Alain Gendron

Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review

BACKGROUND Cytokines play an important role in infection and inflammation and are crucial mediators of the cross-talk between the brain and the immune system. Schizophrenia would be associated with an imbalance in inflammatory cytokines, leading to a decrease in Th1 and an increase in Th2 cytokine secretion. However, data published so far have been inconsistent. The primary objective of the present meta-analysis was to verify whether the cytokine imbalance hypothesis of schizophrenia is substantiated by evidence. METHODS Cross-sectional studies were included if they assessed in vivo plasma or serum cytokine concentrations and/or in vitro secretion of cytokines by peripheral blood leukocytes from schizophrenia patients and healthy volunteers. RESULTS Data from 62 studies involving a total sample size of 2298 schizophrenia patients and 1858 healthy volunteers remained for analysis. Ten cytokines were assessed, including the prototypic Th1 and Th2 cytokines gamma interferon (IFN-gamma) and interleukin 4 (IL-4) as well as IL-2, soluble IL-2 receptor (sIL-2R), IL-1beta, IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-alpha (TNF-alpha), IL-6, soluble IL-6 receptor (sIL-6R), and IL-10. The results show that an increase occurs in in vivo IL-1RA, sIL-2R, and IL-6 and a decrease occurs in in vitro IL-2 in schizophrenia. No significant effect sizes were obtained for the other cytokines. CONCLUSIONS These findings provide the first evidence of establishment of an inflammatory syndrome in schizophrenia, which refutes the current hypothesis of a Th2 slant. Caveats are presented to data interpretation, including the role of stress and the effect of weight gain that develops in schizophrenia.

Quetiapine in patients with comorbid schizophrenia-spectrum and substance use disorders: an open-label trial.

ABSTRACT Background: Preliminary evidence suggests that clozapine relieves the craving for psychoactive substances in schizophrenia patients. Quetiapine shares crucial pharmacological properties with clozapine. Promising results have been described with quetiapine therapy in patients with psychosis and substance use disorder. Methods: Based on Diagnostic and Statistical Manual of Mental Disorders – fourth edition (DSM‐IV) criteria, patients were diagnosed with comorbid schizophrenia-spectrum and substance use disorders. Patients were switched to quetiapine for a 12‐week open-label trial. Craving, quantities used, days of consumption, and severity of substance abuse were assessed every 3 weeks. Alcohol and Drug Use Scales were administered on baseline and end-point. Psychiatric symptoms, depressive symptoms, extrapyramidal symptoms, and cognition were also assessed at baseline, week 6 and week 12. Results: Twenty-four schizophrenia-spectrum patients were included in the last observation carried forward (LOCF) analyses, responding to one or more of the following substance use disorders: cannabis (15 patients), alcohol (10 patients), and other psychoactive substances (nine patients). Overall, severity of substance abuse improved during the study. Less weekly days were spent on drugs of abuse. A decrease in the weekly Canadian dollars spent on psychoactive substances was also observed. Cognition, psychiatric, depressive, and extrapyramidal symptoms also significantly improved ( p < 0.05). Conclusions: In this open-label, uncontrolled trial, significant improvements were noted in substance abuse, psychiatric symptoms, extrapyramidal symptoms, and cognition during quetiapine therapy. The study suffered from three main limitations: (1) the open-label design of the study; (2) the patients’ poor compliance; and (3) the small sample size involved. Controlled studies on the use of quetiapine in dual diagnosis schizophrenia are warranted to confirm that the effects are drug-related.

Quetiapine augmentation of treatment-resistant depression: a comparison with lithium

