Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC. Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 30: 1532-1538

Institute of Mental Health, Peking University, Beijing, PR China.
Neuropsychopharmacology (Impact Factor: 7.05). 09/2005; 30(8):1532-8. DOI: 10.1038/sj.npp.1300756
Source: PubMed


The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic-pituitary-adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators. Growing evidence suggests that neuro-immune-endocrine crosstalk may be impaired in schizophrenia. We determined the relationship between cortisol, cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6), and symptoms in schizophrenia during treatment with typical and atypical antipsychotic drugs. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients. SCH were randomly assigned to 12-week treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum cortisol and IL-2 levels were assayed by radioimmunometric assay, and serum IL-6 levels by quantitative enzyme-linked immunosorbent assay. Following a 2-week washout period, serum levels of cortisol, IL-2, and IL-6 were increased in patients with schizophrenia compared to HC. Elevations in cortisol were associated with increase in both IL-2 and IL-6 in SCH. Moreover, elevations in cortisol were associated with negative symptoms and IL-2 with positive symptoms. In all, 12 weeks of risperidone treatment significantly decreased elevated cortisol and improved negative symptoms, but produced similar effects on IL-2 and IL-6 as well as on positive symptoms compared to haloperidol. The improvement of negative symptoms was related to the change in cortisol. Our results suggest that the imbalance in the HPA axis and cytokine system in patients with SCH is implicated in clinical symptoms, and is improved with atypical antipsychotic treatment.

