Circulating IGFBP-2 levels reveal atherogenic metabolic risk in schizophrenic patients using atypical antipsychotics.

OBJECTIVES: Second generation antipsychotics (SGAs) induce weight gain and dyslipidemia, albeit with important intervariability. Insulin-like growth factor binding protein (IGFBP)-2 is proposed as a circulating biomarker negatively associated with waist circumference and hypertriglyceridemia. Thus, we tested whether metabolic alterations developed upon the use of SGAs are associated with plasma IGFBP-2 levels. METHODS: A cross-sectional study was performed in 87 men newly diagnosed with schizophrenia and administered for approximately 20 months with olanzapine or risperidone as their first antipsychotic treatment. Plasma IGFBP-2 concentration, anthropometric data, as well as glucose and lipid profiles were determined at the end of the treatments. RESULTS: IGFBP-2 levels were similar between patients using olanzapine or risperidone and were negatively correlated with waist circumference, insulin sensitivity, and plasma triglycerides (TG). A higher proportion of men with a hypertriglyceridemic (hyperTG) waist phenotype was found in patients with IGFBP-2 levels lower than 220 ng/mL (43% for olanzapine and 13% for risperidone) compared to those with IGFBP-2 above this threshold (10% and 0%, respectively). CONCLUSIONS: IGFBP-2 may have a role in altering metabolic risk in schizophrenic patients using SGAs. Longitudinal studies are required to evaluate whether IGFBP-2 can predict the development of a hyperTG waist phenotype in this population.

Liability indicators aggregate many years before transition to illness in offspring descending from kindreds affected by schizophrenia or bipolar disorder.

Objectives: Offspring born to patients with affective and non-affective psychoses display indicators of brain dysfunctions that affected parents carry. Such indicators may help understand the risk trajectory. Methods: We followed up the clinical/developmental trajectories of 84 young offspring born to affected parents descending from the Quebec kindreds affected by schizophrenia or bipolar disorder. We longitudinally characterized childhood trajectories using 5 established risk indicators: cognitive impairments, psychotic-like experiences, non-psychotic DSM diagnosis and episodes of poor functioning, trauma and drug use. Results: Overall, offspring individually presented a high rate of risk indicators with 39% having 3 or more indicators. Thirty-three offspring progressed to an axis 1 DSM-IV disorder, 15 of whom transitioned to a major affective or non-affective disorder. The relative risks for each risk indicator were low in these vulnerable offspring (RR = 1.92 to 2.99). Remarkably, transitioners accumulated more risk indicators in childhood-adolescence than non-transitioners (Wilcoxon rank test; Z = 2.64, p = 0.008). Heterogeneity in the risk trajectories was observed. Outcome was not specific to parent's diagnosis. Conclusion: Young offspring descending from kindreds affected by major psychoses would accumulate risk indicators many years before transition. A clustering of risk factors has also been observed in children at risk of metabolic-cardiovascular disorders and influences practice guidelines in this field. Our findings may be significant for the primary care surveillance of millions of children born to affected parents in the G7 nations. Future longitudinal risk research of children at genetic risk should explore concurrently several intrinsic and environmental risk modalities to increase predictivity.

A feasibility study of a new computerised cognitive remediation for young adults with schizophrenia.

Cognitive remediation therapy is effective for improving cognition, symptoms and social functioning in individuals with schizophrenia; however, the impact on visual episodic memory remains unclear. The objectives of this feasibility study were: (1) to explore whether or not CIRCuiTS--a new computerised cognitive remediation therapy programme developed in England--improves visual episodic memory and other cognitive domains in young adults with early course schizophrenia; and (2) to evaluate acceptability of the CIRCuiTS programme in French-Canadians. Three participants with visual episodic memory impairments at baseline were recruited from clinical settings in Canada, and consented to participate. Neuropsychological, clinical and social functioning was evaluated at baseline and post-treatment. Intervention involved 40 sessions of cognitive remediation. First, the reliable change index (RCI) revealed that each participant demonstrated significant post-therapy change in episodic memory and in other cognitive domains. The response profile was characterised by the use of organisational strategies. Second, the treatment was considered acceptable to participants in terms of session frequency (number of sessions per week), intensity (hours per week; total hours), and number of missed sessions and total completed sessions. This preliminary study yielded encouraging data demonstrating the feasibility of the CIRCuiTS programme in French-Canadian young adults with schizophrenia.

Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment.

Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response.

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.

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.

The role of recollection in source memory: an examination of schizophrenia patients and their first-degree relatives.

Source recognition memory deficits have repeatedly been observed in people with schizophrenia (SZ), and have also recently been observed in their first-degree relatives. These deficits have been hypothesized to result, at least in part, from impairments in the conscious recollection process. Although other processes are clearly also affected in SZ, it has been proposed that impairments in the conscious recollection process could be a parsimonious explanation for the source memory deficits observed in their relatives. Here, we tested 25 patients with SZ and 34 of their non-affected parents, as well as two groups of matched healthy controls, on a short-term associative memory task that shares the characteristics of standard source recognition tasks but minimizes the need for recollection of stored information from memory. This task was administered in order to determine if deficits can still be observed in these people when involvement of the conscious recollection process is minimized. We observed deficits on our short-term source memory task in people with SZ, but their first-degree relatives did not share this deficit. These results support the idea that multiple memory processes supporting associative/source memory are affected in SZ, whereas the source memory deficits previously observed in relatives of SZ seem specific to tasks that rely on the conscious recollection process.

