Ethnic density and first episode psychosis in the British Pakistani population: findings from the East Lancashire Early Intervention Service.

BACKGROUND: Elevated risk of psychosis for ethnic minority groups has generally been shown to be mitigated by high ethnic density. However, past survey studies examining UK Pakistani populations have shown an absence of protective ethnic density effects, which is not observed in other South Asian groups. AIMS: To assess the ethnic density effect at a local neighbourhood level, in the UK Pakistani population in East Lancashire. METHOD: Data was collected by the East Lancashire Early Intervention Service, identifying all cases of first episode psychosis (FEP) within their catchment area between 2012 and 2020. Multilevel Poisson regression analyses were used to compare incidence rates between Pakistani and White majority groups, while controlling for age, gender and area-level deprivation. The ethnic density effect was also examined by comparing incidence rates across high and low density areas. RESULTS: A total of 455 cases of FEP (364 White, 91 Pakistani) were identified. The Pakistani group had a higher incidence of FEP compared to the White majority population. A clear effect of ethnic density on rates of FEP was shown, with those in low density areas having higher incidence rates compared to the White majority, whereas incidence rates in high density areas did not significantly differ. Within the Pakistani group, a dose-response effect was also observed, with risk of FEP increasing incrementally as ethnic density decreased. CONCLUSIONS: Higher ethnic density related to lower risk of FEP within the Pakistani population in East Lancashire, highlighting the impact of local social context on psychosis incidence.

A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.

Associations between peripheral inflammation and clinical phenotypes of bipolar depression in a lower-middle income country.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

An integrated parenting intervention for maternal depression and child development in a low-resource setting: Cluster randomized controlled trial.

BACKGROUND: Rates of depression among Pakistani mothers are high, leading to poor developmental outcomes in their children. This study tested the effectiveness of a manualized integrated parenting program; Learning through Play Plus (LTP+) for maternal depression in Karachi, Pakistan. METHODS: A cluster randomized control trial conducted from January 2014 to December 2015 across 120 villages in Karachi. A total of 774 depressed mothers aged 18-44 years with children aged 0-30 months old, were included. Villages were randomized to receive LTP+ added to treatment as usual (TAU) or TAU alone. Primary outcomes were severity of maternal depression at 3 and 6 months measured by the Edinburgh Postnatal Depression Scale and child socio-emotional development at 6 months measured by the Ages and Stages Questionnaire (ASQ). Secondary outcomes included maternal anxiety, quality of life, social support, parenting competence, and knowledge about child development. RESULTS: Mothers in the LTP+ group reported significantly lower depression scores compared to those in the TAU group (6.6 vs. 13.8, effect size [ES]: -7.2; 95% confidence interval [CI]: -8.2, -6.1) at 3 and 6 months (7.2 vs. 12.00; ES: -4.6; 95% CI: -5.9, -3.4). Child socio-emotional development at 6 months was significantly better in the LTP+ group on all domains of the ASQ. There were also statistically significant improvements on all secondary outcomes at 3- and 6-month follow-up. CONCLUSION: In low-resource settings like Pakistan, low-cost integrated parenting interventions delivered by lay health workers can provide effective treatment for depressed mothers, leading to improvements in child development.

Minocycline as adjunctive treatment for major depressive disorder: Pooled data from two randomized controlled trials.

