Characterization of antipsychotic utilization before clozapine initiation for individuals with schizophrenia: an innovative visualization of trajectories using French National Health Insurance data.

AIMS: Despite recommendations to initiate clozapine after two unsuccessful trials of antipsychotics, clozapine is underprescribed and initiated too late. The aim of this study was to describe different antipsychotic treatment sequences in the 36 months before the initiation of clozapine and to characterize clusters of treatment trajectories. METHODS: Using the French National Health Insurance database, a historical cohort study of the population in an area in western France was performed. The data from all new users of clozapine with a diagnosis of schizophrenia or schizoaffective disorder in the period of 2017-2018 were evaluated. All outpatient reimbursements for antipsychotics during the 36 months before clozapine initiation were analysed. Successive reimbursements for identical treatments were grouped into treatment trials (TTs), and different trajectories were clustered using a state sequence analysis. RESULTS: The results showed 1191 TTs for 287 individuals. The mean number of TTs per individual was 3.2. Risperidone, aripiprazole and haloperidol were the main treatments delivered. The frequencies of antipsychotics used differed between monotherapies and combination therapies. A three-cluster typology was identified: one cluster (n = 133) of 'less treated' younger individuals with fewer TTs and shorter TT durations; a second cluster (n = 53) of 'more treated' individuals with higher numbers of TTs and combinations of antipsychotics; and a third cluster (n = 103) of 'treatment-stable' older individuals with longer TT durations. CONCLUSIONS: The results indicate that the median number of TTs during the 36 months before clozapine prescription was higher than the two recommended. The different trajectories were associated with individual characteristics and treatment differences, suggesting that additional studies of clinical parameters are needed to understand barriers to clozapine prescription.

Reviewing the Potential Therapeutic Approaches Targeting the Modulation of Gastrointestinal Microflora in Schizophrenia.

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms.

Remission of schizophrenia after an EMDR session.

We present a case study of the remission of a chemically resistant schizophrenia disorder after a single session of EMDR. Our patient had been followed-up for schizophrenia according to DSM5 criteria, since 4 years. During our subject's fourth hospitalization for major delirious decompensation, a single EMDR session, according to the standard protocol, resulted in a complete and total remission of the delirious disorder and the disorganization/dissociative syndrome in 8 weeks. This allowed us to interrupt the patient's antipsychotic treatment without relapse at 18 months. This case study allows us to highlight, as many authors have previously done, the necessity of researching the traumatic history of patients diagnosed with schizophrenia in order to provide therapies focused on traumatic dissociation. It also questions the relevance of our diagnostic criteria for schizophrenia and other dissociative disorders.

Presentamos un estudio de caso sobre la remisión de una esquizofrenia químicamente resistente tras una sola sesión de EMDR. Nuestro paciente había sido seguido por esquizofrenia según los criterios del DSM 5, desde hace 4 años. Durante la cuarta hospitalización de nuestro sujeto, por descompensación delirante mayor, una única sesión de EMDR según el protocolo estándar, dio lugar a una remisión completa y total del trastorno delirante y del síndrome de desorganización/disociativo en 8 semanas. Esto nos permitió interrumpir el tratamiento antipsicótico de la paciente sin recaídas a los 18 meses. Este estudio de caso nos permite destacar, como muchos autores han hecho anteriormente, la necesidad de investigar la historia traumática de los pacientes diagnosticados de esquizofrenia para ofrecer terapias centradas en la disociación traumática. También cuestiona la pertinencia de nuestros criterios diagnósticos para la esquizofrenia y otros trastornos disociativos.

Causes of death in clozapine-treated patients in a catchment area: a 10-year retrospective case-control study.

Uncertainty regarding the excess of mortality in patients treated with clozapine persists. A decrease in all-cause mortality, and perhaps also in suicide, after clozapine initiation has been reported, but there are no studies in which preventable causes were ascertained in those taking medication in the long term. Here, we aimed to assess a decade of causes of deaths in a catchment area in patients with schizophrenia chronically treated with clozapine and compared them to a clozapine-treated control cohort. Causes of deaths were classified as suicide, expected (e.g. cancer), and unexpected deaths (encompassing causes of death potentially due to clozapine side effects, and unexplained sudden death). We used descriptive statistics for comparing socio-demographic and clinical factors between the three groups. Logistic regression models were used to examine risk factors associated with unexpected death compared to the control group. We found that the overall mortality was similar to that in previous studies (at 0.8% yearly on average) with unexpected deaths accounting for 52% of total deaths. The unexpected deaths group was on average treated with higher clozapine doses (mean 460 mg/day). A small but significant peak of unexpected deaths was found during the 2018 summer heat wave, which might have exacerbated dose-dependent side effects of clozapine. We suggest increased monitoring for those on higher doses of clozapine as one potential intervention to decrease mortality in this population.

