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Background Methods Results Conclusion Antipsychotics increase the risk of developing diabetes, but clinical trials are not generalizable with short follow‐up, while observational studies often lack important information, particularly hemoglobin A1c (HbA1c).We followed two Danish cohorts with schizophrenia. First, using Danish nationwide registers, we identified all individuals diagnosed with first‐episode schizophrenia (FES) between 1999 and 2019 (n = 31,856). Exposure was a redeemed prescription for an antipsychotic, and the outcome was diabetes, defined via hospital‐based diagnosis and redeemed prescriptions for glucose‐lowering drugs. Adjusted Cox regression calculated hazard rate ratios (HRR). Second, using data from the Central Denmark Region, we identified all individuals diagnosed with FES from October 2016 to September 2022 (n = 2671). Using a within‐subject design, we analyzed the change in HbA1c during the 2 years after initiation of specific antipsychotics compared to the 2 years before.In the nationwide cohort, 2543 (8.0%) individuals developed diabetes (incidence rate = 9.39 [95% CI = 9.03–9.76] per 1000 person‐years). Antipsychotics, compared to periods without, were associated with an increased risk of developing diabetes (HRR = 2.04, 95% CI = 1.75–2.38). We found a dose–response association, particularly for second‐generation antipsychotics, and different risk rates for specific antipsychotics. In the Central Denmark Region cohort, a total of 9.2% developed diabetes but mean HbA1c levels remained stable at 37 mmol/mol during the 2 years after initiation of antipsychotic medication.This comprehensive real‐world two‐cohort study emphasizes that diabetes affects almost 10% of patients with FES. Antipsychotics increase this risk, while HbA1c deterioration requires longer treatment. These findings are important for clinicians and young patients with FES. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non‐psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder.Individuals aged 15–65 with bipolar disorder were identified from Finnish national health registers in 1996–2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time‐varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non‐psychiatric hospitalization (treatment safety). Stratified Cox regression in within‐individual design was used.The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow‐up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57–0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56–0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non‐psychiatric hospitalization. Lithium was associated with a decreased risk of non‐psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84–0.93) and standard doses (aHR 0.81, 95% CI 0.74–0.88).Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non‐psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose. [ABSTRACT FROM AUTHOR]

Background: Postpartum psychotic‐ or mood disorders are psychiatric emergencies associated with risk of suicide and infanticide. Except from case reports, there are only few descriptions of its treatment. Therefore, we aimed to describe the treatment of women admitted with postpartum psychotic‐ or mood disorder in Denmark with emphasis on the use of electroconvulsive therapy (ECT). Methods: We conducted a register‐based cohort study of all women with incident postpartum psychotic‐ or mood disorder (no prior diagnoses of psychotic‐ or mood disorder or treatment with ECT) requiring admission in the period from 2011 to 2018. For these patients, we described the treatment and the 6‐month readmission risk. Results: We identified 91 women with postpartum psychotic‐ or mood disorder with a median admission length of 27 days (interquartile range: 10–45). Of those, 19% received ECT with a median time from admission to first ECT of 10 days (interquartile range: 5–16). The median number of ECT sessions was eight (interquartile range: 7–12). In the 6 months following discharge, 90% of the women received some form of psychopharmacological treatment (62% antipsychotics, 56% antidepressants, 36% anxiolytics/sedatives, 19% lithium, and 9% mood stabilizing antiepileptics), and 31% were readmitted. Conclusion: Psychiatric admission for incident postpartum psychotic‐ or mood disorder is rare in Denmark. Among those admitted, ECT and psychopharmacological treatment is commonly used. The 6‐month readmission risk is high, warranting close follow‐up. The fact that there is no international consensus on the optimal treatment of postpartum psychotic‐ or mood disorder is problematic and calls for action. [ABSTRACT FROM AUTHOR]

Background: Long‐term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. Aims: To present systematic population‐based nation‐wide register data on comparative 2‐year non‐response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. Method: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non‐response to first antidepressant within a 2‐year study period was defined as switch to or add‐on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. Results: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98–1.02]) but fluoxetine (1.13 [95% CI: 1.10–1.17]), paroxetine (1.06 [95% CI: 1.01–1.10]) and escitalopram (1.22 [95% CI: 1.18–1.25]) were associated with higher risk ratio of non‐responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin‐norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non‐response, whereas there was no difference for imipramine. Conclusions: These analyses emulating a randomized trial of "real world" observational register‐based data show that 2‐year long‐term non‐responses to some antidepressants within six different drug classes are increased over others. [ABSTRACT FROM AUTHOR]

OBJECTIVES: There is limited information on the characteristics of older adults with bipolar disorder (OABD) treated with lithium, along with safety concerns about its use by older adults. The aim of the present study is to describe the demographic and clinical characteristics of OABD receiving lithium therapy, using data from the Global Ageing & Geriatric Experiments in Bipolar Disorder (GAGE-BD). EXPERIMENTAL PROCEDURES: Cross-sectional analysis of the GAGE-BD dataset to determine differences and similarities between lithium users and non-users. We analysed data from 986 participants aged 50 years or older (mean age 63.5 years; 57.5% females) from 12 study sites. Two subgroups (Lithium; Non-lithium) were defined according to the current prescription of lithium. We compared several outcomes between these groups, controlling for age, gender, and study site. RESULTS: OABD treated with lithium had lower scores on depression rating scales and were less likely to be categorised as with moderate or severe depression. There was a lower proportion of lithium users than non-users among those with evidence of rapid cycling and non-bipolar psychiatric diagnoses. Assessment of global cognitive state and functionality indicated better performance among lithium users. The current use of antipsychotics was less frequent among lithium users, who also reported fewer cardiovascular comorbidities than non-users. CONCLUSION: We found several potentially relevant differences in the clinical profile of OABD treated with lithium compared with those treated with other mood stabilisers. However, the interpretation of the present results must take into account the methodological limitations inherent to the cross-sectional approach and data harmonisation.