BACKGROUND: Randomized controlled clinical trials that have investigated minocycline as an adjunctive treatment for major depressive disorder have proved promising. Data from two studies were pooled to evaluate more definitively whether the addition of minocycline to standard treatment for major depressive disorder leads to an improvement of depressive symptoms when compared with placebo. METHODS: Both studies were multi-site, double-blinded, placebo-controlled trials of minocycline 200 mg/day added to treatment as usual during a 12-week period. The primary outcome measure was change in depressive symptoms (Montgomery-Asberg Depression Rating Scale in Dean et al. and Hamilton Depression Rating Scale in Husain et al.). Secondary outcomes were change in depression severity (Montgomery-Asberg Depression Rating Scale for Dean et al. and 9-item Patient Health Questionnaire in Husain et al.), anxiety severity (Hamilton Anxiety Rating Scale in Dean et al. and Generalized Anxiety Disorder 7-item scale in Husain et al.) and functional status, which were also evaluated as potential mediators on the primary outcome. RESULTS: A total of 112 participants were included in the pooled data (Dean et al., n = 71; Husain et al., n = 41). A significant change from baseline to week 12 was noted in depressive symptoms - differential change (Placebo vs Minocycline): 9.0, 95% confidence interval = [4.2, 13.9], Cohen's D (95% confidence interval): 0.71 [0.29, 1.14], p < 0.001 - anxiety severity - differential change (Placebo vs Minocycline): 0.38, confidence interval = [0.00, 0.75], Cohen's D (95% confidence interval): 0.41 [0.00, 0.82], p = 0.050) and functional status - differential change (Placebo vs Minocycline): 1.0, 95% confidence interval = [0.4, 1.5], Cohen's D (95% confidence interval): 0.76 [0.34, 1.19], p = 0.001). Duration of illness, current use of benzodiazepine and pain medication were identified as moderators, whereas functional status as a mediator/predictor. CONCLUSION: The improvement of depressive symptoms, anxiety severity and functional status is promising and suggests that minocycline has potential as an adjunctive treatment for major depressive disorder. However, further studies are warranted to confirm therapeutic effects of minocycline in major depressive disorder. TRIAL REGISTRATIONS: NCT02263872, registered October 2014, and ACTRN12612000283875, registered March 2012.

Depression and suicidal ideation in schizophrenia spectrum disorder: a cross-sectional study from a lower middle-income country.

OBJECTIVES: Depression has long been considered a significant feature of schizophrenia and is associated with more frequent psychotic episodes, increased service utilisation, substance misuse, poor quality of life and completed suicide. However, there is a distinct lack of literature on this comorbidity from low- and middle-income countries or non-western cultural backgrounds. METHODS: This is a cross-sectional analysis of baseline data from a large randomised controlled trial, examining the prevalence of depression and suicidal ideation in patients with schizophrenia spectrum disorder. A total of 298 participants were recruited from inpatient and outpatient psychiatric units in Karachi, Pakistan. Participants completed the Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), Euro Qol (EQ-5D) and Social Functioning Scale (SFS). RESULTS: Data indicate that 36% of participants in the study were depressed and 18% endorsed suicidal ideation. Depression was associated with higher positive symptom scores and reduced quality of life, but no significant difference in negative symptoms and social functioning. CONCLUSIONS: Depression and suicidal ideation are prevalent in Pakistani patients diagnosed with schizophrenia spectrum disorder. Evaluation of depressive symptoms in this group may help identify individuals at higher risk of completed suicide, allowing for targeted interventions to improve outcomes.Key pointsTo our knowledge, this is the first study describing the prevalence of depression and suicidal ideation in individuals with schizophrenia from Pakistan.Our data indicate that 36% of individuals with schizophrenia in our sample were depressed and 18% endorsed suicidal ideation.Depression in schizophrenia was associated with poorer quality of life and higher positive symptom burden.This study adds to the scarce literature from low- and middle-income countries where the burden of mental illness is great and where the majority of suicide deaths occur.Addressing social inequality, food insecurity, high rates of unemployment and low levels of literacy in these settings may have a profound effect on population mental health and suicide risk.

Culturally adapted family intervention for schizophrenia in Pakistan: a feasibility study.

