Adjunctive simvastatin for treatment-resistant depression: study protocol of a 12-week randomised controlled trial.

BACKGROUND: 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.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). METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.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.

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).

Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.

BACKGROUND: Evidence suggests that anti-inflammatory medication may be effective in the treatment of depressive symptoms. In this study, we aimed to investigate whether minocycline added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression will lead to an improvement in depressive symptoms. METHODS: Multi-site, 12-week, double-blind, placebo-controlled, pilot trial of minocycline added to TAU for patients suffering from DSM-5 major depressive disorder, whose current episode has failed to respond to at least two antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D) quality-of-life questionnaire. Side-effect checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg after 2 weeks. RESULTS: A total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (standardised effect size (ES) -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (odds ratio (OR): 17.6, p < 0.001). PHQ-9, GAD-7 and EQ-5D total showed more moderate improvements (ES ~ 0.4-0.5). CONCLUSION: The findings indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, our findings require replication in a larger sample. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02263872, registered October 2014.

Pilot study of a culturally adapted psychoeducation (CaPE) intervention for bipolar disorder in Pakistan.

BACKGROUND: Despite the use of maintenance medication, recurrence rates in bipolar affective disorder (BPAD) are high. To date, there are no clinical trials that have investigated the use of psychological interventions in bipolar disorder in Pakistan. AIM: The purpose of the study was to assess the feasibility and acceptability of a culturally adapted bipolar psychoeducation programme (CaPE) in Pakistan. METHODS: Thirty-four euthymic bipolar I and II outpatients were randomized to either 12 weekly sessions of individual psychoeducation plus Treatment As Usual (Intervention) or Treatment As Usual (TAU) (Control). Outcomes were assessed using the Young Mania Rating Scale (YMRS), Beck Depression Inventory (BDI), EuroQoL (EQ-5D), Bipolar Knowledge and Attitudes and Questionnaire (BKAQ), and a self-reported measure of medication adherence (Morisky Medication Adherence Scale-4 items, MMAS-4). Effect sizes were derived from baseline adjusted standardized regression coefficients. RESULTS: Retention in the study was good, 80% of patients in the TAU follow-up assessment and 100% of patients in the CaPE group attended all 12 sessions. Patient satisfaction was higher in the CaPE group relative to control (ES = 1.41). Further, there were large effect sizes shown for CaPE versus TAU for medication adherence (MMAS-4: ES = 0.81), knowledge and attitudes towards bipolar (BKAQ: ES = 0.68), mania (YMRS: ES = 1.18), depression (BDI: ES = 1.17) and quality of life measures (EQ-5D: ES ⇒ 0.88). CONCLUSIONS: Culturally adapted psychoeducation intervention is acceptable and feasible, and can be effective in improving mood symptoms and knowledge and attitudes to BPAD when compared with TAU. Larger scale studies are needed to confirm our findings. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02210390.

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.

Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.

BACKGROUND: Depression 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/DESIGN: This 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. DISCUSSION: Anti-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 REGISTRATION: ClinicalTrials.gov NCT02263872 registered 10 October 2014.

Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study.

OBJECTIVES: There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents but have been found to be anti-inflammatory and also decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that adjunctive ondansetron is efficacious against schizophrenia symptoms. We carried out a feasibility study in schizophrenia patients (within 5 years of first diagnosis) to explore the adjunctive use of simvastatin and ondansetron on positive, negative and general psychopathology. METHODS: This was a 12-week rater-blind placebo-controlled study. A total of 36 patients with DSM-IV diagnosis of schizophrenia were recruited, 12 in each arm. Patients were assessed at baseline and at 12 weeks using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) scale, Global Assessment of Functioning (GAF) and Abnormal Involuntary Movement Scale (AIMS). RESULTS: Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared with treatment as usual (TAU) on PANSS total score, although this was not statistically significant. In the secondary analyses, no significant differences were seen on CGI, GAF and AIMS. CONCLUSIONS: Anti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared with TAU. This study has led to a larger Stanley Medical Research Institute (SMRI)-funded, double-blind, randomized control trial.

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.

Rates and risks of complicated grief among psychiatric clinic patients in Karachi, Pakistan.

The aim of this study was to determine rates and risks of Complicated Grief (CG) among psychiatric clinic patients in Karachi, Pakistan. The Inventory of Traumatic Grief, an early version of Inventory of Complicated Grief--Revised, was administered to 151 recently bereaved patients, with validated criteria applied to determine CG "caseness." Thirty-four percent of the sample met criteria for CG. Although violent deaths did not pose a heightened CG risk, gender and kinship to the deceased did significantly increase the likelihood of meeting of criteria for CG.