Background: Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off‐label, unapproved use of first‐generation antipsychotics (FGAs) and second‐generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta‐analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. Objective: The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first‐line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). Methods: An initial search was undertaken to identify systematic reviews and meta‐analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR‐2 (A MeaSurement Tool to Assess Systematic Reviews) scale. Results: The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta‐analyses were included in the analysis. Most of the systematic reviews and meta‐analyses were deemed low‐quality through AMSTAR‐2 with only one review being deemed high‐quality. In evaluating the monotherapies with antipsychotics compared with first‐line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). Conclusions: This umbrella review indicates a lack of high‐quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long‐term and larger‐scale studies of antipsychotics in anxiety disorders are needed. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. Methods: Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007–2016. The participants collected antidepressants with or without antipsychotics from a pharmacy within 14 days after discharge and were followed up for 2 years. The primary outcome was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. Cox regression was used to analyze the data, which were adjusted for sex, age, prior admissions, comorbidity, electroconvulsive therapy, and other pharmacological treatments. Results: We identified 4391 patients, of which 2972 were in the antidepressant + antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. After 2 years, 42.3% and 36.6% of patients were readmitted or committed suicide in the combination therapy and monotherapy group, respectively. Monotherapy was significantly associated with a lower risk of reaching the outcome in the main analysis (hazard ratio = 0.86; 95% confidence interval: 0.77–0.95). The results went in the same direction in all sensitivity analyses. Conclusion: Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted. [ABSTRACT FROM AUTHOR]

Background: According to guidelines, psychotic depression should be treated with both antipsychotics and antidepressants, but current practice is largely unknown. We investigated the prevalence of antipsychotic and antidepressant use in first‐episode psychotic depression and factors related to antipsychotic use after the diagnosis. Methods: We identified individuals aged 16–65 with a first‐episode diagnosis of psychotic depression (ICD‐10 codes F32.3, F33.3) from nationwide data linkage of Finnish healthcare and population registers during 2000–2018. Point prevalence was measured as 2‐week time windows every 3 months, investigating whether the individual had a modeled drug use period ongoing during the window or not, censoring to death and end of data linkage. Results: The study population included 18,490 individuals (58.0% women; mean age 39.9 years, standard deviation 14.7). The prevalence of use for antidepressants (75.0%), antipsychotics (56.4%), and both (50.0%) were highest at 3 months after the diagnosis. The prevalence declined to 51.8%, 34.1%, and 28.7%, respectively, at 3 years after the diagnosis. In a logistic regression analysis, younger age (adjusted odds ratio < 25 vs. ≥55, 0.82 [95% confidence interval 0.73–0.91]), eating disorders (0.78 [0.66–0.92]), substance use disorders (0.80 [0.73–0.87]), and occupational inactivity (0.80 [0.73–0.87]) were associated with decreased odds of using antipsychotics at 3 months after diagnosis. Increased odds were found for diagnosis from inpatient care (1.74 [1.62–1.86]), and later year of cohort entry (2010–2014 vs. 2000–2004, 1.56 [1.42–1.70]). Conclusion: At most, half of the individuals with newly diagnosed psychotic depression used both antidepressants and antipsychotics. This likely has a negative impact on treatment success. [ABSTRACT FROM AUTHOR]

Introduction: Use of antipsychotic drugs, especially second‐generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis. Methods: Nationwide case–control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first‐generation and second‐generation antipsychotic drugs (dispensed prescription <91 and ≥91 days of the index date, respectively) compared with never users of such drugs. Results: In the crude model, first‐generation and second‐generation antipsychotic drugs were associated with increased risk of acute pancreatitis, with slightly higher ORs for past use (1.58 [95% confidence interval 1.48–1.69] and 1.39 [1.29–1.49], respectively) than for current use (1.34 [1.21–1.48] and 1.24 [1.15–1.34], respectively). The ORs were largely attenuated in the multivariable model—which included, among others, alcohol abuse and the Charlson comorbidity index—up to the point where only a statistically significant association remained for past use of first‐generation agents (OR 1.18 [1.10–1.26]). Conclusion: There was no clear association between use of antipsychotic drugs and risk of acute pancreatitis in this very large case–control study, indicating that previous case report data are most likely explained by confounding. [ABSTRACT FROM AUTHOR]

The article discusses the treatment of psychotic depression, a serious psychiatric illness characterized by a combination of depressed mood and psychosis. The presence of psychosis in major depression increases the risk of suicide. Currently, there is no FDA-approved medication for psychotic depression, but combination treatment with an antidepressant and an antipsychotic or electroconvulsive therapy (ECT) has shown efficacy. A recent study compared antidepressant monotherapy and combination therapy for the maintenance phase of psychotic depression and found that monotherapy was associated with a lower risk of relapse. However, further research is needed to determine the best treatment for the maintenance phase of psychotic depression. [Extracted from the article]

