Cognitive remediation therapy for patients with bipolar disorder: A randomised proof-of-concept trial.

OBJECTIVES: Cognitive remediation therapy (CRT) may benefit people with bipolar disorder type I and II for whom cognitive impairment is a major contributor to disability. Extensive research has demonstrated CRT to improve cognition and psychosocial functioning in people with different diagnoses, but randomised trials of evidenced therapy programmes are lacking for bipolar disorders. The Cognitive Remediation in Bipolar (CRiB) study aimed to determine whether an established CRT programme is feasible and acceptable for people with bipolar disorders. METHODS: This proof-of-concept, single-blind randomised trial recruited participants aged 18-65 with bipolar disorder, not currently experiencing an episode. They were 1:1 block randomised to treatment-as-usual (TAU) with or without individual CRT for 12 weeks. The partly computerised CRT programme ("CIRCuiTS") was therapist-led and is evidence-based from trials in those with psychotic illnesses. Data were collected and analysed by investigators blinded to group allocation. The main outcomes (week 13 and 25) examined participant retention, intervention feasibility and putative effects of CRT on cognitive and psychosocial functioning via intention-to-treat analyses. TRIAL REGISTRATION: ISRCTN ID32290525. RESULTS: Sixty participants were recruited (02/2016-06/2018) and randomised to CRT (n = 29) or TAU (n = 31). Trial withdrawals were equivalent (CRT n = 2/29; TAU n = 5/31). CRT satisfaction indicated high acceptability. Intention-to-treat analyses (N = 60) demonstrated greater improvements for CRT- than TAU-randomised participants: at both week 13 and 25, CIRCuiTS participants showed larger improvements in the following domains (week 25 effect sizes reported here): IQ (SES = 0.71, 95% CI [0.29,1.13]), working memory (SES = 0.70, 95% CI [0.31,1.10]), executive function (SES = 0.93, 95% CI [0.33,1.54]), psychosocial functioning (SES = 0.49, 95% CI [0.18,0.80]) and goal attainment (SES = 2.02, 95% CI [0.89,3.14]). No serious adverse events were reported. CONCLUSIONS: CRT is feasible for individuals with bipolar disorders and may enhance cognition and functioning. The reported effect sizes from this proof-of-concept trial encourage further investigation in a definitive trial.

Cognitive enhancement interventions for people with bipolar disorder: A systematic review of methodological quality, treatment approaches, and outcomes.

BACKGROUND: Patients with bipolar disorder (BD) suffer from cognitive deficits across several domains. The association between cognitive performance and psychosocial functioning has led to the emergence of cognition as a treatment target. OBJECTIVE: This study reviews the existing literature on cognitive enhancement interventions for people with BD, focusing on different treatment approaches and methodological quality. METHODS: We conducted a systematic search following the PRISMA guidelines. Sample characteristics and main outcomes for each study and treatment characteristics for each approach were extracted. Study quality was assessed using the Clinical Trials Assessment Measure (CTAM) and Cochrane Collaboration's Risk of Bias tool by independent raters. RESULTS: Eleven articles reporting data from seven original studies were identified encompassing 471 participants. Two treatment approaches were identified, cognitive and functional remediation. For controlled studies, methodological quality was modest (average CTAM score = 60.3), while the overall risk of bias was considered moderate. Beneficial effects on cognitive or functional outcomes were reported in the majority of studies (91%), but these findings were isolated and not replicated across studies. Key methodological limitations included small sample sizes, poor description of randomization process, high attrition rates, and participant exclusion from the analysis. CONCLUSIONS: Findings are promising but preliminary. Quality studies were few and mostly underpowered. Heterogeneity in sample characteristics, outcome measures, and treatment approaches further limit the ability to generalize findings. Adequately powered trials are required to replicate initial findings, while moderators of treatment response and mechanisms of transfer need to be explored.

Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis.

