Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear.

To find the optimal dosage of aripiprazole augmentation.

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).

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.

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.

Relapse and recurrence of depression are common, contributing to the overall burden of depression globally. Accurate prediction of relapse or recurrence while patients are well would allow the identification of high-risk individuals and may effectively guide the allocation of interventions to prevent relapse and recurrence.

To review prognostic models developed to predict the risk of relapse, recurrence, sustained remission, or recovery in adults with remitted major depressive disorder.

We searched the Cochrane Library (current issue); Ovid MEDLINE (1946 onwards); Ovid Embase (1980 onwards); Ovid PsycINFO (1806 onwards); and Web of Science (1900 onwards) up to May 2021. We included development and external validation studies of multivariable prognostic models. We assessed risk of bias of included studies using the Prediction model risk of bias assessment tool (PROBAST).

We identified 12 eligible prognostic model studies (11 unique prognostic models): 8 model development-only studies, 3 model development and external validation studies and 1 external validation-only study. Multiple estimates of performance measures were not available and meta-analysis was therefore not necessary. Eleven out of the 12 included studies were assessed as being at high overall risk of bias and none examined clinical utility.

Due to high risk of bias of the included studies, poor predictive performance and limited external validation of the models identified, presently available clinical prediction models for relapse and recurrence of depression are not yet sufficiently developed for deploying in clinical settings. There is a need for improved prognosis research in this clinical area and future studies should conform to best practice methodological and reporting guidelines.

Cognitive–behavioural therapy (CBT) is frequently used as an umbrella term to include a variety of psychological interventions. It remains unclear whether more complex CBT contributes to greater depression reduction.

To (a) compare the effectiveness of core, complex and ultra-complex CBT against other psychological intervention, medication, treatment-as-usual and no treatment in reducing depression at post-treatment and in the long term and (b) explore important factors that could moderate the effectiveness of these interventions.

MEDLINE, PsycInfo, Embase, Web of Science and the Cochrane Register of Controlled Trials were searched to November 2021. Only randomised controlled trials were eligible for the subsequent network meta-analysis.

We included 107 studies based on 15 248 participants. Core (s.m.d. = −1.14, 95% credible interval (CrI) −1.72 to −0.55 [m.d. = −8.44]), complex (s.m.d. = −1.24, 95% CrI −1.85 to −0.64 [m.d. = −9.18]) and ultra-complex CBT (s.m.d. = −1.45, 95% CrI −1.88 to −1.02 [m.d. = −10.73]) were all significant in reducing depression up to 6 months from treatment onset. The significant benefits of the ultra-complex (s.m.d. = −1.09, 95% CrI −1.61 to −0.56 [m.d. = −8.07]) and complex CBT (s.m.d. = −0.73, 95% CrI −1.36 to −0.11 [m.d. = −5.40]) extended beyond 6 months. Ultra-complex CBT was most effective in individuals presenting comorbid mental health problems and when delivered by non-mental health specialists. Ultra-complex and complex CBT were more effective for people younger than 59 years.

For people without comorbid conditions healthcare and policy organisations should invest in core CBT. For people <59 years of age with comorbid conditions investments should focus on ultra-complex and complex CBT delivered without the help of mental health professionals.

Evidence for risk of dying by suicide and other causes following discharge from in-patient psychiatric care throughout adulthood is sparse.

To estimate risks of all-cause mortality, natural and external-cause deaths, suicide and accidental, alcohol-specific and drug-related deaths in working-age and older adults within a year post-discharge.

Using interlinked general practice, hospital, and mortality records in the Clinical Practice Research Datalink we delineated a cohort of discharged adults in England, 2001–2018. Each patient was matched to up to 20 general population comparator patients. Cumulative incidence (absolute risks) and hazard ratios (relative risks) were estimated separately for ages 18–64 and ≥65 years with additional stratification by gender and practice-level deprivation.

The 1-year cumulative incidence of dying post-discharge was 2.1% among working-age adults (95% CI 2.0–2.3) and 14.1% (95% CI 13.6–14.5) among older adults. Suicide risk was particularly elevated in the first 3 months, with hazard ratios of 191.1 (95% CI 125.0–292.0) among working-age adults and 125.4 (95% CI 52.6–298.9) in older adults. Older patients were vulnerable to dying by natural causes within 3 months post-discharge. Risk of dying by external causes was greater among discharged working-age adults in the least deprived areas. Relative risk of suicide in discharged working-age women relative to their general population peers was double the equivalent male risk elevation.

Recently discharged adults at any age are at increased risk of dying from external and natural causes, indicating the importance of close monitoring and provision of optimal support to all such patients, particularly during the first 3 months post-discharge.

Relapses in major depression are frequent and are associated with a high burden of disease. Although short-term studies suggest a normalisation of depression-associated brain functional alterations directly after treatment, long-term investigations are sparse.

To examine brain function during negative emotion processing in association with course of illness over a 2-year span.

In this prospective case–control study, 72 in-patients with current depression and 42 healthy controls were investigated during a negative emotional face processing paradigm, at baseline and after 2 years. According to their course of illness during the study interval, patients were divided into subgroups (n = 25 no-relapse, n = 47 relapse). The differential changes in brain activity were investigated by a group × time analysis of covariance for the amygdala, hippocampus, insula and at whole-brain level.

A significant relapse × time interaction emerged within the amygdala (PTFCE-FWE = 0.011), insula (PTFCE-FWE = 0.001) and at the whole-brain level mainly in the temporal and prefrontal cortex (PTFCE-FWE = 0.027), resulting from activity increases within the no-relapse group, whereas in the relapse group, activity decreased during the study interval. At baseline, the no-relapse group showed amygdala, hippocampus and insula hypoactivity compared with healthy controls and the relapse group.

This study reveals course of illness-associated activity changes in emotion processing areas. Patients in full remission show a normalisation of their baseline hypo-responsiveness to the activation level of healthy controls after 2 years. Brain function during emotion processing could further serve as a potential predictive marker for future relapse.