ABSTRACT Objective: The prevalence of and morbidity associated with treatment-resistant depression has motivated the exploration of treatment alternatives. In this study, quetiapine was compared with lithium in the augmentation of treatment-resistant depression. Research design and methods: Open-label, comparative study in 20 patients with major depression who had failed to respond after 4 weeks of treatment with an antidepressant at the maximal recommended dose. Patients were randomised to either lithium or quetiapine in addition to the maximally dosed antidepressant and any other concurrent medications. Lithium was initiated at 600 mg/day; quetiapine was titrated to 400 mg by day 7. Results: Depression, measured by the Hamilton Depression Rating Scale (HAM‑D), significantly improved from baseline in both quetiapine (F1,90 = 25.11, p < 0.0001) and lithium (F1,90 = 34.54, p < 0.0001). The difference in improvement between the two groups began at day 14 and was seen at all timepoints thereafter ( p < 0.05), with the quetiapine group showing greater improvement than the lithium group. In the Montgomery–Asberg Depression Rating Scale (MADRS) analysis, the difference between the quetiapine and lithium group was significant from day 28 onwards ( p < 0.05), with subjects improving more in the quetiapine group than the lithium group. The treatment by week interaction showed a significant difference overall between the two groups ( p < 0.0001). The severity of psychomotor retardation showed a significant decrease in the Widlocher Psychomotor Retardation Scale scores in the quetiapine ( p < 0.0001) and lithium ( p < 0.0001) groups. Conclusions: In this pilot study, quetiapine was an effective augmenting agent in treatment-resistant depression.

Quetiapine attenuates the depressive and anxiolytic-like behavioural changes induced by global cerebral ischemia in mice

Recently, we have reported that quetiapine, an atypical antipsychotic drug, prevents memory impairment and hippocampus neurodegeneration induced by global cerebral ischemia (GCI). In the present study, we examined the possible effects of quetiapine on other behavioural deficits, including the depressive and anxiolytic-like behavioural consequences of GCI. Mice were treated with quetiapine (5 or 10mg/kg/day; intraperitoneal (i.p.)) for 14 days. On Day 15, the animals were subjected to GCI. GCI resulted in a decrease of striatal tyrosine hydroxylase (TH) immunostaining and induced depressive and anxiolytic-like behavioural changes. The behavioural changes were indicated by a significant increase in the immobility duration in a tail-suspension test, and an increase in the time spent in the light box in a light/dark box test. Pre-administration of quetiapine significantly alleviated the decreased TH immunostaining and attenuated the depressive and anxiolytic-like behavioural changes induced by GCI. These results enhance our understanding about the mechanisms of quetiapine and suggest a wider perspective for the clinical use of quetiapine.

Endogenous cannabinoids in patients with schizophrenia and substance use disorder during quetiapine therapy

Disturbances in the endogenous cannabinoid (ECB) system in schizophrenia may contribute to their enhanced sensitivity to psychoactive substances, and the beneficial effects of second-generation antipsychotics for substance abuse in schizophrenia may involve modulatory effects on ECB. To verify these two assumptions, 29 patients (24 completers) with schizophrenia and substance use disorders (SUD) were treated with quetiapine for 12 weeks, and peripheral ECB levels were measured, using high-performance liquid chromatography/mass spectrometry, in patients (weeks 0, 6 and 12) and 17 healthy volunteers. Baseline anandamide levels were significantly higher in patients, relative to controls. This result is consistent with studies describing ECB dysfunctions in schizophrenia. SUD parameters improved during treatment, but no changes in ECB occurred over time. Improvements in substance abuse were probably not mediated by modulatory effects of quetiapine on ECB. Lastly, baseline anandamide predicted endpoint SUD scores (alcohol/ cannabis). Anandamide is a potential target for medications aimed at relieving SUD in schizophrenia.

Differential hemodynamic brain activity in schizophrenia patients with blunted affect during quetiapine treatment

Abstract: Blood-oxygenation-level-dependent (BOLD) brain changes underlying response to quetiapine were examined using passive viewing of emotionally negative stimuli. Twelve DSM-IV schizophrenia patients with blunted affect (BA+) were scanned before and after 22 weeks of quetiapine treatment. Whole-brain, voxel-based methods were used to assess the differential hemodynamic response to quetiapine. In addition, a post hoc comparison to an independent group of 11 schizophrenia patients without blunted affect (BA−) was performed to compare them with BA+ (postquetiapine) in response to emotion processing. A 22-week treatment with quetiapine resulted in significant clinical improvement in the 12 study completers (mean ± SD posttreatment PANSS blunted affect score of 5.50 ± 0.76 at baseline to 2.08 ± 1.00 at end point; t = 7.78, df = 11, P < 0.0001). Treatment response was associated with significant BOLD changes: increases in prefrontal cortex activation particularly in the right dorsolateral prefrontal cortex (DLPFC, BA 46) and the right anterior cingulate cortex (ACC, BA 32); and in the left putamen, right anterior temporal pole (ATP), and right amygdala. Conversely, before treatment with quetiapine, the same subjects activated the midbrain bilaterally and the right pons. The post hoc conjunctional analyses demonstrated that BA− subjects activated the left ACC, left insula, left ATP (BA 21), left ATP (BA 38), left amygdala, and right medial prefrontal cortex. Quetiapine seems to affect clinical recovery by modulating the functioning of specific brain regions. Unique BOLD changes in the putamen and DLPFC with quetiapine, in the BA+ postquetiapine, may reflect modality-specific effects. Controlled studies are needed to further assess these preliminary findings.