Schizophrenia patients with polydipsia and water intoxication are characterized by greater severity of psychotic illness and a more frequent history of alcohol abuse.

Polydipsia and water intoxication (PWI) are relatively frequent among schizophrenic subjects, particularly in institutional settings and may lead to severe complications. However, little is known on their association with other characteristics of psychosis. Hence, we took advantage of a cohort of 114 subjects extensively assessed on natural history and clinical variables to examine the correlates of PWI in chronic schizophrenia. We randomly sampled DSM-IV schizophrenic subjects from: i) a lower functioning subgroup, i.e., long-term psychiatric wards or highly structured group housing facilities; and ii) a higher functioning subgroup, i.e., patients living in the community without supervision. Subjects were assessed from multiple sources for lifetime severity of positive, disorganisation, negative and depressive symptoms, premorbid adjustment, age of onset, level of functioning, comorbid diagnoses of substance abuse and lifetime history of PWI. Twelve subjects (10.5%) met our PWI criteria. We observed more severe psychotic symptoms, earlier onset, poorer current adjustment and more frequent prior alcohol use disorder in PWI subjects. When restricting comparisons to patients living in institutional setting, differences on clinical and natural history variables vanished but the association between PWI and prior alcohol abuse persisted (72.7% in PWI vs. 21.4% in non-PWI subjects, p<0.01). Onset of alcohol abuse predated the onset of PWI by a mean of 12.8 years. PWI schizophrenic subjects are characterized by a non-specific greater severity on a broad array of clinical and natural history variables and by a specific association with prior alcohol abuse. Thus, our data suggest that a greater severity of illness and a prior history of alcohol use disorders interact in increasing the risk of developing PWI in chronic schizophrenic patients.

Insights from the examination of verbal and spatial memory errors in relation to clinical symptoms of patients with recent-onset schizophrenia.

INTRODUCTION: Memory deficits in patients with schizophrenia (SZ) are considered as a key feature of the clinical manifestations of the disease. In order to further examine the role and nature of memory deficits in SZ, the pattern of errors in verbal and spatial serial recall tasks committed by SZ patients was compared to that of healthy controls. We also tested the relationship between these memory errors and clinical symptoms. METHODS: Twenty-seven outpatients with recent-onset SZ and 27 age and gender matched healthy controls had to remember sequences of items (digits or localisations) in a serial recall task. Clinical symptoms were assessed with the PANSS and the SAPS. RESULTS: The results indicate that the number of omissions, intrusions, and transpositions can differentiate patients with SZ from healthy controls. Intrusions and transpositions committed in the verbal domain were associated with the negative subscale of the PANSS. Transposition errors were associated with delusions whether the to-be-remembered information was verbal or spatial. CONCLUSION: The examination of the pattern of errors, in particular that of transpositions, is a more informative cognitive index than the mere analysis of overall performance, and provides a promising target for treatment.

Improvement of metabolic risk profile under second-generation antipsychotics: a pilot intervention study.

OBJECTIVE: To assess the impact of a weight management program on metabolic health of second-generation antipsychotic (SGA)-treated patients. METHODS: A prospective 12-week intervention program including individual exercise training and nutritional group sessions was performed as a pilot study. An intervention group of 6 SGA-treated patients (5 men and 1 woman; mean 15.0, SD 11.8 months) was compared with 10 reference patients under SGAs (8 men and 2 women; mean 14.0, SD 14.2 months), presenting similar age and baseline weekly levels of physical activity. For patients of both groups, anthropometric measurements and basic fasting lipid profile were assessed. For patients in the intervention group, an adapted Rockport Test was performed to evaluate their aerobic fitness and compliance to training sessions, and was recorded. RESULTS: After the 12-week period, reference patients significantly gained weight (P = 0.001), whereas intervention patients showed significant weight loss and decreased body mass index (P = 0.02); interaction between groups: P < 0.01. This weight loss was accompanied by a decreased cholesterol-high-density lipoprotein cholesterol ratio (P = 0.04). Overall, the intervention patients' adherence to exercise prescription was 95.1 %, and this adherence induced a significant improvement of their aerobic fitness (P = 0.05). CONCLUSION: This pilot study suggests that patients under SGAs may benefit from a weight management program and improve their metabolic health, as well as their aerobic fitness.