OBJECTIVES: To establish feasibility and acceptability of a Culturally adapted Family Intervention (CulFI) that was developed using an empirically derived conceptual framework in Pakistan. METHODS: A rater-blind, randomised trial to evaluate the feasibility and acceptability of delivering CulFI compared to treatment as usual in Karachi, Pakistan. Indicators of feasibility included evaluation of recruitment rates, retention and randomisation. We also evaluated the acceptability of the intervention and trial procedures. RESULTS: Excellent recruitment and retention rates informed the feasibility of the intervention. CulFI had more than a 90% participant attendance of 8-10 sessions and retained more than 90% who commenced in the intervention. Eighty percent of those who initially provided consent were willing to be randomised and the quality of CulFI was rated as good to excellent by 85.7% of participants. CONCLUSIONS: Importantly, this study determines that pathways into a psychosocial intervention can be established in Pakistan. A combination of factors contribute to low levels of access to psychiatric care including different explanatory models of illness, small numbers of trained staff, limited resources and reliance on traditional healers. These results support the feasibility, acceptability and merit of conducting a full-scale trial of CulFI in comparison with standard care.ClinicalTrials.gov Identifier: NCT02167347KEY POINTSThe significant treatment gap in LMICs leaves families providing much of the care for people with schizophrenia.There is limited evidence from LMICs supporting the effectiveness and feasibility of psychosocial interventions more broadly, and family interventions specifically.This study adds to the scarce literature and demonstrates that pathways into delivering psychosocial interventions can be established in Pakistan.The results of this trial support the feasibility and acceptability of a Culturally adapted Family Intervention (CulFI) for schizophrenia patients and their families in PakistanA full-scale trial of CulFI in comparison with standard care is warranted to determine clinical and cost-effectiveness.

Cognitive function in early psychosis patients from a lower middle-income country.

OBJECTIVES: To establish evidence of cognitive changes in early psychosis (EP) patients compared to healthy controls (HC) in Pakistan. METHODS: Fifty-one participants with EP were recruited from psychiatric units in Karachi and Rawalpindi, Pakistan and matched with 51 HC. Neurocognitive domains were assessed using standardised neuropsychological tests [the Stroop test, block design, Matrix Reasoning, picture completion, object assembly, oral fluency, memory for design, Coughlan learning task (verbal and visual)]. RESULTS: EP patients had higher scores than controls for both Stroop tests (T1: EP = 122 HC = 65, p <.001; T2: EP = 190 HC = 153, p = .007) and memory for design test (EP = 10 HC = 3, p = .005). EP group had lower values for block design (EP = 4, HC = 11, p = .01), category fluency (EP = 18.9, HC = 26.1, p < .001), Coughlan verbal tasks (EP = 36.4 NC = 51.5, p < .001), matrix reasoning (EP = 4 NC = 10, p < .001), picture completion (EP = 4 NC = 6, p = .003) and object assembly (EP = 10.7, HC = 15.5, p = .002). There were limited significant associations between cognitive performance and PANSS scores. CONCLUSIONS: Reduced cognitive performance was found across multiple domains in Pakistani EP patients, which suggests that impaired cognitive performance is homogenous in patients with schizophrenia, regardless of ethnicity.

Pilot randomised controlled trial of culturally adapted cognitive behavior therapy for psychosis (CaCBTp) in Pakistan.

