The impact of bipolar disorder is striking. Despite a lifetime prevalence of 2.4% worldwide for bipolar spectrum disorders, the World Health Organization’s 2011 Report on Disability listed bipolar disorder as the twelfth leading health condition associated with disability worldwide (Merikangas et al. 2011, World Health Organization & World Bank).

In addition to having the highest lifetime risk of suicide, those who suffer from bipolar disorder are also at increased risk for cardiovascular and pulmonary disease, diabetes, and other comorbid medical illnesses, and are subject to decreased life expectancies (Bauer et al. 2018).

Yet for all the gravity of these effects, research in bipolar disorder remains underfunded. There is subsequently an obscurity that surrounds bipolar prediction and symptom management relative to other chronic medical conditions. This holds true when comparing the accuracy of diagnoses for bipolar disorder with non-mental health disorders and even with other mental disorders.

For example, a previous elf blog [How valid are hospital psychiatric diagnoses?] reported that a Hospital Episode Statistics (HES) diagnosis of schizophrenia has a 90% chance of matching a diagnosis based on clinical records, while diagnosis of bipolar affective disorder drops to a 70% chance of matching.

Treatment for bipolar disorder is similarly unestablished, with international treatment guidelines showing low agreement overall [see: How consistent are international treatment guidelines for bipolar disorder?].

With so many questions still in play in the field of bipolar research and clinical practice, it is useful to evaluate current literature to inform further efforts. This is what Michael Bauer et al. have attempted in their recent Lancet Psychiatry review paper; they identified “areas of uncertainties and unmet needs” with the goal of guiding the field towards effective and personalised medical care to those who suffer from bipolar disorder.

Methods

The authors completed a narrative review of current bipolar disorder literature, focused on early identification and intervention, treatment and outcomes. They maintained a clinical vantage in their summary of articles selected through PubMed from the database’s inception until Dec 1, 2017. They also highlighted current weaknesses in bipolar disorder research, diagnosis, and treatment of, then suggested directions for future efforts to fulfil these needs.

Results

Bauer et al.’s overview of unmet needs is broad but supports two central themes:

1. The importance of earliness in mitigating bipolar disorder’s burden of illness
2. As of yet unexplored areas of treatment that may improve long-term responses and decrease mortality.

“Earliness”: early diagnosis, early intervention, responsive maintenance

The first theme (“earliness”) refers to early identification of at-risk populations, early diagnosis of bipolar disorder within individuals, and in extension: early intervention. On a smaller scale, it also refers to detection of warning signs that precede mood episodes within the course of illness.

Bauer et al. recounted several studies that supported increased positive response when intervention occurred following patients’ first hospitalisation or first manic/mixed episode compared to those who experienced delayed treatment.

With an average delay in diagnosis of 8-10 years for bipolar disorder, it is of critical interest to improve identification of at-risk individuals and timely diagnosis to improve long-term patient outcomes.

To this end, the authors advised investment in large-scale, collaborative studies focusing on first-episode interventions to help inform clinical care.

Better long-term treatment

The second theme revolves around weaknesses and unmet needs in clinical care. Treatment options for bipolar depression, for example, are sparse compared to those for mania, and though some medications have found success in short-term treatment of rapid-cycling bipolar disorder, an effective long-term treatment is yet to be found for this particularly unstable subgroup (which experiences four or more episodes per year).

In a more general sense, Bauer et al. described a need for investigation into treatments targeting overall function, as opposed to relapse prevention or alleviation of acute symptoms.

They also supported lithium as a primary source of pharmacological intervention, citing anti-suicidal effects and high success as a maintenance treatment compared to other mood stabilisers.

Conclusions

Clinical recommendations included focus on early diagnosis and intervention and increased use of lithium as pharmacotherapy. From a research perspective, the study of bipolar disorder currently receives less funding than that of other diseases with similar burden of illness. Aside from increased funding opportunities, the field can benefit from the following types of research studies, which currently lack representation:

• Prospective and longitudinal tracking of symptomology for those at high risk of developing bipolar disorder, perhaps incorporating polygenic risk scores in addition to clinical history data to determine risk
• Longitudinal studies of those with identified illness to facilitate better understanding of between-episode symptomatology and early warning signs of relapse
• Double-blind, placebo, and active-controlled trials of primary clinical outcomes following intervention in patients with first-episode mania
• Controlled trials investigating effect of psychosocial education on patients with rapid-cycling bipolar disorder
• Randomised trials comparing maintenance effects of lithium to other mood stabilisers and to psychosocial interventions in patients following remission of first episode
• Evaluation of lithium treatment response using brain imaging markers and blood-based molecular signature.

Strengths and limitations

Bauer et al.’s recommendation to focus on early identification and intervention appeals as a way to improve prognosis in bipolar disorder, and is, in fact, an idea growing in popularity in recent years (Malhi et al. 2017). At the same time, there are key challenges that must be surmounted before this idea can come to use in clinical practice.

