Data on associations between inflammation and depressive symptoms largely originate from high income population settings, despite the greatest disease burden in major depressive disorder being attributed to populations in lower-middle income countries (LMICs).

We assessed the prevalence of low-grade inflammation in adults with treatment-resistant depression (TRD) in Pakistan, an LMIC, and investigated associations between peripheral C-reactive protein (CRP) levels and depressive symptoms.

This is a secondary analysis of two randomised controlled trials investigating adjunctive immunomodulatory agents (minocycline and simvastatin) for Pakistani adults with TRD (n = 191). Logistic regression models were built to assess the relationship between pre-treatment CRP (≥ or <3 mg/L) and individual depressive symptoms measured using the Hamilton Depression Rating Scale. Descriptive statistics and regression were used to assess treatment response for inflammation-associated symptoms.

High plasma CRP (≥3 mg/L) was detected in 87% (n = 146) of participants. Early night insomnia (odds ratio 2.33, 95% CI 1.16–5.25), early morning waking (odds ratio 2.65, 95% CI 1.29–6.38) and psychic anxiety (odds ratio 3.79, 95% CI 1.39–21.7) were positively associated, while gastrointestinal (odds ratio 0.38, 95% CI 0.14–0.86) and general somatic symptoms (odds ratio 0.34, 95% CI 0.14–0.74) were negatively associated with inflammation. Minocycline, but not simvastatin, improved symptoms positively associated with inflammation.

The prevalence of inflammation in this LMIC sample with TRD was higher than that reported in high income countries. Insomnia and anxiety symptoms may represent possible targets for personalised treatment with immunomodulatory agents in people with elevated CRP. These findings require replication in independent clinical samples.

Psychosis is one of the leading causes of disability. First Episode Psychosis (FEP) significantly impacts the long-term course of the disorder. While a majority of FEP service users show signs of ‘recovery' within 12 months of treatment, the early course involves frequent relapses, with up to 80% relapsing within five years. This elevates the risk of persistent psychotic symptoms, affecting cognitive, social, and occupational functioning. Medication, the core treatment, reduces relapse by 75%, necessitating additional psychosocial treatments. Mobile-based interventions are recognized for meeting families' needs in terms of information, guidance, and support. This paper explores stakeholder views on developing mobile interventions for those experiencing their first psychosis episode.

This qualitative paper was part of the TechCare app development process in which face-to-face interviews with patients (17), and 4 focus groups with health professionals were carried out. The qualitative interviews and focus groups explored the views of stakeholders on the need for mobile-based treatment, the structure of the application, the content of the application and barriers and challenges were also explored in detail. All the audio-recorded interviews were transcribed and analyzed through a framework approach.

Qualitative analysis revealed three themes. The first theme centers on stakeholders' views about mobile-based treatment. Health professionals reported that app-based treatment enhances help-seeking behavior, reduces societal stigma, and aids in managing treatment and activities. The second theme focuses on suggestions for the Techcare application, emphasizing logical and easy-to-understand content, with a major focus on crisis management, hallucinations, and psycho-education about symptoms. Participants also highlighted the need for a section providing psycho-education for families. Carers emphasized the necessity of an activity plan in the app, including an activity log for medication management and activities. The third theme delves into barriers and challenges in app-based treatment, including difficulty levels and privacy concerns. Stakeholders stressed the importance of content in simple Urdu language for broader understanding.

In conclusion, mobile-based treatment contributes to reducing stigma, increasing awareness about the illness in its early stages, and facilitating the management of functional activities for patients. The insights gathered from stakeholders provide valuable guidance for the development of an effective and culturally sensitive mobile-based intervention for individuals experiencing FEP.

Suicide is a global public health issue that requires sensitive research to inform effective prevention and treatment strategies. Despite the benefits of such research, it is accompanied by significant ethical challenges such as the potential for harm to participants' wellbeing. Various studies have explored the views of researchers in suicide research. This qualitative study aimed to explore the research ethics committee (REC) members’ experiences with suicide-related study applications to ascertain whether there are differences in approaches to dealing with suicide-related study applications.

We conducted semi-structured interviews with members of RECs (n = 9) from research-intensive universities and ethics committees in Pakistan. We also conducted a discussion group (n = 13) with members of REC from Pakistan, Nigeria and Sri Lanka. The topic guide delved into the opinions of REC members regarding ethical issues that they have come across while reviewing self-harm/suicide-related research proposals, the relevance of these issues with specific study designs, recommendations to resolve these issues, their approach to balancing risk and benefit, and guidance for researchers.