BACKGROUND: Evidence for efficacy of cognitive-behavioural therapy (CBT) in treatment of schizophrenia is growing. CBT is effective and cost efficient in treating positive and negative symptoms. To effectively meet the needs of diverse cultural groups, CBT needs to be adapted to the linguistic, cultural and socioeconomic context. We aimed to assess the feasibility, efficacy and acceptability of a culturally adapted CBT for treatment of psychosis (CaCBTp) in a low-income country. METHODS: Rater-blind, randomised, controlled trial of the use of standard duration CBT in patients with psychosis from a low-income country. Participants with a ICD-10 diagnosis of psychosis were assessed using Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Psychotic Symptom Rating Scales (PSYRATS), and the Schedule for Assessment of Insight (SAI) (baseline, 3 months and 6 months). They were randomized into the intervention group (n = 18) and Treatment As Usual (TAU) group (n = 18). The intervention group received 12 weekly sessions of CaCBTp. RESULTS: The CaCBTp group had significantly lower scores on PANSS Positive (p = 0.02), PANSS Negative (p = 0.045), PANSS General Psychopathology (p = 0.008) and Total PANSS (p = 0.05) when compared to TAU at three months. They also had low scores on Delusion Severity Total (p = 0.02) and Hallucination Severity Total (p = 0.04) of PSYRATS, as well as higher scores on SAI (p = 0.01) at the same time point. At six months only the improvement in PANSS positive scores (p = 0.045) met statistical significance.. CONCLUSIONS: It is feasible to offer CaCBTp as an adjunct to TAU in patients with psychosis, presenting to services in a lower middle-income country. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02202694 (Retrospectively registered).

Medical professionalism education for psychiatry trainees: does it meet standards?

OBJECTIVE: Developing professionalism is an important part of a doctor's training. Developing professional attributes is an expected part of postgraduate psychiatry training, as indicated by the curriculum. It is unknown whether this requirement is being met. Our aim was to explore whether psychiatry trainees are meeting current standards of professionalism education. METHODS: This audit and evaluation was investigated using an online survey, inviting trainees from three National Health Service Trusts in North West England. Invitations were sent by email with a link to an online survey. RESULTS: The results suggest that current standards are not being met. Trainees value professionalism education and feel it is important. However, there is a lack of formal teaching and a lack of adequate educational opportunities: 25% of trainees get any formal teaching and 78% feel this teaching is not adequate. There is also a concern that 20% of supervisors are not considered good role models. CONCLUSIONS: Recommendations to address this educational gap are presented. Recommendations include making time in trainees' academic programmes for formal educational activities for professionalism development, and further exploration of why some supervisors are not considered good role models for professionalism.

Brief psychological intervention after self-harm: randomised controlled trial from Pakistan.

BACKGROUND: Self-harm is a major risk factor for completed suicide. AIMS: To determine the efficacy of a brief psychological intervention - culturally adapted manual-assisted problem-solving training (C-MAP) - delivered following an episode of self-harm compared with treatment as usual (TAU). METHOD: The study was a randomised controlled assessor-masked clinical trial (trial registration: ClinicalTrials.gov NCT01308151). All patients admitted after an episode of self-harm during the previous 7 days to the participating medical units of three university hospitals in Karachi, Pakistan, were included in the study. A total of 250 patients were screened and 221 were randomly allocated to C-MAP plus treatment as usual (TAU) or to TAU alone. All patients were assessed at baseline, at 3 months (end of intervention) and at 6 months after baseline. The primary outcome measure was reduction in suicidal ideation at 3 months. The secondary outcome measures included hopelessness, depression, coping resources and healthcare utilisation. RESULTS: A total of 108 patients were randomised to the C-MAP group and 113 to the TAU group. Patients in the C-MAP group showed statistically significant improvement on the Beck Scale for Suicide Ideation and Beck Hopelessness Inventory, which was sustained at 3 months after the completion of C-MAP. There was also a significant reduction in symptoms of depression compared with patients receiving TAU. CONCLUSIONS: The positive outcomes of this brief psychological intervention in patients attempting self-harm are promising and suggest that C-MAP may have a role in suicide prevention.

Adverse Events Reporting in Digital Interventions Evaluations for Psychosis: A Systematic Literature Search and Individual Level Content Analysis of Adverse Event Reports.

