Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Discontinuity of psychiatric care for patients with schizophrenia, relation to previous psychiatric care and practice variation between providers: a retrospective longitudinal cohort study.

BACKGROUND: Patients with schizophrenia need continuous integrated healthcare, but many discontinue their treatment, often experiencing adverse outcomes. The first objective of this study is to assess whether patient characteristics or treatment history are associated with discontinuity of psychiatric elective care. The second objective is to assess whether practice variation between providers of psychiatric care contributes to discontinuity of elective care. METHODS: A large registry-based retrospective cohort of 9194 schizophrenia patients, who were included if they received elective psychiatric care in December 2014-January 2015. Logistic regression models were used to identify predictive factors of discontinuity of care. The dependent variable was the binary variable discontinuity of care in 2016. Potential independent predictive variables were: age, sex, urbanization, and treatment history in 2013-2014. Practice variation between providers was assessed, adjusting for the case mix of patients regarding their demographic and care utilization characteristics. RESULTS: 12.9% of the patients showed discontinuity of elective psychiatric care in the follow-up year 2016. The risk of discontinuity of care in 2016 was higher in younger patients (between age 18 and 26), patients with a history of receiving less elective psychiatric care, more acute psychiatric care, more quarters with elective psychiatric care without antipsychotic medication, or receiving no elective treatment at all. No evidence for practice variation between providers was found. CONCLUSIONS: Our findings show that the pattern of previous care consumption is an important prognostic factor of future discontinuity of elective care. We propose that previous care consumption can be used to design strategies to improve treatment retention and focus resources on those most at risk of dropping out.

The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis.

BACKGROUND: NEURAPRO was a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) in 304 individuals at ultra-high risk for psychotic disorders. The study failed to show benefits of n-3 PUFAs over placebo. Although the randomized controlled trial design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil randomized controlled trials, as not only is the test agent present in the intervention group, but also n-3 fats are present in the diet and the body tissue of all participants. METHODS: Analysis of biomarker data (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], n-3 index, EPA+DHA) collected as part of NEURAPRO was conducted on 218 participants with longitudinal biomarker data to determine if n-3 PUFAs measured in erythrocytes at baseline and month 6 predicted clinical outcomes. RESULTS: Increases of the n-3 index, EPA, and DHA predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio [95% confidence interval (CI)] = 1.79 [1.30-2.48]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.43 [1.16-1.76]) and at month 12 (n-3 index baseline: adjusted odds ratio [95% CI] = 2.60 [1.71-3.97]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.36 [1.06-1.74]). CONCLUSIONS: These data suggest that n-3 PUFAs can exert therapeutic effects in ultra-high-risk individuals. This finding has implications for early intervention and treatment guidelines, as n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.

Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis.

Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.

Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial.

BACKGROUND: Neurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean = 3.4 years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. METHOD: Analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. RESULTS: Mean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z = -0.24 to -0.47), except for executive functioning (mean z = 0.16). After adjusting for covariates, poorer Executive (p = .010) and Motor (p = .030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12 months (p = .004), and social functioning at medium-term follow-up (p = .015), respectively. CONCLUSIONS: Neurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes.

Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study.

OBJECTIVE: Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. METHODS: A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ). RESULTS: At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images. CONCLUSION: These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission. TRIAL REGISTRATION: 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761.

Medicinal cannabis (Bedrolite) substitution therapy in inpatients with a psychotic disorder and a comorbid cannabis use disorder: A case series.

Cannabis use disorders are frequently comorbid in patients with a psychotic disorder and are associated with worse outcomes. To date there are no proven effective strategies to achieve cannabis abstinence in this population. An alternative for abstinence might be harm reduction, i.e. replacing the use of street cannabis with high tetrahydrocannabinol and low cannabidiol levels by medicinal cannabis variants with relatively low tetrahydrocannabinol and relatively high cannabidiol levels, thereby reducing the psychosis inducing effects of cannabis and enhancing the antipsychotic effects of cannabis. Here we present the data of a case series with seven inpatients diagnosed with a psychotic disorder and a treatment-resistant cannabis use disorder who received substitution therapy with a low tetrahydrocannabinol medicinal cannabis variant (Bedrolite). The results suggest that the low tetrahydrocannabinol medicinal cannabis variant Bedrolite is not effective in the treatment of inpatients with a psychotic disorder and comorbid cannabis use disorder. Bedrolite is thus not very likely to become an effective harm reduction strategy in these patients.

Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial.

IMPORTANCE: A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). OBJECTIVE: To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. DESIGN, SETTING, AND PARTICIPANTS: NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. INTERVENTIONS: A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. MAIN OUTCOMES AND MEASURES: The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. RESULTS: In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). CONCLUSIONS AND RELEVANCE: This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available. TRIAL REGISTRATION: anzctr.org.au Identifier: 12608000475347.

The effect of clozapine and risperidone on attentional bias in patients with schizophrenia and a cannabis use disorder: An fMRI study.

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis.

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [(123)I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [(123)I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Effects of cannabis use on event related potentials in subjects at ultra high risk for psychosis and healthy controls.

Cannabis use has consistently been associated with psychotic symptoms as well as cognitive impairments. Moreover, its use may provoke subclinical psychotic symptoms and is associated with neuropsychological dysfunctions in subjects at ultra high risk (UHR) for developing psychosis. However, to our knowledge, no data are yet available on the relationship between cannabis use, UHR symptoms and information processing as assessed with event related potentials (ERP) in UHR subjects. This cross-sectional study therefore aimed to investigate N100, N200, P200 and P300 ERP components in 48 UHR subjects (19 cannabis users; UHR+C) and 50 healthy controls (21 cannabis users; HC+C). Results showed smaller P300 amplitudes in HC+C and UHR subjects compared to HC-C. Moreover, HC+C showed prolonged P300 and N200 latencies compared to HC-C and UHR-C. No significant ERP differences were found between UHR+C and UHR-C. Regarding the relationship between information processing and psychopathology, we found associations between ERP components and severity of UHR symptoms, findings being most pronounced for N100 latencies and P300 amplitudes and severity of general psychopathology and positive symptoms. We conclude that UHR subjects and healthy cannabis users demonstrate similar P300 amplitude reductions compared to non-using control subjects. In addition, the interrelation of cannabis use with prolonged ERP latencies may signify reduced information processing speed associated with cannabis use. Finally, our findings cautiously support the hypothesis that the clinical phenomena of the UHR state may be associated with abnormalities in stimulus processing.

Feasibility of mindfulness-based therapy in patients recovering from a first psychotic episode: a pilot study.

AIM: Recently, a mindfulness therapy for people with psychotic disorders was developed. However, clinicians and researchers are cautious given case reports in which extensive meditation provoked psychotic symptoms in people with a psychotic disorder. The purpose of this study was to examine the feasibility, adverse effects and possible favourable effects of mindfulness-based therapy (MBT) in people recently recovering from a first episode of psychosis. METHOD: A nonrandomized, non-controlled prospective follow-up study. Patients were offered an MBT that consisted of eight 1-hour sessions within a 4-week time span. Positive and Negative Syndrome Scale, Symptoms Checklist 90 and the Southampton Mindfulness Questionnaire were assessed before and after the therapy. RESULTS: Of the 16 persons who started MBT, 13 completed (81.5%) the therapy. No significant increase in psychotic symptoms was found. Between two meetings, one participant initially misunderstood the mindfulness instructions, which led to an increase in distress. No increased awareness of intrusive thoughts or visual or auditory hallucinations was reported by participants. We found a decrease in agoraphobic symptoms (p < 0.028) and in psychoneuroticism (P < 0.025). CONCLUSION: The MBT had no significant adverse effect on psychotic symptoms in patients in this small pilot study, neither did it raise the level of mindfulness in the participants. A decrease in psychological symptoms was found, although one patient experienced an increase in symptoms of distress. Our study demonstrates that therapists should be cautious that therapy and practice instructions are understood properly. Future studies are feasible and needed, in larger samples with an RCT design, in order to draw conclusions regarding the effects of the MBT.