The preliminary findings from thematic analysis revealed five major themes; 1) Ethical challenges, 2) Reasons for application rejection, 3) Areas of improvement, 4) Suggestions for addressing ethical issues, and 5) Researchers' attitudes towards amendments. Challenges in self-harm and suicide research included the sensitivity and stigma surrounding the topic, lack of interest and support, and difficulties in participant recruitment. The application faced rejection from the ethics committees primarily due to methodological errors, lack of procedural clarity, and insufficient understanding of the research procedure. Identified areas for improvement were the need for enhanced methodology and research patterns, as well as a better understanding of the methodological procedure. Recommendations for developing a robust research proposal included training and supervision for intervention studies, the inclusion of comprehensive ethical elements and practical plans in the proposal, and a focus on data protection, confidentiality, risk management, and harm identification. While a significant number positively acknowledged reviewer comments, some researchers opted for in-depth discussions rather than directly addressing the issues.

The study highlights the importance of ethical considerations and emphasises the need to address the lack of robust methodological procedures in self-harm and suicide research. Addressing these challenges and adopting suggested improvements is paramount for advancing ethical and impactful research in this context.

Bipolar disorder (BD) leads to marked disability, morbidity, and premature death. Although pharmacological agents are an essential part of BD treatment, psychosocial interventions have played an important role in enhancing treatment adherence, functioning and quality of life in patients with BD. Building on a successful pilot randomised controlled trial (RCT) of a Culturally adapted PsychoEducation (CaPE) intervention for BD, CaPE is currently being evaluated in a large multicenter RCT for its clinical and cost-effectiveness across Pakistan. However, innovations are urgently needed due to limited human resources and disproportionately high clinical needs to bring effective interventions to scale. This study aims to develop and test a mHealth iteration of CaPE, digital CaPE (dCaPE), to be delivered via a mobile app.

The study will utilise a two-phased approach to i) develop a user-centred dCaPE mobile application and ii) assess the feasibility and preliminary efficacy of dCaPE for people with BD in a randomised controlled trial in Pakistan. For application development, we have conducted discussion groups with stakeholders i.e., mental health professionals (psychiatrists, psychologists, nurses) (n = 8) and patients and carers (n = 10) to gauge their valuable insights for app design, visual elements, cultural sensitivity, motivational and mood-monitoring features, and app functionality to improve user experience.

The findings from discussion groups informed the importance of visual elements, specifically font size and style. Participants recommended the use of soft and soothing colours like white, grey, and soft shades of pink to prevent overstimulation. Additionally, participants highlighted the need for culturally and linguistically inclusive features, including emojis and audio messages for effective engagement and to address the challenge of low literacy. The mHealth approach was deemed highly valuable, especially given the prevalence of mental health challenges and associated stigma. Endorsed by participants, the dCaPE application will offer customized psychoeducation messages along with daily 5-item (mood, energy, sleep, medication, and irritability) screening, a weekly comprehensive test for manic and depressive episodes based on DSM–5 criteria; weekly reminders to regulate sleep and eating habits, and visual representations of weekly mood monitoring reports with the incentive of badges or rewards for goal achievers.

This research has the potential to enhance clinical outcomes, social and occupational functioning, and the overall quality of life for BD patients while addressing substantial mental health treatment gaps with impact and implications extending to various low-resource settings.

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.

To estimate the prevalence of suicidal ideation and attempts in individuals with psychosis and bipolar disorder in South Asia.

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.

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.

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.

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.

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.

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.

A third of patients diagnosed with major depressive disorder (MDD) experience treatment-resistant depression (TRD). Relatively few pharmacological agents have established efficacy for TRD. Therefore, the evaluation of novel treatments for TRD is a pressing priority. Statins are pleiotropic agents and preclinical studies as well as preliminary clinical trials have suggested that these drugs may have antidepressant properties.

To report on a protocol for a 12-week, randomised, double-blind, placebo-controlled trial of add-on treatment with simvastatin for patients meeting DSM-5 criteria for MDD who have failed to respond to at least two adequate trials with approved antidepressants. The trial has been registered with Clinicaltrials.gov in (ClinicalTrials.gov identifier: NCT03435744).

After screening and randomisation to the two parallel arms of the trial, 75 patients will receive simvastatin and 75 patients will receive placebo as adjuncts to treatment as usual. The primary outcome is change in Montgomery–Åsberg Depression Rating Scale scores from baseline to week 12 and secondary outcomes include changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. Assessments will take place at screening, baseline, and weeks 2, 4, 8 and 12. Checklists for adverse effects will be undertaken at each visit. Simvastatin (20 mg) will be given once daily. Other secondary outcomes include C-reactive protein and plasma lipids measured at baseline and week 12.

This trial will assess simvastatin's efficacy and tolerability as an add-on treatment option for patients with TRD and provide insights into its putative mechanisms of action.

As the first trial investigating the use of simvastatin as an augmentation strategy in patients with TRD, if the results indicate that adjuvant simvastatin is efficacious in reducing depressive symptoms, it will deliver immediate clinical benefit.

I.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. R.R. and M.M.H. have received educational grants and support for academic meetings from Pfizer, Roche, Novartis and Nabiqasim. A.H.Y. has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders. A.H.Y. has undertaken investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. None of the companies have a financial interest in this research.