Second-generation Antipsychotics Monotherapy Research Articles

Prescribing Trends for the Same Patients with Schizophrenia Over 20 Years.

Recent pharmacoepidemiology data show an increase in the proportion of patients receiving second-generation antipsychotic (SGA) monotherapy, but no studies have analyzed the same patients over a long period of time. Therefore, in this study, we retrospectively evaluated schizophrenia patients with available data for 20 years to determine whether the drug treatments in the same patients have changed in the past 20 years. The study began in April 2021 and was conducted in 15 psychiatric hospitals in Japan. Schizophrenia patients treated in the same hospital for 20 years were retrospectively examined for all prescriptions in 2016, 2011, 2006, and 2001 (ie, every 5 years). The mean age of the 716 patients surveyed in 2021 was 61.7 years, with 49.0% being female. The rate of antipsychotic monotherapy use showed a slight increasing trend over the past 20 years; the rate of SGA use showed a marked increasing trend from 28.9% to 70.3% over the past 20 years, while the rate of SGA monotherapy use showed a gradual increasing trend over the past 20 years. The rates of concomitant use of anticholinergics, antidepressants, anxiolytics/sleep medications, and mood stabilizers showed decreasing, flat, flat, and flat trends over the past 20 years, respectively. The results of this study showed a slow but steady substitution of SGAs for first-generation antipsychotics (FGAs) over time, even in the same patients.

The relation between second-generation antipsychotics and laxative use in elderly patients with schizophrenia.

We aimed to investigate factors associated with concomitant laxative use among elderly patients with schizophrenia, discharged on second-generation antipsychotics (SGAs), from two large public psychiatric hospitals in Taiwan. Elderly patients with schizophrenia who were discharged between 2006 and 2019 and received SGA monotherapy at discharge were included in the analysis. Multivariate logistic regression was used to identify factors associated with regular laxative use at discharge. The Cochrane-Armitage trend test was used to evaluate whether significant time trends existed for rates of laxative use at discharge. A total of 2591 elderly patients with schizophrenia were discharged during the study period, and 1727 of 2591 patients who met the inclusion criteria were included for analysis. Of these 1727 patients, 732 (42.4%) also received concomitant laxatives. Female gender, mood stabiliser use and concomitant diabetes mellitus were found to be associated with increased laxative use. Among SGAs, clozapine was associated with the highest rate of laxative use, followed by zotepine, quetiapine, olanzapine and risperidone. Additionally, risperidone, amisulpride, aripiprazole, paliperidone and sulpiride were associated with comparable rates of laxative use. Laxative use rates grew over time from 30.8% in 2006 to 46.6% in 2019 (z = 4.83, P < 0.001). Laxative use is common in elderly schizophrenia patients treated with SGAs. In cases of clinically significant constipation, switching to an SGA with a lower risk for constipation, or discontinuing the use of mood stabilisers should be considered, if clinically feasible.

Medication Gaps and Antipsychotic Polypharmacy in Previously Hospitalized Schizophrenia Patients: An Electronic Cohort Study in Three Canadian Provinces

BackgroundReal world evidence about antipsychotics focuses on rehospitalization. Modeling the time course of pharmacotherapy would show patients' adherence to medications and physicians' adherence to medication guidelines. We aimed to calculate the cumulative time spent in second generation antipsychotics (SGAs), gaps, antipsychotic polypharmacy, and clozapine in discharged schizophrenia patients.MethodsHospitalization and pharmacy dispensing data from 2008–2018 in Manitoba, Saskatchewan, and British Columbia were linked and an electronic cohort (N = 2,997) was created (mean follow-up: 49 months, SD = 38). Cohort members were required to have a minimum of 6 weeks medicated with aripiprazole, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone.ResultsThe multistate model predicted that schizophrenia patients accumulated 44 months in SGA monotherapy, 4 months in polypharmacy, 11 months in medication gaps and 17 days in clozapine over a 5-year period. The majority of transitions were between SGA and medication gap. Accumulated time in medication gaps was seven times as much as in clozapine. Each 10% delay in SGA initiation post-discharge was associated with a 2, 1, and 6% higher risk for polypharmacy (95% CI: 1.01–1.02), gap (95% CI: 1.01–1.01), and clozapine (95% CI: 1.04–1.08), respectively.InterpretationSchizophrenia patients accumulated more time unmedicated and in polypharmacy compared to clozapine. Either treatment guidelines for schizophrenia are not followed, or real-world challenges hamper their implementation.