Objective: Antipsychotics have conflicting data with respect to obsessive–compulsive disorder/symptoms (OCD/OCS), with some reporting causality and some reporting treatment benefits. This pharmacovigilance study aimed to investigate reporting of OCD/OCS in association with the use of antipsychotics in comparison to one another, as well as treatment failure using data derived from the FDA Adverse Event Reporting System (FAERS). Methods: Data from January 1st, 2010 to December 31st, 2020 on suspected adverse drug reactions (ADRs) including OCD/OCS was obtained. The information component (IC) was used to determine a disproportionality signal, and reporting odds ratio (ROR) calculations were performed via intra‐class analyses to discern differences between the evaluated antipsychotics. Results: A total of 1454 OCD/OCS cases were utilized in IC and ROR calculations and 385,972 suspected ADRs were used as non‐cases. A significant disproportionality signal was seen with all second generation antipsychotics. Relative to other antipsychotics, only aripiprazole had a significant ROR of 23.87 (95% CI: 21.01–27.13; p < 0.0001). The ROR for antipsychotic treatment failure in those with OCD/OCS was highest with aripiprazole, and lowest with risperidone and quetiapine. Sensitivity analyses were largely in favor of the primary findings. Our analysis appears to implicate the 5‐HT1A receptor or an imbalance between this receptor and the D2‐receptor in antipsychotic treatment‐emergent OCD/OCS. Conclusions: In contrast to prior reports noting clozapine as the antipsychotic most commonly associated with de novo or exacerbated OCD/OCS, this pharmacovigilance study found aripiprazole was most frequently reported for this adverse effect. While these findings from FAERS offer a unique perspective on OCD/OCS with different antipsychotic agents, due to the inherent limitations of pharmacovigilance studies they should ideally be validated through alternative prospective research studies involving direct comparisons of antipsychotic agents. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long‐term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school‐aged children. Methods: We performed a cross‐sectional neurodevelopmental assessment of 91 children aged 6–14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. Results: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. Conclusions: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school‐aged children (6–14 years). [ABSTRACT FROM AUTHOR]

Objective: Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population. Methods: We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta‐analyses were used to examine weight gain as both a continuous and dichotomous outcome. Results: Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference = 1.10 kg, [0.79, 1.40], p < 0.00001, I2 = 54%; Dichotomous: odds ratio = 3.94, [2.15, 7.23], p < 0.00001, I2 = 0). Sub‐group analysis revealed no significant effect of AP type. Data regarding the effects of APs on other metabolic outcomes were limited. Conclusion: This review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long‐term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals. [ABSTRACT FROM AUTHOR]

Objective: Increasing number of people have been prescribed antipsychotics (APs) off‐label in recent decades. This study aimed to identify the characteristics and predictors of receiving prescription of antipsychotics off‐label. Methods: The study sample was part of the Northern Finland Birth Cohort 1966 (n = 7071). Data included questionnaires and national register data. Information on prescribed medications was extracted from the national register. The sample was divided into three groups: Persons who had been prescribed APs off‐label (n = 137), individuals with non‐psychotic mental disorders without APs off label (n = 1478) and individuals who had been diagnosed with psychosis or bipolar disorder and who had been prescribed APs (n = 151). We compared sociodemographic, lifestyle and clinical characteristics between the off‐label and the comparison groups using logistic regression. Results: The most common diagnoses in the off‐label group were depression (n = 96, 70.1%) and anxiety (n = 55, 40.1%). Compared with individuals with non‐psychotic mental disorders who were not prescribed APs off‐label, individuals with prescribed off‐label APs had a lower level of education, lower socioeconomic status, were less often married, had a higher level of somatic and psychiatric morbidity, were more often smokers and more often had a substance abuse disorder and heavy alcohol consumption. When comparing the off‐label group to individuals with psychosis or bipolar disorder who used APs, there were less differences, though individuals with psychosis or bipolar disorder had more markers of morbidity and a lower level of education. Conclusion: Individuals who had been prescribed APs off label had a higher level of mental and somatic morbidity and poorer socioeconomic status than individuals with non‐psychotic mental disorders who did not use APs. [ABSTRACT FROM AUTHOR]

Objective: To compare the effectiveness and safety of various second‐generation antipsychotics (SGAs), newer oral and long‐acting injectable (LAI) SGAs, and first‐generation antipsychotics (FGAs) treatments in patients with schizophrenia or schizoaffective disorder (SCZ). Methods: This retrospective cohort study included medical administrative information for patients with a diagnosis of SCZ living in Quebec (Canada), initiating or reinitiating at least one antipsychotic (AP) drug (with a clearance baseline period of 12 months without any APs). Effectiveness was defined by a reduced risk of hospitalization for mental disorder and discontinuation, and safety by a reduced risk of all‐cause death and hospitalization for non‐mental disorder, 2 years after AP initiation or reinitiation. Cox proportional hazard models were used to estimate the events associated with different antipsychotics compared with oral olanzapine. Results: The study cohort included 19,615 patients initiating or reinitiating an antipsychotic drug between January 2006 and December 2015. Results showed better effectiveness of clozapine (adjusted HR 0.36, 95% CI 0.30–0.42, p < 0.0001) and LAI SGAs (adjusted HR 0.56, 95% CI 0.51–0.61, p < 0.0001) compared with oral olanzapine when adding discontinuation to hospitalizations for mental disorder as a composite measure of effectiveness, as opposed to oral FGAs (adjusted HR 1.36, 95% CI 1.27–1.46, p < 0.0001) and LAI FGAs (adjusted HR 1.22, 95% CI 1.12–1.32, p < 0.0001). Most APs were as safe as oral olanzapine. Conclusion: The effectiveness of LAI SGAs and clozapine appears to justify their use and are as safe as a recognized treatment (oral olanzapine) in Quebec (Canada). [ABSTRACT FROM AUTHOR]

