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Background: The licensed indications for valproate are narrow, yet this medication is commonly prescribed in mental health services., Objectives: To explore the target symptoms/behaviours for which valproate is prescribed and how well the efficacy and tolerability of this treatment are monitored in routine clinical practice., Design: An audit-based quality improvement (QI) programme in UK mental health services., Methods: Information on valproate prescribing was collected from clinical records using a bespoke data collection tool., Results: Sixty-four NHS mental health Trusts/healthcare organisations submitted data on valproate treatment for 5320 patients. Valproate was clearly prescribed for a licensed indication in 1995 (38%) patients, off-label in 1987 (37%) while the indication was uncertain/not available in 1338 (25%). Of the 919 patients started on valproate treatment within the past year, between a half and two-thirds had each of the relevant baseline physical health checks documented. In 539 (59%) of these patients, valproate was prescribed for an unlicensed indication; the prescription was recognised as off-label in 363 (67%), 20 (6%) of whom were documented as having had this explained to them. Of 631 patients prescribed valproate for between 3 months and a year, early on-treatment assessments of response and side effects were documented in 441 (70%) and 332 (53%), respectively. Of 4401 patients treated for more than a year, annual on-treatment reviews of clinical response and side effects were documented in 2771 (63%) and 2140 (49%), respectively., Conclusion: Our data suggest the majority of prescriptions for valproate in mental health services are not for a licensed indication. Furthermore, patients rarely receive an explanation that their valproate prescription is off-label, perhaps partly because the licensed indications are not widely understood by prescribers. Given the very limited evidence for efficacy for the off-label uses of valproate, failure to routinely conduct early on-treatment and annual reviews of the benefits and side effects of this medication may result in patients remaining on ineffective and poorly tolerated treatment by default., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: L.C. has disclosed that he has received consulting fees from AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Eisai, Enteris BioPharma, HLS Therapeutics, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Merck, Neurocrine, Novartis, Noven, Otsuka, Ovid, Relmada, Reviva, Sage, Sunovion, Teva, University of Arizona, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial or scientific scoping research Speaker: AbbVie/Allergan, Acadia, Alkermes, Angelini, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sage, Sunovion, Takeda, Teva and CME activities organised by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies Stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, stock options: Reviva Royalties: Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). E.F.-E. served as PI for the NIHR-HTA funded ATLANTIS study. C.P., T.R.E.B. and O.R. have nothing to declare., (© The Author(s), 2022.)

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted., Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400 mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at 6 months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at 6 months adjusted for baseline score, allocation group and site., Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at 6 months, of whom 21 (72%) were included in the mITT analysis. At 6 months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at 6 months was -3.86 (95% Confidence Intervals = -10.04 to 2.32). There were 14 serious adverse events; 6 in the clozapine arm and 8 in the placebo arm of the trial. There was little difference in the cost of care between groups., Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units., Trial Registration: ISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article except TREB, who has been a member of an advisory board for Gedeon Richter and NH who has attended educational events organised by various pharmaceutical industries over the last five years., (© The Author(s), 2022.)

Background: A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice., Methods: The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine., Results: There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40-3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group ( p = 0.014), and these were more likely to be cardiac symptoms., Conclusions: Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting., Competing Interests: Conflict of interest statement: Funding for this trial was provided by the Health Technology Assessment programme of the National Institute for Health Research. T.R.E.B. acted as a member of scientific advisory boards for Sunovion, Otsuka/Lundbeck and Newron Pharmaceuticals in relation to antipsychotic medication. C.P. participated in a neurosciences advisory board for Eli Lilly in relation to neurodegenerative diseases. P.K. received personal fees from Otsuka/Lundbeck for speaking at an educational meeting, received support in attending an international conference from Janssen, and acted as a member of a scientific advisory board for Otsuka/Lundbeck. M.H. received a speaker’s honorarium from Otsuka pharmaceuticals. H.B. received personal fees from Janssen Cilag, Lundbeck, and Eli Lilly. P.M.H. received personal fees for lecturing and/or consultancy (including attending advisory boards) from Allergan, Eli Lilly, Galen, Janssen, Lundbeck, Otsuka, Quantum Pharmaceutical, Roche, Servier, Sunovion, Takeda and Teva, and received conference support from Janssen, Lundbeck, Otsuka, Servier and Sunovion. All other authors have nothing to disclose.