Melanie Ashton

Staging in bipolar disorder: from theoretical framework to clinical utility

Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at‐risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end‐stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage‐specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage‐specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at‐risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative‐type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.

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.

Beyond the therapeutic shackles of the monoamines: New mechanisms in bipolar disorder biology

ABSTRACT Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics – much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti‐apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N‐acetylcysteine, the anti‐inflammatory celecoxib, and ketamine ‐ with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space. HIGHLIGHTSOxidation, immunity, neurodegeneration and glutamate are linked to bipolar disorder.Effectiveness of current treatments may partially rely on these pathways.Addressing such pathophysiological targets is key for development of new treatments.

Mitochondrial agents for bipolar disorder

Abstract Background Bipolar disorder is a chronic and often debilitating illness. Current treatment options (both pharmaco- and psychotherapy) have shown efficacy, but for many leave a shortfall in recovery. Advances in the understanding of the pathophysiology of bipolar disorder suggest that interventions that target mitochondrial dysfunction may provide a therapeutic benefit. Methods This review explores the current and growing theoretical rationale as well as existing preclinical and clinical data for those therapies aiming to target the mitochondrion in bipolar disorder. A Clinicaltrials.gov and ANZCTR search was conducted for complete and ongoing trials on mitochondrial agents used in psychiatric disorders. A PubMed search was also conducted for literature published between January 1981 and July 2017. Systematic reviews, randomized controlled trials, observational studies, case series, and animal studies with an emphasis on agents affecting mitochondrial function and its role in bipolar disorder were included. The search was augmented by manually searching the references of key papers and related literature. The results were presented as a narrative review. Results Mitochondrial agents offer new horizons in mood disorder treatment. While some negative effects have been reported, most compounds are overall well tolerated and have generally benign side-effect profiles. Conclusions The study of neuroinflammation, neurodegeneration, and mitochondrial function has contributed the understanding of bipolar disorder’s pathophysiology. Agents targeting these pathways could be a potential therapeutic strategy. Future directions include identification of novel candidate mitochondrial modulators as well as rigorous and well-powered clinical trials.

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.