Objective: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case‐control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics. Methods: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five‐year lag time and diagnosis of dementia was assessed by conditional logistic regression models. Results: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First‐ and second‐generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06–3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10–2.67; p = 0.02 and OR 1.84; 1.03–3.32; p = 0.04, respectively). Conclusion: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether patients with clozapine treatment are at an increased risk of a more severe COVID‐19 infection as compared with patients on other antipsychotic drugs. Methods: In this register‐based cohort study, all residents (age 18 or older) in the Stockholm Region with a psychotic disorder diagnosis and antipsychotic treatment were included (N = 8 233) and followed from 1 March 2020 to 14 January 2021. The exposure was defined as clozapine treatment and the outcome measures (indicating a more severe COVID‐19 infection) were: inpatient care, care within intensive care unit or death due to COVID‐19 infection. Differences in outcome rates between exposed (n = 966) and unexposed (other antipsychotics; n = 7 267) were examined using Cox proportional hazards models and expressed as hazard ratios (HR) with 95% confidence intervals (CI). Results: No statistically significant differences in outcome rates were found between the two groups of patients after adjusting for age, sex and residence in retirement homes. The adjusted HR for the exposed compared to the unexposed was 0.96 (95% CI: 0.54, 1.70) for inpatient care; 1.69 (0.48, 5.93) for care in intensive care unit (ICU); and 0.86 (0.26, 2.80) for death. Regarding inpatient care, additional adjusting for country of birth, living in socioeconomically vulnerable areas, number of care visits during the previous year, and comorbid medical illnesses did not alter the results. Conclusions: Our results may add support to the present guidelines, recommending sustained clozapine treatment during the current COVID‐19 pandemic with careful monitoring and readiness to alter drug doses as needed. [ABSTRACT FROM AUTHOR]

Objective: A substantial proportion of patients with schizophrenia suffer from comorbid obsessive‐compulsive disorder (OCD) possibly associated with antipsychotics. However, little is known about the comparative risks of the antipsychotics. The present study aimed to investigate the risk of new‐onset OCD following the initiation of different antipsychotic medications for schizophrenia relative to haloperidol. Methods: Using the Korean national claims data, patients aged 15–60 years newly diagnosed with schizophrenia between 2010 and 2018 were identified. Of the 47,808 patients with schizophrenia treated with nine commonly prescribed antipsychotics, 775 new‐onset OCD patients were matched to 3,100 patients without OCD using nested case‐control design with 1:4 case‐control matching based on the sex, age of index date, date of schizophrenia diagnosis, observation period, locations of medical institutions, and level of medical facilities. Using multivariable conditional logistic regression analysis, odd ratios (ORs) for new‐onset OCD comparing each antipsychotic agent relative to haloperidol were computed. Results: The risk for new‐onset OCD during treatment with clozapine was significantly higher than that with haloperidol (adjusted OR 2.86; 95% confidence interval [1.63–5.03]). The risks for new‐onset OCD with other antipsychotics were not significantly different from that with haloperidol. In subgroup analysis, the early and intermediate, but not late‐onset schizophrenia group showed significant risk for OCD associated with clozapine use. Conclusion: The present findings, based on real‐world national representative data, provide reliable evidence for the risk of new‐onset OCD in patients with schizophrenia receiving clozapine at a population level. [ABSTRACT FROM AUTHOR]

Objective: Although a relationship between schizophrenia (SCZ), antipsychotic (AP) medication, and metabolic dysregulation is now well established, the effect of adiposity is less well understood. By synthesizing findings from imaging techniques that measure adiposity, our systematic review and meta‐analysis (PROSPERO CRD42020192977) aims to determine the adiposity‐related effects of illness and treatment in this patient population. Methods: We searched MEDLINE, EMBASE, PsychINFO and Scopus for all relevant case‐control and prospective longitudinal studies from inception until February 2021. Measures of adiposity including percent body fat (%BF), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were analyzed as primary outcomes. Results: Our search identified 29 articles that used imaging methods to quantify adiposity among patients with SCZ spectrum disorders. Analyses revealed that patients have greater %BF (mean difference (MD) = 3.09%; 95% CI: 0.75–5.44), SAT (MD = 24.29 cm2; 95% CI: 2.97–45.61) and VAT (MD = 33.73 cm2, 95% CI: 4.19–63.27) compared to healthy controls. AP treatment was found to increase SAT (MD = 31.98 cm2; 95% CI: 11.33–52.64) and VAT (MD = 16.30 cm2; 95% CI: 8.17–24.44) with no effect on %BF. However, change in %BF was higher for AP‐free/AP‐naïve patients compared to treated patients. Conclusion: Our findings indicate that patients with SCZ spectrum disorders have greater adiposity than healthy controls, which is increased by AP treatment. Young, AP‐naïve patients may be particularly susceptible to this effect. Future studies should explore the effect of specific APs on adiposity and its relation to overall metabolic health. [ABSTRACT FROM AUTHOR]

