Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation Across Mental Disorders: A Systematic Review and Dose-Response Meta-Analysis.

Importance: Noninvasive brain stimulation (NIBS) interventions have been shown to be efficacious in several mental disorders, but the optimal dose stimulation parameters for each disorder are unknown. Objective: To define NIBS dose stimulation parameters associated with the greatest efficacy in symptom improvement across mental disorders. Data Sources: Studies were drawn from an updated (to April 30, 2023) previous systematic review based on a search of PubMed, OVID, and Web of Knowledge. Study Selection: Randomized clinical trials were selected that tested transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) for any mental disorder in adults aged 18 years or older. Data Extraction and Synthesis: Two authors independently extracted the data. A 1-stage dose-response meta-analysis using a random-effects model was performed. Sensitivity analyses were conducted to test robustness of the findings. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The main outcome was the near-maximal effective doses of total pulses received for TMS and total current dose in coulombs for tDCS. Results: A total of 110 studies with 4820 participants (2659 men [61.4%]; mean [SD] age, 42.3 [8.8] years) were included. The following significant dose-response associations emerged with bell-shaped curves: (1) in schizophrenia, high-frequency (HF) TMS on the left dorsolateral prefrontal cortex (LDLPFC) for negative symptoms (χ2 = 9.35; df = 2; P = .009) and TMS on the left temporoparietal junction for resistant hallucinations (χ2 = 36.52; df = 2; P < .001); (2) in depression, HF-DLPFC TMS (χ2 = 14.49; df = 2; P < .001); (3) in treatment-resistant depression, LDLPFC tDCS (χ2 = 14.56; df = 2; P < .001); and (4) in substance use disorder, LDLPFC tDCS (χ2 = 33.63; df = 2; P < .001). The following significant dose-response associations emerged with plateaued or ascending curves: (1) in depression, low-frequency (LF) TMS on the right DLPFC (RDLPFC) with ascending curve (χ2 = 25.67; df = 2; P = .001); (2) for treatment-resistant depression, LF TMS on the bilateral DLPFC with ascending curve (χ2 = 5.86; df = 2; P = .004); (3) in obsessive-compulsive disorder, LF-RDLPFC TMS with ascending curve (χ2 = 20.65; df = 2; P < .001) and LF TMS on the orbitofrontal cortex with a plateaued curve (χ2 = 15.19; df = 2; P < .001); and (4) in posttraumatic stress disorder, LF-RDLPFC TMS with ascending curve (χ2 = 54.15; df = 2; P < .001). Sensitivity analyses confirmed the main findings. Conclusions and Relevance: The study findings suggest that NIBS yields specific outcomes based on dose parameters across various mental disorders and brain regions. Clinicians should consider these dose parameters when prescribing NIBS. Additional research is needed to prospectively validate the findings in randomized, sham-controlled trials and explore how other parameters contribute to the observed dose-response association.

Differential effects of sertraline and cognitive behavioural therapy on behavioural inhibition in patients with obsessive compulsive disorder.

Patients with obsessive compulsive disorder (OCD) randomised to sertraline, manualised cognitive behavioural therapy (CBT), or combination (sertraline + CBT), underwent cognitive assessment. Cognitive testing was conducted at baseline and at week 16. The stop signal reaction time task (SSRT) was used to evaluate motor impulsivity and attentional flexibility was evaluated using the intra/extra-dimensional set shifting task. Paired-samples t -tests or nonparametric variants were used to compare baseline and posttreatment scores within each treatment group. Forty-five patients were tested at baseline (sertraline n  = 14; CBT n  = 14; sertraline + CBT n  = 17) and 23 patients at week 16 (sertraline n  = 6; CBT n  = 7; sertraline + CBT n  = 10). The mean dosage of sertraline was numerically higher in those taking sertraline as a monotherapy (166.67 mg) compared with those taking sertraline in combination with CBT (100 mg). Analysis of pre-post treatment scores using an intent-to-treat-analysis found a significant reduction in the SSRT in those treated with sertraline, whilst there was no significant change on this task for those treated with CBT or the combination. This study found that motor inhibition improved significantly following sertraline monotherapy. Suboptimal sertraline dosing might explain the failure to detect an effect on motor inhibition in the group receiving combination of sertraline + CBT. Higher dose sertraline may have broader cognitive effects than CBT for OCD, motor impulsivity may have value as a measure of treatment outcome and, by extension, the SSRT could serve as a biomarker for personalising care.

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Goal setting and goal attainment in patients with major depressive disorder: a narrative review on shared decision making in clinical practice.

