Martin Strassnig

Risperidone plasma levels, clinical response and side–effects

AbstractIntroduction Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter–individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side–effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters.MethodsNeuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6–week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9–OH–risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped.ResultsEighty–two patients were recruited. Mean oral dose of risperidone was 4.3 ± 0.9mg. Mean plasma level of both risperidone and 9–OH–risperidone together (“active moiety”) was 41.6 ± 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9–OH–risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS–Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 ± 30.7 ng/ml) than responders (38.2 ± 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (≥ 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9–OH–risperidone ratio (0.5 ± 0.6 vs. 1.9 ± 1.8; p = 0.120).DiscussionThe major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9–OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9–OH–risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter–individual variability in risperidone and 9–OH–risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety.

Body mass index and quality of life in community-dwelling patients with schizophrenia

OBJECTIVE To examine the associations between sociodemographic variables, body weight and quality of life in schizophrenic outpatients. METHODS Assessments included an interview to obtain sociodemographic data, administration of a Quality of Life questionnaire (the MOS SF-36) and measurement of height and weight. Body mass index was calculated (kg/m(2)). SF-36 subscores were examined for statistical differences based on BMI categories: healthy weight (BMI<or=24.9), overweight (BMI 25-29.9) and obese (BMI>or=30). Correlations with sociodemographic variables were also examined. RESULTS Body weight was inversely correlated (level p<or=0.005) to the SF-36 items: physical functioning (PF, -0.452), role limitations due to physical functioning (-0.279), role limitations due to emotional functioning (-0.256), vitality (-0.200), general health (GH, -0.367) and physical component score (PCS, -0.400). Mental component score (MCS) was not significantly correlated to body weight. When comparing quality of life across BMI categories, obese subjects had worse physical functioning (p<or=0.0005) and general health (p<or=0.005), reported more role limitations due to emotional functioning (p<or=0.05) and a lower physical component score (p<or=0.005). Mental component score was not significantly influenced by BMI. CONCLUSIONS Quality of life in schizophrenic patients is related to body weight. The burden of obesity is primarily experienced as a physical problem.

Weight gain in newly diagnosed first-episode psychosis patients and healthy comparisons: One-year analysis

BACKGROUND Various antipsychotics are associated with body weight gain. However, most study samples include high proportions of patients with chronic schizophrenia. We examined neuroleptic-induced weight gain in drug-naïve first-episode psychotic patients to limit confounding variables such as multiple past medication trials, history of partial adherence; or poor diet and a sedentary lifestyle, associated with chronic mental illness. METHODS Newly diagnosed first-episode psychosis patients treated with antipsychotic medication, a small group of patients not receiving antipsychotics, and healthy comparisons were followed for one year. Body weight differences and proportions of subjects with more than 7% weight gain were calculated. The effects of concomitant psychotropic medication on weight gain were explored. RESULTS Ninety-eight first-episode psychotics patient and 30 healthy controls were examined. Patients receiving neuroleptics gained significantly more weight than healthy controls (p=0.002). Olanzapine (91% gained >7%) increased body weight by 37.3+/-27.7 lb, followed by risperidone (51%; +16.6+/-22) and haloperidol (47%; +9+/-12), and perphenazine (10%; +3.4+/-6). Younger patients (r=-0.24, p=0.02) and patients with more negative symptoms at baseline (SANS global; r=0.22, p=0.04) gained more weight. A greater number of co-medications per patient, and co-prescription of antidepressants significantly and independently increased antipsychotic-associated weight gain. DISCUSSION The results confirm substantial and clinically significant weight gain introduced by antipsychotic treatment in drug-naïve first-episode psychotic patients, and identify several treatment-associated risk factors for weight gain. The magnitude of weight gain induced highlights potential health risks and points to the need for preventive measures such as behavioral weight control programs along with the initiation of pharmacotherapy.

Increased caffeine and nicotine consumption in community-dwelling patients with schizophrenia

INTRODUCTION It is known that people with schizophrenia make poor dietary choices and smoke at alarmingly high rates. There is also anecdotal evidence that they may ingest large amounts of caffeine. However, while smoking habits in this population have been examined, no recent study has quantified caffeine consumption taking into account various dietary caffeine sources unrelated to coffee including convenience foods such as candy bars, chocolate or soft drinks, and compared results to US population data. METHODS We employed 24-h diet recalls to assess dietary habits in a sample of outpatients suffering from schizophrenia or schizoaffective disorder. Caloric intake and caffeine consumption were quantified and the relationship to various sociodemographic variables including body mass index (BMI) and dietary quality was examined. RESULTS 146 patients were recruited. Mean BMI in the sample was 32.7+/-7.9. Patients ingested 3,057+/-1,132 cal on average. Patients smoked at higher rates (59.6% vs. 23.4%, p< or =0.001), higher numbers of cigarettes/day (24+/-14.4 vs. 13.5+/-11.3, t=8.549, p<0.001) and ingested more caffeine (471.6+/-584.6 mg vs. 254.2+/-384.9 mg, t=6.664, p<0.001) than US population comparisons. Caffeine consumption was correlated to the number of cigarettes smoked daily (r=0.299, p< or =0.001), but not to BMI (r=0.134, p=0.107) or dietary parameters such as caloric intake (r=0.105, p=0.207). CONCLUSION Community-dwelling schizophrenia patients consume significantly more caffeine and nicotine than US population comparisons. Clinicians should be aware that while a significant proportion of patients are overweight and have poor dietary quality - which merits lifestyle counseling on its own - there is a lack of correlation between those factors and smoking and caffeine intake. Thus, lifestyle modification counseling in all patients should address smoking and caffeine intake concurrently.