[Development and implementation of clozapine protocol in patients with schizophrenia in Greece].

Clozapine is an atypical antipsychotic used for the treatment of resistant schizophrenia, exhibiting significant advantages over other antipsychotic agents. Clozapine efficacy is well established in people diagnosed with schizophrenia via reducing both positive and negative symptoms. Also, is associated with a low risk of extrapyramidal side effects compared to other antipsychotics. Despite the above, clozapine is an unpopular therapeutic option for patients not previously responded to other antipsychotics, because of adverse side effects, such as hyper-salivation and weight gain or critical side effects, i.e., risk for developing neutropenia and agranulocytosis and the need for a systematic and vigilant patients' monitoring, causing discomfort to them and increased expenses to the healthcare system. The aim of the present article is to describe (a) the development of a "clozapine treatment monitoring protocol", and (b) the monitoring process applied at the Department of Psychiatry of Aghioi Anargyroi Cancer Hospital in patients under clozapine treatment. For the protocol development a systematic review of the existing literature was conducted. An advanced search in Medline, CINAHL, Scopus and Google Scholar was conducted, as well as at the National Organization of Greece for Medicines database, with the following key- words: "clozapine", "clozapine protocol", "clozapine monitoring", "clozapine guidelines". Based on this procedure, the Victorian Consensus View protocol applied in Australia was evaluated as the most appropriate since it encompasses: (a) monitoring of multiple systems based on a holistic healthcare approach towards patients, and (b) Intense cardiovascular functioning monitoring, highly relevant to the Greek population due to increased incidence of myocarditis. Overall, the necessary interventions prior and after clozapine treatment initiation are, monitoring of heamatological and cardiovascular function and related side effects, metabolic monitoring and related side effects, monitoring of metabolic adverse effects, gastrointestinal and neurological adverse effects, hepatic function monitoring and related side effects. Clozapine treatment monitoring protocol applied at special settings, e.g., Clozapine Clinics, is highly beneficial, since the risk of neutropenia, agronulocytosis is minimized, while suicidal behavior and substance use are reduced along with risky health behaviors, i.e., nicotine use and sedentary lifestyle. The current protocol may be applied by mental healthcare professionals aiming to empower individuals with schizophrenia through promoting their independency and quality of life.

Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism.

OBJECTIVE: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. METHODS: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. RESULTS: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. CONCLUSIONS: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

Treatment Strategies for Clozapine-Induced Sialorrhea: A Systematic Review and Meta-analysis.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia. However, it has a high burden of adverse events, including common adverse events such as sialorrhea. Sialorrhea can lead to severe physical complications such as aspiration pneumonia, as well as psychological complications including embarrassment and low self-esteem. Compromised adherence and treatment discontinuation can occur due to intolerability. There have been no meta-analyses examining strategies to mitigate clozapine-induced sialorrhea. METHODS: We systematically searched Chinese and Western research databases for randomised controlled trials examining agents for clozapine-induced sialorrhea. No limit to language or date were applied to the search. Where sufficient data for individual agents was available, pairwise meta-analyses were conducted. Results were provided as risk ratios and number needed to treat. Sensitivity analysis was conducted by study quality. Adverse events were provided as number needed to harm. RESULTS: 19 studies provided data for use in the meta-analysis. Improvement in clozapine-induced sialorrhea was seen in meta-analyses of propantheline (studies = 6, risk ratio [RR] 2.38, 95% confidence interval [CI] 1.52-3.73; number needed to treat [NNT] 3, 95% CI 1.9-2.7), diphenhydramine (studies = 5, RR 3.09, 95% CI 2.36-4.03; NNT 2, 95% CI 1.5-2.0), chlorpheniramine (studies = 2, RR 2.37, 95% CI 1.59-3.55; NNT 3, 95% CI 1.6-3.5), and benzamide derivatives (odds ratio [OR] 6.93, 95% CI 3.03-15.86). When meta-analyses were limited to high-quality studies, all these results remained significant. Single studies of benzhexol, cyproheptadine, doxepin and Kongyan Tang showed promise. Propantheline increased rates of constipation with a number needed to harm (NNH) of 9 (95% CI 4.2-204.1). CONCLUSION: Clozapine-induced sialorrhea is a potentially serious adverse event. Included studies in this meta-analysis were limited by poor study quality. Diphenhydramine, chlorpheniramine and benzamide derivatives appear to have the best supporting evidence and lowest reported adverse events. Caution should be exercised when using propantheline given its increased risk of constipation.

