Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.

Comparing the efficacy of ondansetron and granisetron augmentation in treatment-resistant obsessive-compulsive disorder: a randomized double-blind placebo-controlled study This study aimed to assess the efficacy and tolerability of ondansetron vs. granisetron in patients with treatment-resistant obsessive-compulsive disorder. A randomized clinical trial conducted on 135 patients with a Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of obsessive-compulsive disorder, who were treatment-resistant and receiving stable treatment with selective serotonin reuptake inhibitors and antipsychotic, received 14 weeks (phase I, intervention period) of placebo (n = 45), ondansetron (n = 45, 4 mg), and granisetron (n = 45, 2 mg) daily augmentations. Patients were rated every 2 weeks using the Yale-Brown Obsessive Compulsive Scale. Upon completion of intervention course, patients were followed for 4 weeks (phase II, discontinuation period). The collected data were analyzed in SPSS Version 22, with χ2 test; Fisher’s exact test and independent t-test, according to the intention-to-treat principle. Two-factor repeated measure analysis of variance was used to compare score changes over phases. P < 0.05 was considered to be statistically significant. At week 14, reduction in Yale-Brown Obsessive Compulsive Scale scores in ondansetron, granisetron and placebo groups was 41.5%, 39.7% and 15.2%, respectively (P = 0.001). Complete response in the ondansetron group was significantly higher than in the granisetron group ((P = 0.041), risk ratio (95% confidence interval) = 2.33 (1.18–3.045)]. Relapse occurred by three (7.31%) patients in the granisetron group, whereas it was not seen in the ondansetron group [P < 0.001, risk ratio (95% confidence interval) = 2.81 (1.016–4.51)]. The results of this present study confirm the benefit of using ondansetron and granisetron as augmenting agents in treatment-resistant obsessive-compulsive disorder. Our results supported the potential superiority of ondansetron compared to granisetron. This needs to be confirmed in further placebo-controlled augmentation studies. Randomized controlled trial clinical trial registration number: IRCT20130726014170N2.

Comparison of the association of risperidone and quetiapine with deteriorating performance in walking and dressing in subjects with Parkinson’s disease: a retrospective cohort study using administrative claims data This retrospective cohort study was performed to investigate the association between risperidone and deteriorating performance in walking and dressing in subjects with Parkinson’s disease using the Japanese Diagnosis Procedure Combination data. These data include inpatient claims including information from the time of admission to discharge from 89 acute phase National Hospitals in Japan. The data were evaluated by implementing the inverse probability of treatment weighting, using propensity scores estimated from the clinical characteristics of subjects prescribed risperidone or quetiapine. The generalized estimation equation was used to estimate the adjusted risk ratios (aRRs) and 95% confidence intervals (CIs). In total, 304 subjects were eligible for participation, and were hospitalized between April 2012 and March 2017 (108 and 196 for risperidone and quetiapine groups, respectively). The performance of walking deteriorated at discharge, with 22.2% and 10.2% recorded at admission for the risperidone and quetiapine groups (aRR, 1.7; 95% CI, 0.9 to 3.4), respectively. The performance of dressing also deteriorated: 24.1% and 10.7% in the risperidone and quetiapine groups (aRR, 1.9; 95% CI, 1.04 to 3.7), respectively. These results suggest an association between risperidone and deteriorating performance in dressing in subjects with Parkinson’s disease in comparison with quetiapine.

Cytochrome P450-mediated inhibition of venlafaxine metabolism by trimipramine Objective The aim of this study was to ensure patients’ safety and to enhance treatment efficacy, knowledge about pharmacokinetic interactions even in complex clinical situations of polypharmacy is invaluable. This study is to uncover the potential of pharmacokinetic interactions between venlafaxine and trimipramine in a naturalistic sample. Methods Out of a therapeutic drug monitoring database with plasma concentrations of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV), we considered two groups of patients receiving venlafaxine without known cytochrome P450 confounding medications, taking solely venlafaxine: V0 (n = 905), and a group of patients co-medicated with trimipramine, VTRIM (n = 33). For VEN, ODV and active moiety (sum of VEN + ODV) plasma concentrations and dose-adjusted concentrations as well as ODV/VEN ratios were compared between groups using the Mann–Whitney U test with a significance level of 0.05. Results Patients co-medicated with trimipramine had higher plasma concentrations of VEN (183.0 vs. 72.0, +154%, P = 0.002) and AM (324.0 vs. 267.5, +21%, P = 0.005) and higher dose adjusted plasma concentrations than patients in the control group (P = 0.001 and P = 0.003). No differences were found for ODV and C/D ODV (P < 0.05 for both comparisons). The metabolite to parent ratio, ODV/VEN, was significantly lower in the VTRIM group (1.15 vs. 2.37, P = 0.012). Conclusion Findings suggest inhibitory effects of trimipramine on venlafaxine pharmacokinetics most likely via an inhibition of CYP 2D6 or by saturated enzyme capacity. The lack of in vitro data hampers the understanding of the exact mechanisms. Clinicians should be aware of drug–drug interactions when combining these agents. Therapeutic drug monitoring helps to ensure treatment efficacy and patients’ safety.

