Towards precision in the diagnostic profiling of patients: leveraging symptom dynamics as a clinical characterisation dimension in the assessment of major depressive disorder.

BACKGROUND: International guidelines present overall symptom severity as the key dimension for clinical characterisation of major depressive disorder (MDD). However, differences may reside within severity levels related to how symptoms interact in an individual patient, called symptom dynamics. AIMS: To investigate these individual differences by estimating the proportion of patients that display differences in their symptom dynamics while sharing the same overall symptom severity. METHOD: Participants with MDD (n = 73; mean age 34.6 years, s.d. = 13.1; 56.2% female) rated their baseline symptom severity using the Inventory for Depressive Symptomatology Self-Report (IDS-SR). Momentary indicators for depressive symptoms were then collected through ecological momentary assessments five times per day for 28 days; 8395 observations were conducted (average per person: 115; s.d. = 16.8). Each participant's symptom dynamics were estimated using person-specific dynamic network models. Individual differences in these symptom relationship patterns in groups of participants sharing the same symptom severity levels were estimated using individual network invariance tests. Subsequently, the overall proportion of participants that displayed differential symptom dynamics while sharing the same symptom severity was calculated. A supplementary simulation study was conducted to investigate the accuracy of our methodology against false-positive results. RESULTS: Differential symptom dynamics were identified across 63.0% (95% bootstrapped CI 41.0-82.1) of participants within the same severity group. The average false detection of individual differences was 2.2%. CONCLUSIONS: The majority of participants within the same depressive symptom severity group displayed differential symptom dynamics. Examining symptom dynamics provides information about person-specific psychopathological expression beyond severity levels by revealing how symptoms aggravate each other over time. These results suggest that symptom dynamics may be a promising new dimension for clinical characterisation, warranting replication in independent samples. To inform personalised treatment planning, a next step concerns linking different symptom relationship patterns to treatment response and clinical course, including patterns related to spontaneous recovery and forms of disorder progression.

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Community interventions for anxiety and depression in adults and young people: A systematic review.

BACKGROUND: Growing evidence suggests that community-based interventions may be effective for anxiety and depression. This study aimed to describe studies of community interventions delivered to adults and/or young people, either in person or online, evaluated in randomised controlled trials and provide an indication as to their effectiveness, acceptability, quality of data and where possible, mechanisms of action. We included interventions delivered at and/or by museums, art galleries, libraries, gardens, music groups/choirs and sports clubs. METHOD: We developed and followed a preregistered protocol: PROSPERO CRD42020204471. Randomised controlled trials in adults and young people were identified in an extensive search with no date/time, language, document type and publication status limitations. Studies were selected according to predetermined eligibility criteria and data independently extracted and then assessed using Risk of Bias 1. The studies were deemed too heterogeneous for meta-analysis and were therefore reported using a narrative synthesis. RESULTS: Our analysis included 31 studies, with 2898 participants. Community interventions most studied in randomised controlled trials were community music (12 studies, 1432 participants), community exercise (14 studies, 955 participants) and community gardens/gardening (6 studies, 335 participants). The majority of studies were from high-income countries - many were in specific populations (such as those with physical health problems) and were generally of low quality. Dropout rates across the included studies were low (1 participant on average per 100 participants). The inadequate description of interventions limited identification of potential mechanisms of action. DISCUSSION: The uncertainty of the evidence allows only a weak recommendation in support of community interventions for anxiety and depression. The results suggest community engagement is a promising area for wide-reaching interventions to be implemented and evaluated, but more high-quality trials are needed, especially in young people and under-represented communities.

Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose-effect meta-analysis.

BACKGROUND: Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear. AIMS: To find the optimal dosage of aripiprazole augmentation. METHOD: Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose-effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4-12 weeks). RESULTS: Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose-efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15-1.85) and 5 mg (OR = 1.93, 95% CI 1.33-2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52-2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate. CONCLUSIONS: Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.

COVID-19 and substance use disorders: a review of international guidelines for frontline healthcare workers of addiction services.

BACKGROUND: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore. METHODS: We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4th 2021). We summarized the extracted data as answers to specific clinical questions. RESULTS: We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption. CONCLUSIONS: Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study.