A case report of the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion.

BACKGROUND: Cardiometabolic health significantly impacts on the mortality of people with severe mental illness. Clozapine has the greatest efficacy for Treatment Resistant Schizophrenia (TRS) but the greatest negative impact on cardiometabolic health. Balancing the risks and benefits of treatment, dignity, autonomy, liberty, mental and physical health can be challenging, particularly when imposing interventions with potentially life threatening adverse events, such as clozapine. We describe the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion for a gentleman with TRS in high secure psychiatric services. CASE PRESENTATION: The impact of clozapine on a 44-year-old gentleman with TRS, extreme violence requiring physical restraint and long-term segregation, and numerous other significant physical health complications is described. He had metabolic syndrome; a poor diet, sedentary lifestyle, Body Mass Index (BMI) of 31.5, poorly controlled lipids and had smoked heavily since childhood. During preparations to initiate clozapine, he suffered a myocardial infarction and pulmonary embolism. His compliance with secondary prevention medications was poor due to paranoid persecutory and somatic delusions. Despite these concerns, nasogastric administration of clozapine was approved and prescribed within nine months of his myocardial infarction and a month from his pulmonary embolism but was ultimately not required. Accepting oral medication, his mental state made a rapid and dramatic improvement. After spending 1046 days in seclusion, this was terminated 94 days after clozapine initiation. He has been compliant with all medications for 24 months, had no incidents of violence or seclusion, and has been transferred to medium secure services. His physical health stabilised despite continuing to lead a sedentary lifestyle and remaining obese (BMI of 35). He developed hypertension, Type II Diabetes Mellitus and his triglycerides rose to 22.2 mmol/L in the same month after clozapine initiation. However, with pharmacological intervention, 24 months later these are controlled, and he has had no further thromboembolic events. CONCLUSIONS: We highlight that despite significant physical health concerns, clozapine can be successfully initiated and safely prescribed with a significantly positive effect on both the psychiatric and holistic care of patients with treatment resistant schizophrenia.

Community pharmacists' attitudes and opinions towards supplying clozapine.

Background Clozapine is very effective for treatment-resistant schizophrenia, but its use has been limited due to the risk of agranulocytosis. From July 2015, clozapine has been accessible from Australian community pharmacies following regulatory changes, but pharmacists' attitudes towards these changes remain unknown. Objective To explore pharmacists' perspectives and experiences in supplying clozapine. Setting Australian community pharmacists. Methods A cross-sectional study with a mixed methods approach involving two phases. An online survey containing Likert-type and open-response questions was distributed to community pharmacists (n = 134) via ClopineCentral™ (clozapine monitoring system). Participants were then invited to participate in semi-structured telephone interviews (n = 12) regarding clozapine supply. Quantitative data were statistically analysed, while qualitative responses were thematically content-analysed. Main outcome measures Pharmacists' responses to surveys and interviews. Results Community pharmacists were supportive towards supplying clozapine as it increased access for consumers. Better patient-pharmacist relationships and holistic care approach were identified to benefit both consumers and pharmacists. Pharmacists reported to be confident (89.6%), have adequate support (73.1%), knowledge (86.6%) and skills (93.3%) in dispensing clozapine. Training and support received facilitated pharmacists' roles, whereas administrative issues, especially in obtaining valid haematology results, posed challenges. Educational and technical improvements were suggested to improve service provision. Conclusion Community pharmacists welcomed the regulatory changes positively and were confident in supporting consumers taking clozapine. Despite challenges present, benefits and facilitators identified supported the feasibility of this service in community pharmacies. Future research should explore other aspects of clozapine supply, such as attitudes of other stakeholders, to improve current supply systems.

The 5α-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia.

Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5α-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved.

Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse.

BACKGROUND: Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI. OBJECTIVES: To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse. SEARCH METHODS: On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers). SELECTION CRITERIA: We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data. DATA COLLECTION AND ANALYSIS: We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 294, RR 0.96, 95% CI 0.86 to 1.07, low-quality evidence).For risperidone versus ziprasidone, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 240, RR 0.96, 95% CI 0.85 to 1.10, low-quality evidence).For many comparisons, important outcomes were missing; and no data were reported in any study for metabolic disturbances, global impression of illness severity, quality of life or mortality. AUTHORS' CONCLUSIONS: There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.

Assessment of the efficacy of omega-3 fatty acids on metabolic and inflammatory parameters in patients with schizophrenia taking clozapine and sodium valproate.

