9: How to Prescribe Off-Label With Henry Nasrallah, MD

11: Practical Insights Into the Evolving Treatment of Bipolar Disorder With David Dunner, MD, FACPsych

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. 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. 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. 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 concluded.

10: The Challenge of Medication Adherence With Martha Sajatovic, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Martha Sajatovic, MD, to discuss the multifaceted challenge of medication adherence in psychiatric practice. Sajatovic opened by framing adherence as behavioral and attitude alignment with a prescribed treatment plan, noting that nonadherence was far more common than most clinicians recognized. Evidence suggests that roughly half of patients prescribed psychotropic medications had difficulty maintaining recommended regimens. Sajatovic emphasized that this gap had real consequences, including relapse, hospitalization, and misattributed treatment failure—situations in which clinicians might incorrectly escalate dosing or change medications without recognizing poor adherence as the underlying cause. The discussion turned to practical strategies for initiating nonjudgmental dialogue. Sajatovic advocated normalizing adherence difficulties before asking patients whether they applied personally: “the evidence suggests that it's hard for people to stay on track with medications, and it's really common." Both Goldberg and Sajatovic agreed that the term "compliance" carried adversarial connotations and had been beneficially supplanted by "adherence," which invited shared decision-making rather than punitive evaluation. Sajatovic identified self-efficacy as an emerging correlate of better adherence, drawing on National Institutes of Health-funded research showing that patients who felt empowered to influence their own health outcomes were more likely to remain on track. Additional barriers our experts addressed included fluctuating insight in bipolar disorder, stigma, polypharmacy burden, concurrent substance use, and negative family attitudes; Sajatovic noted that in one sample group of patients with bipolar disorder, up to 40% of family members did not believe medication was indicated. Sajatovic described Customized Adherence Enhancement, a brief modular behavioral intervention she developed with colleague Jennifer Levin, MD, that targeted individualized barriers through psychoeducation, provider communication, substance-use counseling, and medication-routine strategies. The conversation concluded with a discussion of long-acting injectable antipsychotics, periodic medication reviews, and deprescribing—including a forthcoming paper by Goldberg and Sajatovic in JAMA Network Open reporting that over 90% of a Delphi expert panel endorsed regular, structured regimen reviews as standard practice.

9: How to Prescribe Off-Label With Henry Nasrallah, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Henry Nasrallah, MD, to discuss off-label prescribing and polypharmacy. Nasrallah bases the discussion off his landmark analysis that demonstrated 88% of DSM psychiatric diagnoses have no US Food and Drug Administration (FDA)-approved pharmacotherapy, leaving clinicians with no choice but to prescribe off-label for many of the patients they encounter. He argues that the FDA's diagnosis-centric approval framework, rather than a symptom- or circuit-based model, is a primary driver of this gap, noting that a shift toward symptom-level indications could render irrelevant much of current off-label practice. Both clinicians emphasize that off-label prescribing, when rationale-based and neuroscientifically informed, constitutes responsible clinical care rather than reckless deviation. Nasrallah describes examples like using valproate for impulsive aggression in traumatic brain injury, clozapine augmentation for treatment-resistant suicidality, and high-dose modafinil for refractory depression—each grounded in mechanistic reasoning. Goldberg observes that "off-label practices are legitimate…good for patients and save a lot of lives," while cautioning that prescribers must understand what a drug does in the brain, not merely follow or ignore labeling. The conversation also addresses the transdiagnostic model, polypharmacy, insurance barriers to off-label coverage, and the underutilization of clozapine. Nasrallah concludes by characterizing off-label discovery as "a creative process, the cutting edge of scientific advances," urging clinicians to publish case reports and share serendipitous findings to catalyze future trials.

8: Early Intervention & Psychopharmacology in Bipolar Disorder With Robert M. Post, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Robert M. Post, MD, to discuss evolving perspectives on bipolar disorder and treatment, emphasizing early intervention and the underutilization of lithium. There is a high prevalence of childhood-onset bipolar disorder in the United States, noted Post, with approximately a quarter of cases beginning before age 13. Earlier onset and longer delays to first treatment independently predict poorer adult outcomes. Post posited, “untreated illness is the greatest threat to our children,” arguing that concerns about overprescription have overshadowed the risks of delayed or absent care. Goldberg and Post then discuss the duration of untreated illness as a prognostic factor analogous to other areas of medicine. Delayed initiation of effective therapy diminished treatment responsiveness. According to emerging data, lithium was the most effective when introduced after a first episode, potentially preserving cognitive function and preventing neuroprogression. He reiterated that lithium’s benefits extended beyond mood stabilization, describing it as neuroprotective and potentially disease modifying. As Post explained, “The earlier you use it, the better it is, and that it avoids neurological and bone abnormalities and disease progression.” Despite this, lithium remains markedly underused, with far more patients receiving antidepressants despite bipolar diagnoses. Post attributed this pattern to overemphasis on lithium’s adverse effects and underrecognition of its broader benefits, including antisuicidal effects, neurogenesis, preservation of hippocampal volume, reduced all-cause mortality, and possible protection against bone fractures. Both Goldberg and Post suggested that delayed lithium initiation may create a self-fulfilling prophecy in which diminished responsiveness reinforces hesitancy to prescribe it. The discussion called for earlier, evidence-based intervention to improve long-term outcomes in bipolar disorder.

7: The Role of Psychopharmacology in Pediatric Care: Discussing Strategies With Melissa DelBello, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with child and adolescent psychiatrist Melissa DelBello, MD, to discuss the role of psychopharmacology in pediatric mental health treatment. Their conversation emphasized early identification and intervention for mood and related disorders in young patients. DelBello addressed common concerns regarding medication safety in children, noting that when prescribed by clinicians with appropriate expertise, psychotropic medications “can be life-saving” and used in ways that minimized adverse effects while maximizing efficacy. She cautioned against excessive polypharmacy and inadequate duration of therapeutic trials, which could undermine optimal outcomes. DelBello also underscored the developmental consequences of untreated psychiatric illness. She explained that childhood and adolescence represent critical periods for achieving social, academic, and interpersonal milestones. The onset of major depression, bipolar disorder, psychosis, anxiety, or attention disorders during these years could disrupt developmental trajectories, with enduring functional sequelae. She drew parallels to untreated medical conditions affecting growth, arguing that failure to address early psychiatric symptoms could similarly alter long-term outcomes. Goldberg raised the question of whether earlier intervention might mitigate chronicity and comorbidity, echoing the sentiment of many practitioners wishing they could have seen a patient just in time to prevent a disorder worsening. DelBello supported a positive view on early intervention, suggesting that timely treatment could prevent abnormal neurodevelopment and reduce downstream complications. She emphasized that early-phase intervention was often more effective than treatment initiated after recurrent episodes and accumulated morbidity. The discussion also highlighted substance use risk in youth with bipolar disorder, particularly in the context of family history. DelBello described proactive psychoeducation targeting adolescents before college transition. She advised candid discussions about biological vulnerability, for example, letting particular patients know that vulnerability is part of their “genetics and neurochemistry, and if you start using substances, you’re more likely to get addicted faster.” Framing risk in neurobiological terms appeared to enhance insight and facilitate harm-reduction strategies. Goldberg and DelBello advocated for developmentally informed, longitudinal care models that prioritized early recognition, individualized risk assessment, and judicious pharmacotherapy to improve long-term psychiatric and functional outcomes.