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders.

BACKGROUND Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology. METHODS Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis>alcohol>cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n=24) was 466.6mg±227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes. RESULTS On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p=0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p<0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r=-0.524; p=0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms. CONCLUSION These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.

The co-administration of quetiapine or placebo to cognitive-behavior therapy in treatment refractory depression: A preliminary trial

BackgroundPatients with major depression refractory to repeated pharmacological trials (TRD) may remain symptomatic for many years after their index episode. Augmentation strategies (with lithium or an atypical antipsychotic) or combining an antidepressant with short-term psychotherapy have been used with relative success in these patients. The aim of this study was to assess the effectiveness of the concomitant administration of quetiapine, an atypical antipsychotic, or placebo, to cognitive-behavior therapy (CBT) in TRD.MethodsThirty-one patients who met entrance criteria for unipolar major depression (TRD stage II or greater) underwent 3 weeks of lithium augmentation after which non-responders (N = 22) were randomized to receive either quetiapine or placebo as an adjunct to their 12 weekly CBT sessions (quetiapine/CBT or placebo/CBT groups). Primary efficacy measures were the Hamilton and the Montgomery-Asberg rating scales for depression.ResultsOverall, there was a significant reduction in both primary efficacy measure scores at LOCF for the 11 patients in the quetiapine/CBT group but not in the placebo/CBT treated patients. Patients in the quetiapine/CBT group, compared to those receiving placebo/CBT, showed a significantly greater degree of improvement on one primary and one secondary efficacy measure, were more likely to complete the trial and, completed a greater number of CBT sessions.ConclusionAlthough preliminary, our results suggest that the adjunctive administration of quetiapine to CBT may prove useful in the treatment of stage II TRD.Trial RegistrationCurrent Controlled Trials ISRCTN12638696.

Add-on treatment of quetiapine for fibromyalgia: a pilot, randomized, double-blind, placebo-controlled 12-week trial.

Abstract Recently, second-generation antipsychotic drugs have attracted interest in the treatment of chronic pain, including fibromyalgia (FM). Preliminary uncontrolled studies have shown that quetiapine treatment may be helpful for FM patients. In this trial, we sought to examine—for the first time—the efficacy and tolerability of quetiapine as a treatment for FM and its associated psychiatric symptoms. This was a 12-week double-blind, randomized, placebo-controlled trial of quetiapine XR as an add-on treatment for FM syndrome. Fifty-one female FM patients were randomized, and a flexible dosage of 50 to 300 mg/d was used. The primary outcome was the change from baseline to end point in the Fibromyalgia Impact Questionnaire total score. Secondary outcomes included mood symptoms, sleep disturbances, and tender points. Using a low dose (mean = 132.2 mg) of quetiapine, we observed significant benefits of drug treatment on sleep, uncertain effects on FM and mood symptoms, but no effects on pain, in a small group of polymedicated FM patients. Quetiapine was generally well tolerated.

Anhedonia and social adaptation predict substance abuse evolution in dual diagnosis schizophrenia.

The current study sought to identify the variables, derived from the self-medication hypothesis, which predicted substance abuse evolution during a homogeneous 3-month antipsychotic treatment. Twenty-four patients were diagnosed with schizophrenia and substance abuse (mainly cannabis and alcohol). Substance abuse, psychiatric symptoms, anhedonia, and social adjustment were assessed at baseline and study endpoint. Linear regression analyses were performed. Better social adaptation and worse anhedonia predicted substance abuse improvements. Conversely, greater psychoactive substance (PAS) use predicted endpoint positive and depressive symptoms. These results suggest that: (i) substance abuse interferes with psychiatric prognosis in schizophrenia; and (ii) dual diagnosis treatments leading patients to engage in alternative social activities may render substance abuse less appealing. Further studies are warranted to dissociate the causes and consequences of substance abuse in schizophrenia.