Most interventions for treatment-resistant depression (TRD) are added as augmenters. We aimed to determine the relative effectiveness of augmentation treatments for TRD. This systematic review and network meta-analysis (NMA) sought all randomized trials of pharmacological and psychological augmentation interventions for adults meeting the most common clinical criteria for TRD. The NMA compared the intervention effectiveness of depressive symptoms for TRD augmentation. Of 36 included trials, 27 were suitable for inclusion in NMA, and no psychological trials could be included in the absence of a common comparator. Antipsychotics (13 trials), mood stabilizers (three trials), NMDA-targeting medications (five trials), and other mechanisms (3 trials) were compared against placebo. NMDA treatments were markedly superior to placebo (ES = 0.91, 95% CI 0.67 to 1.16) and head-to-head NMA suggested that NMDA therapies had the highest chance of being an effective treatment option compared to other pharmacological classes. This study provides the most comprehensive evidence of augmenters' effectiveness for TRD, and our GRADE recommendations can be used to guide guidelines to optimize treatment choices. Although conclusions are limited by paucity of, and heterogeneity between, trials as well as inconsistent reports of treatment safety. This work supports the use of NMDA-targeting medications such as ketamine.

Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis.

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.

Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases.

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders around the world: a survey from the ISBD Lithium task force.

BACKGROUND: Lithium has long been considered the gold-standard pharmacological treatment for the maintenance treatment of bipolar disorders (BD) which is supported by a wide body of evidence. Prior research has shown a steady decline in lithium prescriptions during the last two decades. We aim to identify potential factors explaining this decline across the world with an anonymous worldwide survey developed by the International Society for Bipolar Disorders (ISBD) Task Force "Role of Lithium in Bipolar Disorders" and distributed by diverse academic and professional international channels. RESULTS: A total of 886 responses were received of which 606 completed the entire questionnaire while 206 completed it partially. Respondents were from 43 different countries comprising all continents. Lithium was the most preferred treatment option for the maintenance of BD patients (59%). The most relevant clinical circumstances in which lithium was the preferred option were in patients with BD I (53%), a family history of response (18%), and a prior response during acute treatment (17%). In contrast, Lithium was not the preferred option in case of patients´ negative beliefs and/or attitudes towards lithium (13%), acute side-effects or tolerability problems (10%) and intoxication risk (8%). Clinicians were less likely to prefer lithium as a first option in BD maintenance phase when practising in developing economy countries [X2 (1, N = 430) = 9465, p = 0.002) ] and private sectors [X2 (1, N = 434) = 8191, p = 0.004)]. CONCLUSIONS: Clinicians' preferences and attitudes towards the use of lithium in the maintenance treatment of bipolar disorders appear to be affected by both the patients' beliefs and the professional contexts where clinicians provide their services. More research involving patients is needed for identifying their attitudes toward lithium and factors affecting its use, particularly in developing economies.

Resting-state fMRI in depressive and (hypo)manic mood states in bipolar disorders: A systematic review.

OBJECTIVE: Abnormalities in spontaneous brain activity, measured with resting-state functional magnetic resonance imaging (rs-fMRI), may be key biomarkers for bipolar disorders. This systematic review compares rs-fMRI findings in people experiencing a bipolar depressive or (hypo)manic episode to bipolar euthymia and/or healthy participants. METHODS: Medline, Web of Science and Embase were searched up until April 2021. Studies without control group, or including minors, neurological co-morbidities or mixed episodes, were excluded. Qualitative synthesis was used to report results and risk of bias was assessed using the National Heart, Lung and Blood Institute tool for case-control studies. RESULTS: Seventy-one studies were included (3167 bipolar depressed/706 (hypo)manic). In bipolar depression, studies demonstrated default-mode (DMN) and frontoparietal network (FPN) dysfunction, altered baseline activity in the precuneus, insula, striatum, cingulate, frontal and temporal cortex, and disturbed regional homogeneity in parietal, temporal and pericentral areas. Functional connectivity was altered in thalamocortical circuits and between the cingulate cortex and precuneus. In (hypo)mania, studies reported altered functional connectivity in the amygdala, frontal and cingulate cortex. Finally, rs-fMRI disturbances in the insula and putamen correlate with depressive symptoms, cerebellar resting-state alterations could evolve with disease progression and altered amygdala connectivity might mediate lithium effects. CONCLUSIONS: Our results suggest DMN and FPN dysfunction in bipolar depression, whereas local rs-fMRI alterations might differentiate mood states. Future studies should consider controlling rs-fMRI findings for potential clinical confounding factors such as medication. Considerable heterogeneity of methodology between studies limits conclusions. Standardised clinical reporting and consistent analysis approaches would increase coherence in this promising field.

