Most of the literature on treatment-resistant bipolar disorder is related to treatment of acute episodes of mania or depression. There is no formal universal definition of treatment resistance; proposed criteria have included a specific number of failed medication trials, incomplete or unsatisfactory response to treatment (usually determined by symptom rating scales), unsuccessful response for a specified duration of treatment, failure to respond to a phase of bipolar disorder, poor response to all medication and nonmedicinal interventions, or lack of response to only “evidence-based” (usually FDA-approved) medications for bipolar disorder.
It should be noted that the FDA has approved both vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS) for treatment-resistant depression: VNS, if the patient has failed 4 or more different medication trials; and TMS after only 1 adequate medication trial. We consider a patient with bipolar disorder treatment resistant if trials of all medications approved by the FDA for bipolar disorder have failed.1
This article focuses on treatment resistance to medications in adult male and non-pregnant adult female outpatients with any type of DSM-5 diagnosed bipolar disorder.
Possible contributing factors to treatment resistance
Although the severity of the bipolar disorder and the degree of response to medical treatments are usually considered predominantly under genetic or other endogenous influences, several non-biological factors often contribute significantly to treatment resistance (Table 1). Some of these factors can be successfully addressed, often resulting in a better prognosis. For clinical purposes, it is more useful to conceptualize bipolar disorder as a spectrum condition rather than a true “bipolar” disorder, since this approach may lead to more accurate recognition of the active symptoms of the current episode. Such recognition is crucial because these findings, rather than the diagnostic subtype of the bipolar disorder as defined by DSM-5, should determine the choice of medications, especially because the diagnosis of MDD has been redefined in DSM-5 to include some hypomanic/manic symptoms.
Some clinicians find symptom checklists or scales helpful in supplementing findings on the mental status examination. Symptom recognition is especially important when medicating patients who have bipolar disorder with mixed symptoms because failure to recognize less obvious or “soft” hypomanic symptoms (insomnia, anxiety, irritability, rapid thoughts, and rumination) can lead to prescribing antidepressants, which will offer no therapeutic benefit and may even worsen activation symptoms. (The reader is referred to 3 helpful and thoughtful references for a more thorough discussion of this important clinical issue.2-4)
Before medications are initiated, several potential obstacles to successful treatment of bipolar disorder should be addressed, especially for outpatients. Significant others of the patient should be included in the initial evaluation and during the course of treatment if necessary, especially if the patient is unable to recognize or communicate symptomatology well.
Patients who use even small or moderate amounts of alcohol or recreational drugs (including marijuana) should be informed that any continued use can interfere with the therapeutic effects of prescribed bipolar medications. Concurrent use of some psychiatric (antidepressants) and non-psychiatric (eg, steroids, opioids) mood-destabilizing medications should be discontinued to determine whether they are opposing the therapeutic effects of antimanic agents.
Volitional unhealthy lifestyle behaviors can also have an adverse effect on the prognosis of bipolar disorder. Patients should be informed that controllable poor sleep habits (staying up late on the internet), predictable and avoidable stressful situations, and irregular medication compliance can neutralize or outweigh the positive effects of prescribed medications. Moreover, frequent exercise and the stability of regular routines, such as healthy eating habits and good sleep hygiene, can enhance treatment outcomes.
Dr. Charles Schaffer is Clinical Professor, Department of Psychiatry and Behavioral Science, UC Davis School of Medicine; Dr. Linda Schaffer is in private practice; and Ms. Howe is Dr. Charles Schaffer’s research assistant.
The authors report no conflicts of interest concerning the subject matter of this article.
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