Prescription of Anticholinergic Drugs in Patients With Schizophrenia: Analysis of Antipsychotic Prescription Patterns and Hospital Characteristics.

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups—low rate group (LG), medium rate group (MG), and high rate group (HG)—according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

Trends in Prescribing Antipsychotics for Children and Adolescents in Japan: A Descriptive Epidemiological Study Using a Large-Scale Pharmacy Dataset.

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17years receiving an initial antipsychotic prescription.

Factors associated with laxative use in schizophrenia patients treated with second-generation antipsychotics

The aim of this study was to investigate factors associated with concomitant laxative use among schizophrenia patients discharged on second-generation antipsychotics (SGAs) at two large psychiatric hospitals in Taiwan. Patients with schizophrenia who were discharged between 2006 and 2017 and received SGA monotherapy at discharge were included in the analysis. Multivariate logistic regression was used to identify factors associated with regular laxative use at discharge. Multivariate Cox regression was used to determine the effect of laxative use at discharge on time to rehospitalization within one year. The Cochran-Armitage trend test was used to evaluate whether significant time trends existed for rates of laxative use at discharge during the study period. Among patients discharged on SGAs (n = 11,861), 3,336 (28.1%) also received concomitant laxatives. Advanced age and higher antipsychotic or anticholinergic doses were found to be associated with an increase in laxative use. Among SGAs, clozapine was associated with the highest rate of laxative use, followed by zotepine, quetiapine, olanzapine and risperidone. Additionally, risperidone, amisulpride, aripiprazole, paliperidone and ziprasidone were associated with comparable rates of laxative use. In contrast, sulpiride was least associated with laxative use among all SGAs. Regular laxative use at discharge was found to be significantly associated with psychiatric rehospitalization. Also, rate of laxative use at discharge increased significantly during the study period. Laxative use is common in schizophrenia patients treated with SGAs. For clinically significant constipation, switching to an SGA with a lower risk for constipation, and decreasing the doses of SGAs and anticholinergics should be considered.

Association Between SIRT1, Cytokines, and Metabolic Syndrome in Schizophrenia Patients With Olanzapine or Clozapine Monotherapy.

Objective: Previous studies consistently showed the interaction between Sirtuin 1 (SIRT1) and immune inflammation is significantly related to metabolic abnormalities, but their role in the pathogenesis of metabolic syndrome caused by second-generation antipsychotics (SGAs) in schizophrenia patients largely remains unknown. Hence, the present study aimed to fill this gap.Methods: A total of 54 schizophrenia patients with olanzapine or clozapine monotherapy [metabolic syndrome (MetS)/non-MetS patients, 27/27] and 67 healthy subjects were recruited in the present study. The Positive and Negative Syndrome Scale was used, and the plasma levels of SIRT1, interleukin 6 (IL-6), IL-8, IL-10, and tumor necrosis factor α (TNF-α) were measured.Results: The results showed that schizophrenia patients treated with olanzapine or clozapine (both MetS and non-MetS groups) had significantly higher plasma levels of IL-6, IL-10, and TNF-α compared to normal controls (all P < 0.05). Moreover, the MetS patients exhibited markedly lower plasma levels of SIRT1 and higher plasma levels of IL-6 than non-MetS patients and normal controls (all P < 0.05). However, there were no significant differences in IL-8 levels between groups. Our correlation analysis showed that SIRT1 was significantly correlated with diastolic blood pressure, triglyceride, and high-density lipoprotein cholesterol in schizophrenia patients. The stepwise logistic regression analysis further identified the IL-6 × SIRT1 (β = −0.463, t = 10.040, P = 0.002) as the influencing factor for the MetS in the patients.Conclusion: Our preliminary findings suggest that SIRT1 interacted with inflammatory cytokines associated with MetS in schizophrenia patients treated with SGA monotherapy.

Antipsychotic prescription and polypharmacy among outpatients with schizophrenia in a Nigerian hospital.