Polyunsaturated fatty acid concentration predicts myelin integrity in early-phase psychosis.

BACKGROUND: White matter (WM) abnormalities have been implicated in schizophrenia, yet the mechanisms underlying these abnormalities are not fully understood. Several lines of evidence suggest that polyunsaturated fatty acids (PUFAs) play a role in myelination, and there is substantial evidence documenting decreased PUFA concentrations in schizophrenia. We therefore hypothesized that lower membrane PUFA concentrations may be related to reduced WM integrity in schizophrenia and related disorders. METHODS: In 30 male patients with a recent-onset psychotic disorder, erythrocyte membrane PUFA concentrations were assessed and diffusion tensor imaging was performed with voxelwise analysis. RESULTS: Lower total PUFA concentration was associated with lower fractional anisotropy (FA) throughout the corpus callosum and bilateral parietal, occipital, temporal and frontal WM (P < .05, corrected). Of the individual PUFAs, lower arachidonic acid concentration, and to a lesser extent, lower nervonic acid, linoleic acid, and docosapentaenoic acid concentration were significantly associated with lower FA. PUFA concentrations were inversely associated with radial diffusivity but showed little association with axial diffusivity. Greater severity of negative symptoms was associated with lower nervonic acid concentration and lower FA values. CONCLUSIONS: Membrane PUFA concentrations appear to be robustly related to brain WM integrity in early phase psychosis. These findings may provide a basis for studies to investigate the effects of PUFA supplementation on WM integrity and associated symptomatology in early psychosis.

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val(158) Met polymorphism in adults with 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts SR.

Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine.

Substance abuse and psychotic disorders have a high rate of comorbidity. Both disorders are associated with changes in the dopaminergic transmission in the mesocorticolimbic pathways of the brain. Since antipsychotic medications interact with the dopamine receptors in these pathways, these medications could affect craving for substances. In the current study, the effect of clozapine (n = 27, mean dosage 350 mg), risperidone (n = 54, mean dosage 3.46 mg) and olanzapine (n = 60, mean dosage 13.78 mg) on subjective craving for cannabis was compared in 123 patients with cannabis dependence and psychotic disorder. Patients treated with risperidone reported significantly more craving compared with patients treated with clozapine (Z = -3.19, p = .001) or olanzapine (Z = -2.24, p = .025). No significant differences in craving between clozapine and olanzapine were found. These results are in concordance with findings in the literature on this subject and could be explained by differences in three dopamine mediated mechanisms of these compounds: 1) occupancy rate of dopamine D(2) receptors, 2) dissociation rate of dopamine D(2) receptors, 3) D(1)/D(2) occupancy ratio. Risperidone and clozapine show a maximal difference in D(2) receptor occupancy rate, dissociation rate and D(1)/D(2) ratio. Olanzapine is intermediate between risperidone and clozapine in these characteristics.

Effect of olanzapine and risperidone on subjective well-being and craving for cannabis in patients with schizophrenia or related disorders: a double-blind randomized controlled trial.

OBJECTIVE: To examine whether subjective well-being and craving for cannabis were different in patients with schizophrenia or related disorders treated with either olanzapine or risperidone. METHOD: A 6-week, double-blind, randomized trial of olanzapine and risperidone was carried out in 128 young adults with recent onset schizophrenia or related disorders. Primary efficacy measures were the mean baseline-to-endpoint change in total scores on the Subjective Well-Being under Neuroleptics scale, the Obsessive-Compulsive Drug Use Scale, the Drug Desire Questionnaire, and the cannabis use self-report. An analysis of covariance was used to test between-group differences. RESULTS: Estimated D(2) receptor occupancy did not differ between olanzapine (n = 63) and risperidone (n = 65). Similar improvements in subjective well-being were found in both groups. In the comorbid cannabis-using group (n = 41, 32%), a similar decrease in craving for cannabis was found in both treatment conditions. CONCLUSIONS: Both olanzapine and risperidone were associated with improved subjective well-being. No evidence was found for a differential effect of olanzapine or risperidone on subjective experience or on craving for cannabis in dosages leading to comparable dopamine D(2) occupancy. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN46365995.