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Summary Points * Existing studies of long-term antipsychotic treatment for people with schizophrenia and related conditions are too short and have ignored the impact of discontinuation-related adverse effects. * Recent evidence confirms that antipsychotics have a range of serious adverse effects, including reduction of brain volume. * The first really long-term follow-up of a randomised trial found that patients with first-episode psychosis who had been allocated to a gradual antipsychotic reduction and discontinuation programme had better functioning at seven-year follow-up than those allocated to maintenance treatment, with no increase in relapse. * Further studies with long-term follow-up and a range of outcomes should be conducted on alternatives to antipsychotic maintenance treatment for people with recurrent psychotic conditions.

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n  = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use ( n  = 1869). Two meta-analyses of overlapping studies examining the 5-HT 1A receptor (largest n  = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n  = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers ( n  = 566), but weak evidence of an effect in those with a family history of depression ( n  = 75). Another systematic review ( n  = 342) and a sample of ten subsequent studies ( n  = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study ( n  = 115,257) and one collaborative meta-analysis ( n  = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Esketamine has been licensed for ‘treatment-resistant depression’ in the USA, UK and Europe. Licensing trials did not establish efficacy: two trials were negative, one showed a statistically significant but clinically uncertain effect, and a flawed discontinuation trial was included, against Food and Drug Administration precedent. Safety signals – deaths, including suicides, and bladder damage – were minimised.

Recruitment and retention challenges are very common in mental health randomised trials. Investigators utilise different methods to improve recruitment or retention. However, evidence of the effectiveness and efficiency of these strategies in mental health has not been synthesised. This systematic review is to investigate and assess the effectiveness and cost-effectiveness of different strategies to improve recruitment and retention in mental health randomised trials. MEDLINE, EMBASE, the Cochrane Methodology Register and PsycINFO were searched from beginning of record up to July 2016. Randomised trials involving participants with mental health problems which compared different strategies for recruitment or retention were selected. Two authors independently screened identified studies for eligibility. A total of 5,157 citations were identified. Thirteen articles were included, 11 on recruitment and 2 on retention. Three randomised controlled trials compared different recruitment strategies, none of which found statistically significant differences between the interventional recruitment strategies and the routine recruitment methods. Retrospective comparisons of recruitment methods showed that non-web-based advertisement and recruitment by clinical research staff each have advantages in efficiency. Web-based adverts had the lowest cost per person recruited (£13.41 per person recruited). Specialised care referral cost £183.24 per person, non-web-based adverts cost £372.03 per patient and recruitment via primary care cost £407.65 for each patient. Financial incentives, abridged questionnaires and pre-notification had a positive effect on retention rates. The recruitment studies included showed differences in strategies, clinical settings, mental health conditions and study design. It is difficult to assess the overall effectiveness of any particular recruitment strategy as some strategies that worked well for a particular population may not work as well for others. Paying attention to the accessibility of information and consent materials may help improve recruitment. More research in this area is needed given its important implications.

The default position in the treatment of psychotic conditions is that lifelong treatment is required after multiple episodes, with some portion of patients able to stop after a single episode. However, there are reasons to question this consensus, including that not everyone who stops antipsychotics relapses, the protective effects of antipsychotics may have been exaggerated due to the possibility that withdrawal itself is associated with adverse effects, including relapse, there is little evidence that antipsychotics target a pathological mechanism and their adverse effects may outweigh their benefits for some users. Recent pragmatic trials that employ a gradual reduction strategy give mixed results. They highlight that relapse is still a potential risk, but there may be gains in terms of social functioning in the long-term. There are no consistent factors that enable identification of people who might be able to discontinue antipsychotics more successfully, suggesting this option should be more widely offered. A gradual, hyperbolic approach to tapering has been proposed to reduce the adverse effects of withdrawal and relapse on stopping—approximated, for example, by reductions of 5-10% of the most recent dose every month. Patients should be supported to make decisions about long-term antipsychotic treatment based on weighing up the pros and cons of antipsychotic effects, in the light of the evidence base and the individual’s priorities. Given that increasing duration of treatment is likely to increase the risk of withdrawal on stopping, long-term antipsychotic treatment should be minimized where possible.

The widely established treatment for psychosis is long-term antipsychotic medication. However, many people stop taking this treatment, and request other options. There are also growing concerns about adverse effects, but currently no professional guidelines to support reducing or stopping these drugs. The views and experiences of individual mental health professionals around reducing and stopping antipsychotics are therefore crucial in treatment decisions. We conducted 7 focus groups with prescribing psychiatrists and other members of community-based statutory mental health services in London. Participants discussed their views about, experiences, and processes of antipsychotic reduction and discontinuation. Data were analysed using thematic analysis. Participants acknowledged that antipsychotics can have severe adverse effects. They were generally supportive of trying to reduce these drugs to the lowest effective dose, although stopping antipsychotics was less acceptable. Prior experiences of adverse events after reduction or discontinuation meant that both were approached with caution. Reduction was also reported to be hampered by organisational and knowledge barriers. Lack of resources, pressure to discharge, and poor continuity of care were seen as organisational barriers. Knowledge barriers included inadequate evidence about who might be best suited to reduction, and lack of guidance about how this could be done safely. This meant that reduction was often prompted by patients, and sometimes actively discouraged, and stability with maintenance treatment was often favoured. Concerns about risk and other barriers means that clinicians are often reluctant to implement reduction or discontinuation of antipsychotic medication. In order to increase the treatment options available to service users, more research and guidance on how to minimise the risks of antipsychotic reduction and discontinuation is required to enable clinicians to engage more constructively with service users requests, offering people more choice and control in managing their mental health condition.

Public Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development. We identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis. Thirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering. We found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice.

A series of editorials in this Journal have argued that psychiatry is in the midst of a crisis. The various solutions proposed would all involve a strengthening of psychiatry's identity as essentially ‘applied neuroscience’. Although not discounting the importance of the brain sciences and psychopharmacology, we argue that psychiatry needs to move beyond the dominance of the current, technological paradigm. This would be more in keeping with the evidence about how positive outcomes are achieved and could also serve to foster more meaningful collaboration with the growing service user movement.

Introduction Social cognition is an important area of mental functioning relevant to psychiatric disorders and social functioning, that may be affected by psychiatric drug treatments. The aim of this review was to investigate the effects of medications with sedative properties, on social cognition. Method This systematic review included experimental and neuroimaging studies investigating drug effects on social cognition. Data quality was assessed using a modified Downs and Black checklist (Trac et al. CMAJ 188: E120-E129, 2016). The review used narrative synthesis to analyse the data. Results 40 papers were identified for inclusion, 11 papers investigating benzodiazepine effects, and 29 investigating antipsychotic effects, on social cognition. Narrative synthesis showed that diazepam impairs healthy volunteer’s emotion recognition, with supporting neuroimaging studies showing benzodiazepines attenuate amygdala activity. Studies of antipsychotic effects on social cognition gave variable results. However, many of these studies were in patients already taking medication, and potential practice effects were identified due to short-term follow-ups. Conclusion Healthy volunteer studies suggest that diazepam reduces emotional processing ability. The effects of benzodiazepines on other aspects of social cognition, as well as the effects of antipsychotics, remain unclear. Interpretations of the papers in this review were limited by variability in measures, small sample sizes, and lack of randomisation. More robust studies are necessary to evaluate the impact of these medications on social cognition.