Effect of Novel Antipsychotics on Energy Metabolism - In Vitro Study in Pig Brain Mitochondria.

The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.

Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs.

OBJECTIVE: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system. METHODS: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group. RESULTS: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine. CONCLUSIONS: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

Effectiveness and Predictors of Discontinuation of Aripiprazole Long-acting Injection: A 12-Month Naturalistic Cohort Study.

PURPOSE/BACKGROUND: This study aimed to explore the discontinuation rate of aripiprazole long-acting injection (LAI) in a naturalistic clinical setting. METHODS/PROCEDURES: A retrospective cohort study of 1 year duration was conducted on the first 200 patients registered to receive aripiprazole LAI in Sussex, UK. Rate of discontinuation and the association of robustly recorded clinical variables with discontinuation or a new acute care episode were explored. FINDINGS/RESULTS: Of 200 registered, 173 patients initiated aripiprazole LAI and 40% discontinued this by 1 year. Mean discontinuation time was 18 weeks. The commonest discontinuation reason was "patient choice," independent of efficacy or adverse effects. Not having a diagnosis of schizophrenia spectrum was the only variable significantly associated with treatment continuation after 1 year. No single diagnostic group accounted for this, although a greater continuation rate was observed in those with bipolar disorder. Illness severity factors at baseline, including apparent treatment resistance, had no impact on later aripiprazole LAI discontinuation or on acute service use over the year. Medication-related variables had no identified impact on acute service use. IMPLICATIONS/CONCLUSIONS: This study supports the clinical utility of aripiprazole LAI for its licensed indications. The 1-year discontinuation rate is equivalent to that in reports of similarly designed studies of paliperidone LAI. Further exploration of nonmedication factors influencing LAI discontinuation is required. Preferential use of aripiprazole LAI over other medications may be supported due to fewer associated metabolic adverse effects.

Antipsychotic Polypharmacy Is Associated With Adverse Drug Events in Psychiatric Inpatients: The Japan Adverse Drug Events Study.

BACKGROUND: Antipsychotic (AP) polypharmacy (APP), the coprescription of more than 1 AP, is frequently practiced in psychiatric inpatients and is considered to be a risk factor for adverse drug events (ADEs). However, the association between APP and ADEs among psychiatric inpatients has not been well investigated. METHODS: The Japan Adverse Drug Events (JADE) study was a series of cohort studies conducted in several clinical settings. In particular, the JADE study for psychiatric inpatients was a retrospective cohort study of 448 psychiatric inpatients with a cumulative 22,733 patient-days. We investigated the relationship between APP, defined as a concurrent prescription of 2 or more APs and ADEs. We also assessed the relationship between potential risk factors for ADEs due to APs. RESULTS: Among the 448 patients included in this study, 106 patients (24%) had APP and the remaining 342 patients were prescribed 1 AP or none. Risperidone was the most frequent drug (25%, 109/442 AP prescriptions) used, and levomepromazine was most frequently prescribed as a concurrent medication with other APs (91%, 29/32). The median number of ADEs among the patients with APP was significantly higher than in those without APP (P = 0.001). Antipsychotic polypharmacy was a risk factor for the occurrence of first (adjusted hazard ratio, 1.54; 95% confidence interval, 1.15-2.04) and second (adjusted hazard ratio, 1.99; 95% confidence interval, 1.40-2.79) ADEs. CONCLUSIONS: Antipsychotic polypharmacy was a risk factor for the occurrence of single and multiple ADEs. Antipsychotic polypharmacy should be conservatively and minimally practiced.

Viewpoint: do antipsychotics protect against early death? A critical view.

In the past 15 years, researchers utilizing prescription databases to assess medication usage have concluded that antipsychotics reduce mortality in patients diagnosed with schizophrenia and other psychotic disorders. These findings stand in contrast to studies in non-psychiatric patients that have found that antipsychotics, because of their adverse effects on physical health, increase the risk of early death. A critical review of the evidence reveals that the worry remains. There is reason to conclude that antipsychotics contribute to the 'mortality gap' between the seriously mentally ill and the general population and that the database studies are plagued with methodological and reporting issues. Most importantly, the database studies tell of mortality rates within a drug-centered paradigm of care, which confounds any comparison of mortality risks when patients are on or off antipsychotics.