Accurate early identification of bipolar disorder requires a strong sense of clinical staging. In particular, it requires characterisation of a bipolar prodrome, and it is here that we run into difficulty. While Bauer et al. state that it is “not unrealistic to develop prediction and stratification tools for clinical use in bipolar disorder” (showing optimism towards new developments in genetics and brain imaging), current advancements also do not cleanly inform bipolar disorder-related early identification (2018). To Bauer et al.’s credit, they allude to this ambiguity when they clarify that associations between neuroimaging biomarkers and later symptom development, while promising, were not found to be specific to any particular disorder, but instead to reflect more general psychopathology. Other studies have presented imaging and genetic data that blur boundaries between diagnoses, which suggests a possible dimensional view of mood disorders (Kelsoe, 2003). In-depth discourse of bipolar disorder reclassification is outside of this review’s scope (and the authors do, indeed, mindfully and explicitly disclose that their focus on bipolar disorder “as it is currently clinically conceptualized”); however, this idea helps inform present-day lack of findings of an isolated bipolar prodrome, and the difficulty determining a reliable model for clinical staging. Advances in neuroscience thus indicate we may need to maintain a flexible outlook on how a bipolar prodrome may look once more robust research has been conducted. We may be able to utilise neuroimaging and genetics in an “integrative approach with several biological measurements using different scales,” which could, in turn, “yield patterns of biomarkers… to help identify biological targets for personalized and new treatments for all affective disorders.” (Phillips & Kupfer, 2013).

In a practical sense, the most salient challenge is that of limited resource availability towards the research required to investigate early prevention and first episode treatment. The studies Bauer et al. have suggested would require extremely large sample sizes and long-term follow-ups. Fulfilling the unmet needs in research described by Bauer et al. would be valuable, as they would inform clinical practice, and because they have potential to improve prognosis for those suffering from bipolar disorder. It would also require a substantial investment across a large network of centres.

In all, Bauer et al. have written a well-thought out and very readable narrative review that clarifies current research accomplishments and brings to light areas of improvement to flesh out our understanding of this complicated illness.

Implications for practice

Though directing focus towards early identification and intervention shows promise in improving prognosis, more research is necessary before this focus can become useful in clinical practice. The authors’ suggestion for more widespread use of lithium represents a much-needed shift from current practice.

In the sixty years since lithium was introduced into psychiatry, studies have supported its efficacy as a mood stabiliser, and even suggest neuroprotective, telomere-preserving, and anti-suicidal effects. Despite these long-standing and robust evidence, lithium remains under-prescribed (Post 2018). Some have noted that this underuse appears most pronounced in North America, where other drugs have been used in lieu of lithium “in spite of weak or even absent evidence of their efficacy” (Grof & Müller-Oerlinghausen 2009; Post 2018). These other medications are often strongly marketed by pharmaceutical companies. Lithium use is also impeded by some practical barriers: For example, with its narrow therapeutic index, lithium is a higher-maintenance drug relative to other medications, as it requires careful monitoring via blood tests. The need for laboratory testing is less desirable for patients. Practitioners unfamiliar or unpracticed with its use and monitoring may thus be especially reluctant to prescribe lithium.

Lithium has much to offer if, like Bauer et al. suggest, we are willing to trust its long-running body of evidence and further promote its use.

Links

Primary paper

Bauer M, Andreassen OA, Geddes JR, Kessing LV, Lewitzka U, Schulze TG, Vieta E. (2018) Areas of uncertainties and unmet needs in bipolar disorders: clinical and research perspectives. The Lancet Psychiatry, 2018, https://doi.org/10.1016/S2215-0366(18)30253-0

Other references

Grof, P. & Müller-Oerlinghausen, B. A critical appraisal of lithium’s efficacy and effectiveness: the last 60 years. Bipolar Disorders: An International Journal of Psychiatry and Neuroscience, 11, 10-19. DOI: https://doi.org/10.1111/j.1399-5618.2009.00707.x

Kelsoe, J.R. 2003. 2002. Arguments for the genetic basis of the bipolar spectrum. Journal of Affective Disorders. 73, 183-197. DOI: http://dx.doi.org/10.1016/S0165-0327(02)00323-3

Malhi, G., Morris, G., Hamilton, A., Outhred, T., Mannie, Z. (2017). Is “early intervention” in bipolar disorder what it claims to be? Bipolar Disorders: An International Journal of Psychiatry and Neuroscience, 19, 8, 627-636.

Merikangas, K. R., Jin, R., He, J. P., Kessler, R. C., Lee, S., Sampson, N. A., Viana, M. C., Andrade, L. H., Hu, C., Karam, E. G., Ladea, M., Medina-Mora, M. E., Ono, Y., Posada-Villa, J., Sagar, R., Wells, J. E., … Zarkov, Z. (2011). Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Archives of general psychiatry, 68(3), 241-51.

Phillips, M.L. & Kupfer, D.J. (2013). Bipolar disorder diagnosis: challenges and future directions. Lancet, 381(9878): 1663-1671.

Post R. M. (2017). The New News about Lithium: An Underutilized Treatment in the United States. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 43(5), 1174-1179. DOI: 10.1038/npp.2017.238

World Health Organization., & World Bank. (2011). World report on disability. Geneva, Switzerland: World Health Organization.

Photo credits

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• Simon Law CC BY 2.0
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