Objective: Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. Methods: Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author‐defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis‐Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. Results: 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14–8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71–7.32; p = 0.0004), severity of hyperthermia (Unit‐OR = 1.30, 95%CI = 1.16–1.46; p < 0.0001), and older age (Unit‐OR = 1.05, 95%CI = 1.02–1.07; p = 0.0014). Even in univariate, patient‐level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long‐acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first‐generation antipsychotic: n = 38/433 (8.8%) vs. second‐generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non‐antipsychotic co‐treatments were not associated with NMS mortality. Conclusion: Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs. [ABSTRACT FROM AUTHOR]

Objective: To compare the mortality in people using clozapine to that of people using other antipsychotics. Methods: Danish incidence cohort of 22,110 patients with a first diagnosis of non‐affective psychotic disorder (1995–2013) and a prevalence cohort of 50,881 patients ever diagnosed with such a disorder (1969–2013). Hazard ratios (HR) were calculated for the antipsychotic drug used at the time of death ("current use": incidence and prevalence cohort) and for the drug used for the longest at that moment ("cumulative use": incidence cohort), using a Cox model with adjustment for somatic comorbidity. Clozapine was the reference drug. Results: As for current drug use, the risk of suicide was higher among users of other antipsychotics in the incidence (HRadj = 1.76; 95% CI 0.72–4.32) and prevalence (HRadj = 2.20; 95% CI 1.35–3.59) cohorts. There was no significant difference in all‐cause or cardiovascular mortality in the two cohorts. Cumulative use of clozapine was not associated with an increased cardiovascular mortality. Cumulative use of other antipsychotics for up to 1 year was associated with a lower all‐cause mortality and suicide risk than a similar period of clozapine use (all‐cause: HRadj = 0.73; 95% CI 0.63–0.85, suicide; HRadj = 0.65; 95% CI 0.46–0.91). Conclusion: The results indicate that the use of clozapine is not associated with increased cardiovascular mortality. We found opposing trends toward a lower risk of suicide during current use of clozapine and a higher risk of suicide associated with cumulative use up to 1 year. This suggests that clozapine cessation marks a period of high risk of suicide. [ABSTRACT FROM AUTHOR]

Objective: As most treatment guidelines for antipsychotics focus on clinical efficacy, we will instead focus on adverse effects and how to manage them. In this review, we aim to provide an up‐to‐date clinical resource for providers who prescribe antipsychotics and have included here "what's new" and "what to do" for numerous antipsychotic‐induced adverse effects. Methods: A review was performed of relevant literature, studies, randomized clinical trials, and systematic reviews. This information was combined with the clinical experience of the authors to formulate a practical guide for treating adverse effects of antipsychotics with an emphasis on metabolic and movement disorder adverse effects and brief mention of some others (sedation and sexual dysfunction). Conclusions: Antipsychotics are an integral part of psychiatric care and are often prescribed lifelong. When choosing an antipsychotic, special consideration must be given to adverse effects which have an undeniable impact on quality of life and can often be the deciding factor in patients' medication compliance. While patients may respond well to one specific medication, they may still experience adverse effects that lead them to discontinue it or switch to a more tolerable but less effective option. However, strategies do exist for managing and treating adverse effects, especially metabolic and movement adverse effects, allowing better personalization of antipsychotic choice. [ABSTRACT FROM AUTHOR]

Converging demographic risk factors for antipsychotic-induced weight gain, young age, antipsychotic-naïve status and schizophrenia should already be considered in routine clinical assessments. Since all current antipsychotics with the indication of psychosis spectrum target the striatal dopamine D2 receptors, amisulpride represents the common denominator of antipsychotics. Although all antipsychotic compounds may induce weight gain,2 some antipsychotics, for example olanzapine and clozapine are associated with considerably greater weight gain.1 Concurrently, it is a common clinical observation that the dysmetabolic response to antipsychotic treatment varies greatly between individuals; some patients rapidly develop weight gain regardless of antipsychotic compound, whereas others exhibit stable body weight and metabolic parameters, regardless of long-term antipsychotic exposure. [Extracted from the article]

This can sometimes be done by augmentation too, by using a clozapine sparing antipsychotic drug that facilitate clozapine dose reduction. Clozapine remains the golden standard for patients with treatment-resistant schizophrenia. As years go by on clozapine, many patients have the desire to reduce the dose or discontinue clozapine, and some patients may manage their disease with reduced dose of clozapine or without clozapine. Paradoxically, later in the course the patient may have developed less vulnerability to adverse effects and may then tolerate the sufficient dose needed in the clozapine eligibility criteria. [Extracted from the article]

Objective: In this paper, we aimed at reviewing evidence‐based treatment options for bipolar mania and proposed tentative evidence‐based clinical suggestions regarding the management of a manic episode, especially regarding the choice of the proper mood stabilizer and antipsychotic medication. Method: A narrative review was undertaken addressing 'treatment of bipolar mania'. Findings have been synthesized and incorporated with clinical experience into a model to support different treatment choices. Results: To date, there is solid evidence supporting the use of several medications, such as lithium, divalproex, and carbamazepine, and antipsychotics, such as chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, inhaled loxapine, asenapine, and cariprazine in acute mania, and some evidence supporting the use of clozapine or electroconvulsive therapy in treatment‐refractory cases. However, in clinical practice, when making decisions about treatment, personalized treatment is needed, according to the different clinical presentations and more complex clinical situations within the manic episode and considering a long‐term view and with the objective of not only a symptomatic but also functional recovery. After remission from acute mania, psychoeducation strategies are useful to ensure adherence. Discussion: Despite the evidence forefficacy of many currently available treatments for mania, the majority of RCTs provide little direction for the clinician as to what steps might be optimal in different presentations of mania as well as in the presence of specific patient characteristics. Manic episodes should be managed on a personalized basis considering the clinical course and patient criteria and with the expectation of maintaining that treatment in the long‐term. [ABSTRACT FROM AUTHOR]