BACKGROUND: Digital health interventions (DHIs) have significant potential to upscale treatment access to people experiencing psychosis but raise questions around patient safety. Adverse event (AE) monitoring is used to identify, record, and manage safety issues in clinical trials, but little is known about the specific content and context contained within extant AE reports. This study aimed to assess current AE reporting in DHIs. STUDY DESIGN: A systematic literature search was conducted by the iCharts network (representing academic, clinical, and experts by experience) to identify trials of DHIs in psychosis. Authors were invited to share AE reports recorded in their trials. A content analysis was conducted on the shared reports. STUDY RESULTS: We identified 593 AE reports from 18 DHI evaluations, yielding 19 codes. Only 29 AEs (4.9% of total) were preidentified by those who shared AEs as being related to the intervention or trial procedures. While overall results support the safety of DHIs, DHIs were linked to mood problems and psychosis exacerbation in a few cases. Additionally, 27% of studies did not report information on relatedness for all or at least some AEs; 9.6% of AE reports were coded as unclear because it could not be determined what had happened to participants. CONCLUSIONS: The results support the safety of DHIs, but AEs must be routinely monitored and evaluated according to best practice. Individual-level analyses of AEs have merit to understand safety in this emerging field. Recommendations for best practice reporting in future studies are provided.

Integrated Moving on After Breast Cancer and Culturally Adapted Cognitive Behavior Therapy intervention for depression and anxiety among Pakistani women with breast cancer: Protocol of a randomized controlled trial.

Objective: The diagnosis and treatment of breast cancer is associated with significant distress that has huge impact on survivors' quality of life. The objective of this study is to assess the effectiveness of an integrated intervention "Moving on After Breast Cancer (ABC) Plus culturally adapted Cognitive Behavior Therapy" (Moving on ABC Plus). Method: This is a randomized controlled trial that aims to recruit 354 breast cancer survivors from the inpatient and outpatient oncology departments in public and private hospitals in Karachi, Hyderabad, Lahore, Multan, and Rawalpindi in Pakistan. Patients scoring 10 or above on either the Patient Health Questionnaire-9 and/or the Generalized Anxiety Disorder scale (GAD-7) will be recruited. Baseline assessments will include Functional Assessment of Cancer Therapy-Breast; EuroQol-5D; Multidimensional Scale for Perceived Social Support; Intrusive Thoughts Scale; and Rosenberg Self-Esteem Scale. Participants randomized into intervention arm, Moving on ABC Plus, will receive 12 individual therapy sessions over 4 months. Follow-up will be completed at 4- and 6-month post-randomization, using all baseline instruments along with the Client Satisfaction Questionnaire (CSQ-8). We will also explore the participants', their family members', and the therapists' experiences of the trial and intervention. Results: We will be assessing the effectiveness of intervention in reducing depression and anxiety in breast cancer survivors as a primary outcome of the trial. The secondary outcomes will include effectiveness of intervention in terms of reduction in intrusive thoughts and improvement in health-related quality of life, self-esteem, and perceived social support. Conclusion: The results of the study will inform the design of a future larger randomized control trial with long-term follow-up.

Antecedents, clinical and psychological characteristics of a large sample of individuals who have self-harmed recruited from primary care and hospital settings in Pakistan.

BACKGROUND: Suicide is one of the leading causes of mortality worldwide, and the majority of suicide deaths occur in low- and middle-income countries. AIMS: To evaluate the demographic and clinical characteristics of individuals who have presented to health services following self-harm in Pakistan. METHOD: This study is a cross-sectional baseline analysis of participants from a large multicentre randomised controlled trial of self-harm prevention in Pakistan. A total of 901 participants with a history of self-harm were recruited from primary care clinics, emergency departments and general hospitals in five major cities in Pakistan. The Beck Scale for Suicide Ideation (BSI), Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS) and Suicide Attempt Self Injury Interview assessment scales were completed. RESULTS: Most participants recruited were females (n = 544, 60.4%) in their 20s. Compared with males, females had lower educational attainment and higher unemployment rates and reported higher severity scores on BSI, BDI and BHS. Interpersonal conflict was the most frequently cited antecedent to self-harm, followed by financial difficulties in both community and hospital settings. Suicide was the most frequently reported motive of self-harm (N = 776, 86.1%). Suicidal intent was proportionally higher in community-presenting patients (community: N = 318, 96.9% v. hospital: N = 458, 79.9%; P < 0.001). The most frequently reported methods of self-harm were ingestion of pesticides and toxic chemicals. CONCLUSIONS: Young females are the dominant demographic group in this population and are more likely to attend community settings to seek help. Suicidal intent as the motivator of self-harm and use of potentially lethal methods may suggest that this population is at high risk of suicide.