INTRODUCTION: Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. METHOD: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. RESULTS: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. CONCLUSION: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns.

Optimal dose of brexpiprazole for augmentation therapy of antidepressant-refractory depression: A systematic review and dose-effect meta-analysis.

BACKGROUND: Brexpiprazole augmentation is an effective treatment strategy for antidepressant-refractory depression, but its optimal dosage remains unclear. AIMS: To find the optimal dosage of brexpiprazole as augmentation of other antidepressants. METHODS: We searched multiple electronic databases (from inception to September 16th, 2021) to identify double-blind, randomized placebo-controlled fixed-dose trials evaluating brexpiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder not adequately responding to one or more antidepressant treatment. Our outcomes of interest at 8 weeks (range 4-12 weeks) were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects) and acceptability (dropouts for any reason). We performed a random-effects, one-stage dose-effect meta-analysis with restricted cubic splines. RESULTS: Six studies met the inclusion criteria, including 1671 participants in total. The dose-efficacy curve showed an increase up to doses around 2 mg (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06) and then a decreasing trend through the higher licensed dose up to 3 mg (OR 1.40, 95% CI 0.95-2.08). The shape of the dose-tolerability curve was comparable to that of the efficacy and the dose-acceptability curve showed a monotonic increasing trend but both had wide confidence bands. CONCLUSIONS: One to two milligrams of brexpiprazole as augmentation treatment may achieve an optimal balance between efficacy, tolerability, and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies limit the reliability of the results. Further research is required to validate the findings.

Aripiprazole (intramuscular) for psychosis-induced aggression or agitation (rapid tranquillisation).

BACKGROUND: People experiencing psychosis may become aggressive. Antipsychotics, such as aripiprazole in intramuscular form, can be used in such situations. OBJECTIVES: To evaluate the effects of intramuscular aripiprazole in the treatment of psychosis-induced aggression or agitation (rapid tranquillisation). SEARCH METHODS: On 11 December 2014 and 11 April 2017, we searched the Cochrane Schizophrenia Group's Study-based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) that randomised people with psychosis-induced aggression or agitation to receive either intramuscular aripiprazole or another intramuscular intervention. DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. We included studies that met our selection criteria. At least two review authors independently extracted data from the included studies. We chose a fixed-effect model. We analysed dichotomous data using risk ratio (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their CIs. We assessed risk of bias for included studies and used GRADE to create 'Summary of findings' tables. MAIN RESULTS: Searching found 63 records referring to 21 possible trials. We could only include three studies, all completed over the last decade, with 885 participants, of which 707 were included for quantitative analyses in this systematic review. Due to limited comparisons, small size of trials and a paucity of investigated and reported 'pragmatic' outcomes, evidence was mostly graded as low or very low quality. No trials reported useful data for one of our primary outcomes of tranquil or asleep by 30 minutes. Economic outcomes were also not reported in the trials.When compared with placebo, fewer people in the aripiprazole group needed additional injections compared to the placebo group (2 RCTs, n = 382, RR 0.69, 95% CI 0.56 to 0.85, very low-quality evidence). Clinically important improvement in agitation at two hours favoured the aripiprazole group (2 RCTs, n = 382, RR 1.50, 95% CI 1.17 to 1.92, very low-quality evidence). The numbers of non-responders after the first injection also favoured aripiprazole (1 RCT, n = 263, RR 0.49, 95% CI 0.34 to 0.71, low-quality evidence). Although no effect was found, more people in the aripiprazole compared to the placebo group experienced adverse effects (1 RCT, n = 117, RR 1.51, 95% CI 0.93 to 2.46, very low-quality evidence).Aripiprazole required more injections compared to haloperidol (2 RCTs, n = 477, RR 1.28, 95% CI 1.00 to 1.63, very low-quality evidence), with no significant difference in agitation (2 RCTs, n = 477, RR 0.94, 95% CI 0.80 to 1.11, very low-quality evidence), and similar non-responders after first injection (1 RCT, n = 360, RR 1.18, 95% CI 0.78 to 1.79, low-quality evidence). Aripiprazole and haloperidol did not differ when taking into account the overall number of people that experienced at least one adverse effect (1 RCT, n = 113, RR 0.91, 95% CI 0.61 to 1.35, very low-quality evidence).Compared to aripiprazole, olanzapine was better at reducing agitation (1 RCT, n = 80, RR 0.77, 95% CI 0.60 to 0.99, low-quality evidence) and had a more favourable effect on global state change scores (1 RCT, n = 80, MD 0.58, 95% CI 0.01 to 1.15, low-quality evidence), both at two hours. No differences were found in terms of experiencing at least one adverse effect during the 24 hours after treatment (1 RCT, n = 80, RR 0.75, 95% CI 0.45 to 1.24, very low-quality evidence). However, participants allocated to aripiprazole experienced less somnolence (1 RCT, n = 80, RR 0.25, 95% CI 0.08 to 0.82, low-quality evidence). AUTHORS' CONCLUSIONS: The available evidence is of poor quality but there is some evidence aripiprazole is effective compared to placebo and haloperidol, but not when compared to olanzapine. However, considering that evidence comes from only three studies, caution is required in generalising these results to real-world practice. This review firmly highlights the need for more high-quality trials on intramuscular aripiprazole in the management of people with acute aggression or agitation.