International guidelines recommend antipsychotic monotherapy as the ideal treatment option in pharmacotherapy for schizophrenia, though this yields modest outcomes in a third of patients. Antipsychotic polypharmacy (APP) has been tried in many patients with schizophrenia to improve outcomes in those with poor treatment response. This study examined the pattern of antipsychotic prescription and polypharmacy among outpatient attendees with schizophrenia in a Nigerian psychiatric hospital. A cross-sectional study of 320 attendees with schizophrenia at the consultant outpatient department was undertaken. We administered a socio-demographic questionnaire, antipsychotic medication and health questionnaire to record the general health indices and the prescribed antipsychotic medication of participants and the Mini-International Neuropsychiatric Interview (MINI) Version 6.0 (psychosis module). Oral second-generation antipsychotics (SGAs) monotherapy was most commonly prescribed. The prevalence of APP was 50.9%. Participants on simultaneous anticholinergic agents (P < 0.001), a twice-daily antipsychotic dosing interval (P < 0.001,) alcohol use (P = 0.02), antidepressant use (P = 0.02) and a current episode of schizophrenia on the MINI (P < 0.001) were more likely to be on an APP regimen. Although a preference for SGA monotherapy was observed, the prevalence of APP remained high. Clinicians, therefore, should be cautious regarding the clinical utility of APP and discourage its persistent use.

Long-Term Metabolic Effects in French-Canadian Children and Adolescents Treated with Second-Generation Antipsychotics in Monotherapy or Polytherapy: A 24-Month Descriptive Retrospective Study.

To compare weight and glucose changes of long-term second-generation antipsychotic (SGA) monotherapy versus polytherapy (switching or combining SGAs) in children and adolescents. This is a 24-month retrospective study conducted between November 2005 and June 2013. From 147 antipsychotic-naive patients selected (mean age, 12.8 years; 95% confidence interval [CI], 9.8-15.9), 116 (78.9%) received SGA monotherapy and 31 (21.1%) SGA polytherapy for up to 24 months. Height, weight, and fasting glucose (FG) were measured at baseline and 1, 3, 6, 12, and 24 months. Linear mixed-model analysis was used to compare weight, body mass index z score (BMI z score), and glucose changes between the 2 SGA treatment groups, with the repeated factor being the time relative to baseline at 1, 3, 6, 12, and 24 months. Overall, after 24 months of SGA treatment, mean weight increased significantly by 12.8 kg (95% CI, 10.4-15.0), BMI z score by 0.44 (95% CI, 0.21-0.68), and FG levels by 0.29 mmol/L (95% CI, 0.11-0.47). Incidence of overweight/obesity was 22.6%, BMI z score increase over 0.5 was 9.4%, impaired fasting glucose was 9.4%, and type 2 diabetes mellitus was 3.1%. Regarding metabolic effects, no significant difference was found between the subjects taking a single SGA and those exposed to an SGA polytherapy. Our study confirms the significant increase of metabolic complications during 24 months of SGA treatment without excluding or confirming a difference between the 2 groups of treatment (mono vs. poly).

Trends in antipsychotic prescriptions for Japanese outpatients during 2006-2012: a descriptive epidemiological study.

This study aimed to assess the trends in antipsychotic prescriptions for outpatients in Japan, where a community-based approach to mental healthcare is emphasized. This descriptive epidemiological study used claims data from 1038 community pharmacies across Japan. Outpatients who were ≥18years old and receiving their initial antipsychotic prescription during 2006-2012 were evaluated. The annual trends were reported for monotherapies, polypharmacy, antipsychotic doses, and the concurrent prescription of psychotropic medications. The 152592 outpatients included 101133 (66%) adults (18-64years old) and 51459 (34%) older adults (≥65years old). Among the adults, second-generation antipsychotic monotherapy prescriptions increased from 49% in 2006 to 71% in 2012, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 14%, and antipsychotic polypharmacy decreased from 23 to 15%, respectively. Among the older adults, second-generation antipsychotic monotherapy prescriptions increased from 64 to 82%, first-generation antipsychotic monotherapy prescriptions decreased from 29 to 12%, and antipsychotic polypharmacy decreased from 7 to 6%, respectively. During the study period, >80% of the adults and >90% of the older adults received antipsychotics at risperidone-equivalent doses of <6mg/day. Anxiolytics/hypnotics, antidepressants, antiparkinson agents, mood stabilizers, and anti-dementia agents were concurrently prescribed with antipsychotics for 70, 33, 20, 20, and 0.3% of the adults and for 43, 16, 19, 8, and 16% of the older adults, respectively. The present study evaluated large-scale claims-based datasets and found that high-dose prescriptions and antipsychotic polypharmacy among Japanese outpatients were not as prevalent as has been previously thought. Copyright © 2017 John Wiley & Sons, Ltd.