Tratamientos disruptivos en psiquiatría / Disruptive treatments in psychiatry

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Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents.

Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.

Effect of vitamin D deficiency on BMI in patients treated with Multi-acting Receptor Target Antipsychotics.

OBJECTIVES: Our aim was to examine the effect of vitamin D deficiency on BMI in patients treated with Multi-acting Receptor Target Antipsychotics (MARTA). METHODS: We measured serum 25-hydroxyvitamin D [25(OH)D] levels and body mass index (BMI) in patients with (≥1 months) and without long-term exposure to MARTA to evaluate the role of 25(OH)D deficiency on BMI. RESULTS: The BMI was significantly higher after long-term MARTA exposure in 25(OH)D-deficient patients than in non-deficient patients. No significant difference was found in antipsychotic exposure between the long-term MARTA exposure groups. The BMI was significantly higher in long-term MARTA exposure 25(OH)D-deficient patients than in 25(OH)D-deficient patients without long-term exposure. CONCLUSION: Vitamin D deficiency could be a risk factor for MARTA-induced weight gain. Further studies are necessary to replicate this finding.

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain.

Second-generation antipsychotics (SGAs) are the cornerstone of treatment for schizophrenia because of their high clinical efficacy. However, SGA treatment is associated with severe metabolic alterations and body weight gain, which can increase the risk of type 2 diabetes and cardiovascular disease, and greatly accelerate mortality. Several underlying mechanisms have been proposed for antipsychotic-induced weight gain (AIWG), but some studies suggest that metabolic changes in insulin-sensitive tissues can be triggered before the onset of AIWG. In this review, we give an outlook on current research about the metabolic disturbances provoked by SGAs, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances. Specifically, we discuss the mechanistic insights gleamed from cellular and preclinical animal studies that have reported on the impact of SGAs on insulin signaling, endogenous glucose production, glucose uptake and insulin secretion in the liver, skeletal muscle and the endocrine pancreas. Finally, we discuss some of the genetic and epigenetic changes that might explain the different susceptibilities of SGA-treated patients to the metabolic side-effects of antipsychotics.

Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism.

OBJECTIVE: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism. METHODS: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m2). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 µM - 20 µM) and aripiprazole (0.002 µM - 100 µM). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis. RESULTS: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term pre-incubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondrial functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG. CONCLUSION: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach

Objective: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. Methods: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. Results: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. Conclusion: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. Systematic review registry number: CRD42017054440.

Second-generation antipsychotic drugs and short-term somatic serious adverse events: a systematic review and meta-analysis.

