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March 5, 2018

Preventing the Malignant Transformation of Bipolar Disorder

Author Affiliations
  • 1George Washington University School of Medicine, Bethesda, Maryland
  • 2Bipolar Collaborative Network, Bethesda, Maryland
JAMA. Published online March 5, 2018. doi:10.1001/jama.2018.0322

Stigma is one of the factors contributing to inadequate recognition and treatment of recurrent mood disorders, including unipolar depression and bipolar disorder. In addition, the potential seriousness of these illnesses is often underestimated. This Viewpoint describes an analogy to the development and spread of a malignancy as a way of trying to emphasize the pernicious course of bipolar disorder in particular, but many of the comments are also relevant to recurrent depression.

Why an analogy to cancer? Similar to mood disorders, cancer often progresses through a series of stages to become an overt malignancy. First there is cytological evidence of dysplasia, then increasing cellular disorganization eventually leading to a localized lesion that can then increase in size and invasiveness, and ultimately may metastasize. This sequential process involves increasing numbers of somatic mutations, including both the loss of tumor suppressor factors and the gain of function with cellular proliferative factors.1

The therapeutic focus of a cancer is early detection and treatment. In contrast, a first episode of mania is often treated less intensively. A short hospitalization is typically followed by a referral to a psychiatrist or primary care physician in the community who may, at the patient’s urging, agree that it is reasonable for the patient to stop the medications once a stable mood has been achieved.

This all-too-common occurrence, as well as nonadherence to medications in approximately 50% of patients,2 likely contributes to a poor long-term course of illness and outcome. Episodes of illness, stressors, and bouts of substance abuse (which are particularly common among patients with bipolar disorder) each tend to recur and accumulate, and each is associated with a process of sensitization or increased reactivity to the next recurrence.3

In the analogy to cancer progression associated with an increasing accumulation of somatic mutations, each type of sensitization occurring with mood disorders is associated with a progressive accumulation of epigenetic changes.3 Epigenetic alterations are induced by events in the environment that lead to chemical groups being added to or subtracted from DNA and histones or microRNA is altered, thus changing the ease with which DNA is activated and transcribed. These epigenetic marks can have long-term, if not lifelong, adverse effects on neurochemistry and behavior. Whether this phenomenon occurs in bipolar disorder is unknown, but plausible.

Sensitization appears to have an epigenetic basis.3 This is demonstrated by the observation that an inhibitor of DNA methylation, zebularine, prevents increases in behavioral reactivity to repeated exposure to cocaine or stressors. In an animal model of depression involving repeated defeat stress, the resulting depressive-like behaviors also have an epigenetic basis.4 This model is likely relevant to humans because adults with either a diagnosis of depression or who experienced abuse during childhood, or both, have greater numbers of epigenetic marks (DNA methylation or histone alterations) in their white blood cells and brains at autopsy than those without these experiences.5

Data from 3 studies suggest that intensive treatment should be started after a first manic episode. Kessing et al6 conducted a randomized clinical trial of 158 patients having a first hospitalization for mania. Compared with patients receiving treatment as usual, those randomized to 2 years of expert treatment in a specialty clinic showed a longer time to rehospitalization, and the between-group differences persisted and increased during the next 6 years (shown in the Kaplan-Meier curves) with fewer patients (36.1%) readmitted compared with patients who received treatment as usual (54.7%) and the duration of readmissions was shorter. Kozicky et al7 reported that after a first hospitalization for mania, cognition on a comprehensive battery of tests improved more (returned toward normal) in the 27 patients who experienced no further manic episodes during the next year compared with the 26 who experienced recurrences.

In another trial, Berk et al8 randomized 61 patients who had a first hospitalization for mania to 1 year of treatment with either lithium or the atypical antipsychotic quetiapine (≤800 mg/d). In mixed-model repeated-measures analyses, lithium was more effective than quetiapine on every outcome measure, including mood, functioning, cognition, and brain imaging alterations with large differences emerging during the second half of the year.

The recommendation for vigorous treatment after a first manic episode is reinforced by the extensive literature that early initiation of lithium and most other treatments is more effective than beginning treatment later after many episodes have occurred.3 Similarly, treatment of a primary malignancy is typically more effective than after the cancer has metastasized.

What are the consequences of treating a first manic episode without the care, caution, and follow-up that would be used for treating cancer? With inadequate long-term treatment and follow-up of patients with a manic episode, the recurrence of greater numbers of episodes is associated with increasing dysfunction, disability, cognitive dysfunction, treatment resistance, telomere shortening, medical comorbidity, prefrontal cortex deficits, and the risk of receiving a diagnosis of dementia during old age.3 The accumulation of so many illness-related liabilities would appear to merit the term malignant transformation of bipolar disorder.

Some might think that the analogy to cancer is exaggerated because malignancies are life-threatening illnesses and potentially fatal. However, so are mood disorders. Suicide is one of the leading causes of mortality among 13- to 18-year-olds and suicide rates are high among those with a diagnosis of depression or bipolar disorder. Moreover, there is a loss in life expectancy of 1 decade or longer that is predominantly attributable to the increases in cardiovascular disorders associated with mood disorders.9

Further complicating the problem is a relative lack of randomized clinical trials among highly recurrent patients with bipolar disorder. In contrast, very complex combinations of treatment are both available and well-studied among patients with metastatic malignancies. As a consequence, during the late stages of bipolar disorder, the patient and physician are essentially left to their own clinical experiences without high-quality evidence to guide decision making. This too would appear to have much to do with stigma. Some may view these illnesses as not serious enough to deserve the necessary funding even for what could be relatively inexpensive clinical trials that compare 2 active randomized treatments.

The situation and need for treatment guidance is especially critical in the United States compared with many European countries.10 Compared with European patients, US patients with bipolar disorder have a more adverse course of illness, including more treatment refractoriness to prospective naturalistic treatment (administered according to the best judgment of physicians), more anxiety and substance abuse comorbidities, and more episodes and faster cycling between mania and depression. Two-thirds of US patients with bipolar disorder have childhood and adolescent onsets, and these are associated with a greater delay to first treatment compared with in Europe where only one-third of patients have childhood onset of bipolar disorder. Both early onset illness and treatment delay are independent risk factors for a poor outcome during adulthood. The excess of early onset and the associated adverse course of illness have been associated with both more genetic and familial vulnerability and more psychosocial adversity during childhood in the United States compared with the Netherlands and Germany.10

Perhaps emphasizing to physicians, patients, and funders of research that the first episode of mania has to be handled with the same care as an initial malignant lesion to prevent illness progression and transformation to a more treatment refractory illness will better highlight and help reverse the potentially catastrophic consequences of inadequate treatment of patients with bipolar disorder.

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Article Information

Corresponding Author: Robert M. Post, MD, George Washington University School of Medicine, Bipolar Collaborative Network, 5415 W Cedar Ln, Ste 201-B, Bethesda, MD 20814 (robert.post@speakeasy.net).

Published Online: March 5, 2018. doi:10.1001/jama.2018.0322

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Post reported receiving speaking fees from AstraZeneca, Sunovion, Takeda-Lundbeck, Validus, and Pam Labs.

Additional Contributions: I acknowledge the editorial assistance of Jessica Pollack, BS (Bipolar Collaborative Network). Ms Pollack was not compensated.

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