Psilocybin-assisted therapy for the treatment of resistant major depressive disorder (PsiDeR): protocol for a randomised, placebo-controlled feasibility trial.

INTRODUCTION: Psilocybin-assisted therapy may be a new treatment for major depressive disorder (MDD), with encouraging data from pilot trials. In this trial (short name: PsiDeR) we aimed to test the feasibility of a parallel-group, randomised, placebo-controlled design. The primary outcomes in this trial are measures of feasibility: recruitment rates, dropout rates and the variance of the primary outcome measure of depression. METHODS AND ANALYSIS: We are recruiting up to 60 participants at a single centre in London, UK who are unresponsive to, or intolerant of, at least two evidence-based treatments for MDD. Participants are randomised to receive a single dosing session of 25 mg psilocybin or a placebo. All participants receive a package of psychological therapy. The primary outcome measure for depression is the Montgomery Asberg Depression Rating Scale collected by blinded, independent raters. The primary endpoint is at 3 weeks, and the total follow-up is 6 weeks. With further informed consent, this study collects neuroimaging and omics data for mechanism and biomarker analyses and offers participants an open label extension consisting of a further, open label dose of 25 mg of psilocybin. ETHICS AND DISSEMINATION: All participants will be required to provide written informed consent. The trial has been authorised by the National Research Ethics Committee (20-LO/0206), Health Research Authority (252750) and Medicine's and Healthcare Products Regulatory Agency (CTA 14523/0284/001-0001) in the UK. Dissemination of results will occur via a peer-reviewed publication and other relevant media. TRIAL REGISTRATION NUMBERS: EUDRACT2018-003573-97; NCT04959253.

The Maudsley 3-item Visual Analogue Scale (M3VAS): Validation of a scale measuring core symptoms of depression.

AIMS: Low mood and anhedonia are the core symptoms of major depressive disorder (MDD). However, there is no established visual analogue scale that measures pervasiveness of both symptoms. We aimed to validate the Maudsley 3-item Visual Analogue Scale (M3VAS) as a measure of core depressive symptoms and suicidality. METHODS: This is a cross-sectional secondary analysis combining data from two randomised controlled trials covering a broad range of depression severity from euthymia to severe depression. We validated the M3VAS by testing: 1) latent construct domains using factor analysis; 2) internal consistency using Cronbach's alpha; and 3) convergent validity by correlating M3VAS scores against scores on the Quick Inventory of Depressive Symptomatology-16 item (QIDS-SR-16), which is validated for use in clinical trials. RESULTS: Of 180 patients in the combined cohort, 177 (98.3%) provided complete data on the M3VAS and QIDS-SR-16. The mean (SD) age was 41.6 (13.0) years and 59.3% were female. Using factor analysis, one eigenvalue above 1 was produced (2.39) that explained 79.6% of the variance, indicating a one-factor model. Cronbach's alpha was 0.87, demonstrating good internal consistency. Total M3VAS scores correlated strongly (r = 0.72, p<0.001) with QIDS-SR-16 scores, indicating good convergent validity. LIMITATIONS: This was a cross-sectional study and was not validated against a clinician-rated assessment for depression. CONCLUSION: The M3VAS is a simple, valid instrument for the assessment of core depressive symptoms and suicidality across the depression spectrum. Future studies should test the longitudinal validity of the M3VAS in detecting changes in core depressive symptoms and suicidality over time.