High doses of antipsychotic polypharmacy are related to an increase in serum levels of pentosidine in patients with schizophrenia

BackgroundCarbonyl stress in patients with schizophrenia has been reported to be reflected by an increase in peripheral pentosidine levels. This cohort study tested whether the accumulation of pentosidine was related to the disease severity or the treatment (routine administration of high antipsychotic doses). MethodsWe followed up our original investigation using a new group of 137 patients with acute schizophrenia and 45 healthy subjects, and then pooled the two cohorts to conduct the following analysis on a total of 274 patients. The associations of serum pentosidine and pyridoxal levels with duration of education, estimated duration of medication, the severity of symptoms, and daily doses of antipsychotics, antiparkinsonian drugs, and anxiolytics were evaluated by multiple linear regression analysis. ResultsThe combined cohort of 274 patients exhibited abnormally high serum levels of pentosidine, were associated with a higher daily dose of antipsychotic drugs and a longer estimated duration of medication without statistical significance of diagnosis. This was also observed in the patients treated with antipsychotic polypharmacy, but the serum pentosidine levels of patients treated with first- or second-generation antipsychotic monotherapy showed no relationship with these two variables. ConclusionHigh levels of serum pentosidine were associated with high daily doses of antipsychotic drugs and a longer estimated duration of medication in patients treated with antipsychotic polypharmacy.

Treatment recommendations for DSM-5-defined mixed features.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier provides a less restrictive definition of mixed mood states, compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), including mood episodes that manifest with subthreshold symptoms of the opposite mood state. A limited number of studies have assessed the efficacy of treatments specifically for DSM-5-defined mixed features in mood disorders. As such, there is currently an inadequate amount of data to appropriately inform evidence-based treatment guidelines of DSM-5 defined mixed features. However, given the high prevalence and morbidity of mixed features, treatment recommendations based on the currently available evidence along with expert opinion may be of benefit. This article serves to provide these interim treatment recommendations while humbly acknowledging the limited amount of evidence currently available. Second-generation antipsychotics (SGAs) appear to have the greatest promise in the treatment of bipolar disorder (BD) with mixed features. Conventional mood stabilizing agents (ie, lithium and divalproex) may also be of benefit; however, they have been inadequately studied. In the treatment of major depressive disorder (MDD) with mixed features, the comparable efficacy of antidepressants versus other treatments, such as SGAs, remains unknown. As such, antidepressants remain first-line treatment of MDD with or without mixed features; however, there are significant safety concerns associated with antidepressant monotherapy when mixed features are present, which merits increased monitoring. Lurasidone is the only SGA monotherapy that has been shown to be efficacious specifically in the treatment of MDD with mixed features. Further research is needed to accurately determine the efficacy, safety, and tolerability of treatments specifically for mood episodes with mixed features to adequately inform future treatment guidelines.

A population‐based study of the comparative effectiveness of second‐generation antipsychotics vs older antimanic agents in bipolar disorder

Numerous antimanic treatments have been introduced over the past two decades, particularly second-generation antipsychotics (SGAs). However, it is not clear whether such newer agents provide any advantage over older treatments. A historical cohort design investigated the nationwide population of outpatients with bipolar disorder treated in the Department of Veterans Affairs who were newly initiated on an antimanic agent between 2003 and 2010 (N=27727). The primary outcome was likelihood of all-cause hospitalization during the year after initiation, controlling for numerous demographic, clinical, and treatment characteristics. Potential correlates of effect were explored by investigating time to initiation of a second antimanic agent or antidepressant. After control for covariates, those initiated on lithium or valproate monotherapy, compared to those beginning SGA monotherapy, were significantly less likely to be hospitalized, had a longer time to hospitalization, and had fewer hospitalizations in the subsequent year. Those on combination treatment had a significantly higher likelihood of hospitalization, although they also had a longer time to addition of an additional antimanic agent or antidepressant. The present analysis of a large and unselected nationwide population provides important complementary data to that from controlled trials. Although various mechanisms may be responsible for the results, the data support the utilization of lithium or valproate, rather than SGAs, as the initial antimanic treatment in bipolar disorder. A large-scale, prospective, randomized, pragmatic clinical trial comparing the initiation of SGA monotherapy to that of lithium or valproate monotherapy is a logical next step.