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. OBJECTIVE: To explore eating behaviors among SGA-treated patients and compare them with nonschizophrenic healthy sedentary individuals (controls). METHODS AND PROCEDURES: Appetite sensations were recorded before and after a standardized breakfast using visual analog scales. Three hours after breakfast, a buffet-type meal was offered to participants to document spontaneous food intake and food preferences. Satiety quotients (SQs) were calculated to determine the satiation of both meals and the Three-Factor Eating Questionnaire (TFEQ) was used to document eating behaviors. Body composition and abdominal fat distribution were assessed. RESULTS: Compared with controls (n = 20), SGA-treated patients (n = 18) showed greater adiposity indices (P < or = 0.04). Patients' degree of hunger was also higher following the standardized breakfast (P = 0.03). Moreover, patients had significantly higher cognitive dietary restraint, disinhibition, and susceptibility to hunger scores than the reference group (P < or = 0.05). Disinhibition in the reference group was positively associated with hunger triggered by external cues (r = 0.48, P = 0.03) whereas internal cues seem to mainly regulate emotional susceptibility to disinhibition in patients (r = 0.56, P = 0.02). Higher strategic restraint behavior in patients was associated with decreased satiation right after the buffet-type meal (r = -0.56, P = 0.02). DISCUSSION: These exploratory findings suggest that patients under SGA seem to develop disordered eating behaviors in response to altered appetite sensations and increased susceptibility to hunger, a factor which may influence the extent of body weight gain triggered by these drugs.

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.

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.

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

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.

A pilot feasibility study of an extension of the acquaintanceship recruitment procedure in recent-onset psychosis.

The acquaintanceship recruitment procedure is an appealing yet infrequently used method to recruit controls, allowing a very close match between patients and controls. We used an extension of the acquaintanceship procedure to investigate the feasibility of this method to recruit controls in a neuropsychological study of recent-onset psychotic patients. Twenty-five recent-onset psychotic patients attending a multidisciplinary program devoted to recent-onset psychoses were contacted, among whom 13 agreed to participate to the study. At the end of the process, only four control participants were assessed. This pilot study suggests that several obstacles prevent the use of this procedure to recruit controls in this research focusing on recent-onset psychotic disorders.

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.

A factor analysis of the Strauss and Carpenter revised outcome criteria scale: a validation of the French translation.

This article seeks to validate the French translation of the Strauss and Carpenter revised outcome criteria scale (SCOCS-R) through the study of its interrater reliability, its convergent validity, and its factor structure. Using a sample of 113 DSM-IV schizophrenic subjects, we assessed the interrater reliability of the SCOCS-R and its convergent validity with an already validated scale (Social and Occupational Functioning Assessment Scale). The factor structure of the SCOCS-R was assessed using a principal components analysis. Interrater reliability was excellent (ri > or = 0.88 for each of the individual items), and the convergent validity with the Social and Occupational Functioning Assessment Scale proved to be highly satisfactory (r = 0.89; p < .0001). Factor analyses yielded two factors corresponding to social functioning and professional functioning. These factors accounted for 78% of the variance of outcome. These results demonstrate the reliability and the validity of the French translation of the SCOCS-R. Moreover, the two dimensions yielded by our factor analysis add to the evidence of the multidimensional structure of outcome. This article supports the relevance of the SCOCS-R to assess the dimensions of outcome in schizophrenic subjects.

Development of an atherogenic metabolic risk factor profile associated with the use of atypical antipsychotics.

BACKGROUND: It is important to assess cardiovascular risk factors to properly verify the potential consequences of atypical antipsychotic-related weight gain. The objective of the present study was to evaluate whether 2 atypical antipsychotics differ regarding their impact on the cardiovascular disease risk profile compared with a reference group. METHOD: We conducted a cross-sectional, multicenter study to assess anthropometric indices of obesity and to obtain a comprehensive fasting metabolic risk profile. Either risperidone or olanzapine had to be prescribed as the first and only antipsychotic for a minimum of 6 months. Patients were compared with a reference group of nondiabetic men. Data were collected from August 1999 to August 2001. RESULTS: Eighty-seven patients treated with olanzapine (N = 42) or risperidone (N = 45) were evaluated. Olanzapine-treated patients had significantly higher plasma triglyceride concentrations (2.01 +/-1.05 vs. 1.34 +/-0.65 mmol/L, p < or =.05), lower high-density lipoprotein (HDL)-cholesterol levels (0.92 +/-0.17 vs. 1.04 +/- 0.21 mmol/L, p < or =.05), higher cholesterol/HDL-cholesterol ratios (5.62 +/-1.70 vs. 4.50 +/- 1.44, p < or =.05), higher apolipoprotein B levels (1.07 +/- 0.35 vs. 0.92 +/- 0.27 g/L, p < or =.05), smaller low-density lipoprotein peak particle diameters (252.6 +/-4.1 vs. 255.2 +/-4.3 A, p <.01), and higher fasting insulin concentrations (103.9 +/- 67.6 vs. 87.5 +/- 56.1 pmol/L, p < or =.05) than risperidone-treated patients. Moreover, 33% of olanzapine-treated patients were carriers of 3 atherogenic features of the metabolic syndrome as opposed to a prevalence of only 11% of risperidone-treated patients. CONCLUSION: These results suggest that olanzapine-treated patients are characterized by a more deteriorated metabolic risk factor profile compared with risperidone-treated patients. These observations raise concerns about the potential differential long-term deleterious effects of some antipsychotics, such as olanzapine, on cardiovascular health.