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.

A culturally adapted manual-assisted problem-solving intervention (CMAP) for adults with a history of self-harm: a multi-centre randomised controlled trial.

BACKGROUND: Self-harm is an important predictor of a suicide death. Culturally appropriate strategies for the prevention of self-harm and suicide are needed but the evidence is very limited from low- and middle-income countries (LMICs). This study aims to investigate the effectiveness of a culturally adapted manual-assisted problem-solving intervention (CMAP) for patients presenting after self-harm. METHODS: This was a rater-blind, multicenter randomised controlled trial. The study sites were all participating emergency departments, medical wards of general hospitals and primary care centres in Karachi, Lahore, Rawalpindi, Peshawar, and Quetta, Pakistan. Patients presenting after a self-harm episode (n = 901) to participating recruitment sites were assessed and randomised (1:1) to one of the two arms; CMAP with enhanced treatment as usual (E-TAU) or E-TAU. The intervention (CMAP) is a manual-assisted, cognitive behaviour therapy (CBT)-informed problem-focused therapy, comprising six one-to-one sessions delivered over three months. Repetition of self-harm at 12-month post-randomisation was the primary outcome and secondary outcomes included suicidal ideation, hopelessness, depression, health-related quality of life (QoL), coping resources, and level of satisfaction with service received, assessed at baseline, 3-, 6-, 9-, and 12-month post-randomisation. The trial is registered on ClinicalTrials.gov. NCT02742922 (April 2016). RESULTS: We screened 3786 patients for eligibility and 901 eligible, consented patients were randomly assigned to the CMAP plus E-TAU arm (n = 440) and E-TAU arm (N = 461). The number of self-harm repetitions for CMAP plus E-TAU was lower (n = 17) compared to the E-TAU arm (n = 23) at 12-month post-randomisation, but the difference was not statistically significant (p = 0.407). There was a statistically and clinically significant reduction in other outcomes including suicidal ideation (- 3.6 (- 4.9, - 2.4)), depression (- 7.1 (- 8.7, - 5.4)), hopelessness (- 2.6 (- 3.4, - 1.8), and improvement in health-related QoL and coping resources after completion of the intervention in the CMAP plus E-TAU arm compared to the E-TAU arm. The effect was sustained at 12-month follow-up for all the outcomes except for suicidal ideation and hopelessness. On suicidal ideation and hopelessness, participants in the intervention arm scored lower compared to the E-TAU arm but the difference was not statistically significant, though the participants in both arms were in low-risk category at 12-month follow-up. The improvement in both arms is explained by the established role of enhanced care in suicide prevention. CONCLUSIONS: Suicidal ideation is considered an important target for the prevention of suicide, therefore, CMAP intervention should be considered for inclusion in the self-harm and suicide prevention guidelines. Given the improvement in the E-TAU arm, the potential use of brief interventions such as regular contact requires further exploration.

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.

BACKGROUND: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting. METHODS: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363. FINDINGS: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident). INTERPRETATION: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression. FUNDING: Stanley Medical Research Institute.

Is integrated private-clinic based early child development care effective? A clustered randomised trial in Pakistan.