Long-Acting Injectable Antipsychotics for Prevention of Relapse in Bipolar Disorder: A Systematic Review and Meta-Analyses of Randomized Controlled Trials.

Background:This meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder.Methods:Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications.Results:We identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials)=449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio=0.63, P<.0001), relapse of manic symptoms (risk ratio=0.42, P<.00001), and all-cause discontinuation (risk ratio=0.75, P=.007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio=4.82, P=.001) and weight gain (risk ratio=3.80, P<.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I2=0%, RR=0.58, P=.0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR=2.66, P=.03).Conclusions:Long-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.

Pain perception in schizophrenia: influence of neuropeptides, cognitive disorders, and negative symptoms.

ObjectivesThe causes and nature of insensitivity to pain in schizophrenia remain unknown. The role of endorphins and the association of cognitive dysfunction and negative symptoms are postulated.MethodsIn this study, 43 patients with schizophrenia, five first-degree relatives, and 34 healthy controls were examined. Participants’ plasma concentrations of substance P, β-endorphin, and calcitonin gene-related peptide (CGRP) were assessed. In patients, the Trail-Making Test, the Color Reading Interference Test (Stroop test), and the Positive and Negative Syndrome Scale Negative Syndrome subscale (PANSS N) test were performed. We also evaluated pain threshold using nociceptive reflex (RTIII) testing.ResultsThe mean β-endorphin concentration was about 20% higher in patients than in healthy controls (P<0.05). CGRP concentrations were significantly higher in patients than in controls (5.34 ng/mL versus 4.16 ng/mL; P<0.01). Subjects treated with antipsychotic polytherapy had higher concentrations of CGRP than did patients treated with second-generation antipsychotic monotherapy (5.92 ng/mL versus 5.02 ng/mL; P<0.05). There were no correlations between any biochemical parameters and Trail-Making Test, Stroop test, and PANSS N scores. There were no differences in RTIII among study groups. Strong negative correlation (P<0.001) was found between PANSS N scores and subjective pain threshold on the right lower limb.ConclusionThe insensitivity to pain in schizophrenia is a complex phenomenon that is probably not related to changes in nociceptive pathways. Increase in β-endorphin level may be related to this issue, but it is uncertain if such concentration ensures analgesic effect. It is unknown if patients with schizophrenia in fact experience less pain. Cognitive impairment and excess negative symptoms may strongly influence the patient’s expression of pain.

Risk of manic switch associated with antidepressant therapy in pediatric bipolar depression.

The purpose of this study was to assess the risk of manic switch associated with antidepressants in Medicaid-enrolled pediatric patients with bipolar depression. This retrospective cohort study involved 2003-2007 Medicaid Analytic eXtract (MAX) data from four geographically diverse states. The study sample included children and adolescents (ages 6-18 years) who had received a diagnosis of bipolar disorder on two or more separate occasions or during a hospital discharge, followed by a diagnosis of depression. According to the pharmacotherapy received by these patients in the 30 days around the index bipolar depression diagnosis, patients were categorized into five mutually exclusive groups. Manic switch was defined as having received a diagnosis of mania within 6 weeks after the initiation of bipolar depression treatment. Relative risks of manic switch between antidepressant monotherapy/polytherapy and their alternatives were assessed using Cox proportional hazards model. The robustness of the conventional Cox proportional hazards model toward possible bias caused by unobserved confounders was tested using instrumental variable analysis, and the uncertainty regarding manic switch definition was tested by altering the duration of follow-up. After applying all the selection criteria, 179 antidepressant monotherapy, 1047 second-generation antipsychotic (SGA) monotherapy, 570 mood stabilizer monotherapy, 445 antidepressant polytherapy, and 1906 SGA-mood stabilizer polytherapy users were identified. In Cox proportional hazard analyses, both antidepressant monotherapy and polytherapy exhibited higher risk of manic switch than their alternatives (antidepressant monotherapy vs. SGA monotherapy, hazard ratio [HR]=2.87 [95% CI: 1.10-7.49]; antidepressant monotherapy vs. mood stabilizer monotherapy, HR=1.41 [95% CI: 0.52-3.80); antidepressant polytherapy vs. SGA-mood stabilizer polytherapy, HR=1.61 [95% CI: 0.90-2.89]). However, only the comparison between antidepressant monotherapy and SGA monotherapy was statistically significant. The instrumental variable analysis did not detect endogeneity of the treatment variables. Extending the follow-up period from 6 weeks to 8 and 12 weeks generated findings consistent with the main analysis. Study findings indicated a higher risk of manic switch associated with antidepressant monotherapy than with SGA monotherapy in pediatric patients with bipolar depression. The finding supported the clinical practice of cautious prescribing of antidepressants for brief periods.