Risperidone for psychosis-induced aggression or agitation (rapid tranquillisation).

BACKGROUND: Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation. OBJECTIVES: To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis. DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' tables. MAIN RESULTS: The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our other main outcomes of agitation or aggression, needing restraint, and incidence of adverse effects.Risperidone versus haloperidol (up to 24 hours follow-up)For the outcome, specific behaviour - agitation, no clear difference was found between risperidone and haloperidol in terms of efficacy, measured as at least 50% reduction in the Positive and Negative Syndrome Scale - Psychotic Agitation Sub-score (PANSS-PAS) (RR 1.04, 95% CI 0.86 to 1.26; participants = 124; studies = 1; very low-quality evidence) and no effect was observed for need to use restraints (RR 2.00, 95% CI 0.43 to 9.21; participants = 28; studies = 1; very low-quality evidence). Incidence of adverse effects was similar between treatment groups (RR 0.94, 95% CI 0.54 to 1.66; participants = 124; studies = 1; very low-quality evidence).Risperidone versus olanzapineOne small trial (n = 29) reported useable data for the comparison risperidone versus olanzapine. No effect was observed for agitation measured as PANSS-PAS endpoint score at two hours (MD 2.50, 95% CI -2.46 to 7.46; very low-quality evidence); need to use restraints at four days (RR 1.43, 95% CI 0.39 to 5.28; very-low quality evidence); specific movement disorders measured as Behavioural Activity Rating Scale (BARS) endpoint score at four days (MD 0.20, 95% CI -0.43 to 0.83; very low-quality evidence).Risperidone versus quetiapineOne trial reported (n = 40) useable data for the comparison risperidone versus quetiapine. Aggression was measured using the Modified Overt Aggression Scale (MOAS) endpoint score at two weeks. A clear difference, favouring quetiapine was observed (MD 1.80, 95% CI 0.20 to 3.40; very-low quality evidence). No evidence of a difference between treatment groups could be observed for incidence of akathisia after 24 hours (RR 1.67, 95% CI 0.46 to 6.06; very low-quality evidence). Two participants allocated to risperidone and one allocated to quetiapine experienced myocardial ischaemia during the trial.Risperidone versus risperidone + oxcarbazepineOne trial (n = 68) measured agitation using the Positive and Negative Syndrome Scale - Excited Component.(PANSS-EC) endpoint score and found a clear difference, favouring the combination treatment at one week (MD 2.70, 95% CI 0.42 to 4.98; very low-quality evidence), but no effect was observed for global state using Clinical Global Impression - Improvement (CGI-I) endpoint score at one week (MD -0.20, 95% CI -0.61 to 0.21; very-low quality evidence). Incidence of extrapyramidal symptoms after 24 hours was similar between treatment groups (RR 1.59, 95% CI 0.49 to 5.14; very-low quality evidence).Risperidone versus risperidone + valproic acidTwo trials compared risperidone with a combination of risperidone plus valproic acid. No clear differences between the treatment groups were observed for aggression (MOAS endpoint score at three days: MD 1.07, 95% CI -0.20 to 2.34; participants = 54; studies = 1; very low-quality evidence) or incidence of akathisia after 24 hours: RR 0.75, 95% CI 0.28 to 2.03; participants = 122; studies = 2; very low-quality evidence). AUTHORS' CONCLUSIONS: Overall, results for the main outcomes show no real effect for risperidone. The only data available for use in this review are from nine under-sampled trials and the evidence available is of very low quality. This casts uncertainty on the role of risperidone in rapid tranquillisation for people with psychosis-induced aggression. High-quality pragmatic RCTs are feasible and are needed before clear recommendations can be drawn on the use of risperidone for psychosis-induced aggression or agitation.

Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation).

BACKGROUND: Haloperidol used alone is recommended to help calm situations of aggression or agitation for people with psychosis. It is widely accessible and may be the only antipsychotic medication available in limited-resource areas. OBJECTIVES: To examine whether haloperidol alone is an effective treatment for psychosis-induced aggression or agitation, wherein clinicians are required to intervene to prevent harm to self and others. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (26th May 2016). This register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings, with no language, date, document type, or publication status limitations for inclusion of records into the register. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving people exhibiting aggression and/or agitation thought to be due to psychosis, allocated rapid use of haloperidol alone (by any route), compared with any other treatment. Outcomes of interest included tranquillisation or asleep by 30 minutes, repeated need for rapid tranquillisation within 24 hours, specific behaviours (threat or injury to others/self), adverse effects. We included trials meeting our selection criteria and providing useable data. DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), and for cognitive outcomes we derived standardised mean difference (SMD) effect sizes, all with 95% confidence intervals (CI) and using a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce 'Summary of findings' tables which included our pre-specified main outcomes of interest. MAIN RESULTS: We found nine new RCTs from the 2016 update search, giving a total of 41 included studies and 24 comparisons. Few studies were undertaken in circumstances that reflect real-world practice, and, with notable exceptions, most were small and carried considerable risk of bias. Due to the large number of comparisons, we can only present a summary of main results.Compared with placebo, more people in the haloperidol group were asleep at two hours (2 RCTs, n=220, RR 0.88, 95%CI 0.82 to 0.95, very low-quality evidence) and experienced dystonia (2 RCTs, n=207, RR 7.49, 95%CI 0.93 to 60.21, very low-quality evidence).Compared with aripiprazole, people in the haloperidol group required fewer injections than those in the aripiprazole group (2 RCTs, n=473, RR 0.78, 95%CI 0.62 to 0.99, low-quality evidence). More people in the haloperidol group experienced dystonia (2 RCTs, n=477, RR 6.63, 95%CI 1.52 to 28.86, very low-quality evidence).Four trials (n=207) compared haloperidol with lorazepam with no significant differences with regard to number of participants asleep at one hour (1 RCT, n=60, RR 1.05, 95%CI 0.76 to 1.44, very low-quality of evidence) or those requiring additional injections (1 RCT, n=66, RR 1.14, 95%CI 0.91 to 1.43, very low-quality of evidence).Haloperidol's adverse effects were not offset by addition of lorazepam (e.g. dystonia 1 RCT, n=67, RR 8.25, 95%CI 0.46 to 147.45, very low-quality of evidence).Addition of promethazine was investigated in two trials (n=376). More people in the haloperidol group were not tranquil or asleep by 20 minutes (1 RCT, n=316, RR 1.60, 95%CI 1.18 to 2.16, moderate-quality evidence). Acute dystonia was too common in the haloperidol alone group for the trial to continue beyond the interim analysis (1 RCT, n=316, RR 19.48, 95%CI 1.14 to 331.92, low-quality evidence). AUTHORS' CONCLUSIONS: Additional data from new studies does not alter previous conclusions of this review. If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical. Addition of the sedating promethazine has support from better-grade evidence from within randomised trials. Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence. Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries risk of additional harm.After six decades of use for emergency rapid tranquillisation, this is still an area in need of good independent trials relevant to real-world practice.

Combining endpoint and change data did not affect the summary standardised mean difference in pairwise and network meta-analyses: An empirical study in depression.

