Why Personalized Treatment Decisions Are Important

Optimal management decisions in bipolar depression entail carefully personalized balancing of potential benefits (efficacy) and harms (side effects). With respect to potential benefits, there are only three medications with Food and Drug Administration approval for acute bipolar depression, and these all entail a second-generation antipsychotic (SGA) component (the olanzapine plus fluoxetine combination, quetiapine monotherapy, and lurasidone as monotherapy or added to lithium or valproate).

For many patients, however, the risks of harm with these treatments exceed those seen with other agents commonly administered to patients with bipolar disorder, such as mood stabilizers or antidepressants.

Perhaps due to their efficacy in unipolar major depressive disorder and somatic tolerability that for many patients is superior to that of mood stabilizers or SGAs, antidepressants are commonly administered to patients with bipolar depression, despite having only limited evidence of efficacy in such patients. However, evidence suggests that antidepressants, although somatically fairly well tolerated, may yield psychiatric harms such as exacerbation of depression and emergence of suicidal ideation—particularly in pediatric and young-adult populations—as well as treatment-emergent affective switch (into mood elevation).

Thus, caution is warranted when considering administering antidepressants to bipolar disorder patients with mixed bipolar I (rather than bipolar II) depression with a rapid-cycling course and a history of problems with antidepressant administration. In contrast, certain bipolar disorder patients lacking such clinical characteristics may be reasonable candidates for antidepressant administration. We present a case that demonstrates the former principle.

“Grace” is a 35-year-old, recently separated, Chinese-American bank teller who presented with complaints of irritability, impulsivity, and depression. She noted that in the month since bupropion (current maximum tolerated dose 300 mg/day) was added to her ongoing lithium (current maximum tolerated dose 900 mg/day, level 0.8 mEq/L), she had experienced attenuation of sadness, fatigue, and hypersomnia, but marked increases in irritability and impulsivity; she was requesting medication to address her irritability and anhedonia.

Current depressive symptoms included anhedonia, poor self-esteem and concentration, insomnia, psychomotor agitation, and passive suicidal ideation without intent, preparation, or plans. Current mood-elevation symptoms, which emerged after starting bupropion, included prominent irritability as well as decreased need for sleep (feeling alert and energized despite sleeping only three hours a night), increased goal-directed activity (working 70 hours and socializing 40 hours a week), and impulsivity (starting a romantic affair with a married coworker). The patient denied having substantive anxiety symptoms.

Grace acknowledged having had three depressive and one hypomanic episodes in the prior year, and although she reported being hospitalized for mania at age 18, she denied any lifetime history of anxiety or alcohol/substance use disorder. She admitted to having declined individual and couples’ psychotherapy on multiple occasions for a variety of reasons, including “lack of time.” She reported having prior pharmacotherapy with mood stabilizers, with lithium having yielded some improvement, but dosage was limited by side effects; lamotrigine having yielded a rash; carbamazepine being refused due to rash risk; and divalproex was refused due to risk of exacerbating her polycystic ovarian syndrome. She also stated that the SGA aripiprazole had been ineffective for depression, and the antidepressant paroxetine had not only been ineffective for depression, but had also yielded insomnia, agitation, irritability, and sexual dysfunction.

Grace’s family history was remarkable for having a mother with bipolar I disorder who had experienced psychotic mania, requiring hospitalization on three occasions and not achieving long-term mood stability despite aggressive pharmacotherapy with unspecified mood stabilizers and antidepressants. Grace also reported having a sister with bipolar I disorder who had been hospitalized for psychotic mania on one occasion, but she had eventually achieved adequate control of mood elevation symptoms with lithium 1,200 mg/day and the SGA quetiapine, although its dosage was limited to 75 mg at bedtime due to somnolence.

Thus, Grace had mixed bipolar I depression with rapid cycling, prominent irritability and impulsivity, and a history of problems with antidepressant administration that very recently included “converting” from pure to mixed depression with the antidepressant bupropion. Important alternatives to antidepressants for her did not appear to include mood stabilizers but did appear to include the SGAs lurasidone and olanzapine combined with fluoxetine (although this combination has substantial weight and metabolic tolerability limitations).

Clinicians will commonly encounter cases of patients with bipolar depression, and in these patients, antidepressant treatment needs to be approached with extreme caution. Arriving at the optimal therapeutics entails making carefully personalized treatment decisions. In this case, SGAs rather than mood stabilizers and antidepressants appeared to be priority interventions. ■