Antipsychotic Polypharmacy in a Treatment-Refractory Schizophrenia Population Receiving Adjunctive Treatment With Electroconvulsive Therapy

Antipsychotic polypharmacy (APP) is frequent, but its pattern is unknown in treatment-refractory schizophrenia-spectrum patients receiving electroconvulsive therapy (ECT). We performed a retrospective chart review of ECT-treated inpatients hospitalized at 2 Danish University hospitals from 2003 to 2008, focusing on APP patterns in patients with schizophrenia-spectrum disorders (n = 79, 13.2%). In addition to univariate analyses, a multivariate logistic regression analysis was performed to identify independent predictors of APP. Of 79 antipsychotic-treated patients (aged 48.6 ± 14.2 years; illness duration, 18.3 ± 10.6 years) ultimately treated with ECT, 86.1% received 2 or more psychotropic medications, including mood stabilizers (19.0%), antidepressants (32.9%), and APP (72.2%; 2 antipsychotics = 41.8%, 3 = 21.5%, 4-5 = 7.6%). Most patients received first-generation antipsychotic (FGA) + second-generation antipsychotic (SGA) (48.1%), followed by SGA + SGA (24.1%), SGA monotherapy (22.8%), and FGA monotherapy (5.1%). Individual antipsychotics included olanzapine (44.3%), risperidone (26.6%), clozapine (26.6%), quetiapine (22.1%), ziprasidone (13.9%), aripiprazole (10.1%), and sertindole (3.8%). Antipsychotic polypharmacy was associated with a greater number of FGAs (0.8 ± 0.7 vs 0.1 ± 0.4, P < 0.0001) and SGAs (1.7 ± 0.8 vs 0.8 ± 0.4, P < 0.0001), zuclopenthixol use (31.6% vs 0%, P = 0.0019), olanzapine use (52.6% vs 22.7%, P = 0.017), less serotonin-noradrenaline reuptake inhibitor use (3.5% vs 18.2%, P = 0.027), and a trend toward more good to excellent ECT response (86.0% vs 68.2%, P = 0.071). In the logistic regression analysis, APP was independently associated with a higher number of FGAs (P = 0.0002) and olanzapine use (P = 0.0098) (r = 0.314, P < 0.0001). Only 22.6% of this treatment-refractory population received clozapine, yet 72.4% received APP. Following the results from our study as well as the general level of evidence, patients with refractory schizophrenia-spectrum disorder should receive clozapine or ECT before being tried on APP.

Pregnancy outcomes following maternal exposure to second generation antipsychotics: considering polytherapy

Studies on the reproductive safety of second generation antipsychotics (SGAPs) are scarce, and none have compared monotherapy to polytherapy. A cohort study using a prospectively collected database was conducted. Pregnancy outcomes of 133 women exposed to SGAPs and other psychotropic drugs and 133 matched healthy controls were assessed. Psychotropic drug polytherapy was documented in 72% of exposed women. The exposed women had significantly higher pre‐pregnancy weight, smoked more cigarettes, experienced more associated comorbidities and instrumental deliveries and delivered more large for gestational age children. More of the exposed neonates were born premature, admitted to the intensive care unit and presented with poor neonatal adaptation signs and higher major malformations rates. In the monotherapy subgroup, no malformations were reported. In utero exposure to antipsychotic polytherapy is associated with adverse pregnancy outcomes for both mother and child. SGAP monotherapy appears to be associated with less risk to the fetus. Future studies should differentiate among the effects of psychotropic medication exposure and the underlying psychopathology and associated comorbidities.