OBJECTIVE: Narrative review of the processes of goal setting and goal attainment scaling, as practical approaches to operationalizing and implementing the principles of shared decision making (SDM) in the routine care of people living with major depressive disorder (MDD). METHODS: We searched electronic databases for clinical studies published in English using key terms related to MDD and goal setting or goal attainment scaling. Two clinical studies of goal setting in MDD are considered in detail to exemplify the practicalities of the goal setting approach. RESULTS: While SDM is widely recommended for people living with mental health problems, there is general agreement that it has thus far been implemented variably. In other areas of medicine, the process of goal setting is an established way to engage the patient, facilitate motivation, and assist the recovery process. For people living with MDD, the concept of goal setting is in its infancy, and only few studies have evaluated its clinical utility. Two clinical studies of vortioxetine for MDD demonstrate the utility of goal attainment scaling as an appropriate outcome for assessing functional improvement in ways that matter to the patient. CONCLUSIONS: Goal setting is a pragmatic approach to turning the principles of SDM into realities of clinical practice and aligns with the principles of recovery that encompasses the notions of self-determination, self-management, personal growth, empowerment, and choice. Accumulating evidence supports the use of goal attainment scaling as an appropriate personalized outcome measure for use in clinical trials.

Shared decision making is a structured approach in which a doctor assists their patient in making informed choices about treatment that consider the patient's own preferences. However, while acknowledged as the ideal approach, many doctors working in the mental health area say it can be difficult to apply in their daily clinical practice. In other areas of medicine, such as physical rehabilitation, the structured process of patients setting treatment goals in dialogue with their doctor has been recommended as a practical way to put the principles of shared decision making into practice.In this paper, we reviewed the medical literature to better understand how goal setting can be used to improve the care of people with major depressive disorder. The available evidence supports goal setting as a powerful way to engage patients in healthcare decisions, and ultimately improve health-related outcomes. The goal setting process provides patients the opportunity to verbalize their own, tangible goals for treatment; and following some negotiation, receive endorsement of their goals from their doctor. Patients feel supported and are better motivated to continue with their treatment.While still in its infancy, the growing evidence base supporting goal setting for people with major depressive disorder is encouraging. For example, the Goal Attainment Scaling (GAS) method of evaluating treatment success has been suitably adapted for use in people living with depression (GAS-D) and provides an easy, structured format for discussing personal treatment goals, as well as a method for tracking success, both in clinical practice and research studies.

Placebo effects in mental health disorders: protocol for an umbrella review.

INTRODUCTION: Given the high prevalence of mental health disorders and their significant socioeconomic burden, there is a need to develop improved treatments, and to evaluate them through placebo-controlled trials. However, the magnitude of the placebo response in randomised controlled trials to test medications may be substantial, affecting their interpretation. Therefore, improved understanding of the patient, trial and mental disorder factors that influence placebo responses would inform clinical trial design to better detect active treatment effects. There is a growing literature exploring the placebo response within specific mental health disorders, but no overarching synthesis of this research has been produced to date. We present a protocol for an umbrella review of systematic reviews and/or meta-analyses in which we aim to understand the effect size and potential predictors of placebo response within, and across, mental health disorders. METHODS AND ANALYSIS: We will systematically search databases (Medline, PsycINFO, EMBASE+EMBASE Classic, Web of Knowledge) for systematic reviews and/or meta-analyses that report placebo effect size in clinical trials in patients with mental health disorders (initial search date 23 October 2022). Screening of abstracts and full texts will be done in pairs. We will extract data to qualitatively examine how placebo effect size varies across mental health disorders. We also plan to qualitatively summarise predictors of increased placebo response identified either quantitatively (eg, through meta-regression) or qualitatively. Risk of bias will be assessed using the AMSTAR-2 tool. We aim to not only summarise the current literature but also to identify gaps in knowledge and generate further hypotheses. ETHICS AND DISSEMINATION: We do not believe there are any specific ethical considerations relevant to this study. We will publish the results in a peer-reviewed journal.

A randomised pilot feasibility study of eye movement desensitisation and reprocessing recent traumatic episode protocol, to improve psychological recovery following intensive care admission for COVID-19.

