Stéphane Potvin

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.

Widespread and sustained cognitive deficits in alcoholism: a meta‐analysis

The cognitive repercussions of alcohol dependence are well documented. However, the literature remains somewhat ambiguous with respect to which distinct cognitive functions are more susceptible to impairment in alcoholism and to how duration of abstinence affects cognitive recovery. Some theories claim alcohol negatively affects specific cognitive functions, while others assert that deficits are more diffuse in nature. This is the first meta‐analysis to examine cognition in alcohol abuse/dependence and the duration of abstinence necessary to achieve cognitive recovery. A literature search yielded 62 studies that assessed cognitive dysfunction among alcoholics. Effect size estimates were calculated using the Comprehensive Meta‐Analysis V2, for the following 12 cognitive domains: intelligence quotient, verbal fluency/language, speed of processing, working memory, attention, problem solving/executive functions, inhibition/impulsivity, verbal learning, verbal memory, visual learning, visual memory and visuospatial abilities. Within these 12 domains, three effect size estimates were calculated based on abstinence duration. The three groups were partitioned into short‐ (<1 month), intermediate‐ (2 to 12 months) and long‐ (>1 year) term abstinence. Findings revealed moderate impairment across 11 cognitive domains during short‐term abstinence, with moderate impairment across 10 domains during intermediate term abstinence. Small effect size estimates were found for long‐term abstinence. These results suggest significant impairment across multiple cognitive functions remains stable during the first year of abstinence from alcohol. Generally, dysfunction abates by 1 year of sobriety. These findings support the diffuse brain hypothesis and suggest that cognitive dysfunction may linger for up to an average of 1 year post‐detoxification from alcohol.

The Deficit of Pain Inhibition in Fibromyalgia Is More Pronounced in Patients With Comorbid Depressive Symptoms

BackgroundOn pathophysiologic grounds, fibromyalgia (FM) is characterized by a deficit in diffuse noxious inhibitory controls (DNIC), but the role of depressive symptoms on these mechanisms has not been investigated. We hypothesized that the deficit in pain inhibition would be more pronounced in FM patients with depressive symptoms (FM+D), relative to patients without such symptoms (FM−D). MethodsFifty-two women diagnosed with FM (American College of Rheumatology criteria) and 10 healthy women participated in this study. Thermal stimuli were used to measure pain thresholds and DNIC efficacy (spatial summation paradigm). Clinical pain was measured using visual analog scales. ResultsWe found that the amplitude of DNIC was smaller in FM+D patients, relative to the FM−D group; and that daily pain (unpleasantness) was higher in the FM+D group, relative to FM−D patients. DiscussionWe found that FM+D patients have a more pronounced deficit in pain inhibition as well increased clinical pain. As such, these results show the usefulness of combining psychologic factors and psychophysical measures to identify subgroups of FM patients. These results may have implications for future treatment of FM patients with and without comorbid depressive symptoms.

Contradictory cognitive capacities among substance-abusing patients with schizophrenia: a meta-analysis.

Although a substance use disorder (SUD) is traditionally associated with psycho-bio-social impairments, recent investigations among persons with schizophrenia (Sz) generated divergent results. Certain persons with Sz+SUD might in fact present better social and cognitive functioning than persons with Sz without SUD. This meta-analysis was conducted to verify this counterintuitive possibility and to determine whether factors such as substance type, severity or nature of psychotic symptoms and age of the patients help discriminate these subgroups. Twenty-three studies met the inclusion criteria and data from 1807 persons with schizophrenia, with or without comorbid SUD, were available for analyses. As a group, persons with Sz+SUD did not obtain significantly higher scores at a Global Cognitive Index than persons with Sz without SUD, although they were better at the Trail Making Task and the speed processing domain. Secondary analyses showed the importance of considering intermediate factors, particularly the preferred substance used and the mean age. While consumption of alcohol was associated with a global cognitive scores similar to that of persons with Sz without an SUD and lower working memory capacities, preferential use of cannabis was instead associated with higher scores for problem solving and reasoning and visual memory. Age was inversely related to the size of the effects. It is concluded that previous mixed results obtained with cognitive evaluations of persons with Sz+SUD might reflect the heterogeneity of participants and that subgroups of patients might be defined on the basis of intermediate factors.

Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis.

OBJECTIVES Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined. METHODS A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment. RESULTS We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1β and interferon-γ. CONCLUSIONS These results show that antipsychotics produce anti-inflammatory effects in schizophrenia.

Human evidence of a supra‐spinal modulating role of dopamine on pain perception

Over the last decades, remarkable progresses have been accomplished regarding the understanding of the neurophysiologic and neuropharmacological bases of pain. A growing preclinical literature supports a role for substance P, endogenous opioids, glutamate, serotonin, and norepinephrine in pain perception. Recently, a series of studies explored the function of dopamine in pain perception, which we review here, while focusing on human studies.

