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Introduction: Major depressive disorder (MDD) is a common debilitating illness worldwide. The vast majority of patients with MDD will not achieve remission with first-line treatment and despite the availability of different treatment modalities, at least one-third of patients experience treatment-resistant depression (TRD). There continues to be a paucity of research focused on treatment options for patients with TRD thus treatment decisions are largely based on patient and clinician preference as opposed to evidence-based practice. Herein we propose a systematic review and network meta-analysis (NMA) of available pharmacological and psychological augmentation treatments for TRD, to inform evidence-based management of TRD., Methods and Analysis: We plan to conduct a search of electronic databases (MEDLINE and ISIWEB) of all dates from inception for randomised controlled trials of pharmacological and psychological augmentation interventions for adults with TRD. Articles for review will be included based upon consensus from two authors. Pharmaceutical companies will be contacted for access to any unpublished data. An NMA will compare the effectiveness pharmacological adjunctive agents for TRD using preanalysis/postanalysis, assuming consistency and transitivity., Ethics and Dissemination: This project does not require research ethics board approval. The dissemination plan is to present findings at international scientific meetings and publishing results in a peer-reviewed academic journal., Prospero Registration Number: CRD42019132588., Competing Interests: Competing interests: AY has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen, in the last 3 years., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD., Method: Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions., Results: Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52)., Conclusions: Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.

Background: Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic-pituitary-adrenal (HPA) axis alterations. As cortisol is known to modulate cognitive processes, those patients may be less likely to profit from psychological therapy., Aims: To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response., Method: The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure., Results: Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change., Conclusions: Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy., (© The Royal College of Psychiatrists 2017.)

Background: England's primary care service for psychological therapy (Improving Access to Psychological Therapies [IAPT]) treats anxiety and depression, with a target recovery rate of 50%. Identifying the characteristics of patients who achieve recovery may assist in optimizing future treatment. This naturalistic cohort study investigated pre-therapy characteristics as predictors of recovery and improvement after IAPT therapy. Methods: In a cohort of patients attending an IAPT service in South London, we recruited 263 participants and conducted a baseline interview to gather extensive pre-therapy characteristics. Bayesian prediction models and variable selection were used to identify baseline variables prognostic of good clinical outcomes. Recovery (primary outcome) was defined using (IAPT) service-defined score thresholds for both depression (Patient Health Questionnaire [PHQ-9]) and anxiety (Generalized Anxiety Disorder [GAD-7]). Depression and anxiety outcomes were also evaluated as standalone (PHQ-9/GAD-7) scores after therapy. Prediction model performance metrics were estimated using cross-validation. Results: Predictor variables explained 26% (recovery), 37% (depression), and 31% (anxiety) of the variance in outcomes, respectively. Variables prognostic of recovery were lower pre-treatment depression severity and not meeting criteria for obsessive compulsive disorder. Post-therapy depression and anxiety severity scores were predicted by lower symptom severity and higher ratings of health-related quality of life (EuroQol questionnaire [EQ5D]) at baseline. Conclusion: Almost a third of the variance in clinical outcomes was explained by pre-treatment symptom severity scores. These constructs benefit from being rapidly accessible in healthcare services. If replicated in external samples, the early identification of patients who are less likely to recover may facilitate earlier triage to alternative interventions. [ABSTRACT FROM AUTHOR]

Background: A substantial proportion of people with bipolar disorder (BD) experience persistent cognitive difficulties associated with impairments in psychosocial functioning and a poorer disorder course. Emerging evidence suggests that cognitive remediation (CR), a psychological intervention with established efficacy in people with schizophrenia, can also benefit people with BD. Following a proof-of-concept trial showing that CR is feasible and potentially beneficial for people with BD, we are conducting an adequately powered trial in euthymic people with BD to 1) determine whether an individual, therapist-supported, computerised CR can reduce cognitive difficulties and improve functional outcomes; and 2) explore how CR exerts its effects. Methods: CRiB2 is a two-arm, assessor-blind, multi-site, randomised controlled trial (RCT) comparing CR to treatment-as-usual (TAU). Participants are people with a diagnosis of BD, aged between 18 and 65, with no neurological or current substance use disorder, and currently euthymic. 250 participants will be recruited through primary, secondary, tertiary care, and the community. Participants will be block-randomised (1:1 ratio, stratified by site) to continue with their usual care (TAU) or receive a 12-week course of therapy and usual care (CR + TAU). The intervention comprises one-on-one CR sessions with a therapist supplemented with independent cognitive training for 30–40 h in total. Outcomes will be assessed at 13- and 25-weeks post-randomisation. Efficacy will be examined by intention-to-treat analyses estimating between-group differences in primary (i.e., psychosocial functioning at week 25 measured with the Functional Assessment Short Test) and secondary outcomes (i.e., measures of cognition, mood, patient-defined goals, and quality of life). Global cognition, metacognitive skills, affect fluctuation, and salivary cortisol levels will be evaluated as putative mechanisms of CR through mediation models. Discussion: This study will provide a robust evaluation of efficacy of CR in people with BD and examine the putative mechanisms by which this therapy works. The findings will contribute to determining the clinical utility of CR and potential mechanisms of action. Trial registration: Cognitive Remediation in Bipolar 2 (CRiB2): ISRCTN registry: https://www.isrctn.com/ISRCTN10362331. Registered 04 May 2022. Overall trial status: Ongoing; Recruitment status: Recruiting. [ABSTRACT FROM AUTHOR]