When studies use different scales to measure continuous outcomes, standardised mean differences (SMD) are required to meta-analyse the data. However, outcomes are often reported as endpoint or change from baseline scores. Combining corresponding SMDs can be problematic and available guidance advises against this practice. We aimed to examine the impact of combining the two types of SMD in meta-analyses of depression severity. We used individual participant data on pharmacological interventions (89 studies, 27,409 participants) and internet-delivered cognitive behavioural therapy (iCBT; 61 studies, 13,687 participants) for depression to compare endpoint and change from baseline SMDs at the study level. Next, we performed pairwise (PWMA) and network meta-analyses (NMA) using endpoint SMDs, change from baseline SMDs, or a mixture of the two. Study-specific SMDs calculated from endpoint and change from baseline data were largely similar, although for iCBT interventions 25% of the studies at 3 months were associated with important differences between study-specific SMDs (median 0.01, IQR -0.10, 0.13) especially in smaller trials with baseline imbalances. However, when pooled, the differences between endpoint and change SMDs were negligible. Pooling only the more favourable of the two SMDs did not materially affect meta-analyses, resulting in differences of pooled SMDs up to 0.05 and 0.13 in the pharmacological and iCBT datasets, respectively. Our findings have implications for meta-analyses in depression, where we showed that the choice between endpoint and change scores for estimating SMDs had immaterial impact on summary meta-analytic estimates. Future studies should replicate and extend our analyses to fields other than depression.

Comparing interventions for early psychosis: a systematic review and component network meta-analysis.

Background: 'Early Intervention in Psychosis' (EIP) services have been associated with improved outcomes for early psychosis. However, these services are heterogeneous and many provide different components of treatment. The impact of this variation on the sustained treatment effects is unknown. Methods: We performed a systematic review and component network meta-analysis (cNMA) of randomised controlled trials (RCTs) that compared specialised intervention services for early psychosis. We searched CENTRAL (published and unpublished), EMBASE, MEDLINE, CINAHL, PsycINFO and Web of Science from inception to February 2023. Primary outcomes were negative and positive psychotic symptoms at 3-month and 1-year follow-up and treatment dropouts. Secondary outcomes were depressive symptoms and social functioning at 1-year follow-up. We registered a protocol for our study in PROSPERO (CRD42017057420). Findings: We identified 37 RCTs including 4599 participants. Participants' mean age was 25.8 years (SD 6.0) and 64.0% were men. We found evidence that psychological interventions (this component grouped all psychological treatment intended to treat, or ameliorate the consequences of, psychotic symptoms) are beneficial for reducing negative symptoms (iSMD -0.24, 95% CI -0.44 to -0.05, p = 0.014) at 3-month follow-up and may be associated with clinically relevant benefits in improving social functioning scores at 1-year follow-up (iSMD -0.52, 95% CI -1.05 to 0.01, p = 0.052). The addition of case management has a beneficial effect on reducing negative symptoms (iSMD -1.17, 95% CI -2.24 to -0.11, p = 0.030) and positive symptoms (iSMD -1.05, 95% CI -2.02 to -0.08, p = 0.033) at 1-year follow-up. Pharmacotherapy was present in all trial arms, meaning it was not possible to examine the specific effects of this component. Interpretation: Our findings suggest psychological interventions and case management in addition to pharmacotherapy as the core components of services for early psychosis to achieve sustained clinical benefits. Our conclusions are limited by the small number of studies and sparsely connected networks. Funding: National Institute for Health and Care Research.

Digital Mental Health for Schizophrenia and Other Severe Mental Illnesses: An International Consensus on Current Challenges and Potential Solutions.

