Adjunctive Therapies for Bipolar Disorder Show Promise, Need More Evidence

bipolar and pills
bipolar and pills
As pharmacologic options have largely remained the same during the last decade, there exists a need to consider adjunctive therapies for bipolar disorder treatment.

Options for adjunctive therapy in treating bipolar disorder are increasing, although further research is needed, according to a recent research review published in Bipolar Disorders.

An estimated 0.1% to 4.4% of the population has a diagnosis of bipolar disorder at some point in their lives, but pharmacologic options have largely remained the same during the last decade, particularly as pharmaceutical companies have mostly stopped investing in mental health treatments.

“There is a clear recognition that adjunctive therapies are likely to hold a place in the treatment regimens of people with bipolar disorder,” lead author Olivia M. Dean, PhD, from the IMPACT Strategic Research Centre at Deakin University in Geelong, Victoria, Australia, told Psychiatry Advisor. “While we know that current treatments, both pharmacologic and psychologic, are beneficial, there is often a shortfall between symptom remission and full functional recovery.”

The big takeaways from the review, Dr Dean said, are the need to consider adjunctive therapies for bipolar disorder treatment; awareness of the slow speed of research, given less industry investment; the low risk of many of these therapies; and the promise of further biological psychiatry research in pointing toward personalized medicine options for patients.

“What is most exciting about this study is that it identifies studies that have examined a diverse range of treatments for bipolar disorder, things as distinct (and seemingly disparate) as smartphone apps [and] breast cancer medications,” said Alan Teo, MD, an assistant professor of psychiatry in the Oregon Health & Science University School of Medicine in Portland and a staff psychiatrist in the VA Portland Health Care System.

“As a psychiatrist, we often see patients who have problematic adverse effects from bipolar medications or simply do not get a full response from the medications,” Dr Teo, who was not involved in the study, told Psychiatry Advisor. “The typical treatment for bipolar disorder involves mood stabilizers or antipsychotics, as these types of medications have the best evidence of effectiveness, [but] it is also important to examine research on nonmedication treatment options, especially since many patients prefer such options.”

The study is a narrative, not systematic, review, and explored a wide range of therapies beyond simply pharmacotherapy, including nutraceuticals, hormone therapy, psychoeducation, various psychotherapy approaches, brain stimulation methods, and telehealth and mobile health.

“Due to the complex nature of these disorders, including the influence of genetics and environment, identifying the best agent for a particular individual in psychiatry is difficult,” Dr Dean told Psychiatry Advisor. “However, there is a lot of research being conducted to improve our understanding of the underlying pathophysiology of these disorders and how we might tailor treatments to each individual.”

Targeted, Nutritional, and Hormone Therapies

With the pathophysiology of bipolar disorder now linked to inflammation, altered antioxidant defense, and mitochondrial dysfunction, the authors noted, researchers are exploring agents targeting these pathways. Still, evidence on efficacy remains scant and weak. N-acetyl cysteine, celecoxib, minocycline, and ketamine are some of the agents being considered.

At this time, several randomized trials of N-acetyl cysteine have shown benefits from 2000 mg/day as adjunctive therapy, with minimal adverse effects. Less evidence exists for celecoxib, although 1 trial showed slight increases in tumor necrosis factor-alpha levels and another showed efficacy for mania after 6 weeks. Minocycline has even less evidence, although a few trials are ongoing. Despite a recent meta-analysis showing no benefit from ketamine used with electroconvulsive therapy, other research has shown it may have adjunctive benefits with other therapies.

The evidence base is particularly weak, albeit growing, for nutritional adjunctive therapies, including omega-3 fatty acids (most studies have substantial methodological limitations), inositol (conflicting results not reaching statistical significance), and folic acid (mixed results in small studies). Similarly, some researchers are investigating magnesium, melatonin, and choline, but studies to date are few and small.

The hormone showing the most promise as adjunctive therapy is tamoxifen, typically used for patients with breast cancer but showing improved bipolar mood symptoms, such as mania reduction, in several studies. Researchers have also explored progestin medroxyprogesterone, which modulated manic symptoms in one study compared with placebo, and interestingly, tamoxifen, pointing to the need for research on these agents.

Psychoeducation and Psychotherapy

Psychoeducation benefits seen in the literature include increased adherence to medication and other treatments, lower relapse rates, less time spent ill, fewer days hospitalized, fewer readmissions, and fewer and reduced duration of manic, hypomanic, mixed, and depressive episodes. However, efficacy declines as episodes increase, so early intervention is best, and group therapy has a greater effect than individual therapy.