Background: Approximately 50% of intensive care survivors experience persistent psychological symptoms. Eye-movement desensitisation and reprocessing (EMDR) is a widely recommended trauma-focussed psychological therapy, which has not been investigated systematically in a cohort of intensive care survivors: We therefore conducted a randomised pilot feasibility study of EMDR, using the Recent Traumatic Episode Protocol (R-TEP), to prevent psychological distress in intensive care survivors. Findings will determine whether it would be possible to conduct a fully-powered clinical effectiveness trial and inform trial design. Method: We aimed to recruit 26 patients who had been admitted to intensive care for over 24 h with COVID-19 infection. Consenting participants were randomised (1:1) to receive either usual care plus remotely delivered EMDR R-TEP or usual care alone (controls). The primary outcome was feasibility. We also report factors related to safety and symptom changes in post-traumatic stress disorder, (PTSD) anxiety and depression. Results: We approached 51 eligible patients, with 26 (51%) providing consent. Intervention adherence (sessions offered/sessions completed) was 83%, and 23/26 participants completed all study procedures. There were no attributable adverse events. Between baseline and 6-month follow-up, mean change in PTSD score was -8 (SD = 10.5) in the intervention group versus +0.75 (SD = 15.2) in controls (p = 0.126). There were no significant changes to anxiety or depression. Conclusion: Remotely delivered EMDR R-TEP met pre-determined feasibility and safety objectives. Whilst we achieved group separation in PTSD symptom change, we have identified a number of protocol refinements that would improve the design of a fully powered, multi-centre randomised controlled trial, consistent with currently recommended rehabilitation clinical pathways. Trial registration: ClinicalTrials.gov: NCT04455360.

Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: A systematic review.

PURPOSE: Adverse effects of selective serotonin reuptake inhibitors (SSRIs) on sexual function have been an important area of research for many years. However, the duration of SSRI-associated sexual adverse effects, and their possible persistence after treatment discontinuation, is still uncertain. The aims of the current systematic review were first to identify existing evidence of sexual dysfunction following SSRI discontinuation, and to provide an account of reported symptoms and proposed treatment options; and second, to establish whether current literature allows accurate estimates of the prevalence of such sexual dysfunction. METHODS: A systematic review was conducted on PubMed, Embase, and Google Scholar; papers with clinical data regarding patients with persistent sexual dysfunction after SSRI treatment suspension were included. RESULTS: Overall, two retrospective interventional studies, six observational studies and 11 case reports were judged eligible for inclusion. It was not possible to determine reliable estimates of prevalence. Similarly, a cause-effect relationship between SSRI exposure and persistent sexual impairment could not be ascertained. Nonetheless, the potential for continued sexual disturbances despite discontinuation could not be entirely ruled out. CONCLUSIONS: There is a need to investigate a possible dose-response relationship between SSRI exposure and persistent sexual adverse effects. Treatment options for persistent dysfunctions remain limited, but novel therapeutic approaches may be required in order to address an otherwise neglected need for sexual well-being.

Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions.

INTRODUCTION: Generalized Anxiety Disorder (GAD) is a common psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry. Current management consists of a range of pharmacological and psychological treatments. However, many patients do not respond to first-line pharmacological treatments and novel anxiolytic drugs are being developed. AREAS COVERED: In this review, the authors first discuss the diagnostic criteria and epidemiology of GAD. The effective pharmacological treatments for GAD and their tolerability are addressed. Current consensus guidelines for treatment of GAD are discussed, and maintenance treatment, the management of treatment resistance, and specific management of older adults and children/adolescents are considered. Finally, novel anxiolytics under development are discussed, with a focus on those which have entered clinical trials. EXPERT OPINION: A range of effective treatments for GAD are available, particularly duloxetine, escitalopram, pregabalin, quetiapine, and venlafaxine. There is a limited evidence base to support the further pharmacological management of patients with GAD who have not responded to initial treatment. Although many novel anxiolytics have progressed to clinical trials, translation from animal models has been mostly unsuccessful. However, the potential of several compounds including certain psychedelics, ketamine, oxytocin, and agents modulating the orexin, endocannabinoid, and immune systems merits further study.

The relationship of separation anxiety with the age of onset of panic disorder.

AIM: This study aimed to investigate whether separation anxiety (SA) constitutes a dimension related to age at onset of panic disorder (PD), in homogeneous subgroups of outpatients with PD, based on their age of onset and symptom severity. METHODS: A sample of 232 outpatients with PD was assessed with the Panic Disorder Severity Scale (PDSS) and the Sheehan Disability Scale (SDS) for functional impairments. Separation anxiety was evaluated using structured interviews and questionnaires. We applied a K-Means Cluster Analysis based on the standardized "PD age of onset" and "the PDSS total score" to identify distinct but homogeneous groups. RESULTS: We identified three groups of patients: group 1 ("PD early onset/severe", N = 97, 42%, onset 23.2 ± 6.7 years), group 2 ("PD early onset/not severe", N = 76, 33%, onset 23.4 ± 6.0 years) and group 3 ("PD adult onset/not severe", N = 59, 25%, onset 42.8 ± 7.0 years). Patients with early onset/severe PD had significantly higher scores on all SA measures than PD late-onset/not severe. Regression analyses showed that SA scores, but not PDSS scores, were predictive of impairment in SDS work/school, social life, and family functioning domains. CONCLUSIONS: Our data indicate a significant relationship between SA and PD with an earlier age of onset and an impact on individual functioning. This may have important implications for implementing preventive interventions targeting early risk factors for the subsequent onset of PD.

Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology developed an evidence-based consensus guideline on the management of catatonia. A group of international experts from a wide range of disciplines was assembled. Evidence was gathered from existing systematic reviews and the primary literature. Recommendations were made on the basis of this evidence and were graded in terms of their strength. The guideline initially covers the diagnosis, aetiology, clinical features and descriptive epidemiology of catatonia. Clinical assessments, including history, physical examination and investigations are then considered. Treatment with benzodiazepines, electroconvulsive therapy and other pharmacological and neuromodulatory therapies is covered. Special regard is given to periodic catatonia, malignant catatonia, neuroleptic malignant syndrome and antipsychotic-induced catatonia. There is attention to the needs of particular groups, namely children and adolescents, older adults, women in the perinatal period, people with autism spectrum disorder and those with certain medical conditions. Clinical trials were uncommon, and the recommendations in this guideline are mainly informed by small observational studies, case series and case reports, which highlights the need for randomised controlled trials and prospective cohort studies in this area.

Validity of root cause analysis in investigating adverse events in psychiatry.

Root cause analysis (RCA), imported from high-reliability industries into health two decades ago, is the mandated methodology to investigate adverse events in most health systems. In this analysis, we argue that the validity of RCA in health and in psychiatry must be established, given the impact of these investigations on mental health policy and practice.

Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. METHODS: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a 'washout' period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. RESULTS: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = -0.5 [95% CI -1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. CONCLUSIONS: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step. TRIAL REGISTRATION: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049.

Apathy associated with antidepressant drugs: a systematic review.

OBJECTIVES: Administration of antidepressant drugs - principally selective serotonin reuptake inhibitors (SSRIs) - may induce clinically significant 'apathy' which can affect treatment outcomes adversely. We aimed to review all relevant previous reports. METHODS: We performed a PUBMED search of English-language studies, combining terms concerning psychopathology (e.g. apathy) and classes of antidepressants (e.g. SSRI). RESULTS: According to certain inclusion (e.g. use of DSM/ICD diagnostic criteria) and exclusion (e.g. presence of a clinical condition that may induce apathy) criteria, 50 articles were eligible for review. Together, they suggest that administration of antidepressants - usually SSRIs - can induce an apathy syndrome or emotional blunting, i.e. a decrease in emotional responsiveness, to circumstances which would have triggered intense mood reactions prior to pharmacotherapy. The reported prevalence of antidepressant-induced apathy ranges between 5.8 and 50%, and for SSRIs ranges between 20 and 92%. Antidepressant-induced apathy emerges independently of diagnosis, age, and treatment outcome and appears dose-dependent and reversible. The main treatment strategy is dose reduction, though some data suggest the usefulness of treatment with olanzapine, bupropion, agomelatine or amisulpride, or the methylphenidate-modafinil-olanzapine combination. CONCLUSION: Antidepressant-induced apathy needs careful clinical attention. Further systematic research is needed to investigate the prevalence, course, aetiology, and treatment of this important clinical condition.

Prevention of suicide by clozapine in mental disorders: systematic review.

BACKGROUND: Previous research has investigated the efficacy of clozapine in reducing suicidality in patients with schizophrenia and schizoaffective disorder. We aimed to systematically review published evidence, including studies concerning clozapine administration to treat: (a) refractory suicidality in other mental disorders, including bipolar disorder and borderline and other personality disorders; and (b) refractory cases of non-suicidal self-injury. METHOD: We performed a PUBMED-search (last day: July 17, 2022) of English-language studies, combining the keywords "clozapine", "suicidality", and "suicide" with various psychopathological terms (e.g. "schizophrenia"). All duplications were eliminated. RESULTS: Fifty-one studies were eligible for inclusion in the review. Most studies suggest a superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder, compared to other antipsychotics, or no antipsychotic therapy, which is not due to the close monitoring of patients for blood dyscrasias. No consensus exists as to whether other antipsychotic drugs share this effect. Discontinuation of clozapine is associated with increases in suicidality. Reductions in refractory suicidality/NSSI are observed in clozapine-treated patients with bipolar disorder or borderline personality disorder, but the evidence is limited. Potential biological underpinnings of the anti-suicide effect of clozapine include its unique profile of modulation of brain neurotransmitters; its non-selectivity for neurotransmitter receptors; specific genetic and hormonal factors; effects on neuroinflammation; and ability to elicit epileptiform activity. CONCLUSION: The superior anti-suicide effect of clozapine in schizophrenia/schizoaffective disorder patients is well established. It may have a role in severe and refractory cases of suicidality and non-suicidal self-injury in patients with bipolar disorder or borderline personality disorder, but the level and quality of supporting evidence is limited.