Roch-Hugo Bouchard

A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region.

CANTAB explicit memory is less impaired in addicted schizophrenia patients

It has been suggested that in order to sustain the lifestyle of substance abuse, addicted schizophrenia patients would have less negative symptoms, better social skills, and less cognitive impairments. Mounting evidence supports the first two assumptions, but data lack regarding cognition in dual diagnosis schizophrenia. Seventy-six schizophrenia outpatients (DSM-IV) were divided into two groups: with (n = 44) and without (n = 32) a substance use disorder. Motor speed and visuo-spatial explicit memory were investigated using CANTAB. As expected, dual diagnosis patients showed a better cognitive performance. Our results suggest either that substance abuse relieves the cognitive deficits of schizophrenia or that the patients with less cognitive deficits are more prone to substance abuse.

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.

Adiposity and eating behaviors in patients under second generation antipsychotics.

Background: Second generation antipsychotics (SGA) induce substantial weight gain but the mechanisms responsible for this phenomenon remain speculative.

Increased extrapyramidal symptoms in patients with schizophrenia and a comorbid substance use disorder

Few data have been gathered about the impact of psychoactive substances on extrapyramidal symptoms (EPS) in schizophrenia, and so far, inconsistent results have been reported. We studied 41 outpatients with schizophrenia (based on DSM-IV criteria), who were divided into two groups: with (n = 17) and without (n = 24) a substance use disorder (alcohol, cannabis, and/or cocaine). Both groups were matched for sociodemographic data and psychiatric symptoms (Positive and Negative Syndrome Scale). EPS were evaluated with the Extrapyramidal Symptoms Rating Scale and the Barnes Akathisia Scale, and all patients were stable on either quetiapine or clozapine. Patients receiving anticholinergic drugs were excluded. Analyses of variance were conducted on both groups and showed that schizophrenia patients with a comorbid substance use disorder (especially cocaine) displayed more EPS compared with non-abusing patients.

Longitudinal comparative study of risperidone and conventional neuroleptics for treating patients with schizophrenia. The Quebec Schizophrenia Study Group.

This study compared the long-term (12 months) effectiveness of risperidone (RP) with that of conventional neuroleptics (CNs) in a population with chronic schizophrenia who had shown suboptimal response to CNs. A randomized, open, parallel, multicenter design was used. One hundred eighty-four subjects meeting DSM-IV criteria for schizophrenia were randomly assigned to receive either RP or a CN, and 165 of them completed the follow-up. Outcome measures were taken at 3, 6, and 12 months and included the Positive and Negative Syndrome Scale (PANSS) and the Extrapyramidal Symptom Rating Scale. Within this 12-month follow-up, RP was found to be superior to CNs in terms of both the average change in score from baseline on the PANSS (p = 0.006) and the proportion of good responders (as defined by a 20% decrease in total PANSS scores;p = 0.03). For positive symptoms, the effectiveness of the RP treatment tended to increase over time. At 12 months, the percentage of good responders in the RP group was twice as large as that in the CN group (30% vs. 15%;p = 0.03). The superiority of RP over CNs was constant over the three dose categories. In both the RP and the CN groups, the maximum decrease in psychopathology was achieved with the lowest dose range. A worsening of akathisia was less frequent in subjects receiving RP than in those receiving CNs (p = 0.02). In conclusion, this study showed that, compared with CNs, RP is beneficial in the treatment of patients with chronic schizophrenia and that some of these benefits may appear only after longer-term treatment.

Verbal and Visual Memory Impairments Among Young Offspring and Healthy Adult Relatives of Patients With Schizophrenia and Bipolar Disorder: Selective Generational Patterns Indicate Different Developmental Trajectories

Objective: Memory deficits have been shown in patients affected by schizophrenia (SZ) and bipolar (BP)/mood disorder. We recently reported that young high-risk offspring of an affected parent were impaired in both verbal episodic memory (VEM) and visual episodic memory (VisEM). Understanding better the trajectory of memory impairments from childhood to adult clinical status in risk populations is crucial for early detection and prevention. In multigenerational families densely affected by SZ or BP, our aim was to compare the memory impairments observed in young nonaffected offspring with memory functioning in nonaffected adult relatives and patients. Methods: For 20 years, we followed up numerous kindreds in the Eastern Québec population. After having characterized the Diagnostic and Statistical Manual of Mental Disorders phenotypes, we assessed cognition (N = 381) in 3 subsamples in these kindreds and in controls: 60 young offspring of a parent affected by SZ or BP, and in the adult generations, 92 nonaffected adult relatives and 40 patients affected by SZ or BP. VEM was assessed with the California Verbal Learning Test and VisEM with the Rey figures. Results: The VEM deficits observed in the offspring were also found in adult relatives and patients. In contrast, the VisEM impairments observed in the young offspring were present only in patients, not in the adult relatives. Conclusion: Implications for prevention and genetic mechanisms can be drawn from the observation that VEM and VisEM would show distinct generational trajectories and that the trajectory associated with VisEM may offer a better potential than VEM to predict future risk of developing the disease.

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.

Possible association of the pro-melanin-concentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine.

Following our report of a linkage at 12q24 with a phenotype of obesity under antipsychotics, we tested the pro‐melanin‐concentrating hormone (PMCH) candidate gene for a possible association in humans with the body mass index (BMI; kg/m2) in unrelated schizophrenic patients (SZ) receiving antipsychotics (N = 300) and in controls (CTL; N = 150). Subjects were classified in obese (OB) (BMI ≥ 30 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and normal weight (BMI < 25 kg/m2) groups. Single nucleotide polymorphisms (SNP) rs7973796 and rs11111201, located 5′ at −4.5 kb and 3′ at +1.8 kb, respectively, of PMCH were genotyped. Interaction effects of genotypes and antipsychotic treatment on BMI were tested in a covariance analysis with age and gender as covariates. Interaction effects on the prevalence of obesity were tested in a logistic regression analysis. For subjects under 50 years, the effect of the rs7973796 genotype on BMI differed between the SZ patients taking olanzapine and CTL group (interaction P = 0.025). Olanzapine‐treated SZ patients carrying the ancestral homozygote genotype showed a higher BMI for rs7973796 (P = 0.016 with the LSMeans t‐test) than the variant homozygotes. Accordingly, the ORs for obesity associated with rs7973796 genotypes differed in the SZ patients taking olanzapine compared to the CTL group (interaction P = 0.0094). The G allele was associated with an increase in the odds of obesity in SZ patients taking olanzapine. No association was observed for those over 50 years, or for rs11111201. These results suggest that the common allele of PMCH rs7973796 may be associated with a greater BMI in olanzapine‐treated SZ patients.

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.