Castro Menezes et al. examine factors differentiating bipolar and unipolar depression [[3]], which has translational potential given the well-documented, persistently high rates of mis- and delayed-diagnosis for BD, where the most frequent misdiagnosis is unipolar major depression [[4]]. Of the 154 participants with BD, 10% had an existing thyroid disorder prior to lithium therapy and almost one third of the remaining sample developed a thyroid disorder during lithium treatment. Despite the clear uncertainty, given the outstanding treatment challenges in BD, it was concluded that acetazolamide should be further examined for its putative role in managing BD [[15]]. [Extracted from the article]

Background: Major depressive disorder (MDD) is a highly burdensome health condition, for which there are numerous accepted pharmacological and psychological interventions. Adjunctive treatment (augmentation/combination) is recommended for the ~50% of MDD patients who do not adequately respond to first-line treatment. We aimed to evaluate the current evidence for concomitant approaches for people with early-stage treatment-resistant depression (TRD; defined below). Methods: We systematically searched Medline and Institute for Scientific Information Web of Science to identify randomised controlled trials of adjunctive treatment of ⩾10 adults with MDD who had not responded to ⩾1 adequate antidepressant. The cochrane risk of bias (RoB) tool was used to assess study quality. Pre-post treatment meta-analyses were performed, allowing for comparison across heterogeneous study designs independent of comparator interventions. Results: In total, 115 trials investigating 48 treatments were synthesised. The mean intervention duration was 9 weeks (range 5 days to 18 months) with most studies assessed to have low (n = 57) or moderate (n = 51) RoB. The highest effect sizes (ESs) were from cognitive behavioural therapy (ES = 1.58, 95% confidence interval (CI): 1.09–2.07), (es)ketamine (ES = 1.48, 95% CI: 1.23–1.73) and risperidone (ES = 1.42, 95% CI: 1.29–1.61). Only aripiprazole and lithium were examined in ⩾10 studies. Pill placebo (ES = 0.89, 95% CI: 0.81–0.98) had a not inconsiderable ES, and only six treatments' 95% CIs did not overlap with pill placebo's (aripiprazole, (es)ketamine, mirtazapine, olanzapine, quetiapine and risperidone). We report marked heterogeneity between studies for almost all analyses. Conclusions: Our findings support cautious optimism for several augmentation strategies; although considering the high prevalence of TRD, evidence remains inadequate for each treatment option. [ABSTRACT FROM AUTHOR]

Objectives: Rapid cycling is a common and disabling phenomenon in individuals with bipolar disorders. In the absence of a recent literature examination, this systematic review and meta‐analysis aimed to synthesise the evidence of efficacy, acceptability and tolerability of treatments for individuals with rapid cycling bipolar disorder (RCBD). Method: A systematic search was conducted to identify randomised controlled trials assigning participants with RCBD to pharmacological and/or non‐pharmacological interventions. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was continuous within‐subject RCBD illness severity before and after treatment. Pre‐post random effects meta‐analyses were conducted for each outcome/intervention arm studied, generating a standardised effect size (hedge's g) and 95% confidence interval (CI). Results: A total of 34 articles describing 30 studies were included. A total of 16 separate pharmacological treatments were examined in contrast to 1 psychological therapy study. Only quetiapine and lamotrigine were assessed in >5 studies. By assessing 95% CI overlap of within‐subject efficacy effects compared to placebo, the only interventions suggesting significant depression benefits (placebo g = 0.60) were olanzapine (with/without fluoxetine; g = 1.01), citalopram (g = 1.10) and venlafaxine (g = 2.48). For mania, benefits were indicated for quetiapine (g = 1.01), olanzapine (g = 1.19) and aripiprazole (g = 1.09), versus placebo (g = 0.33). Most of these effect sizes were from only one trial per treatment. Heterogeneity between studies was variable, and 20% were rated to have a high risk of bias. Conclusions: While many interventions appeared efficacious, there was a lack of robust evidence for most treatments. Given the limited and heterogeneous evidence base, the optimal treatment strategies for people with RCBD are yet to be established. [ABSTRACT FROM AUTHOR]