Prevalence of suicidal ideation and suicide attempts in individuals with psychosis and bipolar disorder in South Asia: systematic review and meta-analysis.

BACKGROUND: Suicidal ideation and attempts are growing public health concerns globally. Evidence from high-income countries suggests that individuals with psychosis and bipolar disorder are at increased risk of suicidal ideation and attempts, but there is a scarcity of evidence from South Asia. AIMS: To estimate the prevalence of suicidal ideation and attempts in individuals with psychosis and bipolar disorder in South Asia. METHOD: In this systematic review and meta-analysis, four databases (PsycINFO, Web of Science, EMBASE and Medline) were searched until December 2022. Pooled prevalence was estimated with random-effects models. Heterogeneity was quantified with the I2-statistic. RESULTS: The pooled sample size across the 21 studies was 3745 participants, 1941 (51.8%) of which were male. The pooled prevalence of suicide attempts in South Asian people with either psychosis or bipolar disorder was 22% (95% CI 17-27; n = 15). The pooled prevalence of suicidal ideation with psychosis or bipolar disorder combined was 38% (95% CI 27-51; n = 10). Meta-regression, subgroup and sensitivity analysis showed that the pooled prevalence estimates for both suicide attempt and ideation remained unaffected by variations in critical appraisal ratings and study designs. Only one study reported data on suicide-related deaths. CONCLUSIONS: One in four individuals diagnosed with psychosis or bipolar disorder have reported suicide attempts, whereas up to one in three have experienced suicidal ideation. These findings underscore the urgent need for clinicians to regularly assess and monitor suicidal ideation and attempts among individuals with these disorders in South Asia.

Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Immune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD. Objective: To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD. Design, Setting, and Participants: This 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models. Intervention: Participants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo. Main Outcomes and Measures: The primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12. Results: A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, -0.61; 95% CI, -3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin. Conclusions and Relevance: In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care. Trial Registration: ClinicalTrials.gov Identifier: NCT03435744.

Metabolic function in patients with bipolar depression receiving anti-inflammatory agents: Findings from the MINDCARE study, a multicentre, randomised controlled trial.

BACKGROUND: Metabolic dysfunction is prevalent in bipolar disorder (BD) and associated with illness severity and treatment outcomes. There is little research exploring this relationship in low and middle-income countries (LMICs) and little is known about the moderating effect of metabolic health on treatment response to anti-inflammatory drugs in BD. METHODS: MINDCARE, a randomized-controlled-trial conducted in Pakistan, investigated the efficacy of minocycline and celecoxib in 266 adults with bipolar depression. This secondary analysis evaluated the association between depression severity at baseline and treatment outcome with metabolic parameters including body mass index (BMI), waist circumference (WC), heart rate (HR), systolic blood pressure (s-BP), and diastolic blood pressure (d-BP). Depression severity was measured using the Hamilton Depression Rating Scale-17. The exploratory aim was to assess whether treatment impacted change in metabolic variables. Associations were evaluated using linear regression. RESULTS: Higher BMI (B=-0.38, 95%CI: -0.55 to -0.21) and WC (B=-0.68, 95%CI: -0.97 to -0.39) were associated with lower baseline depression severity in both the unadjusted and the adjusted models. Baseline metabolic parameters were not associated with treatment response to minocycline or celecoxib nor did treatment significantly impact metabolic variables. LIMITATIONS: Our sample represents patients in an RCT and may not be fully representative of the overall BD population in Pakistan. CONCLUSIONS: Our findings indicate a potential association of poor metabolic health and lower severity of bipolar depression but not treatment outcomes. Future work should evaluate potential relationships of metabolic parameters and BD in diverse populations to increase the transferability of this line of work.

