γ/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-γ or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-γ/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.

Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis

There is now evidence that major depression is accompanied by activation of the inflammatory response system (IRS) as indicated by an increased production of pro-inflammatory cytokines. There is circumstantial evidence implicating pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha) in the pathogenesis of multiple sclerosis (MS). The aims of the present study were to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-8, TNFalpha, IL-2 receptor (IL-2R) and CC16 (uteroglobulin), an endogenous anti-cytokine, in depressed and MS patients compared to normal controls, and (ii) the effects of treatment with antidepressants on the above IRS variables in depressed patients. Serum TNFalpha was significantly higher in depressed and MS patients than in normal controls. Serum IL-8 was significantly higher in depressed patients than in patients with MS. Serum CC16 was significantly higher in patients with MS than in normal controls and depressed patients. Nonresponders to treatment with antidepressants had significantly higher serum IL-2R and lower serum CC16 concentrations than responders to treatment. The results show that (i) depression is accompanied by activation of the IRS and that this activation is more pronounced in depression than in MS, and (ii) IRS activation in depressed patients is related to a nonresponse to treatment with antidepressants.

Serum levels of brain-derived neurotrophic factor in major depressive disorder: state–trait issues, clinical features and pharmacological treatment

Recent evidence supports ‘the neurotrophin hypothesis of depression’ in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (⩾6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St Johns wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

Activation of the inflammatory response system in autism.

Background/Aim: There is now some evidence that autism may be accompanied by abnormalities in the inflammatory response system (IRS). Products of the IRS, such as proinflammatory cytokines, may induce some of the behavioral symptoms of autism, such as social withdrawal, resistance to novelty and sleep disturbances. The main aim of the present study was to examine whether autism is accompanied by an activation of the IRS. Methods: We measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-γ and tumor necrosis factor (TNF)-α by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. Results: This study showed a significantly increased production of IFN-γ and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-α by whole blood of autistic children. There were no significant differences in the serum concentrations of IL-6, IL-2R and IL-1RA between autistic and normal children. Conclusions: These results suggest that autism may be accompanied by an activation of the monocytic (increased IL-1RA) and Th-1-like (increased IFN-γ) arm of the IRS. It is hypothesized that increased production of proinflammatory cytokines could play a role in the pathophysiology of autism.

The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression

BACKGROUND It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions. AIMS AND METHODS The aims of the present study were to examine: (i) immune-inflammatory markers, i.e. serum interleukin-6 (IL-6), IL-8, IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA), gp130, and prostaglandin E2 (PGE2) production by mitogen-stimulated whole blood and the availability of plasma tryptophan in patients with primary sleep disorders, major depression and healthy volunteers; and (ii) the relationships between the availability of tryptophan and indicators of the immune-inflammatory response system. RESULTS Mitogen-stimulated release of PGE2, and serum IL-6 and IL-8, were significantly increased in both depressed and sleep disordered patients compared to normal controls. Serum IL-1RA was significantly higher in depressed patients than in normal controls. Patients with depression and sleep disorders had a significantly lower availability of tryptophan than normal controls. There were significant and inverse relationships between the availability of plasma tryptophan and serum IL-1RA, IL-6 and IL-8. CONCLUSIONS The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.

Increased 24‐hour urinary cortisol excretion in patients with post‐traumatic stress disorder and patients with major depression, but not h patients with fibromyalgia

There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic‐pituitary‐adrenal (HPA) axis, as assessed by means of 24‐h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post‐traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24‐h UC excretion. The aim of the present study was to examine 24‐h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24‐h UC excretion than normal controls and fibromyalgia patients. At a threshold value of ≥240 μg/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24‐h UC excretion with a specificity of 100%. There were no significant differences in 24‐h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24‐h UC excretion and The HDRS score. In fibromyalgia, no significant correlations were found between 24‐h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24‐h UC excretion and severity of either depression‐avoidance or anxiety‐arousal symptoms. In conclusion, this study found increased 24‐h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24‐h UC were found.