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Available from: Xiang Yang Zhang, Oct 02, 2015
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    • "Brain structure 1. Whole brain volume Reduced in maltreated children; earlier exposures seem to have greater effects [59] [60] Also seen in drug-naive patients with schizophrenia [61] 2. Ventricular enlargement Some studies have found an association between ventricular enlargement and early childhood abuse [62] Frequently reported in patients with schizophrenia [61] 3. Hippocampal volume Reduced both in children who have experienced trauma [62] and in healthy adults who have experienced childhood maltreatment [63] Hippocampal volume, particularly gray matter volume, reduced in schizophrenia [61] 4. White matter changes Reduced white matter tract integrity has been reported in adults exposed to verbal abuse during childhood [64] Similar changes have been reported in schizophrenia [61] Neurotransmitter release 1. Dopamine transmission Lower maternal care associated with increased dopamine release in response to stress [35] Potentially relevant for the formation of delusions [40] 2. Serotonin transmission Increased prolactin response to 5-hydroxytryptophan seen in depressed children with a history of neglect [65] Similar changes seen in drug-naive patients with schizophrenia [66] Neuroendocrine changes Hypercortisolemia and overactivation of the hypothalamo–pituitary–adrenal (HPA) axis Has been found as a consequence of child neglect and abuse in several studies [62] [67] Often found in patients with schizophrena; may reflect a stress response [61] Others Immune dysregulation and proinflammatory activity Elevated auto-antibody titres have been reported in abused girls by some researchers [68] Recent evidence of immune and inflammatory dysfunction, including autoimmunity, in schizophrenia [69] [70] supported by existing literature, and extends the efforts of some authors (such as Read's ''traumagenic model'') to examine the relationship between childhood adversity and psychosis. It also provides an empirically valid theoretical framework – attachment theory – in which this relationship can be examined. "
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    ABSTRACT: Schizophrenia is a complex psychiatric syndrome whose exact causes remain unclear. However, current scientific consensus has highlighted the importance of neurodevelopmental and neurocognitive processes in the development of schizophrenic symptoms. Research over the past three decades, motivated by the findings of the World Health Organization’s large-scale studies, has highlighted the importance of psychosocial adversities – including childhood abuse and neglect – in this disorder. In this paper, I propose a hypothesis based on John Bowlby’s framework of attachment theory, which I have termed the attachment-developmental-cognitive (ADC) hypothesis. The ADC hypothesis integrates recent developments related to (1) existing models of schizophrenia, (2) studies examining the effect of attachment on brain biology and cognitive development, and (3) various known facts about the course and outcome of this disorder. In doing so, it explains how disturbed childhood attachment leads to core psychological and neurochemical abnormalities which are implicated in the genesis of schizophrenia and also affect its outcome. The ADC hypothesis compasses and expands on earlier formulations, such as the “social defeat” and “traumagenic” models, and has important implications regarding the prevention and treatment of schizophrenia. Ways of testing and refining this hypothesis are outlined as avenues for future research. Though provisional, the ADC hypothesis is entirely consistent with both biological and psychosocial research into the origins of schizophrenia.
    Medical Hypotheses 09/2014; 83(3). DOI:10.1016/j.mehy.2014.05.017 · 1.07 Impact Factor
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    • "Positive correlations were noted between basal plasma cortisol and positive symptoms in some studies (Christie et al., 1986; Keshaven et al., 1989; Rybakowsi et al., 1991), whereas no significant correlations were noted in others (Zhang et al., 2005; Iancu et al., 2007; Goyal et al., 2004; Yilmaz et al., 2007). Studies mainly recruiting individuals with chronic schizophrenia found positive associations between basal plasma cortisol levels and the severity of negative symptoms (Altamura et al., 1989, Kaneko et al., 1992, Shirayama et al., 2002, Zhang et al., 2005, and Iancu et al., 2007). Yet, other studies found no significant association between plasma cortisol and negative symptom levels (Yilmaz et al., 2007; Montelone et al., 1999; Venkatasubraminian et al., 2007; Garner et al., 2010). "
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    ABSTRACT: Research investigating the association between negative symptoms and plasma cortisol levels in individuals with schizophrenia has produced inconsistent findings. This study investigated whether deficit syndrome schizophrenia (characterised by high levels of primary negative symptoms) is associated with comparatively high morning plasma cortisol levels, more negative appraisals about illness and higher levels of depression. Participants were 85 individuals diagnosed with schizophrenia and 85 individuals with no history of contact with psychiatric services matched for age and gender. All participants provided fasting 9.00am plasma cortisol samples. There were no significant differences between the schizophrenia and control participants in plasma cortisol levels. The Proximal Deficit Syndrome method was used to identify individuals with deficit syndrome schizophrenia. Contrary to what had been hypothesised, participants with deficit syndrome schizophrenia had significantly lower plasma cortisol levels than both non-deficit syndrome participants and control participants. Participants with the deficit syndrome reported significantly less negative appraisals about illness (assessed by PBIQ) and lower levels of depression (assessed by BDI-II). Differences in cortisol levels continued to trend toward significance when levels of depression were controlled for. The patterns of illness-related appraisals and plasma cortisol levels raise the possibility that the deficit syndrome could be a form of adaptation syndrome.
    Psychiatry Research 08/2014; 220(3). DOI:10.1016/j.psychres.2014.08.043 · 2.47 Impact Factor
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    • "Additionally, the influence of illness duration on cortisol level remains unclear, with several studies showing a positive relationship between illness duration and cortisol levels (Havermans et al., 2011; Yilmaz et al., 2007) that has not always been replicated (Hempel et al., 2010). Unfortunately, studies of the relationship between illness stage and cortisol levels are often confounded by the use of psychotropic medications (Lee et al., 2011; Venkatasubramanian et al., 2010; Zhang et al., 2005). "
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    ABSTRACT: Increased peripheral levels of morning cortisol have been reported in people with schizophrenia (SZ) and bipolar disorder (BD), but findings are inconsistent and few studies have conducted direct comparisons of these disorders. We undertook a meta-analysis of studies examining single measures of morning cortisol (before 10 a.m.) levels in SZ or BD, compared to controls, and to each other; we also sought to examine likely moderators of any observed effects by clinical and demographic variables. Included studies were obtained via systematic searches conducted using Medline, BIOSIS Previews and Embase databases, as well as hand searching. The decision to include or exclude studies, data extraction and quality assessment was completed in duplicate by LG, SM and AS. The initial search revealed 1459 records. Subsequently, 914 were excluded on reading the abstract because they did not meet one or more of the inclusion criteria; of the remaining 545 studies screened in full, included studies were 44 comparing SZ with controls, 19 comparing BD with controls, and 7 studies directly comparing schizophrenia with bipolar disorder. Meta-analysis of SZ (N=2613, g=0.387, p=0.001) and BD (N=704, g=0.269, p=0.004) revealed moderate quality evidence of increased morning cortisol levels in each group compared to controls, but no difference between the two disorders (N=392, g=0.038, p=0.738). Subgroup analyses revealed greater effect sizes for schizophrenia samples with an established diagnosis (as opposed to 'first-episode'), those that were free of medication, and those sampled in an inpatient setting (perhaps reflecting an acute illness phase). In BD, greater morning cortisol levels were found in outpatient and non-manic participants (as opposed to those in a manic state), relative to controls. Neither age nor sex affected cortisol levels in any group. However, earlier greater increases in SZ morning cortisol were evident in samples taken before 8 a.m. (relative to those taken after 8 a.m.). Multiple meta-regression showed that medication status was significantly associated with morning cortisol levels in SZ, when the effects of assay method, sampling time and illness stage were held constant. Heightened levels of morning cortisol in SZ and BD suggest long-term pathology of the hypothalamic-pituitary-adrenal (HPA) axis that may reflect a shared process of illness development in line with current stress-vulnerability models.
    Psychoneuroendocrinology 07/2014; 49C(1):187-206. DOI:10.1016/j.psyneuen.2014.07.013 · 4.94 Impact Factor
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