BACKGROUND: In Pakistan, high prevalence of delays in early child development (ECD) is associated with poverty and lack of mothers' caregiving skills. GP clinics, the main sources of care in poor urban localities, lack quality ECD care delivery. A contextualised intervention was developed and tested to enable GPs to deliver clinic-based, tool-assisted ECD counselling of mothers on a quarterly basis. AIM: To assess the effectiveness of delivering a contextualised ECD mother-counselling intervention. DESIGN & SETTING: Clustered randomised controlled trial, in poor urban localities of Pakistan. Locality clusters were allocated to intervention and control arm using simple randomisation. METHOD: A total of 2327 mother-child pairs were recruited at 32 GP clinics, one from each cluster-locality; 16 GP clinics per arm. The clinic-based counselling intervention covering child stimulation, nutrition, and maternal mental health was delivered mainly by clinic assistants to mothers at ≤6 weeks, and 3, 6, and 9 months of child age. At 12 months of child age, each mother-child pair was assessed for the primary outcome, that is, delays in the five development domains (determined by Ages and Stages Questionnaire-3 [ASQ-3] score); and secondary outcomes, namely the prevalence of stunting and maternal depression (determined by Patient Health Questionnaire-9 [PHQ-9] score). The outcome assessors were blinded to the cluster-arm allocation. Outcome analyses were calculated on cluster-level. RESULTS: At 12 months, the number of children with delay in two or more development domains was significantly lower in the intervention arm (-0.17 [95% confidence interval {CI} = -0.26 to -0.09]; P<0.001) compared to the control arm. The difference in the prevalence of child stunting and maternal depression were also significant at -0.21% (95% CI = -0.30 to -0.13; P<0.001) and -0.23% (95% CI = -0.29 to -0.18; P = 0.000) respectively. CONCLUSION: Contextualised ECD care, when delivered at GP clinics in poor urban localities, can effectively reduce the developmental delays during the first 12 months of the child's life.

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 (NAYAB): study protocol.

BACKGROUND: The at-risk mental state (ARMS) describes individuals at high risk of developing schizophrenia or psychosis. The use of antipsychotics in this population is not supported, because most individuals with ARMS are unlikely to develop psychosis. Anti-inflammatory treatments and polyunsaturated fatty acids (PUFAs) may have some beneficial effects in the treatment of ARMS. There have been no controlled clinical trials in which researchers have investigated the use of minocycline for ARMS and no trials involving PUFAs in combination with other proposed treatments. There is a need to find effective, tolerable and inexpensive interventions for individuals with ARMS that are available in high-, low- and middle-income countries. METHODS/DESIGN: A 6-month intervention study of minocycline and/or omega-3 fatty acids added to treatment as usual (TAU) in patients with ARMS will be conducted in Pakistan using a randomised, placebo-controlled, double-blind factorial design. A total of 320 consenting patients with capacity will be recruited from the community, general practitioner clinics and psychiatric units. Allowing for a 25% dropout rate, we will recruit 59 completing participants into each study arm, and in total 236 will complete the study. We will determine whether the addition of minocycline and/or omega-3 fatty acids to TAU attenuates the rate of transition from ARMS to first-episode psychosis and improves symptoms and/or level of functioning in ARMS. We will also investigate whether any candidate risk factors, such as negative symptoms, influence treatment response in the ARMS group. The primary efficacy endpoint is conversion to psychotic disorder at 12 months after study entry. Analysis will be done according to the intention to treat principle using analysis of variance, chi-square tests and adjusted ORs to assess between-group differences. Cox regression analysis will be used to evaluate potential between-group differences in time to onset of psychosis. DISCUSSION: The outcomes of this trial will provide evidence of the potential benefits of minocycline and PUFAs in the treatment of ARMS. Both minocycline and PUFAs are inexpensive, are readily available in low-/middle-income countries such as Pakistan, and if proven, may be safe and effective for treating individuals with ARMS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02569307 . Registered on 3 October 2015.

Delivering integrated child development care in Pakistan: protocol for a clustered randomised trial.

BACKGROUND: Early childhood developmental delay is associated with significant disadvantage in adult life. In Pakistan, high prevalence of developmental delay is associated with poverty, under-nutrition, and maternal depression. AIM: To assess the effectiveness of an early child development counselling intervention delivered at private GP clinics, in poor urban communities. DESIGN & SETTING: A clustered randomised trial in Pakistan. METHOD: The intervention was developed following a period of formative research, and in consultation with local experts. A total of 2112 mother-child pairs will be recruited at 32 clinics, from within the locality (cluster); 16 clinics per arm. A primary care counselling intervention (promoting child development, nutrition, and maternal mental health) will be delivered at 6 weeks, 3, 6, and 9 months of the child's age. Monitoring, assessment, and treatment will also be performed at quarterly visits in intervention clinics. Primary outcome is the developmental delay at 12 months (ASQ-3 scores). Secondary outcomes are stunting rate, and maternal depression (PHQ-9 score). In addition, a process evaluation and costing study will be conducted. DISCUSSION: This trial will be the first to assess an early child development intervention, delivered in private GP clinics for poor urban communities in Pakistan. If found to be effective, this public-private model may offer a more sustainable, and feasible option for populations in poor urban settings, where private GP clinics are the most accessible provider of primary health care. There is scope for scale-up at provincial level, should the intervention be effective. TRIAL REGISTRATION: The trial has been registered with the Current Controlled Trials ISRCTN48032200.