Background: To date, there have been no studies evaluating adherence to clozapine with electronic adherence monitoring (EAM) such as the Medication Event Monitoring System (MEMS®). Methods: In outpatients with schizophrenia, we conducted a 3‐month prospective study investigating antipsychotic adherence with EAM (eCAP®). Participants were treated with different oral antipsychotics, including clozapine, and blind to EAM monitoring; all were on antipsychotic monotherapy administered once daily. Outcome measures included adherence rate, missed dose, and medication gap. Adherence trajectory patterns were also analyzed for clozapine vs. other antipsychotics collectively. Results: A total of 111 patients were included in the study; 33 and 78 patients received clozapine or other antipsychotics, respectively. Adherence rates, defined as proportion of days that the subject took the medication at the prescribed time ± 3 h and proportion of subjects with ≥80% adherence, were numerically higher in patients receiving clozapine vs. other antipsychotics (72.0% vs. 65.1%, P = 0.10; 49.5% vs. 35.7%, P = 0.11, respectively). Along similar lines, some of the missed dose and medication gap outcomes were significantly better in patients receiving clozapine vs. other antipsychotics. Three adherence trajectory patterns were identified for both clozapine and other antipsychotics, with two shared by both groups (i.e., low adherence with a slight decrease over time; high and stable adherence). Conclusion: Findings suggest that in patients with schizophrenia clozapine adherence is at least comparable, if not slightly better, compared with other antipsychotics. [ABSTRACT FROM AUTHOR]

Objective: By using a self‐controlled design, we investigated whether antipsychotic medication exposure was associated with increased pneumonia risk and whether patients receiving clozapine were more likely to develop pneumonia than patients receiving other antipsychotic medications. Methods: Through nationwide health registers, we identified all out‐patients with schizophrenia initiating antipsychotic treatment. First, we estimated whether antipsychotic‐naïve patients with schizophrenia increased their risk of pneumonia after initiation of either a first‐ or second‐generation antipsychotic medication using a one‐year mirror‐image model. Afterward, similar analyses were made for individual second‐generation antipsychotics. Lastly, the rate of pneumonia for patients initiated on clozapine was compared to patients commenced on other second‐generation antipsychotics. Results: In total, 8355 antipsychotic‐naïve patients with schizophrenia were initiated on a first‐generation antipsychotic medication; 0.95% of the patients had developed pneumonia before exposure, compared to 0.68% after exposure (P = 0.057). Similar findings were made for the 8001 antipsychotic‐naïve patients with schizophrenia initiated on second‐generation antipsychotic medications, with 0.56% developing pneumonia before exposure compared to 0.55% after exposure (P = 1.00). Second‐generation antipsychotic medications did not increase the pneumonia risk, except for risperidone (increased by 0.32%; P = 0.007) and clozapine, which gave the largest absolute increase in pneumonia risk although not significant (increased by 0.64%; P = 0.10). The rate of pneumonia was higher after initiation of clozapine than for other second‐generation antipsychotic medications. Conclusion: Most antipsychotic medications were not found to increase the risk of pneumonia. Clozapine exposure might be associated with increased risk of developing pneumonia. [ABSTRACT FROM AUTHOR]

Objective: Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta‐analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Method: Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta‐regression, and multiple linear regression on available patient data. Results: A total of 276 studies were retrieved. Thirty‐four studies were included in the meta‐analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta‐regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI −0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. Conclusion: The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta‐analysable data for future use. [ABSTRACT FROM AUTHOR]

Objective: The longitudinal course of neuropsychological functioning after the first manic episode in bipolar disorder is unknown. The present study evaluated cognitive change in bipolar disorder in the first 3 years after the initial manic episode. Methods: Ninety‐one newly diagnosed patients with bipolar disorder and 61 demographically similar healthy participants received a neuropsychological evaluation assessing multiple cognitive domains at baseline, 1‐year, and 3‐year time points. Patients also received clinical assessments including mood ratings at all time points. Results: Patients showed deficits in all domains at baseline, but similar longitudinal trajectories across time relative to healthy participants in most cognitive domains. For processing speed, patients showed more gains than controls from baseline to 1 year, but these gains stabilized thereafter. Patients with alcohol/substance abuse showed an initial delay but subsequent recovery in executive functioning. Patients who discontinued antipsychotic treatment showed better cognitive outcomes in verbal memory. Conclusion: Appropriately treated patients with bipolar disorder showed favorable cognitive outcome in the first 3 years after experiencing an initial manic episode, arguing against cognitive neuroprogression at this stage of the illness. Discontinuation of antipsychotic treatment may be associated with better cognitive outcomes, but clarification of the role of antipsychotics on cognitive functioning requires further investigation. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotics may increase serum prolactin, which has particularly been observed with risperidone. Further, hyperprolactinemia has been linked to osteoporosis‐related fractures. Therefore, we investigated fracture risk in a nationwide cohort exposed to antipsychotics. Methods: Swedish registers were used to identify adults with two consecutive dispensations of risperidone (n = 38 211), other atypical antipsychotics not including paliperidone (n = 60 691), or typical antipsychotics (n = 17 445) within three months between 2006 and 2013. An osteoporosis‐related fracture was defined as a non‐open hip/femur fracture in primary analyses. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Risperidone users were on average older (mean age of 68, 44, and 63 years for risperidone, other atypical antipsychotics, and typical antipsychotics respectively). Compared with other atypical antipsychotics, there was no association between risperidone and osteoporosis‐related fractures in the overall (HR = 1.04, CI: 0.91–1.19) or age‐stratified analyses. A significantly increased risk of typical antipsychotics (HR = 1.24, CI: 1.07–1.45) compared with other atypical antipsychotics remained for ages >45 years. Conclusion: Risperidone does not appear to be associated with an increased risk of osteoporosis‐related fracture compared with other atypical antipsychotic agents as a group. For typical antipsychotics, a moderately elevated risk of hip fractures was noted compared with other atypical antipsychotics, possibly because of residual confounding. [ABSTRACT FROM AUTHOR]