Addressing clozapine under-prescribing and barriers to initiation: a psychiatrist, advanced practice provider, and trainee survey Clozapine use has declined, despite its superior antipsychotic efficacy in treatment-resistant schizophrenia. Implications for clozapine underutilization include suboptimal treatment outcomes and increased hospitalizations. Many barriers preventing the use of clozapine have been described in the literature, including suboptimal knowledge and poor perceptions. The aim of this study was to assess psychiatry prescribers’ perception and knowledge of clozapine. A survey was distributed to advanced practice providers, psychiatrists, and trainees (i.e. residents and fellows) at 10 medical centers within the US and Canada. The survey asked respondents about their perception of clozapine use and assessed their pharmacotherapeutic knowledge of clozapine. Two hundred eleven individual submitted completed surveys of a possible 1152; a response rate of 18.3%. There were no statistically significant differences between the advanced practice provider plus psychiatrist groups and the trainee group for most perception (eight of nine) and knowledge (eight of nine) questions. The knowledge questions with the lowest scores pertained to clozapine reinitiation and myocarditis. The majority of all respondents (144, 68.2%) felt that clozapine prescribing was a burden. Findings of this study support the need for continued clozapine education regardless of a prescriber’s age/experience. Future studies to assess barriers to clozapine prescribing should extend beyond academic centers.

Clozapine-associated neutropenia in Latin America: incidence report of 5380 Chilean users Systematic information about Latino clozapine users is still scarce. Our aim was to evaluate the risk of clozapine-associated neutropenia in a Chilean cohort using the last Food and Drug Administration’s recommendations for clozapine monitoring. Findings should improve clinical practice and promote changes in clozapine guidelines in Latin America. We conducted a retrospective observational study of 5380 Chilean clozapine users that started clozapine treatment between 2003 and 2015. The absolute risk of severe neutropenia was 0.61% (33/5380) with an incidence of 0.086 cases per 100 person-years of follow-up. 87.9% of cases with severe neutropenia appeared during first 18 weeks. Cases of mild neutropenia were 3.9% of total sample and occurred almost constantly without a specific risk time. 77.5% of cases of moderate or severe neutropenia didn’t present an event of mild neutropenia before. 22.8% of clozapine users (1227/5380) discontinued treatment for any cause and 4.2% (225/5380) due to neutropenia in any severity level. Clozapine-associated neutropenia risk in Latino users is similar than in the rest of the world. The evidence of a very low risk for severe neutropenia and the behaviour of mild neutropenia cases confirm the feasibility of changes in Latin American clozapine guidelines using current Food and Drug Administration’s recommendations as a model.

Need to bleed? Clozapine haematological monitoring approaches a time for change Regular haematological monitoring during clozapine treatment reduces the risk of complications and death from clozapine-related blood dyscrasias. However, many patients in the course of clozapine treatment develop neutropenia unrelated to drug treatment which leads to treatment discontinuation. The minimum haematological threshold allowed for the continuation of clozapine treatment was recently lowered in the US, but not in the UK. In this case series, we present four cases where lowering the haematological cut-off to that used in the US, allowed treatment continuation. Lowering the current UK threshold for clozapine cessation could avoid unnecessary interruptions in treatment with minimal impact on safety.

Delayed complications after severe clozapine intoxication: a case report. The pharmacokinetic profile of clozapine and it’s important role in the course of symptoms Clozapine intoxications have a varied clinical presentation and may have severe complications. Management and treatment guidelines rarely highlight the risks of delayed clinical presentations. We present the case of a 50-year-old man showing severe complications 15 hours after intoxication with 4200 mg clozapine. Treatment consisted of strict monitoring, including vital support and regular clozapine blood levels. Clinical presentations may be delayed up to 5 days after intoxication, for which strict monitoring of clinical symptoms and vital functions during this period is of major importance. We discuss the clinical course of clozapine intoxication, the value of sampling clozapine blood levels and provide an overview of the current treatment guidelines, which we suggest to update to include the management of delayed complications.

Patient attitudes to clozapine initiation: Erratum No abstract available