Receipt of Guideline-Concordant Pharmacotherapy Among Children With New Diagnoses of Bipolar Disorder

This study examined the extent to which children with bipolar I disorder received recommended treatment of mood-stabilizer or second-generation antipsychotic monotherapy and factors associated with its receipt. Administrative claims data collected from January 1, 2005, to December 31, 2007, were used to construct a cohort of 412 privately insured children with bipolar I disorder. The primary outcome measure was the receipt of mood-stabilizer or second-generation antipsychotic monotherapy within 90 days of an index diagnosis of bipolar disorder. Only 82 (20%) children received recommended first-line treatment for bipolar I disorder within 90 days of the index diagnosis, and 130 (32%) received no psychotropic medications. Of children receiving any medications, 200 (71%) received nonrecommended pharmacotherapy, most commonly antidepressant monotherapy (N=67, 24%) and combination pharmacotherapy (N=51, 18%). Youths who had been treated by a psychiatrist on the day of or 180 days before the fill date of medication were more likely to receive guideline-recommended care (risk ratio [RR]=1.64, 95% confidence interval [CI]=1.10-2.45) and to receive any psychotropic medications (RR=1.13, CI=1.02-1.24). Nevertheless, only 51 of the 209 (24%) children who visited a psychiatrist and 31 of the 203 (15%) who visited a nonpsychiatrist received recommended pharmacotherapy. This study highlights significant gaps in the treatment of pediatric bipolar disorder. Most children in this sample received either no medications or nonrecommended pharmacotherapies. Additional research is needed to further assess factors related to the nonuse of recommended psychotropic medications and to the persistent use of nonrecommended pharmacotherapies for children with bipolar disorder.

Association between second-generation antipsychotic medication half-life and hospitalization in the community treatment of adult schizophrenia

Objective:To examine the effect of antipsychotic medication half-life on the risk of psychiatric hospital admission and emergency department (ED) visits among adults with schizophrenia.Methods:Retrospective claims-based cohort study of adult Medicaid patients with schizophrenia who were prescribed second-generation antipsychotic monotherapy following hospital discharge between 1/1/04 and 12/31/06. Cox proportional hazards models were applied to compare adjusted hazards of mental disorder admission among patients treated with oral antipsychotics that have either a long [risperidone (t1/2 = 20 h), olanzapine (t1/2 = 30 h), aripiprazole (t1/2 = 75 h)] (n = 1479) or short [quetiapine (t1/2 = 6 h), ziprasidone (t1/2 = 7 h)] (n = 837) half-life. Day-level models controlled for baseline background characteristics and antipsychotic adherence over time as measured by gaps in the prescription record. Similar analyses examined either hospitalization or ED visits as separate endpoints.Results:A significantly lower rate of hospitalization/ED visits was evident for long (0.74/patient-year) vs short (1.06/patient-year) half-life antipsychotics (p < 0.001). The unadjusted rate of hospitalization alone was significantly lower for long (0.38/patient-year) vs short (0.52/patient-year) half-life antipsychotics (p = 0.005). Compared with short half-life antipsychotic drugs, the adjusted hazard ratio associated with long half-life medications was 0.77 (95% CI = 0.67–0.88) for combined hospitalization/ED visits and 0.80 (95% CI = 0.67–0.96) for hospitalization. The corresponding number needed to treat with long, rather than short, half-life medications to avoid one hospitalization was 16 patients for 1 year and to avoid one hospitalization or ED visit was 11 patients for 1 year.Limitations:This study demonstrated an association between antipsychotic medication half-life and hospitalization, not a causal link. Patients using long half-life medications had fewer comorbid mental health conditions and took fewer psychiatric medications at baseline. Other unmeasured differences may have existed between groups and may partially account for the findings.Conclusions:In schizophrenia management, longer-acting second-generation antipsychotics were associated with a lower risk of hospital admission/ED visits for mental disorders.