Instead of sticking only to explaining bipolar disorder and drug options, psychoeducation today involves “an integrative approach emphasizing illness and symptom awareness, treatment adherence, self-management, the importance of regular habits, avoiding drug misuse and promoting good physical health,” the authors wrote. “Although the active ingredients of this treatment are yet to be clearly established, it is speculated that psychoeducation helps individuals recognize early signs and symptoms and adopt behavioral measures to prevent a full-blown episode.”

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Three other specific psychotherapeutic approaches used as adjunctive therapy for bipolar disorder include interpersonal and social rhythm therapy, mindfulness, and cognitive remediation. Interpersonal and social rhythm therapy aims to “regulate social and circadian rhythms, maintain regular routines, promote positive social relationships and social roles, and to reduce interpersonal conflict,” given the common dysregulated rhythms among patients with bipolar disorder. Some research has shown it reduces mood recurrence and has potential as monotherapy for bipolar II.

Mindfulness-based cognitive therapy (MBCT), initially used for anxiety disorders, teaches patients to disengage from negative thoughts and feelings instead of fighting them. “Results of MBCT in bipolar disorder have been positive overall, ranging from significant improvements in executive functioning, memory, task completion, and attentional readiness, to significant decreases in depression scores, anxiety scores, and dysfunctional attitudes about achievement,” the authors write. “These findings are promising; however, it is not yet clear how long-lasting the effects of MBCT are in bipolar disorder.”

A gradually increasing awareness of certain cognitive deficits and an understanding of brain plasticity has led to research using cognitive remediation as adjunctive therapy. This behavioral therapy uses computer and/or face-to-face training, usually during at least 10 sessions, to teach patients “adaptive and compensatory strategies” to improve attention, memory, and executive function. Evidence to date for bipolar disorder has shown moderate benefits in cognitive performance, reduced depressive symptoms, and improved occupational and daily functioning.

Telehealth, Mobile Technology, and Related E-Strategies

E-health approaches to bipolar treatment range from Internet-based interventions and peer support via online forums to mobile apps and teletherapy. However, a dearth of evidence and weak and/or mixed results to date suggest it will be a while before research can identify the most effective, long-lasting e-interventions.

Online programs so far have usually incorporated psychoeducation and cognitive-behavioral therapy, with slightly better results when peer coaching and support components are included. Current mobile apps, in contrast, have very low quality and do not use validated screening measures. Few monitor sleep and medication intake, and information frequently strays from practice guidelines. The authors also noted ethical and safety challenges inherent in telehealth approaches.

“Ensuring appropriate user safety monitoring, maintaining secure data privacy controls, and clearly communicating the adjunctive nature of an intervention are crucial,” they wrote. “Online and mobile technologies provide a number of solutions to these issues through automated safety assessments, password-protected and encrypted data files, and automated reminder notifications to seek face-to-face care when required.”

Finally, the review explored repetitive transcranial magnetic stimulation, which has shown efficacy with few adverse effects for depression when administered to the left dorsolateral prefrontal cortex. Results for repetitive transcranial magnetic stimulation as adjunctive therapy for bipolar disorder have been mixed and underpowered.

“Although efforts to investigate [repetitive transcranial magnetic stimulation] treatment specifically for bipolar depression to date have been scant, it is a promising, relatively safe and low-risk treatment for bipolar depression,” the authors wrote. Risk for mania as an adverse event appears overstated, the researchers noted, but a rare risk of seizures does exist, primarily when stimulation exceeded transcranial magnetic stimulation safety guidelines or in patients with preexisting neurological conditions.

The review’s primary limitation is its subjective presentation of the evidence, Dr Teo pointed out.

“It is unclear how they selected studies to be included, what time frame of published studies they considered, or even what the underlying quality of the studies they reviewed,” he told Psychiatry Advisor. Although the study was not designed to change practice, he added, it still offers clinical insights.

“I think clinicians might use this study to inform their patients of the wide range of new treatments being investigated,” Dr Teo told Psychiatry Advisor. “It offers real hope to patients, and sometimes hope is a powerful medicine.”

Funding and Disclosures

The research was funded by the Ian Parker Bipolar Research Fund, Australian Rotary Health, and the National Health and Medical Research Council in Australia. Dr Dean has received grant funding from the Brain & Behavior Research Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Lilly, and ASBDD/Servier, as well as in-kind support from BioMedica Nutraceuticals, NutritionCare, and Bioceuticals.


Dean OM, Gliddon E, Van Rheenen TE, et al. An update on adjunctive treatment options for bipolar disorder [published online January 25, 2018]. Bipolar Disord. doi:10.1111/bdi.12601