Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory.

One hundred and twenty-six persons aged 18–85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics.

Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model.

Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.

Studies about brain structure in bipolar disorder have reported conflicting findings. These findings may be explained by the high degree of heterogeneity within bipolar disorder, especially if structural differences are mapped to single brain regions rather than networks.

We aim to complete a systematic review and meta-analysis to identify brain networks underlying structural abnormalities observed on T1-weighted magnetic resonance imaging scans in bipolar disorder across the lifespan. We also aim to explore how these brain networks are affected by sociodemographic and clinical heterogeneity in bipolar disorder.

We will include case–control studies that focus on whole-brain analyses of structural differences between participants of any age with a standardised diagnosis of bipolar disorder and controls. The electronic databases Medline, PsycINFO and Web of Science will be searched. We will complete an activation likelihood estimation analysis and a novel coordinate-based network mapping approach to identify specific brain regions and brain circuits affected in bipolar disorder or relevant subgroups. Meta-regressions will examine the effect of sociodemographic and clinical variables on identified brain circuits.

Findings from this systematic review and meta-analysis will enhance understanding of the pathophysiology of bipolar disorder. The results will identify brain circuitry implicated in bipolar disorder, and how they may relate to relevant sociodemographic and clinical variables across the lifespan.

Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone.

To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone).

In a 4-week, three-arm, ‘double dummy’ trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure.

This trial will advance the understanding of psilocybin's mechanism of antidepressant action.

This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.

There has been increased interest in repurposing anti-inflammatories for the treatment of bipolar depression. Evidence from high-income countries suggests that these agents may work best for specific depressive symptoms in a subset of patients with biochemical evidence of inflammation but data from lower-middle income countries (LMICs) is scarce. This secondary analysis explored the relationship between pretreatment inflammatory markers and specific depressive symptoms, clinical measures, and demographic variables in participants with bipolar depression in Pakistan.

The current study is a cross-sectional secondary analysis of a randomized controlled trial of two anti-inflammatory medications (minocycline and celecoxib) for bipolar depression (n = 266). A series of logistic and linear regression models were completed to assess the relationship between C-reactive protein (CRP) (CRP > or < 3 mg/L and log10CRP) and clinical and demographic features of interest and symptoms of depression. Baseline clinical trial data was used to extract clinical and demographic features and symptoms of depression were assessed using the 24-item Hamilton Depression Rating Scale.

The prevalence of low-grade inflammation (CRP > 3 mg/L) in the sample was 70.9%. After adjusting for baseline body mass index, socioeconomic status, age, gender, symptoms related to anhedonia, fatigue, and motor retardation were most associated with low-grade inflammation.

Bipolar disorder (BD) patients from LMICs may experience higher rates of peripheral inflammation than have been reported in Western populations with BD. Future trials of repurposed anti-inflammatory agents that enrich for participants with these symptom profiles may inform the development of personalized treatment for bipolar depression in LMICs.

To investigate the relationship between lean muscle mass and treatment response in treatment-resistant late-life depression (TR-LLD). We hypothesized that lower lean muscle mass would be associated with older age, higher physical comorbidities, higher depressive symptom severity, and poorer treatment response.

Secondary analysis of a randomized, placebo-controlled trial.

Three academic hospitals in the United States and Canada.

Adults aged 60+ years with major depressive disorder who did not remit following open treatment with venlafaxine extended-release (XR) (n = 178).

We estimated lean muscle mass using dual-energy X-ray absorptiometry (DEXA) scans prior to and following randomized treatment with aripiprazole or placebo added to venlafaxine XR. Multivariate regressions estimated influence of demographic and clinical factors on baseline lean muscle mass, and whether baseline lean muscle mass was associated with treatment response, adjusted for treatment arm.

Low lean muscle mass was present in 22 (12.4%) participants. Older age and female sex, but not depressive symptom severity, were independently associated with lower lean muscle mass at baseline. Marital status, baseline depressive symptom severity, and treatment group were associated with improvement of depressive symptoms in the randomized treatment phase. Baseline lean muscle mass was not associated with improvement, regardless of treatment group.

As expected, older age and female sex were associated with lower lean muscle mass in TR-LLD. However, contrary to prior results in LLD, lean muscle mass was not associated with depression severity or outcome. This suggests that aripiprazole augmentation may be useful for TR-LLD, even in the presence of anomalous body composition.

clinicaltrials.gov Identifier: NCT00892047.

Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging.

We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder [‘Healthy Controls’ – HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction.

Our results support both an early impairment (‘early hit’) model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition.

Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.