BACKGROUND: Digital approaches may be helpful in augmenting care to address unmet mental health needs, particularly for schizophrenia and severe mental illness (SMI). OBJECTIVE: An international multidisciplinary group was convened to reach a consensus on the challenges and potential solutions regarding collecting data, delivering treatment, and the ethical challenges in digital mental health approaches for schizophrenia and SMI. METHODS: The consensus development panel method was used, with an in-person meeting of 2 groups: the expert group and the panel. Membership was multidisciplinary including those with lived experience, with equal participation at all stages and coproduction of the consensus outputs and summary. Relevant literature was shared in advance of the meeting, and a systematic search of the recent literature on digital mental health interventions for schizophrenia and psychosis was completed to ensure that the panel was informed before the meeting with the expert group. RESULTS: Four broad areas of challenge and proposed solutions were identified: (1) user involvement for real coproduction; (2) new approaches to methodology in digital mental health, including agreed standards, data sharing, measuring harms, prevention strategies, and mechanistic research; (3) regulation and funding issues; and (4) implementation in real-world settings (including multidisciplinary collaboration, training, augmenting existing service provision, and social and population-focused approaches). Examples are provided with more detail on human-centered research design, lived experience perspectives, and biomedical ethics in digital mental health approaches for SMI. CONCLUSIONS: The group agreed by consensus on a number of recommendations: (1) a new and improved approach to digital mental health research (with agreed reporting standards, data sharing, and shared protocols), (2) equal emphasis on social and population research as well as biological and psychological approaches, (3) meaningful collaborations across varied disciplines that have previously not worked closely together, (4) increased focus on the business model and product with planning and new funding structures across the whole development pathway, (5) increased focus and reporting on ethical issues and potential harms, and (6) organizational changes to allow for true communication and coproduction with those with lived experience of SMI. This study approach, combining an international expert meeting with patient and public involvement and engagement throughout the process, consensus methodology, discussion, and publication, is a helpful way to identify directions for future research and clinical implementation in rapidly evolving areas and can be combined with measurements of real-world clinical impact over time. Similar initiatives will be helpful in other areas of digital mental health and similarly fast-evolving fields to focus research and organizational change and effect improved real-world clinical implementation.

Components and Delivery Formats of Cognitive Behavioral Therapy for Chronic Insomnia in Adults: A Systematic Review and Component Network Meta-Analysis.

Importance: Chronic insomnia disorder is highly prevalent, disabling, and costly. Cognitive behavioral therapy for insomnia (CBT-I), comprising various educational, cognitive, and behavioral strategies delivered in various formats, is the recommended first-line treatment, but the effect of each component and delivery method remains unclear. Objective: To examine the association of each component and delivery format of CBT-I with outcomes. Data Sources: PubMed, Cochrane Central Register of Controlled Trials, PsycInfo, and International Clinical Trials Registry Platform from database inception to July 21, 2023. Study Selection: Published randomized clinical trials comparing any form of CBT-I against another or a control condition for chronic insomnia disorder in adults aged 18 years and older. Insomnia both with and without comorbidities was included. Concomitant treatments were allowed if equally distributed among arms. Data Extraction and Synthesis: Two independent reviewers identified components, extracted data, and assessed trial quality. Random-effects component network meta-analyses were performed. Main Outcomes and Measures: The primary outcome was treatment efficacy (remission defined as reaching a satisfactory state) posttreatment. Secondary outcomes included all-cause dropout, self-reported sleep continuity, and long-term remission. Results: A total of 241 trials were identified including 31 452 participants (mean [SD] age, 45.4 [16.6] years; 21 048 of 31 452 [67%] women). Results suggested that critical components of CBT-I are cognitive restructuring (remission incremental odds ratio [iOR], 1.68; 95% CI, 1.28-2.20) third-wave components (iOR, 1.49; 95% CI, 1.10-2.03), sleep restriction (iOR, 1.49; 95% CI, 1.04-2.13), and stimulus control (iOR, 1.43; 95% CI, 1.00-2.05). Sleep hygiene education was not essential (iOR, 1.01; 95% CI, 0.77-1.32), and relaxation procedures were found to be potentially counterproductive(iOR, 0.81; 95% CI, 0.64-1.02). In-person therapist-led programs were most beneficial (iOR, 1.83; 95% CI, 1.19-2.81). Cognitive restructuring, third-wave components, and in-person delivery were mainly associated with improved subjective sleep quality. Sleep restriction was associated with improved subjective sleep quality, sleep efficiency, and wake after sleep onset, and stimulus control with improved subjective sleep quality, sleep efficiency, and sleep latency. The most efficacious combination-consisting of cognitive restructuring, third wave, sleep restriction, and stimulus control in the in-person format-compared with in-person psychoeducation, was associated with an increase in the remission rate by a risk difference of 0.33 (95% CI, 0.23-0.43) and a number needed to treat of 3.0 (95% CI, 2.3-4.3), given the median observed control event rate of 0.14. Conclusions and Relevance: The findings suggest that beneficial CBT-I packages may include cognitive restructuring, third-wave components, sleep restriction, stimulus control, and in-person delivery but not relaxation. However, potential undetected interactions could undermine the conclusions. Further large-scale, well-designed trials are warranted to confirm the contribution of different treatment components in CBT-I.