BACKGROUND: Antipsychotic drugs might cause acutely occurring, serious side-effects and thus contribute to the increased physical morbidity and mortality observed in patients with severe mental health disorders. We examined this hypothesis by doing a meta-analysis of International Conference on Harmonisation-Good Clinical Practice-defined serious adverse events occurring in placebo-controlled trials of antipsychotics. METHODS: For this systematic review and meta-analysis, we included randomised controlled trials (RCTs) comparing second-generation antipsychotics with placebo. We searched MEDLINE, Embase, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for trials published in any language from database inception up until Jan 27, 2017. Trials were included without limitations in population (diagnostic category, age, sex, ethnicity), dosing regimen, blinding status, duration, or publication year. Only psychological studies lasting less than 1 day and trials done in mainland China were excluded. We contacted pharmaceutical companies, drug regulatory authorities, and study investigators for additional data. The primary outcome was the number of patients with at least one somatic serious adverse event. We estimated minimum and maximum numbers of patients with the outcome in each study group and synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. This study is registered with PROSPERO, number CRD42016033930. FINDINGS: We identified 597 RCTs, comprising 108 664 participants, that met the inclusion criteria. 314 trials (67 642 participants) with details on individual serious adverse events available constituted the main dataset for meta-analysis. 88% of these were 13 weeks (approximately 3 months) or shorter in duration (median 6 weeks, IQR 4-9). At least one somatic serious adverse event occurred in 698 (1·63%) to 862 (2·02%) of 42 600 patients on antipsychotics, and in 343 (1·37%) to 419 (1·67%) of 25 042 patients on placebo. The odds ratios (ORs) were 1·24 (95% CI 1·08-1·42) and 1·24 (1·10-1·41) based on the minimum and maximum estimate, respectively. In predefined subgroup analyses we found evidence suggesting a larger effect in older patients (>65 years; OR 1·56, 95% CI 1·22-1·98; 1·58, 1·25-1·99) as compared with adults (18-65 years; 1·09, 0·91-1·29; 1·10, 0·95-1·28); likewise in children or adolescents (<18 years) although the evidence was more uncertain (1·49, 0·81-2·75; 1·54, 0·85-2·77). Of 597 included RCTs, 30 (5%), 358 (60%), and 209 (35%) were rated at high, moderate, or low risk of bias, respectively. τ2 was zero for both analyses of the primary outcome (minimum estimate, maximum estimate). A Bayesian sensitivity analysis using external information on heterogeneity gave similar results. INTERPRETATION: We found evidence that antipsychotics cause short-term somatic serious adverse events on top of somatic serious adverse events occurring independent of treatment. This effect appears to be mainly driven by results in older patients. Hence, clinicians should be aware that antipsychotics are potentially toxic, particularly when treating patients sharing risk factors with the older population. FUNDING: German Ministry of Education and Research.

Antipsychotic Use and Stroke: A Retrospective Comparative Study in a Non-Elderly Population.

OBJECTIVE: To evaluate stroke risk among users of typical antipsychotics compared to users of atypical antipsychotics in a non-elderly and non-demented US population. METHODS: New users of antipsychotics aged 18-64 years without dementia were identified via electronic health care data from 13 health plans participating in the Sentinel System from January 2001 to September 2015. The risk of hospitalized stroke events, identified via ICD-9-CM diagnostic criteria, was compared between typical and atypical antipsychotic users using 1:1 matching on propensity score. Adjusted hazard ratios (HRs) and 95% CIs during the entire follow-up period and during 1- to 15-day and 16- to 90-day risk windows were estimated. The risk associated with haloperidol use was estimated separately. RESULTS: A total of 45,495 typical antipsychotic users were matched 1:1 to atypical antipsychotic users. While unmatched HRs suggest an increased stroke risk among typical antipsychotic users compared to atypical antipsychotic users, no increased risk was observed after matching during the entire follow-up period (HR = 0.87; 95% CI, 0.54-1.41), the 1- to 15-day risk window (HR = 1.16; 95% CI, 0.41-3.32), or the 16- to 90-day risk window (HR = 0.52; 95% CI, 0.20-1.36). The adjusted HR for haloperidol was 1.31 (95% CI, 0.54-3.21). CONCLUSION: These findings were not suggestive of an increased stroke risk in typical antipsychotic users compared to atypical antipsychotic users in a non-elderly and non-demented population.

Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach.

OBJECTIVE: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. METHODS: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. RESULTS: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. CONCLUSION: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. SYSTEMATIC REVIEW REGISTRY NUMBER: CRD42017054440.

Antipsychotic-induced tardive dyskinesia: update on epidemiology and management.

PURPOSE OF REVIEW: To provide an update on the frequency of antipsychotic-induced tardive dyskinesia and its management in patients with schizophrenia spectrum disorders in studies published since the last systematic review in 2008. RECENT FINDINGS: Recent data about antipsychotic-induced tardive dyskinesia in patients with schizophrenia underscore the superiority of newer generation antipsychotics (21%) over first-generation antipsychotics (30%) with respect to prevalence and incidence rates. Regarding recently tested management strategies, the new vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine have been found to be effective and may be considered as first-line pharmacotherapy for tardive dyskinesia. Owing to quality issues of randomized controlled trials and/or small sample sizes, limited and conflicting evidence remains for most treatment strategies. SUMMARY: The reviewed literature reveals lower prevalence rates of antipsychotic-induced tardive dyskinesia in patients treated with newer generation compared with first-generation antipsychotics. The evidence of vesicular monoamine transporter 2 inhibitors as a first-line therapy for tardive dyskinesia is well supported by several controlled clinical trials.