Bipolar disorder is a source of marked disability, morbidity and premature death. There is a paucity of research on personalised psychosocial interventions for bipolar disorder, especially in low-resource settings. A pilot randomised controlled trial (RCT) of a culturally adapted psychoeducation intervention for bipolar disorder (CaPE) in Pakistan reported higher patient satisfaction, enhanced medication adherence, knowledge and attitudes regarding bipolar disorder, and improvement in mood symptom scores and health-related quality of life measures compared with treatment as usual (TAU).

The current protocol describes a larger multicentre RCT to confirm the clinical and cost-effectiveness of CaPE in Pakistan. Trial registration: NCT05223959.

A multicentre individual, parallel-arm RCT of CaPE in 300 Pakistani adults with bipolar disorder. Participants over the age of 18, with a diagnosis of bipolar I or II disorder who are currently euthymic, will be recruited from seven sites: Karachi, Lahore, Multan, Rawalpindi, Peshawar, Hyderabad and Quetta. Time to recurrence will be the primary outcome assessed using the Longitudinal Interval Follow-up Evaluation (LIFE). Secondary measures will include mood symptoms, quality of life and functioning, adherence to psychotropic medications, and knowledge and attitudes regarding bipolar disorder.

This trial will assess the effectiveness of the CaPE intervention compared with TAU in reducing the time to recurrence for people with bipolar disorder currently in remission in Pakistan and determine the effect on clinical outcomes, quality of life and functioning.

A successful trial might lead to rapid implementation of CaPE in clinical practice, not only in Pakistan, but also in other low-resource settings, including those in high-income countries, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority group patients with bipolar disorder.

This study examined the effectiveness of an integrated care pathway (ICP), including a medication algorithm, to treat agitation associated with dementia.

Analyses of data (both prospective and retrospective) collected during routine clinical care.

Geriatric Psychiatry Inpatient Unit.

Patients with agitation associated with dementia (n = 28) who were treated as part of the implementation of the ICP and those who received treatment-as-usual (TAU) (n = 28) on the same inpatient unit before the implementation of the ICP. Two control groups of patients without dementia treated on the same unit contemporaneously to the TAU (n = 17) and ICP groups (n = 36) were included to account for any secular trends.

ICP.

Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory Questionnaire (NPIQ), and assessment of motor symptoms were completed during the ICP implementation. Chart review was used to obtain length of inpatient stay and rates of psychotropic polypharmacy.

Patients in the ICP group experienced a reduction in their scores on the CMAI and NPIQ and no changes in motor symptoms. Compared to the TAU group, the ICP group had a higher chance of an earlier discharge from hospital, a lower rate of psychotropic polypharmacy, and a lower chance of having a fall during hospital stay. In contrast, these outcomes did not differ between the two control groups.

These preliminary results suggest that an ICP can be used effectively to treat agitation associated with dementia in inpatients. A larger randomized study is needed to confirm these results.

Among low- and middle-income countries (LMICs), bipolar disorder is recognized as one of the leading causes of disease burden for adults and is associated with marked suicide risk. There are limited data on suicidal ideation in bipolar disorder from LMICs. This study presents cross-sectional data on the prevalence of suicidality and associated patient characteristics among patients with bipolar depression in Pakistan, a lower-middle income country and the fifth most populous country in the world.

Participants were recruited through outpatient psychiatric clinics in between 2016–2019 in Karachi, Lahore, Hyderabad and Rawalpindi between 2016–2019. Participants were aged 18 to 65 years with a known diagnosis of bipolar disorder and currently in a depressive episode. Suicidality was assessed using the suicide item of the 17-item Hamilton Depression Rating Scale (HAM-D) and levels of severity were categorized as absent, mild/moderate, or severe. Biometric data and biomarkers were obtained. Descriptive statistics were used to describe prevalence and proportional odds regression models were applied to establish correlates to suicidal ideation.

Among the 266 participants, 67% indicated suicidality of any level and 16% endorsed severe suicidality. Lower body mass index (BMI) (OR = 0.93, 95% CI = 0.88–0.98), higher HAM-D score (OR = 1.29, 95% CI = 1.16–1.43), lower C-reactive protein (CRP) level (OR = 0.53, 95% CI = 0.40–0.70), and increased number of inpatient hospitalizations (OR = 1.16, 95% CI = 1.03–1.31) were identified as significant predictors of suicidality in the fully adjusted regression model. No patient demographic data, including age, gender, marital status, socioeconomic status, and years of education were associated with severity of suicidality.

There exists a high prevalence of suicidal ideation among patients with bipolar depression in Pakistan. Our findings add to the limited literature on suicidality in bipolar disorder in the LMIC context and suggest roles of biological variables such as BMI and CRP level in predicting suicidal ideation and potentially suicidal behaviours in bipolar depression. More studies are needed to see whether such findings can be replicated in other similar LMIC settings, and to explore potential physiological pathways linking BMI, inflammatory biomarkers and suicidality in bipolar disorder.

