A Slow Road Toward Personalized Treatment of Bipolar Disorder

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Bipolar disorder is considered a major cause of mortality and psychiatric disability worldwide.
Bipolar disorder is considered a major cause of mortality and psychiatric disability worldwide.

The goals of personalized medicine for many disease states are to improve upon past trial-and-error strategies and optimize therapeutic outcomes for patients. In psychiatric diseases such as bipolar disorder, where the risk of suicide is extremely high, achieving these goals is crucial to maintaining patient safety. Although a range of therapies are used for bipolar disorder, supporting evidence is limited, efficacy is low and varies significantly from patient to patient, and adverse effects and potential harms are many.1-3

Bipolar disorder — characterized by recurring, interrelated episodes of extreme excitability and depression — is considered one of the major causes of mortality and psychiatric disability worldwide. It is associated with a range of serious comorbidities, such as diabetes and migraine, as well as cardiovascular and respiratory conditions.1 More than 1% of the world's population is affected by bipolar disorder, independent of factors such as race, nationality, or socioeconomic status.1

Bipolar disorder tends to develop in stages over years (often during childhood and puberty) when preclinical signs such as anxiety, impairment of cognitive function, and sleep disruptions may become frequent. The initial defining episode is usually depressive, and it may be several years before a hypomanic phase helps to fully define the bipolar cycle.1

One of the most important challenges to personalized management is establishing a diagnosis of bipolar disorder that appropriately evaluates bipolar depression and separates medical and psychiatric comorbidities. Subtypes of bipolar disorder have been suggested, including types 1 and 2, which are distinguished by the severity and duration of symptoms.3 Increasingly, however, it is the persistence of mood instability between the depressed and manic state that has become a primary focus of investigation.3

Why Therapies Often Don't Work

Despite availability of a broad range of pharmacologic treatments, successful management of the manic and depressive states in bipolar disorder is often difficult to achieve. “The difficulty is that the disorder is quite heterogeneous, so some people do quite well on specific drugs while others don't,” said Martin Alda, MD, professor and Killam Chair in Mood Disorders in the department of psychiatry at Dalhousie University and director of the Mood Disorders Program at the Health Authority in Nova Scotia, Canada, in an interview with Psychiatry Advisor. “It's not that you can stay with 5 or 6 medications that work for most people. The potential number of choices is quite high, and we have relatively little to guide us.”

Therapies for depressive states have been more successful than those for manic episodes. In patients with mixed forms of the disease, the consequences are often problematic, as the drugs can exacerbate other conditions or even other phases of the bipolar cycle. “The potential for things going wrong with drug therapies for bipolar disease is quite high,” Dr Alda reported. For instance, lithium, the most effective treatment for bipolar depression, can produce many unwanted effects on lipid and glucose levels, as well as impairment of kidney and liver function.

A 2015 review by Hasler and Wolf 4 pointed to disparity among treatment guidelines and how the application of complex combination therapies that are not well supported by evidence contribute to relatively low rates of effective symptom management.

New Therapeutic Perspectives

A new approach that stratifies patients by their potential response to therapy is needed to guide clinicians in providing individualized care. Research has begun to shift focus from treating individual episodes of depression or mania to reducing the extent and frequency of mood swings in bipolar disorder, which have been shown to be predictive of relapse, hospitalization, and disability. The attainment of mood stability, therefore, has become a primary goal of therapy for bipolar disorder.5,6

Predicting response to therapies is the single most important factor in improving therapeutic outcomes. As more than 80% of bipolar disease is genetic, family history is extremely important for determining outcomes to therapy. “For some patients with a family history, their relatives may have already responded to lithium,” Dr Alda suggested, although the presence of comorbid conditions suggests avoiding the use of lithium. “The problem is that for long-term treatment, it can take several years to determine whether somebody is responding. It would be much better not to have to go through these multiple cycles of trying this drug and that one until we finally see a response,” he observed.

The lack of efficacy of many bipolar treatment strategies also seems to encourage a high rate of nonadherence among patients, Dr Alda said. “Adherence is dependent on a good understanding of the effects of treatments. Many of these drugs have side effects, and in the hands of someone who does not have good understanding, the patients may be pushed away from using them.”

New Directions for Research

According to Hasler and Wolf,4  improvements to targeting specific agents for specific patients would need to be driven by biomarkers and clinical markers of the physiological swings that are not yet known. “To date, the most reliable markers are derived from psychopathology and history-taking, while no biomarker has been found that reliably predicts individual treatment responses,” they wrote.4

“We are hoping that we can make more progress with genetic markers as well as brain imaging,” Dr Alda said, “and we have reasonably good tools to predict outcomes to drugs like lithium and lamotrigine.” He pointed to investigations where the behavior of excitable stem cells from people with bipolar disease was normalized in response to lithium. “These are very early potential markers. We need to have some reliable markers that can be quickly utilized. If that's done, I'm optimistic that we might actually be quite close to personalized therapy options,” he said.

References

  1. Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387(10027):1561-1572.
  2. Alda M, Manchia M. Personalized management of bipolar disorder [published online December 5, 2017]. Neurosci Lett. doi: 10.1016/j.neulet.2017.12.005
  3. Harrison PJ, Cipriani A, Harmer CJ, et al. Innovative approaches to bipolar disorder and its treatment. Ann N Y Acad Sci. 2016;1366;76-89.
  4. Hasler G, Wolf A. Toward stratified treatments for bipolar disorders. Eur Neuropsychopharmacol. 2015;25:283-294.
  5. Bonsall MB, Wallace-Hadrill SM, Geddes JR, Goodwin GM, Holmes EA. Nonlinear time-series approaches in characterizing mood stability and mood instability in bipolar disorder. Proc Biol Sci. 2012;279:916-924.
  6. Faurholt-Jepsen M, Munkholm K, Frost M, Bardram JE, Kessing LV. Electronic self-monitoring of mood using IT platforms in adult patients with bipolar disorder: a systematic review of the validity and evidence. BMC Psychiatry. 2016;16:7
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