Discrepancies Between Nomenclature and Indications of Psychotropics.

INTRODUCTION: While the current nomenclature of psychotropic drugs is disease-based, their approved indications do not always match their classifications. METHODS: Information on approved indications of "second-generation antipsychotics" and "newer antidepressants" that are available in the United States (US), the United Kingdom (UK), France, Germany, and Japan were extracted from their packet inserts. RESULTS: A significant proportion of "atypical antipsychotics" were approved for psychiatric conditions other than psychotic disorders (i. e., bipolar disorder, major depressive disorder, and autistic disorder) as follows: 76.9% in the US, 66.7% in the UK, 66.7% in France, 60.0% in Germany, and 44.4% in Japan. Likewise, more than half of "newer antidepressants" had approved indications for psychiatric conditions other than depression (e. g., panic disorder, obsessive compulsive disorder, social anxiety disorder, general anxiety disorder, and post-traumatic stress disorder): 56.3% in the US, 69.2% in the UK, 69.2% in France, 50.0% in Germany, and 62.5% in Japan. CONCLUSIONS: Our results raise concerns regarding generic terminologies of "antipsychotics" and "antidepressants" since the conventional indication-based nomenclature does not fit well with the official indication.

Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning.

BACKGROUND: Bipolar and other psychiatric disorders are associated with considerably increased risk of suicidal behaviour, which may include self-poisoning with medication used to treat the disorder. Therefore, choice of medication for treatment should include consideration of toxicity, especially for patients at risk. The aim of this study was to estimate the relative toxicity of specific drugs within two drug categories, antipsychotics and mood stabilizers, using large-scale databases to provide evidence that could assist clinicians in making decisions about prescribing, especially for patients at risk of suicidal behaviour. METHOD: Two indices were used to assess relative toxicity of mood stabilisers and antipsychotics: case fatality (the ratio between rates of fatal and non-fatal self-poisoning) and fatal toxicity (the ratio between rates of fatal self-poisoning and prescription). Mood stabilisers assessed included lithium [reference], sodium valproate, carbamazepine, and lamotrigine, while antipsychotics included chlorpromazine [reference], clozapine, olanzapine, quetiapine and risperidone. Fatal self-poisoning (suicide) data were provided by the Office for National Statistics (ONS), non-fatal self-poisoning data by the Multicentre Study of Self-harm in England, and information on prescriptions by the Clinical Practice Research Datalink. The primary analysis focussed on deaths due to a single drug. Cases where the drug of interest was listed as the likely primary toxic agent in multiple drug overdoses were also analysed. The study period was 2005-2012. RESULTS: There appeared to be little difference in toxicity between the mood stabilisers, except that based on case fatality where multiple drug poisonings were considered, carbamazepine was over twice as likely to result in death relative to lithium (OR 2.37 95% CI 1.16-4.85). Of the antipsychotics, clozapine was approximately18 times more likely to result in death when taken in overdose than chlorpromazine (single drug case fatality: OR 18.53 95% CI 8.69-39.52). Otherwise, only risperidone differed from chlorpromazine, being less toxic (OR 0.06 95% CI 0.01-0.47). CONCLUSIONS: There was little difference in toxicity of the individual mood stabilisers. Clozapine was far more toxic than the other antipsychotics. The findings are relevant to prescribing policy, especially for patients at particular risk of suicidal behaviour.

Knowledge of the Pharmacology of Antidepressants and Antipsychotics Yields Results Comparable With Pharmacogenetic Testing.

