Rapid Cycling, Lithium, and the Landscape of Bipolar Disorder: A Conversation With David Dunner, MD

BRAIN TRUST: CONVERSATIONS IN PSYCHOPHARMACOLOGY

-Series Editor Joseph F. Goldberg, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with David Dunner, MD, FACPsych, to discuss practical insights into the evolving treatment of bipolar disorder and treatment-resistant depression.

Dunner described the origins of the rapid cycling concept, which emerged from his chart review of lithium nonresponders at the Columbia University lithium clinic in the early 1970s.¹ He explained that patients with 4 or more mood episodes per year were consistently poor lithium responders, a finding later replicated and incorporated into DSM-IV.² He also recounted his earlier work at the National Institute of Mental Health, where review of inpatient records led to the first characterization of bipolar II disorder: patients with hypomania and depression who did not meet criteria for full mania but demonstrated high rates of suicidality and family history of suicide.³

Dunner cautioned against conflating ultra-rapid cycling—which he attributed to neurological causes such as multiple sclerosis or substance use—with true bipolar rapid cycling. He also addressed the differential diagnosis of mood variability, distinguishing episodic bipolar cycling from the briefer, interpersonally triggered reactivity seen in borderline personality disorder, noting that the 2 conditions could coexist but that lithium addressed only some features of the latter.

On pharmacotherapy, Dunner pointed out the commercial displacement of lithium by promoted anticonvulsants, observing that many lacked robust maintenance trial data. Regarding second-generation antipsychotics, Dunner acknowledged their efficacy as augmentation agents but noted unresolved questions about sequencing and duration of use. He emphasized neuromodulatory interventions—transcranial magnetic stimulation, vagus nerve stimulation, esketamine, and deep brain stimulation—for treatment-resistant depression. He expressed caution about psilocybin, noting that "the safety issue is more concerning to me unless they show that this is a long-term safe compound to use."

On the broader state of the field, Dunner observed that mania phenotypes had shifted markedly toward mixed and dysphoric presentations. He reflected that while outcomes have improved substantially over his career, fundamental uncertainties in antidepressant selection persist: "It's clear that we lack a lot of insight into what's the absolute best drug for this patient. We're making an educated guess," he said.

Dr Goldberg is a clinical professor of psychiatry at The Icahn School of Medicine at Mount Sinai in New York, NY and the immediate-past president of the American Society of Clinical Psychopharmacology.

Dr Dunner is professor emeritus at the University of Washington and director of the Center for Anxiety and Depression in Mercer Island, Washington.

References

1. Dunner DL, Fieve RR. Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry. 1974;30(2):229–233.

2. Dunner DL. Bipolar disorders in DSM-IV: impact of inclusion of rapid cycling as a course modifier. Neuropsychopharm. 1998;19(3):189-193.

3. Dunner DL. A review of the diagnostic status of “bipolar II” for the DSM-IV work group on mood disorders. Depression. 1993;1(1):2-10.