Objective: To explore the temporal dynamic of antidepressant and antipsychotic co‐prescribing in real‐life conditions. Methods: The study was performed using reimbursement data from the French Insurance Healthcare system in a cohort of 118 454 persons with at least one dispensing of antidepressants and/or antipsychotics over the period 2006–2016. Latent class analyses were used to identify homogeneous groups of persons following similar multi‐trajectories of antidepressant and/or antipsychotic dispensing. Multivariate polynomial logistic regression models were used to explore the characteristics independently associated with distinct trajectories. Results: Five multi‐trajectories of antidepressant and/or antipsychotic dispensing were identified: more than half of the sample (58%) had very low antidepressant and antipsychotic use; two groups had chronic (12%) or decreasing (11%) antidepressant use with very low antipsychotic use; two groups used both antidepressants and antipsychotics simultaneously either in an increasing (12%) or chronic (7%) way. Persons with chronic antidepressant–antipsychotic use presented with markers of poor social and mental health conditions. Conclusions: Most persons using antipsychotics over the follow‐up also used antidepressants over the same period. The benefit/risk ratio of these prescribing practices should be further explored as the long‐term efficacy of antidepressant–antipsychotic polypharmacy is poorly documented, while this combination increases the risk of adverse effects. [ABSTRACT FROM AUTHOR]

Objective: The experience of pre‐onset subthreshold psychotic symptoms (STPS, signifying a clinical high‐risk state) in first episode psychosis (FEP) predicts poorer outcomes during treatment, possibly through differential adherence to medication. We explored whether adherence differs between FEP patients with and without pre‐onset STPS. Methods: Antipsychotic medication adherence was compared in 263 STPS+ and 158 STPS− subjects in a specialized early intervention program for FEP. Data were gathered from a larger observational study conducted between 2003 and 2016. STPS status, sociodemographic, and baseline clinical variables were tested as predictors of non‐adherence using univariate and multivariate logistic regressions. Time to onset of non‐adherence was analyzed using Kaplan–Meier curves. The same predictors were tested as predictors of time to onset of non‐adherence using Cox regression models. Results: Medication non‐adherence was higher in STPS+ participants (78.9% vs. 68.9%). STPS status (OR 1.709), substance use disorder (OR 1.767), and milder positive symptoms (OR 0.972) were significant baseline predictors of non‐adherence. Substance use disorder (HR 1.410), milder positive symptoms (HR 0.990), and lack of contact between the clinical team and relatives (HR 1.356) were significant baseline predictors of time to non‐adherence. Conclusion: FEP patients who experience pre‐onset STPS are more likely to be non‐adherent to antipsychotic medication over 2 years of intervention. FEP programs should routinely evaluate pre‐onset symptomatology to deliver more personalized treatments, with emphasis on engaging both patients and family members from the beginning of care. [ABSTRACT FROM AUTHOR]

Objective: To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method: Data of 672 patients with schizophrenia randomized to placebo in nine double‐blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5‐Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results: Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per‐protocol analysis or a 15% reduction in last‐observation‐carried‐forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion: These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of CYP1A2 genetic polymorphisms on the pharmacokinetics of CYP1A2‐metabolized antipsychotic drugs in humans by means of systematic review and meta‐analysis. Method: A systematic search was conducted in PubMed and Scopus databases as of June 26, 2018. Studies reporting the pharmacokinetic parameters of CYP1A2‐metabolized antipsychotic drugs in individuals who were genotyped for CYP1A2 genetic polymorphisms were retrieved. Pharmacokinetic parameters of individuals who have mutant alleles of a CYP1A2 genetic polymorphism were compared with the wild‐type individuals. Pooled‐effect estimates, presented as standardized mean difference, were calculated by means of the fixed‐effect or random‐effects model, as appropriate. Results: Ten studies involving 872 clozapine users, seven studies involving 712 olanzapine users, and two studies involving 141 haloperidol users were included. All but one study reported no associations between any CYP1A2 genetic polymorphisms and the pharmacokinetics of CYP1A2‐metabolized antipsychotic drugs. The pooled‐effect estimates through meta‐analyses of seven studies demonstrated no significant associations between the ‐163C>A or ‐2467delT polymorphism and clozapine or olanzapine concentrations in the blood. Conclusions: This study suggests that CYP1A2 genetic polymorphisms have no significant impact on the pharmacokinetics of CYP1A2‐metabolized antipsychotic drugs. CYP1A2 genotyping may have no clinical implications for personalized dosing of CYP1A2‐metabolized antipsychotic drugs. [ABSTRACT FROM AUTHOR]