Objectives Although cognitive dysfunction is a prominent feature of bipolar disorder (BD), previous research presents limitations in estimating the proportion of euthymic patients experiencing clinically relevant deficits and identifying predictors of cognitive difficulties. We explored the relevance of recommended definitions of clinically significant cognitive impairment for functional outcomes, estimated its prevalence, and identified patient characteristics associated with cognition. Methods We assessed cognitive performance across four domains in 80 euthymic participants with BD. Participants were categorized based on two criteria for clinically significant cognitive impairment and we assessed the ability of these criteria to differentiate participant performance on established functional outcomes. Variable selection with elastic net regression was used to identify sociodemographic and clinical factors associated with cognitive performance. Selected variables were examined as predictors of clinically significant cognitive impairment with logistic regression. Results According to the selected criterion, 34% presented with clinically significant cognitive impairment. Poorer current cognitive performance was associated with older age, lower estimated premorbid IQ, more currently prescribed psychotropic medications, fewer previous psychological therapies, and current use of antipsychotics. A model with premorbid IQ, psychotropic medications and previous psychological therapies as predictors of cognitive impairment correctly classified 75% of the participants. Conclusions This is one of the first studies to use a model selection approach to identify factors associated with cognitive difficulties in BD. Our findings offer the initial steps towards a predictive model for cognitive impairment. This could improve treatment decisions and prioritization for euthymic patients with BD, particularly the implementation of cognitive interventions. [ABSTRACT FROM AUTHOR]

Comment & Response B To the Editor b Miklowitz et al[1] present a meta-analysis of psychosocial interventions in bipolar disorder, concluding adjunctive psychotherapy to pharmacotherapy is more effective than treatment as usual in reducing recurrence and treating depression symptoms, among other outcomes. No definition of residual symptoms is evident, and some studies assumed to fall into this category did not assess functioning or item-level symptom analysis, which should be considered in ascertaining "residual symptoms.". [Extracted from the article]

In people with depression, immune dysfunctions have been linked with treatment non-response, but examinations of psychological therapy outcomes, particularly longitudinal biomarker studies, are rare. This study investigated relationships between inflammation, depressive subtypes and clinical outcomes to psychological therapy. Adults with depression (n = 96) were assessed before and after a course of naturalistically-delivered psychological therapy. In total, 32 serum inflammatory proteins were examined alongside therapy outcomes and depressive subtypes (somatic/cognitive symptom subtype, and bipolar/unipolar depression). Overall, 49% of participants responded to treatment. High levels of tumour necrosis factor (TNFα), interleukin-6 (IL-6) and soluble intracellular adhesion molecule-1 (sICAM1), and low interferon-γ (IFNγ), preceded a poorer response to therapy. After therapy, non-responders had elevated c-reactive protein (CRP), thymus and activation-regulated chemokine (TARC) and macrophage chemoattractant protein-4 (MCP4), and attenuated IFNy. Non-somatic depressive symptoms were universally not associated with proteins, while somatic-depressive symptom severity was positively correlated with several pro-inflammatory markers. In the somatic subgroup only, IL-6 and serum amyloid alpha (SAA) decreased between pre- and post-therapy timepoints. Regardless of treatment response, IL-7, IL-8, IL-15 and IL-17 increased over time. These results suggest that inflammation is associated with somatic symptoms of depression and non-response to psychological therapy. Future work may enhance the prospective prediction of treatment-response by examining larger samples of individuals undertaking standardised treatment programmes. [ABSTRACT FROM AUTHOR]

Background: Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic-pituitary-adrenal (HPA) axis alterations. As cortisol is known to modulate cognitive processes, those patients may be less likely to profit from psychological therapy.Aims: To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response.Method: The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure.Results: Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change.Conclusions: Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy. [ABSTRACT FROM AUTHOR]

Background: Treatment resistant depression (TRD) poses a significant clinical challenge, despite a range of efficacious specialist treatments. Accurately predicting response a priori may help to alleviate the burden of TRD. This study sought to determine whether outcome prediction can be achieved in a specialist inpatient setting.Methods: Patients at the Affective Disorders Unit of the Bethlam Royal Hospital, with current depression and established TRD were included (N = 174). Patients were treated with an individualised combination of pharmacotherapy and specialist psychological therapies. Predictors included clinical and sociodemographic characteristics, and polygenic risk scores for depression and related traits. Logistic regression models examined associations with outcome, and predictive potential was assessed using elastic net regularised logistic regressions with 10-fold nested cross-validation.Results: 47% of patients responded (50% reduction in HAMD-21 score at discharge). Age at onset and number of depressive episodes were positively associated with response, while degree of resistance was negatively associated. All elastic net models had poor performance (AUC<0.6). Illness history characteristics were commonly retained, and the addition of genetic risk scores did not improve performance.Limitations: The patient sample was heterogeneous and received a variety of treatments. Some variable associations may be non-linear and therefore not captured.Conclusions: This treatment may be most effective for recurrent patients and those with a later age of onset, while patients more severely treatment resistant at admission remain amongst the most difficult to treat. Individual level prediction remains elusive for this complex group. The assessment of homogenous subgroups should be one focus of future investigations. [ABSTRACT FROM AUTHOR]