Self-reported body weight perception and dieting practices in community-dwelling patients with schizophrenia

INTRODUCTION Many patients with schizophrenia are exposed to serious health risks associated with their excess body weight. Evidence exists that even a moderate amount of weight loss may have significant health benefits. Thus, weight control in schizophrenia patients has become an important treatment goal. Although studies in the general population show that satisfaction with body weight is an important predictor for engagement in various weight loss measures, the perspective of schizophrenia patients has not been assessed. METHOD Information on self-reported weight perception, desire to lose weight as well as weight loss attempts was obtained according to methods employed in the National Health and Nutrition Examination Survey, Cycle III (NHANES III). Body weight and height were measured and body mass index (BMI) was calculated. RESULTS Perception of body weight and desire to lose weight were correlated to BMI. Both obese female and male subjects (BMI30) were aware of their weight status. However, whereas overweight females (BMI>25< or =29.9) accurately perceived themselves so, males in this category had difficulties perceiving themselves overweight, and consequently neither wanted to lose weight, nor tried to lose weight. As means of weight loss, caloric restriction (diet) was most frequently employed (by more than 80% of study subjects); yet only a third of study subjects (34.4%) engaged in the recommended combination of diet and exercise to lose weight. Questionable weight loss practices were also frequently employed, especially among women. CONCLUSIONS Obese patients (BMI> or =30) were generally aware of their excess body weight and wanted to lose weight. Only non-obese, yet overweight males (BMI>25< or =29.9) did not perceive themselves as overweight and consequently did not try to lose weight. Weight loss practices did not always follow established recommendations. Especially women were likely to approach weight loss with questionably appropriate and unsafe methods.

COX-2 inhibitors as adjunctive therapy in schizophrenia: rationale for use and evidence to date.

A better understanding of the human immune system and its complex interactions has resulted in new insights into the pathoaetiological mechanisms of psychiatric disorders. As a result, new treatment options are being explored. Several findings suggest that an imbalanced immune response is involved in the pathophysiology of schizophrenia. COX-2 inhibitors are known to influence the immune system in a way that may redirect this imbalance. Based on these suggestions, the COX-2 inhibitor celecoxib has been tested as a possible adjunctive therapeutic approach in the treatment of schizophrenia. While the first trial using celecoxib as add-on therapy to an atypical antipsychotic showed a significant beneficial effect, recent studies demonstrated that this effect may be limited to patients with recent-onset schizophrenia.

Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms

Atypical antipsychotics are generally thought to be more effective than conventional agents in treating the negative symptoms of schizophrenia; however, there have been few direct comparisons among atypicals. We therefore investigated risperidone and quetiapine with respect to their efficacy against negative symptoms in a 12–week,double–blind, comparative pilot study involving 44 patients with schizophrenia with predominantly negative symptoms, as defined by Positive and Negative Syndrome Scale (PANSS) scores. Other efficacy measures included the Scale for the Assessment of Negative Symptoms (SANS) and the Clinical Global Impression (CGI) rating scale. Antipsychotic tolerability was assessed using the Simpson–Angus Scale (SAS) and various laboratory measures. Mean doses were 589.7 mg/ day quetiapine and 4.9 mg/day risperidone (observed cases). Both antipsychotics produced significant decreases in PANSS total, positive and negative scores, and SANS scores. Patients receiving risperidone were significantly more likely to experience extrapyramidal symptoms (EPS) [p <0.05], or to require anticholinergic medication (p <0.05), and had significantly higher prolactin levels (p <0.001) than quetiapine–treated patients. In conclusion, there is no significant difference in efficacy between quetiapine and risperidone in alleviating the negative symptoms of schizophrenia. Quetiapine is also well tolerated, with a lower incidence of EPS and prolactin increase than risperidone.

