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

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.

6: The Complex Psychopharmacology of Personality Disorders: Prioritizing Symptom Management With Michael Gitlin, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Michael Gitlin, MD, to discuss psychopharmacologic options for personality disorders. They highlighted the dimensional nature of personality disorders, contrasting them with the categorical DSM model. “The relationship between treating personality disorders and the use of medicines is not as natural as it would be for classic symptom-based disorders, such as mood disorders, anxiety disorder, and psychotic disorders. Because, when we describe symptom-based disorders, we have symptoms, we have time frames, and it fits the medical model. The DSM is categorical, meaning there are allegedly boundaries around all of the disorders. The problem is all of psychopathology, but most of all personality pathology, is dimensional, not categorical,” said Gitlin. Gitlin emphasized the importance of treating specific symptom complexes like impulsive aggression and affective liability rather than the entire disorder. He suggested using anticonvulsants, low-dose antipsychotics, and serotonergic drugs for different symptom profiles. “Instead of saying, do I know how to treat borderline personality disorder with medicine, what we should do is take a step back say, what are the symptom complexes that dominate the features of that personality disorder? And then say, do I know how to treat that?” said Gitlin. They also discussed the role of therapeutic alliance and placebo effects in enhancing treatment outcomes. A collaborative approach, where the patient is an active participant in the treatment plan, can enhance adherence and treatment outcomes. Overall, the conversation underscores the need for personalized, goal-oriented approaches in managing personality disorders.

5: Pharmacogenetic Testing in Psychiatry: Exploring Personalized Medicine With John J. Miller, MD

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Psychiatric Times' very own editor in chief, John J. Miller, MD, to discuss the current state and future directions of pharmacogenetic testing. According to Goldberg, pharmacogenetics is almost like a Rorschach test in the eyes of many practitioners and patients: “It is thought to be a projective that you sort of identify in various ways. It is going to tell me things about myself. It is going to make predictions. It is going to help me guide treatment. It is going to override clinical factors, patient specific features that influence outcome, and really get to the heart of things.” Miller also shared his initial reactions to the introduction of this testing: "When pharmacogenetic testing first became available about 12 to 14 years ago, I was excited. And then, as I learned more about it, read the literature, and became aware of the institutions that exist to vet genes and whether or not they are clinically actionable, I became very frustrated by how overly adoptive pharmacogenomics has become when really the evidence base is not there. In fact, as we have learned more, it has become less evidence based in terms of clinical applications." Recently, the International Society of Psychiatric Genetics published a review article on genetics and psychiatry, and they concluded that there are 4 genes that are evidence based and actionable: CYP2D6, CYP2C19, HLA-B*1502, and HLA-A*3101. "I think there is a mythology that all you have to do is do the gene testing, and you can choose a drug based on the results," shared Miller. When it comes to testing, Miller believes we need to alter the thinking around testing in psychiatry: "We are very selective, and we do it for a reason, because we have a hypothesis. Maybe there is atrophy. Maybe we have some neurological sign. It really should spark the curiosity of the clinician to think, would a test—any test, for that matter—be informative to answer a question. That is how I always think about any test in medicine." Together, Goldberg and Miller stress the importance of therapeutic drug monitoring and personalized medicine, while acknowledging the limitations and ongoing evolution of pharmacogenetic testing. "We have a common goal. We want to do a test that is scientifically informative for you. If there is a test out there that I think will help us answer a question, I promise you, I will order it, but not everything comes down to a particular test, right? There are certain clinical impressions we have in medicine. How do you diagnose migraine headaches? There is no test for that. How do you diagnose your bowel syndrome or tinnitus? There is no test for that. So we look for tests to someday enhance or augment what we think is an observation that we would like some corroboration for," said Goldberg of speaking to patients about testing. Miller agreed, concluding that, "We do not want to put the car before the horse, and so let's stick to the what the experts who really know this stuff are guiding us, and then incrementally use what becomes clinically actionable or evidence based."