ClinicalTrials.gov identifier: NCT02263872, registered October 2014.

No abstract

BackgroundDepression is one of the leading causes of disability worldwide. A high proportion of patients do not respond to standard drug treatments. Recent evidence has suggested that anti-inflammatory treatment may have beneficial effects in major depression. Minocycline is a tetracycline antibiotic with good CNS penetration that exerts effects on multiple interacting symptoms implicated in the pathophysiology of mood disorders. Open-label studies have suggested that minocycline is effective as an adjunct drug in improving depressive symptoms.Methods/DesignThis is a multi-centre, 3-month, double-blind, placebo-controlled, pilot trial of minocycline added to treatment as usual for patients suffering from DSM-IV major depressive disorder. This will be a double-blind, randomised, controlled, two parallel-arm study with 20 participants in each arm, giving a total of 40 participants. There will be a screening visit, a randomization visit and four follow-up visits. Clinical assessments using the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ −9) and the Generalised Anxiety Disorder scale (GAD-7) will be carried out at every visit. Side effects checklists will also be undertaken at each visit. Biomarkers (inflammatory cytokines and CRP) will be measured at baseline and at the end of the treatment phase. Minocycline will be started at 100 mg once daily (OD) and will be increased to 200 mg at two weeks.DiscussionAnti-inflammatory treatments have been shown to have some beneficial effects in the treatment of major depressive disorder. The aim of this pilot randomised controlled trial is to establish the degree of improvement in depressive symptoms with the addition of minocycline to treatment as usual.Trial registrationClinicalTrials.gov NCT02263872 registered 10 October 2014.

ImportanceImmune-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.ObjectiveTo assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD.Design, Setting, and ParticipantsThis 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.InterventionParticipants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo.Main Outcomes and MeasuresThe 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.ResultsA 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 RelevanceIn this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care.Trial RegistrationClinicalTrials.gov Identifier: NCT03435744

BackgroundA 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.AimsTo 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).MethodAfter 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.ResultsThis 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.ConclusionsAs 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.Declaration of interestI.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.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (β = −2.5; [95% CI −4.7 to −0.4]), whereas negative symptoms were unaffected by treatment (β = −0.39; [95% CI −2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

Efforts to build research capacity and capability in low and middle income countries (LMIC) has progressed over the last three decades, yet it confronts many challenges including issues with communicating or even negotiating across different cultures. Implementing global research requires a broader understanding of community engagement and participatory research approaches. There is a considerable amount of guidance available on community engagement in clinical trials, especially for studies for HIV/AIDS, even culturally specific codes for recruiting vulnerable populations such as the San or Maori people. However, the same cannot be said for implementing research in global health. In an effort to build on this work, the Pakistan Institute of Living and Learning and University College London in the UK sought to better understand differences in beliefs, values and norms of local communities in Pakistan. In particular, they have sought to help researchers from high income countries (HIC) understand how their values are perceived and understood by the local indigenous researchers in Pakistan. To achieve this end, a group discussion was organised with indigenous researchers at Pakistan Institute of Living and Learning. The discussion will ultimately help inform the development of a cultural protocol for researchers from HIC engaging with communities in LMIC. This discussion revealed five common themes; (1) religious principles and rules, (2) differing concepts of and moral emphasis on autonomy and privacy, (3) importance of respect and trust; (4) cultural differences (etiquette); (5) custom and tradition (gift giving and hospitality). Based on the above themes, we present a preliminary cultural analysis to raise awareness and to prepare researchers from HIC conducting cross cultural research in Pakistan. This is likely to be particularly relevant in collectivistic cultures where social interconnectedness, family and community is valued above individual autonomy and the self is not considered central to moral thinking. In certain cultures, HIC ideas of individual autonomy, the notion of informed consent may be regarded as a collective family decision. In addition, there may still be acceptance of traditional professional roles such as ‘doctor knows best’, while respect and privacy may have very different meanings.

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.