How representative of everyday clinical populations are schizophrenia patients enrolled in clinical trials

AbstractIntroductionThere has been considerable discussion whether clinical trials accurately depict everyday practice. Restrictive inclusion/exclusion criteria, ethical considerations, differences in the severity of psychopathology between clinical and trial patients, or safety issues may bias results, which in turn may rather represent outcome for the “ideal” than for the “average” patient. Therefore, translation into psychiatric practice may be difficult.MethodsA retrospective case–control study was performed. Schizophrenia inpatients at the LMU Department of Psychiatry, Munich, Germany, who had participated in clinical trials were compared to regular patients serving as controls. Probands and controls were matched by DSM–IV diagnosis, gender and age. The AMDP module, CGI and GAF were used to compare psychopathology. In addition, charts were reviewed for medication dosages, concurrent medical and neurological illness, and clinical history such as age of onset or family history.ResultsA total of 200 probands (100/100) were enrolled in the study. With respect to psychopathology, formally thought disordered or suicidal patients were significantly less likely to be study participants (n = 3) than controls (n = 22; p ≤ 0.05). Similarly, negative schizophrenia symptoms were significantly less often present in study participants (n = 17) than in controls (n = 38; p ≤ 0.05). Study participants were also medically and neurologically healthier than controls. (p = 0.05 respectively). No differences in overall illness severity as depicted by CGI and GAF were observed.ConclusionWe found the patients included in our clinical trials representative of the patient encountered in routine clinical practice. Adherence to inclusion and exclusion criteria prevents inclusion of severely ill (e. g. suicidal) patients requiring a more intensive treatment setting. Illness severity was found to be similar in trial participants and controls, and indicates an overall comparably severe psychopathology. The more chronic, rather treatment refractory patients were also not reflected in the trial participant pool; this population may arguably not represent the average clinical patient either. A more careful administration of antipsychotic medication was found in trial participants and may effectively be considered “good clinical practice”.

Dietary fatty acid and antioxidant intake in community-dwelling patients suffering from schizophrenia

INTRODUCTION Brain phospholipids are uniquely rich in polyunsaturated fatty acids (PUFAs). Most PUFAs such as alpha-linolenic acid 18:3(n-3), eicosapentaenoic acid 20:5(n-3), and docosahexaenoic acid 22:6(n-3) are essential and must be provided through the diet. PUFAs are also very sensitive to oxidative stress. Decreased essential fatty acid content has been observed in cell membranes of various tissue types of schizophrenia patients, including neural cell membranes. A number of mechanisms may account for these deficits, such as inadequate dietary supply or increased oxidation. It is known that patients with schizophrenia make poor dietary choices. However, whether their dietary fatty acid or antioxidant intake is insufficient and contributes to the observed deficiencies has not been assessed. METHODS After obtaining informed consent, a 24-h diet recall was administered to elicit nutritional information in 146 outpatients with schizophrenia. Intake of fatty acids and antioxidants including vitamins A, C, and E was compared to U.S. population standards according to the National Health and Nutrition Examination Survey Cycle III (NHANES III) results. RESULTS Saturated and polyunsaturated fatty acid (PUFA) intake was significantly higher in schizophrenia patients than in controls (p<or=0.05; p<or=0.005, respectively). No differences were found with regard to dietary intake of gamma-linolenic acid (18:3n-3), eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3). Similarly, antioxidant intake was not different between schizophrenia patients and controls. CONCLUSION The observed cell membrane deficits in PUFA and essential fatty acid content do not appear to derive from decreased dietary supply. Rather, intrinsic membrane phospholipid metabolism abnormalities may be causative. Overall increased fat intake in schizophrenia patients may contribute to the development of serious medical comorbidities, and further advance the risk for cumbersome metabolic side effects of antipsychotic treatment such as new-onset diabetes mellitus.

COX-2 inhibitors as adjunctive therapy in schizophrenia

Cyclooxygenase-2 (COX-2) is constitutively expressed in the central nervous system, and is thought to have an important functional role therein. COX-2 interacts with neurotransmitters such as acetylcholine, 5-hydroxytryptamine and glutamate but is also involved in the regulation of the central nervous system immune system and in inflammation via the effects of prostaglandins, in particular prostaglandin E2. A general therapeutic effect of the COX-2 inhibitor celecoxib on symptoms of schizophrenia was observed during a prospective, randomised, double-blind study of celecoxib add-on treatment to the atypical antipsychotic risperidone. The results from this trial of adjunctive therapy with a COX-2 inhibitor in schizophrenia are encouraging, and the findings support the view that an immunological/inflammatory process is involved in the pathogenesis of the disease. The add-on to an antipsychotic design of the study was chosen due to ethical reasons; in less acute schizophrenic states a monotherapy with COX-2 inhibitors would be interesting. From a theoretical point of view, other psychiatric indications for selective COX-2 inhibitors are discussed. COX-2 inhibitors have failed to show therapeutic effects in Alzheimer’s disease but studies from basic research and a clinical perspective suggest it has an effect on disturbed cognition. In depression, however, signs of inflammation have been described for many years. Although results of clinical studies with COX-2 inhibitors in depression are still lacking, clinical improvement of a depressive syndrome has been observed in patients who have been treated with the COX-2 inhibitor rofecoxib due to other indications. These preliminary clinical data are encouraging for clinical therapeutic effects of the selective COX-2 inhibitors in psychiatric disorders, although these effects have to be confirmed in larger clinical studies.