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a study protocol for a multicenter factorial design randomized controlled trial.

BACKGROUND: Evidence suggests that the use of anti-inflammatory agents may improve depressive symptoms in patients with bipolar affective disorder. However, there are few well-designed clinical trials demonstrating the efficacy of these newer treatment strategies. PATIENTS AND METHODS: This is a multicenter, 3-month, randomized, placebo-controlled, double-blind, factorial design trial of minocycline and/or celecoxib added to TAU for the treatment of depressive symptoms in patients experiencing a DSM-5 bipolar I or II disorder and a current major depressive episode. A total of 240 participants will undergo screening and randomization followed by four assessment visits. The primary outcome measure will be mean change from baseline to week 12 on the Hamilton Depression Scale scores. Clinical assessments using the Clinical Global Impression scale, Patient Health Questionnaire-9, and the Generalized Anxiety Disorder 7-item scale will be carried out at every visit as secondary outcomes. Side-effect checklists will be used to monitor the adverse events at each visit. Complete blood count and plasma C-reactive protein will be measured at baseline and at the end of the treatment. Minocycline will be started at 100 mg once daily and increased to 200 mg at 2 weeks. Celecoxib will be started at 200 mg once daily and increased to 400 mg at 2 weeks. DISCUSSION: Anti-inflammatory agents have been shown to be potentially efficacious in the treatment of depressive symptoms. The aim of this study is to determine whether the addition of minocycline and/or celecoxib to TAU improves depressive symptoms in patients with bipolar affective disorder.

Development of a psychiatric liaison service in Rawalpindi, Pakistan.

The paper reports a descriptive survey of the referrals received by a new psychiatric liaison service in Rawalpindi in the first 2 years. The survey showed a rapid increase in use of the service, particularly by the emergency department. There was a lower proportion of referrals for self-harm and substance misuse than occurs in similar services in high-income countries but a higher proportion of patients presenting with dissociative (conversion) disorders. The large proportion of patients who had abnormal findings on physical examination remains unexplained and warrants further investigation.

Knowledge of depression among community members and health care providers in two selected areas of district Rawalpindi.

OBJECTIVE: To determine the level of knowledge about depression in two selected areas of district Rawalpindi. STUDY DESIGN: Cross-sectional survey report. PLACE AND DURATION OF STUDY: Union council Rehmatabad and mohalla Sultanpura, Rawalpindi, from June to December 2007. METHODOLOGY: Strata of community were interviewed regarding the knowledge about depression using an indigenously developed questionnaire. To determine any association between difference of level of knowledge and different strata of community Chi-square (X)2 tests was applied at 5% level of significance and p-value less than 0.05 was considered significant. RESULTS: Most of the respondents (63%) thought that diabetes was the major health problem in our country. Most of participants thought that drug abuse and addiction (74.3%), adolescent emotional and behavioral problems (66.8%) followed by alcohol abuse (50.3%) and personality disorders (49.2%) were the common mental illnesses. Chi-square (X)2 statistics showed a highly significant association between difference of level of knowledge and the two strata of community i.e. health care providers and community members (p < 0.001). CONCLUSION: People in the selected areas of district Rawalpindi had a poor knowledge about depression.

Somatoform disorders: perspectives from Pakistan.