Omega-3 fatty acid (FA) supplementation has been reported to improve several cardio-metabolic risk factors. We aimed to assess the efficacy of omega-3 fatty acids on metabolic and inflammatory indices in patients with schizophrenia who were taking clozapine and sodium valproate. All patients were on a stable dose of 300-400mg of clozapine for 3 months. Subjects were randomized to treatment with either omega-3 fatty acid (4gr/day) or a placebo for 8 weeks. Height, weight, abdominal circumference, serum lipid profile, fasting blood glucose (FBG), and serum high sensitivity-C-reactive protein (hs-CRP) were determined at baseline and after 8 weeks of treatment. Fifty six subjects were recruited into the study. Patients with schizophrenia who were in the group receiving omega-3 FA capsules had an improvement in some anthropometric indices including weight, BMI, wrist and waist circumference, compared to the placebo group. Only changes in waist circumferences remained significantly different after adjustment for serum fasted TG. Our results showed omega-3 FA supplementation can improve some anthropometric indices in patients with schizophrenia who are taking clozapine pharmacotherapy.

Clozapine use in patients with schizophrenia and a comorbid substance use disorder: A systematic review.

Lifetime prevalence of substance use disorders (SUD) in patients with schizophrenia is nearly 50%. Nicotine, alcohol, and cannabis are the substances most frequently used, with a high percentage of poly-substance users. There are few available data about pharmacological approaches in this population. Amongst antipsychotics, clozapine shows positive evidence in the literature. The aim of the present article is to provide systematic review on the efficacy of clozapine in SUD improvement in schizophrenic patients. PRISMA recommendations were followed (PROSPERO id: CRD42017059299). Five studies for nicotine use and nine studies for SUD (other than nicotine) were analyzed. Regarding nicotine use, results from randomized controlled trials (RCT) have found a decrease in nicotine use after 12 weeks of 200-600mg/day clozapine, as compared with lower doses. In SUD improvement (other than nicotine), RCT have shown superiority of clozapine when compared with risperidone, in short-term studies (from 4 to 12 weeks) performed in cannabis users. In long-term studies (1 year), clozapine was equal to ziprasidone in reducing cannabis use and equal to treatment as usual in reducing alcohol use. We conclude that positive results on nicotine use are scarce and derived from studies with a low degree of evidence. Evidence of clozapine on SUD (other than nicotine) is stronger, especially when clozapine is compared with first generation antipsychotics in poly-substance users. When compared with second generation antipsychotics, clozapine was superior to risperidone but equal to olanzapine or ziprasidone in poly-substance and cannabis users.

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.

Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis.

AIMS: Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables. METHODS: Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators. RESULTS: One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups. CONCLUSIONS: Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.

Guía práctica clínica para el tratamiento farmacológico y psicológico de los pacientes adultos con un trastorno mental grave y un trastorno por uso de sustancias / A clinical guideline for the pharmacological and psychological treatment of adult patients with a serious mental disorder and substance use disorder

Objetivos: El objetivo principal de esta Guía es recoger recomendaciones concretas basadas en los resultados de la literatura científica para tratar a pacientes con un trastorno mental grave y un consumo de sustancias atendidos en centros de tratamiento hospitalarios y ambulatorios. Incluye: 1) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno depresivo mayor y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 2) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con trastorno del espectro esquizofrénico y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 3) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno de ansiedad y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 4) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno bipolar y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 5) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno por déficit de atención e hiperactividad y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina).

Evaluation of the performance of a point-of-care method for total and differential white blood cell count in clozapine users.

INTRODUCTION: We evaluated the performance of the HemoCue WBC DIFF, a point-of-care device for total and differential white cell count, primarily to test its suitability for the mandatory white blood cell monitoring in clozapine use. METHOD: Leukocyte count and 5-part differentiation was performed by the point-of-care device and by routine laboratory method in venous EDTA-blood samples from 20 clozapine users, 20 neutropenic patients, and 20 healthy volunteers. From the volunteers, also a capillary sample was drawn. Intra-assay reproducibility and drop-to-drop variation were tested. RESULTS: The correlation between both methods in venous samples was r > 0.95 for leukocyte, neutrophil, and lymphocyte counts. The correlation between point-of-care (capillary sample) and routine (venous sample) methods for these cells was 0.772; 0.817 and 0.798, respectively. Only for leukocyte and neutrophil counts, the intra-assay reproducibility was sufficient. CONCLUSION: The point-of-care device can be used to screen for leukocyte and neutrophil counts. Because of the relatively high measurement uncertainty and poor correlation with venous samples, we recommend to repeat the measurement with a venous sample if cell counts are in the lower reference range. In case of clozapine therapy, neutropenia can probably be excluded if high neutrophil counts are found and patients can continue their therapy.

Optogenetic and chemogenetic strategies for sustained inhibition of pain.

Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.