Assessing the Impact of Evidence-Based Mental Health Guidance During the COVID-19 Pandemic: Systematic Review and Qualitative Evaluation.

BACKGROUND: During the COVID-19 pandemic, the Oxford Precision Psychiatry Lab (OxPPL) developed open-access web-based summaries of mental health care guidelines (OxPPL guidance) in key areas such as digital approaches and telepsychiatry, suicide and self-harm, domestic violence and abuse, perinatal care, and vaccine hesitancy and prioritization in the context of mental illness, to inform timely clinical decision-making. OBJECTIVE: This study aimed to evaluate the practice of creating evidence-based health guidelines during health emergencies using the OxPPL guidance as an example. An international network of clinical sites and colleagues (in Australia, New Zealand, and the United Kingdom) including clinicians, researchers, and experts by experience aimed to (1) evaluate the clinical impact of the OxPPL guidance, as an example of an evidence-based summary of guidelines; (2) review the literature for other evidence-based summaries of COVID-19 guidelines regarding mental health care; and (3) produce a framework for response to future global health emergencies. METHODS: The impact and clinical utility of the OxPPL guidance were assessed using clinicians' feedback via an international survey and focus groups. A systematic review (protocol registered on Open Science Framework) identified summaries or syntheses of guidelines for mental health care during and after the COVID-19 pandemic and assessed the accuracy of the methods used in the OxPPL guidance by identifying any resources that the guidance had not included. RESULTS: Overall, 80.2% (146/182) of the clinicians agreed or strongly agreed that the OxPPL guidance answered important clinical questions, 73.1% (133/182) stated that the guidance was relevant to their service, 59.3% (108/182) said that the guidelines had or would have a positive impact on their clinical practice, 42.9% (78/182) that they had shared or would share the guidance, and 80.2% (146/182) stated that the methodology could be used during future health crises. The focus groups found that the combination of evidence-based knowledge, clinical viewpoint, and visibility was crucial for clinical implementation. The systematic review identified 2543 records, of which 2 syntheses of guidelines met all the inclusion criteria, but only 1 (the OxPPL guidance) used evidence-based methodology. The review showed that the OxPPL guidance had included the majority of eligible guidelines, but 6 were identified that had not been included. CONCLUSIONS: The study identified an unmet need for web-based, evidence-based mental health care guidance during the COVID-19 pandemic. The OxPPL guidance was evaluated by clinicians as having a real-world clinical impact. Robust evidence-based methodology and expertise in mental health are necessary, but easy accessibility is also needed, and digital technology can materially help. Further health emergencies are inevitable and now is the ideal time to prepare, including addressing the training needs of clinicians, patients, and carers, especially in areas such as telepsychiatry and digital mental health. For future planning, guidance should be widely disseminated on an international platform, with allocated resources to support adaptive updates.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.

Impact of the COVID-19 Pandemic on the Global Delivery of Mental Health Services and Telemental Health: Systematic Review.