Building Resilience Against ViolencE (BRAVE): protocol of a parenting intervention for mothers and fathers with post-traumatic stress disorder in Pakistan.

Background: Prevalence of post-traumatic stress disorder (PTSD) is high in Pakistan both due to natural disasters and ongoing conflicts. Offspring of trauma survivors are at increased risk for mental and physical illnesses. Parental PTSD has been linked to troubled parent-child relationships, behaviour problems, trauma symptoms, and depression in children. This study aims to explore the acceptability, feasibility and indications of the effectiveness of group learning through play plus trauma-focused cognitive behaviour therapy (LTP Plus TF-CBT) for parents experiencing PTSD. Methods/Design: This is a two-arm pilot cluster randomised controlled trial (RCT). We aim to recruit 300 parents with a diagnosis of PTSD. The screening will be done using the Impact of Event Scale-Revised. Diagnosis of PTSD will be confirmed using the Clinician-Administered PTSD Scale-5 (CAPS-5). Union Councils from Peshawar and Karachi will be randomised into either group LTP Plus TF CBT arm or treatment as usual (TAU). The intervention includes 12 sessions of LTP Plus TF-CBT delivered weekly in the first 2 months and then fortnightly in a group setting by trained psychologists. The groups will be co-facilitated by the community health workers (CHWs). Parents will be assessed at baseline and 4th month (end of the intervention), using the Patient Health Questionnaire (PHQ-9), Generalised Anxiety Disorder (GAD-7) Scale, Client Service Receipt Inventory (CSRI), and Ages and Stages Questionnaire (ASQ-3). Discussion: This trial would help build an understanding of the acceptability, feasibility and indications of the effectiveness of a low-cost parenting intervention.

Culturally adapted psychoeducation for bipolar disorder in a low-resource setting: protocol for a multicentre randomised controlled trial.

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

Youth Culturally adapted Manual Assisted Problem Solving Training (YCMAP) in Pakistani adolescent with a history of self-harm: protocol for multicentre clinical and cost-effectiveness randomised controlled trial.

INTRODUCTION: Suicide is a global health concern. Sociocultural factors have an impact on self-harm and suicide rates. In Pakistan, both self-harm and suicide are considered as criminal offence's and are condemned on both religious and social grounds. The proposed intervention 'Youth Culturally Adapted Manual Assisted Problem Solving Training (YCMAP)' is based on principles of problem-solving and cognitive-behavioural therapy. YCMAP is a brief, culturally relevant, scalable intervention that can be implemented in routine clinical practice if found to be effective. METHOD AND ANALYSIS: A multicentre rater blind randomised controlled trial to evaluate the clinical and cost-effectiveness of YCMAP including a sample of 652 participants, aged 12-18 years, presenting to general physicians/clinicians, emergency room after self harm or self referrals. We will test the effectiveness of 8-10 individual sessions of YCMAP delivered over 3 months compared with treatment as usual. Primary outcome measure is repetition of self-harm at 12 months. The seconday outcomes include reduction in suicidal ideation, hopelessness and distress and improvement in health related quality of life. Assessments will be completed at baseline, 3, 6, 9 and 12 months postrandomisation. The nested qualitative component will explore perceptions about management of self-harm and suicide prevention among adolescents and investigate participants' experiences with YCMAP. The study will be guided by the theory of change approach to ensure that the whole trial is centred around needs of the end beneficiaries as key stakeholders in the process. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of University of Manchester, the National Bioethics Committee in Pakistan. The findings of this study will be disseminated through community workshops, social media, conference presentations and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04131179.