Several companies offer pharmacogenetic testing for psychiatry on the basis of the claim that the outcome of drug selection is better when guided by such testing than when such testing is not used. This column examines the results of the GeneSight Psychotropic Test which groups various antidepressants and antipsychotics into 3 bins: green ("use as directed"), yellow ("use with caution"), and red ("use with increased caution and more frequent monitoring"). The authors examined how frequently the same drugs appeared in these different bins in 19 patients. They found that of the 22 antidepressants evaluated, 2 were virtually always (>90%) in the green bin: desvenlafaxine and levomilnacipran; and 8 were almost never (≤10.5%) in the green bin: citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, and sertraline. Of the 16 antipsychotics evaluated, they found that 4 were virtually always (>90%) in the green bin: asenapine, lurasidone, paliperidone, and ziprasidone; and 2 were almost never (≤10.5%) in the green bin: chlorpromazine and thioridazine. What was common among those drugs almost always in the green bin versus those almost never in the green bin were newer versus older marketed drugs and those not dependent versus dependent on oxidative metabolism for their clearance. The authors concluded that the results of this pharmacogenetic testing could be predicted on the basis of knowledge of the pharmacology of the drugs, particularly whether their clearance was dependent on oxidative drug metabolism.

Antipsychotic polypharmacy in the treatment of schizophrenia in China and Japan.

BACKGROUND: Although antipsychotic monotherapy is recommended as the main treatment for schizophrenia, antipsychotic polypharmacy is not rare in practice. However, longitudinal data on antipsychotic polypharmacy in schizophrenia treatment are limited. METHODS: This longitudinal database study described antipsychotic polypharmacy in the treatment of schizophrenia in real-world settings in China and Japan. We retrieved information about antipsychotic treatment for schizophrenia from January 2010 to December 2014 from two hospital Electronic Medical Records databases in China and one claims database, Japan Medical Data Centre in Japan. Eligible patients had a diagnosis of schizophrenia (International Classification of Diseases, Tenth Revision F20.x) and at least one prescription for first or second generation antipsychotics. Antipsychotic polypharmacy was defined as having more than one antipsychotic medication overlapping for ⩾60 days. The Japan Medical Data Centre study cohort was further stratified by employees (insurance beneficiaries) and their dependents. RESULTS: The study cohorts comprised 11,961 patients from China and 25,034 (10,661 employee sub-cohort and 14,373 dependent sub-cohort) from 14 days Japan Medical Data Centre in Japan. Most patients were prescribed monotherapy (87.3% in China and 80.1% in Japan), of which oral second-generation antipsychotics were the majority (78.9% in China and 65.8% in Japan). The prevalence rate of antipsychotic polypharmacy was 12.7% in China and 19.9% in Japan (13.7% in employees vs 24.5% in dependents). The most common combinations were two oral antipsychotics. Combinations of more than two drugs were uncommon in China (0.3%) but were prescribed for 5.3% of patients in Japan. Among patients treated with monotherapy, 12.6/100 person-years (11.8%) in China and 9.6/100 person-years (11.0%) in Japan switched to antipsychotic polypharmacy during follow-up. Younger patients were more likely to switch to antipsychotic polypharmacy than older patents in all study cohorts. CONCLUSION: The observed rates of antipsychotic polypharmacy ranged from 12.7% in China to 19.9% in Japan. Switching from monotherapy to antipsychotic polypharmacy was most likely to occur in younger patients with schizophrenia.

Second-generation antipsychotics in children: Risks and monitoring needs.

Question A 10-year-old male patient presented to my clinic with irritability associated with autism spectrum disorder, and previous therapeutic efforts had not been successful. Treatment with quetiapine has considerably reduced irritability and improved his quality of life; however, the patient's mother has stated that her child's clothes are no longer fitting because his waist size has increased substantially, and that he has gained 5 kg since treatment initiation 8 weeks ago. Should second-generation antipsychotic (SGA) treatment be stopped or continued, and how can these side effects be best mitigated in a family practice setting?Answer Use of SGAs in pediatric patients has increased in recent years, which has brought to light a number of worrisome metabolic side effects that occur in children. Owing to the efficacy of treatment, SGAs must often be continued despite side effects. Even if the drug has been prescribed elsewhere, family physicians should closely monitor these patients following the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children guidelines. When starting an SGA, patients and their families should be educated on the importance of healthy eating and physical activity to preemptively mitigate potential side effects. Recent studies have also shown adjunctive metformin to have a potential role in reducing weight gain.