Little is known about the relationship between psychomotor disturbance (PMD) and treatment outcome of psychotic depression. This study examined the association between PMD and subsequent remission and relapse of treated psychotic depression.

Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission or near-remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine (n = 64) with sertraline plus placebo (n = 62). PMD was measured with the psychiatrist-rated sign-based CORE at acute phase baseline and at RCT baseline. Spearman's correlations and logistic regression analyses were used to analyze the association between CORE total score at acute phase baseline and remission/near-remission and CORE total score at RCT baseline and relapse.

Higher CORE total score at acute phase baseline was associated with lower frequency of remission/near-remission. Higher CORE total score at RCT baseline was associated with higher frequency of relapse, in the RCT sample as a whole, as well as in each of the two randomized groups.

PMD is associated with poorer outcome of psychotic depression treated with sertraline plus olanzapine. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.

Pilot randomized double-blind-controlled trial of repetitive paired associative stimulation (rPAS), a paradigm that combines transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) with peripheral median nerve stimulation.

To study the impact of rPAS on DLPFC plasticity and working memory performance in Alzheimer’s disease (AD).

Thirty-two patients with AD (females = 16), mean (SD) age = 76.4 (6.3) years were randomized 1:1 to receive a 2-week (5 days/week) course of active or control rPAS. DLPFC plasticity was assessed using single session PAS combined with electroencephalography (EEG) at baseline and on days 1, 7, and 14 post-rPAS. Working memory and theta–gamma coupling were assessed at the same time points using the N-back task and EEG.

There were no significant differences between the active and control rPAS groups on DLPFC plasticity or working memory performance after the rPAS intervention. There were significant main effects of time on DLPFC plasticity, working memory, and theta–gamma coupling, only for the active rPAS group. Further, on post hoc within-group analyses done to generate hypotheses for future research, as compared to baseline, only the rPAS group improved on post-rPAS day 1 on all three indices. Finally, there was a positive correlation between working memory performance and theta–gamma coupling.

This study did not show a beneficial effect of rPAS for DLPFC plasticity or working memory in AD. However, post hoc analyses showed promising results favoring rPAS and supporting further research on this topic. (Clinicaltrials.gov-NCT01847586)

Mood disorders, i.e. major depressive disorder (MDD) and bipolar disorders, are leading sources of disability worldwide. Currently available treatments do not yield remission in approximately a third of patients with a mood disorder. This is in part because these treatments do not target a specific core pathology underlying these heterogeneous disorders. In recent years, abnormal inflammatory processes have been identified as putative pathophysiological mechanisms and treatment targets in mood disorders, particularly among individuals with treatment-resistant conditions.

In this selective review, we aimed to summarise recent advances in the field of immunopsychiatry, including emerging pathophysiological models and findings from treatment ttrials of immunomodulatory agents for both MDD and bipolar disorders.

We performed a literature review by searching Medline for clinical trials of immunomodulating agents as monotherapy or adjunctive treatments in MDD and bipolar disorders. Included studies are randomised controlled trials (RCTs), cluster RCTs or cross-over trials of immunomodulating agents that had an active comparator or a placebo-arm.

Current evidence shows an association between inflammation and mood symptoms. However, there is conflicting evidence on whether this link is causal.

Future studies should focus on identifying specific neurobiological underpinnings for the putative causal association between an activated inflammatory response and mood disorders. Results of these studies are needed before further treatment trials of immunomodulatory agents can be justified.

The primary objective of this study was to determine whether a brief education session about Alzheimer's disease (AD) stages and associated behavioral and psychological symptoms of dementia (BPSD) changes healthy seniors’ treatment choices. A secondary objective was to determine whether pharmacotherapy to reduce BPSD would be preferred over other potentially more restrictive interventions.

Participants (n = 32; 8 men; aged > 64years; no self-reported dementia diagnosis) were assigned to one of ten group sessions during which they received information about AD and BPSD. Our a-priori hypotheses were: (1) education about AD stages significantly changes care preferences in moderate and severe stages, i.e. less active treatment options (no CPR/hospitalization) are chosen as the disease progresses; and (2) most participants prefer pharmacotherapy over restraints and seclusion to manage BPSD. The main outcome measure was a change in the interventions chosen including CPR and hospitalization. Participants completed three questionnaires and two decisional grids before and after the information session. Qualitative data were derived from discussions during the session.

Participants expressed a wide range of attitudes about AD, BPSD, and their management. Those who are born in Canada, had a proxy, and a university education, each have around half of the odds of receiving treatment compared to those in the complementary group. (OR 0.47, 0.40, 0.43) Finally, not knowing someone with AD increases the odds of wanting a treatment by around six times (OR 6.4). Pharmacological measures were preferred over restraints.

Education about dementia and advance directives should consider the person's educational background and experience with dementia. Discussing BPSD may impact a person's advance directives and preferences.