Nathan Dowling

Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression

OBJECTIVE Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder. METHODS This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase. RESULTS The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment. CONCLUSION This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression. TRIAL REGISTRATION Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.

Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial

Objective: Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder. Methods: A total of 71 adults with major depressive disorder (Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery–Asberg Depression Rating Scale (primary outcome), Clinical Global Impression–Improvement and Clinical Global Impression–Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au, #ACTRN12612000283875. Results: Based on mixed-methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery–Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression–Improvement score – effect size (95% confidence interval) = −0.62 [−1.8, −0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score – effect size (confidence interval) = −0.12 [0.0, 0.2], p < 0.001; and Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool score – 0.79 [−4.5, −1.4], p < 0.001. These effects remained at follow-up (week 16), and Patient Global Impression also became significant, effect size (confidence interval) = 0.57 [−1.7, −0.4], p = 0.017. Conclusion: While the primary outcome was not significant, the improvements in other comprehensive clinical measures suggest that minocycline may be a useful adjunct to improve global experience, functioning and quality of life in people with major depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise treatment outcomes.

A Randomized Controlled Trial of Brief and Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy

Background: Some studies suggest better overall outcomes when right unilateral electroconvulsive therapy (RUL ECT) is given with an ultrabrief, rather than brief, pulse width. Methods: The aim of the study was to test if ultrabrief-pulse RUL ECT results in less cognitive side effects than brief- pulse RUL ECT, when given at doses which achieve comparable efficacy. One hundred and two participants were assigned to receive ultrabrief (at 8 times seizure threshold) or brief (at 5 times seizure threshold) pulse RUL ECT in a double-blind, randomized controlled trial. Blinded raters assessed mood and cognitive functioning over the ECT course. Results: Efficacy outcomes were not found to be significantly different. The ultrabrief group showed less cognitive impairment immediately after a single session of ECT, and over the treatment course (autobiographical memory, orientation). Conclusions: In summary, when ultrabrief RUL ECT was given at a higher dosage than brief RUL ECT (8 versus 5 times seizure threshold), efficacy was comparable while cognitive impairment was less.

Effects of comt , drd2 , bdnf , and apoe Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy

Objectives The aim of this study was to explore the main and interaction effects of the COMT Val158Met, DRD2 C957T, BDNF Val66Met, and APOE polymorphisms on treatment efficacy and cognitive side effects of electroconvulsive therapy (ECT). Methods A total of 117 adult inpatients with a diagnosis of major depressive disorder recruited from 3 hospitals were administered the Montgomery-Äsberg Depression Rating Scale and a cognitive battery assessing global cognition, anterograde memory, executive function, speed and concentration, as well as retrograde memory at baseline and after ECT treatment. Results DRD2 C957T heterozygotes had 3.7 (95% confidence interval, 1.13–12.25; P = 0.032) greater odds of remission compared with CC homozygotes. Among the men, COMT Val/Val carriers had greater depressive symptom reduction compared with Met/Met carriers (Montgomery-Äsberg Depression Rating Scale percentage of reduction, 76% vs 35%; P = 0.020) but not among the women (P = 0.903) after ECT. For cognitive outcomes, an interaction effect on anterograde memory was observed between the DRD2 and BDNF polymorphisms (P = 0.016), in which carriers of the DRD2 TT and BDNF Val/Val genotypes had significantly less decline in anterograde performance than those that carried the TC and Met-allele (P = 0.001) or CC and Met-allele (P = 0.003) genotypes. However, no results withstood correction for multiple comparisons. Conclusions These observations provide preliminary evidence supporting an association between common functional genotypic variation and ECT efficacy as well as anterograde memory side effects after ECT. Validation of these findings is required before firm conclusions can be made and clinical utility can be assessed.

Efficacy of adjunctive Garcinia mangostana Linn (mangosteen) pericarp for bipolar depression: study protocol for a proof-of-concept trial

Objective: Bipolar depression is characterized by neurobiological features including perturbed oxidative biology, reduction in antioxidant levels, and a concomitant rise in oxidative stress markers. Bipolar depression manifests systemic inflammation, mitochondrial dysfunction, and changes in brain growth factors. The depressive phase of the disorder is the most common and responds the least to conventional treatments. Garcinia mangostana Linn, commonly known as mangosteen, is a tropical fruit. The pericarp’s properties may reduce oxidative stress and inflammation and improve neurogenesis, making mangosteen pericarp a promising add-on therapy for bipolar depression. Methods: Participants will receive 24 weeks of either 1,000 mg mangosteen pericarp or placebo per day, in addition to their usual treatment. The primary outcome is change in severity of mood symptoms, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), over the treatment phase. Secondary outcomes include global psychopathology, quality of life, functioning, substance use, cognition, safety, biological data, and cost-effectiveness. A follow-up interview will be conducted 4 weeks post-treatment. Conclusion: The findings of this study may have implications for improving treatment outcomes for those with bipolar disorder and may contribute to our understanding of the pathophysiology of bipolar depression. Clinical trial registration: Australian and New Zealand Clinical Trial Registry, ACTRN12616000028404.

Adjunctive low-dose docosahexaenoic acid (DHA) for major depression: An open-label pilot trial

Overview: Whilst the majority of evidence supports the adjunctive use of eicosapentaenoic acid (EPA) in improving mood, to date no study exists using low-dose docosahexaenoic acid (DHA) alone as an adjunctive treatment in patients with mild to moderate major depressive disorder (MDD). Methods: A naturalistic 8-week open-label pilot trial of low-dose DHA, (260 mg or 520 mg/day) in 28 patients with MDD who were non-responsive to medication or psychotherapy, with a Hamilton Depression Rating Scale (HAM-D) score of greater than 17, was conducted. Primary outcomes of depression, clinical severity, and daytime sleepiness were measured. Results: After 8 weeks, 54% of patients had a ≥50% reduction on the HAM-D, and 45% were in remission (HAM-D ≤ 7). The eta-squared statistic (0.59) indicated a large effect size for the reduction of depression (equivalent to Cohens d of 2.4). However confidence in this effect size is tempered due to the lack of a placebo. The mean score for the Clinical Global Impression Severity Scale was significantly improved by 1.28 points (P < 0.05). Despite a significant reduction in the HAM-D score for middle insomnia (P = 0.02), the reduction in excessive daytime somnolence on the total Epworth Sleepiness Scale (ESS) did not reach significance. No significant adverse reactions to DHA were found. Conclusion: Within the major limits of this open-label pilot study, the results suggest that DHA may provide additional adjunctive benefits in patients with mild- to -moderate depression.

Methylphenidate in the treatment of an adolescent female with obsessive-compulsive disorder and attention deficit hyperactivity disorder: a case report:

Objectives: We describe a case whereby a 15-year-old female with treatment-resistant obsessive-compulsive disorder (OCD) was treated with methylphenidate for co-morbid attention deficit hyperactivity disorder (ADHD). The ADHD-OCD co-morbidity has often been overlooked clinically due to conflicting opinions about their underlying neurobiology and treatment options. Conclusions: In this adolescent with co-morbid ADHD and OCD, we observed that the adjunctive use of methylphenidate resulted in enhanced treatment response to both psychological and pharmacological interventions for OCD. This case highlights the need to identify and treat co-morbid ADHD in OCD cases where progress has stalled.