Role of cognitive reserve in cognitive variability in euthymic individuals with bipolar disorder: cross-sectional cluster analysis.

BACKGROUND: People with bipolar disorder have moderate cognitive difficulties that tend to be more pronounced during mood episodes but persist after clinical remission and affect recovery. Recent evidence suggests heterogeneity in these difficulties, but the factors underlying cognitive heterogeneity are unclear. AIMS: To examine whether distinct cognitive profiles can be identified in a sample of euthymic individuals with bipolar disorder and examine potential differences between subgroups. METHOD: Cognitive performance was assessed across four domains (i.e. processing speed, verbal learning/memory, working memory, executive functioning) in 80 participants. We conducted a hierarchical cluster analysis and a discriminant function analysis to identify cognitive profiles and considered differences in cognitive reserve, estimated cognitive decline from premorbid cognitive functioning, and clinical characteristics among subgroups. RESULTS: Four discrete cognitive profiles were identified: cognitively intact (n = 25; 31.3%); selective deficits in verbal learning and memory (n = 15; 18.8%); intermediate deficits across all cognitive domains (n = 30; 37.5%); and severe deficits across all domains (n = 10; 12.5%). Cognitive decline after illness onset was greater for the intermediate and severe subgroups. Cognitive reserve scores were increasingly lower for subgroups with greater impairments. A smaller proportion of cognitively intact participants were using antipsychotic medications compared with all other subgroups. CONCLUSIONS: Our findings suggest that individuals with cognitively impaired profiles demonstrate more cognitive decline after illness onset. Cognitive reserve may be one of the factors underlying cognitive variability across people with bipolar disorder. Patients in the intermediate and severe subgroups may be in greater need of interventions targeting cognitive difficulties.

Unipolar mania: Identification and characterisation of cases in France and the United Kingdom.

BACKGROUND: Unipolar mania is a putative subtype of bipolar disorder (BD) in which individuals experience recurrent manic but not major depressive episodes. Few studies of unipolar mania have been conducted in developed countries and none in the UK. This study aimed to identify and characterise people with unipolar mania in the UK and France. METHODS: People with unipolar mania were ascertained using a South London UK electronic case register and a French BD case series. Each unipolar mania group was compared to a matched group of people with BD who have experienced depressive episodes. RESULTS: 17 people with unipolar mania were identified in South London and 13 in France. The frequency of unipolar mania as a percentage of the BD clinical population was 1.2% for the South London cohort and 3.3% for the French cohort. In both cohorts, people with unipolar mania experienced more manic episodes than people with BD, and in the French cohort were more likely to experience a psychotic illness onset and more psychiatric admissions. Treatment and self-harm characteristics of people with unipolar mania were similar to people with BD. LIMITATIONS: The relatively small number of people with unipolar mania identified by this study limits its power to detect differences in clinical variables. CONCLUSIONS: People with unipolar mania can be identified in France and the UK, and they may experience a higher frequency of manic episodes but have similar treatment and self-harm characteristics as people with BD.

A new inner-city specialist programme reduces readmission rates in frequently admitted patients with bipolar disorder.

Aims and methodThe OPTIMA mood disorders service is a newly established specialist programme for people with bipolar disorder requiring frequent admissions. This audit compared data on hospital admissions and home treatment team (HTT) spells in patients before entry to and after discharge from the core programme. We included patients admitted between April 2015 and March 2017 who were subsequently discharged. Basic demographic data and numbers of admissions and HTT spells three years before and after discharge were collected and analysed. RESULTS: Thirty patients who completed the programme were included in the analyses. The median monthly rate of hospital admissions after OPTIMA was significantly reduced compared with the rate prior to the programme. HTT utilisation was numerically reduced, but this difference was not statistically significant.Clinical implicationsThese results highlight the effectiveness and importance of individually tailored, specialist care for patients with bipolar disorder following discharge from hospital.Declaration of interestNone.