Somatoform disorders represent widespread and largely unsolved problems at the border between psychiatry and medicine. Patients with somatoform disorders often present difficult diagnostic and management problems. A series of three community-based epidemiological surveys of rural and urban populations in Pakistan found high prevalence of common mental disorders where the core presentations were somatic complaints. All the three epidemiological surveys used the Bradford Somatic Inventory (BSI), which was developed from symptom reports by psychiatric patients in Pakistan; these enquired about somatic symptoms in the local language, taking into account local cultural idioms of distress. At a conservative estimate, 66% of women and 25% men suffered from anxiety and depressive disorders whereby the complaints predominantly were somatic in nature. People in rural non-Western cultures are not psychologically minded and do not have abstract language or concepts of emotional distress and therefore communicate their emotions somatically. In Pakistan somatoform disorders possess a prominent diagnostic dilemma. The cornerstone of the management is a comprehensive medical, psychiatric and psychosocial evaluation of the patient. Patients with multiple somatic complaints not only present formidable management problems but also often have severe functional impairments that may outweigh those of patients with other so-called severe mental illnesses. Since somatoform disorders are the most common psychiatric disorders to present in non-psychiatric settings, it is important that training about them begin at undergraduate level. It should also be incorporated in the training of a wide variety of non-psychiatric specialists, both medical and non-medical.

Process, rationale, and interventions of Pakistan's National Action Plan on Chronic Diseases.

Most developing countries do not comprehensively address chronic diseases as part of their health agendas because of lack of resources, limited capacity within the health system, and the threat that the institution of national-level programs will weaken local health systems and compete with other health issues. An integrated partnership-based approach, however, could obviate some of these obstacles. In Pakistan, a tripartite public-private partnership was developed among the Ministry of Health, the nongovernmental organization (NGO) Heartfile, and World Health Organization. This was the first time an NGO participated in a national health program; NGOs typically assume a contractual role. The partnership developed a national integrated plan for health promotion and the prevention and control of noncommunicable diseases (NCDs), which as of January 2006 is in the first stage of implementation. This plan, called the National Action Plan on NCD Prevention, Control, and Health Promotion (NAP-NCD), was released on May 12, 2004, and attempts to obviate the challenges associated with addressing chronic diseases in countries with limited resources. By developing an integrated approach to chronic diseases at several levels, capitalizing on the strengths of partnerships, building on existing efforts, and focusing primary health care on chronic disease prevention, the NAP-NCD aims to mitigate the effects of national-level programs on local resources. The impact of the NAP-NCD on population outcomes can only be assessed over time. However, this article details the plan's process, its perceived merits, and its limitations in addition to discussing challenges with its implementation, highlighting the value of such partnerships in facilitating the missions and mandates of participating agencies, and suggesting options for generalizability.

Prevention and control of mental illnesses and mental health: National Action Plan for NCD Prevention, Control and Health Promotion in Pakistan.

As part of the National Action Plan for Non-communicable Disease Prevention, Control and Health Promotion in Pakistan (NAP-NCD), mental illnesses have been grouped alongside non-communicable diseases (NCD) within a combined strategic framework in order to synchronize public health actions. The systematic approach for mental illnesses is centred on safeguarding the rights of the mentally ill, reducing stigma and discrimination, and de-institutionalisation and rehabilitation of the mentally ill in the community outlining roles of healthcare providers, the community, legislators and policy makers. The approach has implications for support functions in a number of areas including policy building, manpower and material development and research. Priority action areas for mental health as part of NAP-NCD include the integration of surveillance of mental illnesses in a comprehensive population-based NCD surveillance system; creating awareness about mental health as part of an integrated NCD behavioural change communication strategy; integration of mental health with primary healthcare; the development of sustainable public health infrastructure to support community mental health initiatives; building capacity of the health system in support of prevention and control activities; effective implementation of existing legislation and harmonizing working relationships with law enforcing agencies. NAP-NCD also stresses on the need to integrate mental health into health services as part of a sustainable and integrated medical education programme for all categories of healthcare providers and the availability of essential psychotropic drugs at all healthcare levels. It lays emphasis on protecting the interests of special groups such as prisoners, refugees and displaced persons, women, children and individuals with disabilities. Furthermore, it promotes need-based research for contemporary mental health issues.