BACKGROUND: The COVID-19 pandemic required mental health services around the world to adapt quickly to the new restrictions and regulations put in place to reduce the risk of transmission. As face-to-face contact became difficult, virtual methods were implemented to continue to safely provide mental health care. However, it is unclear to what extent service provision transitioned to telemental health worldwide. OBJECTIVE: We aimed to systematically review the global research literature on how mental health service provision adapted during the first year of the pandemic. METHODS: We searched systematically for quantitative papers focusing on the impact of the COVID-19 pandemic on mental health services published until April 13, 2021, in the PubMed, Embase, medRxiv, and bioXriv electronic bibliographic databases, using the COVID-19 Open Access Project online platform. The screening process and data extraction were independently completed by at least two authors, and any disagreement was resolved by discussion with a senior member of the team. The findings were summarized narratively in the context of each country's COVID-19 Stringency Index, which reflects the stringency of a government's response to COVID-19 restrictions at a specific time. RESULTS: Of the identified 24,339 records, 101 papers were included after the screening process. Reports on general services (n=72) showed that several countries' face-to-face services reduced their activities at the start of the pandemic, with reductions in the total number of delivered visits and with some services forced to close. In contrast, telemental health use rapidly increased in many countries across the world at the beginning of the pandemic (n=55), with almost complete virtualization of general and specialistic care services by the end of the first year. Considering the reported COVID-19 Stringency Index values, the increased use of virtual means seems to correspond to periods when the Stringency Index values were at their highest in several countries. However, due to specific care requirements, telemental health could not be used in certain subgroups of patients, such as those on clozapine or depot treatments and those who continued to need face-to-face visits. CONCLUSIONS: During the pandemic, mental health services had to adapt quickly in the short term, implementing or increasing the use of telemental health services across the globe. Limited access to digital means, poor digital skills, and patients' preferences and individual needs may have contributed to differences in implementing and accessing telemental health services during the pandemic. In the long term, a blended approach, combining in-person and virtual modalities, that takes into consideration the needs, preferences, and digital skills of patients may better support the future development of mental health services. It will be required to improve confidence with digital device use, training, and experience in all modalities for both clinicians and service users.

Antidepressant prescriptions have not fully reflected evolving evidence from cumulative network meta-analyses and guideline recommendations.

OBJECTIVES: This study compares three major elements of evidence-based medicine (EBM) practices, namely evidence synthesis, clinical practice guidelines (CPGs), and real-world prescriptions in the United States, regarding antidepressant treatments of major depression over the past 3 decades. STUDY DESIGN AND SETTING: We conducted network meta-analyses (NMAs) of antidepressants every 5 years up to 2016 based on a comprehensive data set of double-blind randomized controlled trials. We identified CPGs and extracted their recommendations. We surveyed the prescriptions in the United States at 5-year intervals up to 2015. RESULTS: Most drugs recommended by CPGs presented favorable performance in efficacy and acceptability in NMAs. However, CPG recommendations were often in terms of drug classes rather than individual drugs, whereas NMAs suggested distinctive difference between drugs within the same class. The update intervals of all CPGs were longer than 5 years. All the antidepressants prescribed frequently in the United States were recommended by CPGs. However, changes in prescriptions did not correspond to alterations in CPGs or to apparent changes in the effects indicated by NMAs. Many factors including marketing efforts, regulations, or patient values may have played a role. CONCLUSION: Enhancements including accelerating CPG updates and monitoring the impact of marketing on prescriptions should be considered in future EBM implementation.

Different control conditions can produce different effect estimates in psychotherapy trials for depression.

OBJECTIVES: Control conditions' influence on effect estimates of active psychotherapeutic interventions for depression has not been fully elucidated. We used network meta-analysis to estimate the differences between control conditions. STUDY DESIGN AND SETTING: We have conducted a comprehensive literature search of randomized trials of psychotherapies for adults with depression up to January 1, 2019 in four major databases (PubMed, PsycINFO, Embase, and Cochrane). The network meta-analysis included broadly conceived cognitive behavior therapies in comparison with the following control conditions: Waiting List (WL), No Treatment (NT), Pill Placebo (PillPlacebo), Psychological Placebo (PsycholPlacebo). RESULTS: 123 studies with 12,596 participants were included. The I-squared was 55.9% (95% CI: 45.9%; to 64.0%) (moderate heterogeneity). The design-by-treatment global test of inconsistency was not significant (P = 0.44). Different control conditions led to different estimates of efficacy for the same intervention. WL appears to be the weakest control (odds ratio of response against NT = 1.93 (1.30 to 2.86), PsycholPlacebo = 2.03 (1.21 to 3.39), and PillPlacebo = 2.66 (1.45 to 4.89), respectively). CONCLUSIONS: Different control conditions produce different effect estimates in psychotherapy randomized controlled trials for depression. WL was the weakest, followed by NT, PsycholPlacebo, and PillPlacebo in this order. When conducting meta-analyses of psychotherapy trials, different control conditions should not be lumped into a single group.