Objective: To test the validity and sensitivity of the six‐item version (PANSS‐6) of the 30‐item Positive and Negative Syndrome Scale (PANSS‐30) in treatment‐resistant schizophrenia (TRS). Method: Using data from the clozapine phase (2E) of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, we investigated the following: (i) The scalability of PANSS‐6 and PANSS‐30; (ii) The correlation between PANSS‐6 and PANSS‐30 total scores; (iii) Whether PANSS‐6 could identify cross‐sectional symptom remission; and (iv) The efficacy of clozapine, olanzapine, risperidone and quetiapine in TRS using the 'speed of change' on PANSS‐6 and PANSS‐30 (change in total score per week) as outcome measures. Results: We found that (i) only PANSS‐6 and not PANSS‐30 was scalable; (ii) The correlation between PANSS‐6 and PANSS‐30 total scores was high (Spearman coefficient: 0.85), (iii) PANSS‐6 accurately identified cross‐sectional symptom remission as defined by the Andreasen et al. criteria; and (iv) The only antipsychotic that caused improvement (speed of change significantly lower than 0 during the first three months of treatment) was clozapine, both when using PANSS‐6 (speed of change: −0.50 points/week; 95%CI: −0.84, −0.17) and PANSS‐30 (speed of change: −1.41 points/week; 95%CI: −2.80, −0.02) as outcome measures. Conclusion: PANSS‐6 validly measures severity, remission and antipsychotic efficacy in TRS. [ABSTRACT FROM AUTHOR]

Objective: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein‐1 (MCP‐1) and chitinase‐3‐like protein 1 (YKL‐40) were investigated in plasma and cerebrospinal fluid (CSF) in first‐episode psychosis (FEP) patients. Method: CSF and blood were sampled from 42 first‐episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL‐40 and MCP‐1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN‐9000‐hematology analyzer. Results: We found higher plasma levels of MCP‐1 and YKL‐40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL‐40 levels in the CSF of tobacco‐free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. Conclusion: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL‐40 and MCP‐1 in the initiation and progression of schizophrenia. [ABSTRACT FROM AUTHOR]

Objectives: Depression is a frequent but potentially treatable clinical dimension in patients with schizophrenia spectrum disorders (PWS). However, there is a lack of consensual recommendations regarding the optimal strategy to manage depression in PWS. In this study, we aimed to compare the various proposed strategies to define a core set of valid care recommendations for depression management in PWS. Methods: After a systematic search of the literature, the methodological quality of 10 international guidelines from four continents was compared using a validated guideline appraisal instrument (AGREE II). Key recommendations for the management of depression in PWS were subsequently reviewed and discussed. Results: The methodological quality of the guidelines was heterogeneous. Although all guidelines proposed pharmacotherapy, psychosocial interventions were a minor concern. Waiting for antipsychotic effects mostly was recommended during the acute phase of schizophrenia. During the postpsychotic phase of the illness, a switch to a second‐generation antipsychotic and/or the adjunction of an antidepressant were the primary recommendations. Cognitive behavioural therapy and other medications were considered with strong variations. Conclusions: Further studies are needed to strengthen the level of evidence for antidepressive approaches in PWS. The inclusion of PWS as stakeholders is also considered to be a major issue for future guideline development. [ABSTRACT FROM AUTHOR]

Objective: No consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta‐analysis therefore focus on the use of clozapine as first‐line or second‐line treatment in non‐treatment‐resistant patients. Methods: Articles were eligible if they investigated clozapine compared to another antipsychotic as a first‐ or second‐line treatment in non‐treatment‐resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random‐effects meta‐analyses. Results: Fifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta‐analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges’ g = 0.220, P = 0.026, 95% CI = 0.026–0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges’ g = 0.274, P = 0.030, 95% CI = 0.027–0.521). Conclusion: The few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first‐ or second‐line treatment. Only large clinical trials may comprehensively probe disease stage‐dependent superiority of clozapine and investigate overall tolerability. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between long-term antipsychotic polypharmacy use and mortality; and determine whether this risk varies by cause of death and antipsychotic dose. Methods: Using data from a large anonymised mental healthcare database, we identified all adult patients with serious mental illness (SMI) who had been prescribed a single antipsychotic or polypharmacy, for six or more months between 2007 and 2014. Multivariable Cox regression models were constructed, adjusting for sociodemographic, socioeconomic, clinical factors and smoking, to examine the association between APP use and the risk of death. Results: We identified 10 945 adults with SMI who had been prescribed long-term antipsychotic monotherapy (76.9%) or APP (23.1%). Patients on long-term APP had a small elevated risk of mortality, which was significant in some but not all models. The adjusted hazard ratios for death from natural and unnatural causes associated with APP were 1.2 (0.9-1.4, P = 0.111) and 1.1 (0.7-1.9, P = 0.619) respectively. The strengths of the associations between APP and mortality outcomes were similar after further adjusting for % BNF antipsychotic dose (P = 0.031) or olanzapine equivalence (P = 0.088). Conclusion: The findings suggest that the effect of long-term APP on mortality is not clear-cut, with limited evidence to indicate an association, even after controlling for the effect of dose. [ABSTRACT FROM AUTHOR]

Objective: A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. Method: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. Results: Data of 26 studies were used in the present analysis because suffcient data were available only for olanzapine, risperidone and the no- medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. Conclusion: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported. [ABSTRACT FROM AUTHOR]