Hypoalgesia in schizophrenia is independent of antipsychotic drugs: A systematic quantitative review of experimental studies

&NA; Diminished sensitivity to pain in schizophrenia has been reported since the early works of Bleuler [Bleuler E. Textbook of psychiatry (trans. Brill HA, 1951). New York: Dover Publications; 1911] and Kraepelin [Kraepelin E. Dementia praecox and paraphrenia. Edinburgh, Scotland: E and S Livingstone; 1919]. Over the last decade, experimental studies have measured pain perception in schizophrenia and produced mixed results. This meta‐analysis sought to determine if the scientific literature confirms the hypothesized hypoalgesia in schizophrenia. The search was performed with computerised literature databases. A study was retained in the meta‐analysis if: (i) it comprised a group of schizophrenia patients, compared to a control group of healthy volunteers; and (ii) pain was measured via experimental procedures (e.g. thermal, electrical, or mechanical stimuli). Using Comprehensive Meta‐Analysis‐2, effect size estimates of the differences in pain scores (all pain scores derived from all pain tests) between schizophrenia patients and healthy volunteers were calculated. Eleven studies were included in the meta‐analysis. For the composite analysis, a positive, moderate, and significant effect size estimate emerged (N = 497; Hedges’s g = 0.437; p = 0.005), suggesting that patients with schizophrenia show a diminished response to experimentally‐induced pain. Secondary analyses showed that: (i) drug‐free patients also have hypoalgesic responses; and that (ii) sensory thresholds are increased in schizophrenia patients. This meta‐analysis substantiates the hypothesis of a diminished pain response in schizophrenia. The study also suggests that hypoalgesia in schizophrenia cannot be solely explained by the effects of antipsychotic drugs, and that it may not be a pain‐specific blunted response. Further studies are warranted to determine the clinical and biological correlates, and the social and health consequences, of hypoalgesia in schizophrenia.

DRD3 Ser9Gly Polymorphism Is Related to Thermal Pain Perception and Modulation in Chronic Widespread Pain Patients and Healthy Controls

UNLABELLED Experimental studies showed that dopamine influences pain perception in healthy volunteers. Dopamine dysfunctions have been linked to the physiopathology of fibromyalgia (FM), which is associated with hyperalgesia and deficient pain inhibition. We sought to investigate the relationships between catecholamine-related polymorphisms [dopamine-D(3) receptor (DRD3) Ser9Gly and catechol-O-methyltransferase (COMT) Val158Met] and thermal pain measures in healthy subjects and FM patients. Seventy-three subjects (37 FM patients and 36 controls) participated in this study. Thermal pain thresholds (TPTs) were measured using a Peltier thermode. Inhibitory systems were elicited using a thermal tonic pain stimulation administered before and after activation of the diffuse noxious inhibitory controls (DNIC) by means of a cold-pressor test. Genetic analyses were performed using polymerase chain reaction. Regression analyses were performed across and within groups. FM was associated with lower TPTs and deficient pain inhibition. DRD3 Ser9Gly polymorphism predicted (1) DNIC efficacy across groups and (2) thermal TPTs in FM patients. COMT Val158Met and thermal pain measures were not related. These preliminary results suggest that the DRD3 Ser9Gly polymorphism influences DNIC efficacy and TPTs and that this latter relationship is present only in FM patients. Two core psychophysical features of FM appear to be significantly influenced by limbic dopamine functioning. PERSPECTIVE This experimental study is the first to relate DNIC and TPTs to a functional polymorphism of limbic dopamine-D3 receptors. As lowered pain thresholds and deficient pain inhibition are 2 core features of fibromyalgia, these preliminary results may help identify a subgroup of FM patients who require closer medical attention.

Fibromyalgia subgroups: profiling distinct subgroups using the Fibromyalgia Impact Questionnaire. A preliminary study.

The main goal of this project was to identify the presence of fibromyalgia (FM) subgroups using a simple and frequently used clinical tool, the Fibromyalgia Impact Questionnaire (FIQ). A total of 61 women diagnosed with FM participated in this study. FM subgroups were created by applying a hierarchical cluster analysis on selected items of the FIQ (pain, fatigue, morning tiredness, stiffness, anxiety and depressive symptoms). We also tested for group differences on experimental pain, psychosocial functioning and demographic characteristics. Two cluster profiles best fit our data. FM-Type I was characterized by the lowest levels of anxiety, depressive and morning tiredness symptoms, while FM-Type II was characterized by elevated levels of pain, fatigue, morning tiredness, stiffness, anxiety and depressive symptoms. Both FM subgroups showed hyperalgesic responses to experimental pain. These results suggest that pain and stiffness are universal symptoms of the disorder but that psychological distress is a feature present only in some patients.

Clozapine, quetiapine and olanzapine among addicted schizophrenic patients: towards testable hypotheses.

&NA; Although life prevalence of substance use disorders among patients with schizophrenia is close to 50%, few studies have been carried out to date to identify an integrated pharmacological treatment for this comorbidity. So far, the most promising results, that we report here, have been obtained with clozapine. To a lesser extent, quetiapine and olanzapine, both clozapine analogues, have also shown promising results. Further to these observations, the present paper critically reviews the advantages associated with clozapine, quetiapine and olanzapine, and their relevance to the treatment of addiction among schizophrenic patients. Six characteristics seem to distinguish clozapine, quetiapine and olanzapine from the firstgeneration antipsychotics: (1) acting preferentially on the reward system, these second‐generation antipsychotics (mainly clozapine and quetiapine) induce almost no extrapyramidal symptoms; (2) quickly dissociating from D2, theses drugs (mainly clozapine and quetiapine) seem not to induce dysphoria, unlike conventional antipsychotics like haloperidol;(3) these drugs (mainly clozapine) seem more effective in the treatment of negative symptoms than conventional antipsychotics; (4) because of a diversified activity on several serotoninergic and noradrenergic receptors, these drugs positively alter mood, which does not seem to be the case with conventional antipsychotics, except for flupenthixol; (5) these drugs have a positive impact on cognition, which is not the case with the firstgeneration antipsychotics; (6) unlike conventional antipsychotics, these drugs seem to have a moderate affinityfor 5‐HT3, the receptor on which ondansetron, an anti‐craving medication, acts.