Cortisol and Cytokines in Chronic and Treatment-Resistant Patients with Schizophrenia: Association with Psychopathology and Response to Antipsychotics

ArticleinNeuropsychopharmacology 30(8):1532-8 · September 2005with26 Reads
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.
    • "Antipsychotic treatment has shown dampening effects on HPA activation and normalizes diurnal cortisol hyper-secretion in schizophrenia patients (Mondelli et al., 2010; Walker et al., 2008). In particular, atypical antipsychotic medications have been found to produce significant improvements in clinical outcomes and HPA axis functioning over typical antipsychotic treatment in previous studies (Altamura et al., 1999; Cohrs et al., 2006; Zhang et al., 2005). Current research literature on schizophrenia focuses on its developmental course among first-episode or high-risk samples (Carol and Mittal, 2015; Cullen et al., 2014; Simeonova et al., 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: The present study examined the relationships between diurnal cortisol patterns and perceived stress, lifestyle factors, psychotic symptoms, neurological deficits, and daily functioning in patients with chronic schizophrenia. The participants were 149 Chinese patients with chronic schizophrenia, who provided salivary cortisol measures upon waking, before lunchtime, and before bedtime at baseline (Time 1). Self-report measures on perceived stress and lifestyle factors such as body-mass index and daily exercise span were recorded at Time 1. Diagnostic assessments on psychotic symptoms, neurological deficits, and daily functioning were made at Time 1 and Time 2 (3 months later). Latent growth modeling and path modeling analysis were performed to investigate the diurnal cortisol patterns and the relationships with the study variables, respectively. Greater perceived stress and body-mass index and less physical activity were significantly linked to reduced cortisol decline. Reduced cortisol decline at Time 1 significantly predicted greater psychotic (positive and negative) symptoms and more severe neurological deficits in motor coordination and sequencing of complex motor acts at Time 2. The present results contribute to a better understanding of the diurnal cortisol patterns among chronic schizophrenia patients and the associations with lifestyle factors, psychotic symptoms, and neurological deficits. The findings lend support to the neural diathesisestress model and suggest that hypothalamicepituitaryeadrenal axis may potentially mediate the effects of lifestyle factors on psychotic symptoms and neurological deficits.
    Full-text · Article · Oct 2016
    • "In line with our findings, another study also reported significant suppression of cortisol during laboratory induced stress conditions following acute haloperidol administration in healthy volunteers (Hennig et al., 1995). Furthermore, other compounds characterised by high D2 receptor antagonism have demonstrated similar suppressive effects on cortisol levels during stress-induced conditions (Itoh et al., 2005 ); consistently, FGA treatment has been associated with normalisation of previously raised cortisol levels also in patients with psychosis (Zhang et al., 2005). The mechanisms through which haloperidol decreases cortisol levels could be related to the strong antagonistic effect of this drug on dopamine in the mesolimbic pathway, particularly in the striatum. "
    [Show abstract] [Hide abstract] ABSTRACT: This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.
    Article · Apr 2016
    • "After improvements in both positive and negative symptoms, schizophrenia patients still have residual biomarkers' abnormalities that can increase the likelihood of recurrence and hamper the restoration of social function. The increase in plasma cortisol levels at baseline and restoration of cortisol to control levels at the final session after 8 weeks of clozapine treatment were consistent with previous studies in firstepisode schizophrenia patients (Garner et al., 2011; Mondelli et al., 2010; Walker et al., 2008; Zhang et al., 2005). Psychosocial stress has been widely acknowledged to play a role in the development and course of psychotic disorders. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated. Methods: Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin. Results: Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin. Conclusion: These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.
    Full-text · Article · Feb 2016
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