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

In a recent episode of “Brain Trust: Conversations in Psychopharmacology,” host Joseph F. Goldberg, MD, spoke with Jonathan M. Meyer, MD, voluntary clinical professor of psychiatry at the University of California, San Diego, about therapeutic drug monitoring of antipsychotics in schizophrenia spectrum disorders. Meyer recommended 12-hour trough levels, which track oral dose in predictable ratios. Aripiprazole levels run roughly 11 times the nightly dose, and the total risperidone active moiety roughly 7 times the dose. A level more than 50% below the expected value most often reflects nonadherence. A repeat level separates erratic adherence from ultrarapid metabolism. Before raising a dose, he suggested drawing a level on the current dose so that 2 data points are available. Thresholds vs Therapeutic Levels Meyer cautioned against calling a level therapeutic simply because it exceeds the response threshold, such as 350 ng/mL for clozapine. Patients with an inadequate response above the threshold may need higher levels, up to what he terms the point of futility, beyond which fewer than 5% of patients respond. He places that point at approximately 1000 ng/mL for clozapine and 18 ng/mL for haloperidol. Patients who respond below a threshold should be managed according to their clinical status rather than the number. Most positive-symptom benefit from a given oral dose appears within 2 weeks, with little added gain after 4 weeks. Practical Pearls Meyer said laboratory-reported antipsychotic ranges are often unreliable, noting upper limits for fluphenazine that vary 5-fold between laboratories. An unexpectedly high result should prompt a patient assessment and a repeat level, because laboratory error and doses taken just before the draw are common. A lithium sample drawn in a tube containing lithium heparin can also produce a falsely elevated level. He does not recommend levels for iloperidone, ziprasidone, or quetiapine. For patients with clozapine-induced tachycardia, he advised recalculating QTc with a linear formula such as Framingham rather than Bazett. Meyer described plasma levels as more useful than pharmacogenetic testing because they capture genetics, smoking, and drug interactions in a single measurement. He recommended checking levels every 6 months in stable outpatients taking oral antipsychotics. “Don’t guess, measure,” concluded Meyer.

In this “Brain Trust Conversations in Clinical Psychopharmacology” episode, host Joseph F. Goldberg, MD, spoke with Anita Clayton, MD, who is the Wolford Spratlin professor and past chair of psychiatry and neurobehavioral sciences at the University of Virginia and current president of the American Society of Clinical Psychopharmacology (ASCP), about sexual dysfunction as an underrecognized but critical dimension of psychiatric care. Clayton opened by noting that only about 1% of people identify as asexual, meaning sexual function matters to the vast majority of patients, yet stigma keeps roughly 75% of patients from raising the topic unprompted. She advised clinicians to normalize the conversation by folding sexual function into routine lifestyle questioning alongside diet and exercise, and to track changes over time, particularly in perimenopausal women, where genitourinary syndrome of menopause is driving a surge in interest in vaginal dryness, diminished desire, and orgasmic changes. The discussion connected sexual dysfunction to core diagnostic work: anhedonia and loss of libido are hallmark depressive symptoms captured on the Hamilton Depression Rating Scale, and roughly 70% of patients with major depressive disorder episodes have baseline sexual dysfunction, which SSRIs often worsen further. Clayton described sexual complaints as a useful diagnostic assay that should prompt screening for depression, substance use, thyroid dysfunction, diabetes, and, in men over 45, declining testosterone. Impairments limited to arousal or orgasm rather than desire, she noted, point toward biological or medication-related causes; chronic opioid and NSAID use, antihypertensives, and hormonal contraceptives were flagged as underrecognized contributors. She also described how algorithm-driven pornography use can escalate and desensitize patients, straining relationships. On hypoactive sexual desire disorder, Clayton traced its diagnostic history through DSM-5's merger with arousal disorder and the regulatory fight over flibanserin (Addyi), an FDA approval process she said reflected the agency's limited institutional understanding of sexual dysfunction. Flibanserin's approval was recently expanded to postmenopausal women, and Clayton also discussed bremelanotide (Vyleesi), an as-needed injectable alternative that acts on the melanocortin system. On mechanisms, Clayton explained that serotonergic activity is broadly inhibitory to sexual function, while norepinephrine and dopamine are excitatory, and that elevated prolactin worsens dysfunction across the board. She reviewed relatively sexually sparing options, including bupropion, which can actively improve rather than merely spare function, plus mirtazapine, vortioxetine, vilazodone, and prolactin-sparing antipsychotics such as aripiprazole, brexpiprazole, and lumateperone. She also discussed antidote strategies, including bupropion at 300 mg/day, buspirone, sildenafil, and gepirone, noting that gepirone's QT concerns stem from its older immediate-release formulation rather than the newer product. Clayton closed by urging clinicians to weigh 3 receptor-level factors—prolactin effects, 5-HT2A activity, and 5-HT1A activity—when selecting psychotropics. "Sex is important to almost everybody," she said, adding that clinicians should remember older adults remain sexually active and that both medications and illness can affect their function too.

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sits down with Carl Salzman, MD, to discuss the appropriate clinical use, misuse, and safety of benzodiazepines, including special considerations for older adults and their debated association with Alzheimer disease. Benzodiazepines have been used since the 1960s, Salzman reviewed, and largely replaced barbiturates and meprobamate-type drugs, which carried greater toxicity. Sixty years of research established that, when appropriately prescribed, benzodiazepines were safe and effective. Salzman highlighted survey data which indicated roughly 10% of people had taken a benzodiazepine at least once in the past 12 months, with about 5% to 6% using them regularly on prescription; unprescribed use—often for occasional sleep or travel anxiety—was common even among physicians, with no clear evidence it led to addiction. Regular use over a period of weeks produced physiologic dependence, but withdrawal symptoms at therapeutic doses were typically mild and resolved with a gradual taper over 1 to 2 weeks. Salzman emphasized that benzodiazepines, at anxiolytic doses, did not show dose escalation or tolerance over time. Comparing long-term options for chronic anxiety disorders, Salzman noted, "We know that both serotonin antidepressants, the SSRIs, can be very useful for treating long-term chronic anxiety disorders, and anxiety disorders tend to be long-term and chronic," though sexual side effects could limit acceptability. Short half-life agents such as lorazepam were preferred for acute use to avoid next-day sedation, while longer half-life agents suited chronic, once-daily dosing. On the Beers criteria's caution against benzodiazepine use after age 65, Salzman favored lower doses over discontinuation, noting, "Benzodiazepines, long half-life and short half-life, may increase the risk of falls. If you look at the risk of falls with antidepressants or antipsychotic drugs at therapeutic doses, the risk is greater than with benzodiazepines." He also addressed the misconception that benzodiazepines cause Alzheimer disease, attributing early associational data to protopathic bias (anxious, early-dementia patients being more likely to receive a prescription) rather than a causal effect. In a controlled nursing home study Salzman conducted, discontinuing benzodiazepines improved recent recall on formal testing, but most residents still preferred remaining on the medication for its anxiolytic effect.

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sat down with Walter Brown, MD, to discuss the placebo effect in clinical psychopharmacology, including its mechanisms, the nocebo effect, ethical considerations, and practical strategies for harnessing placebo responses in everyday psychiatric practice. Brown traced his interest in the placebo effect to his involvement in early SSRI clinical trials in the 1980s, in which approximately 58–60% of patients responded to active drug versus 40–45% to placebo—a gap he found surprisingly narrow. He spent the next 30 years reviewing the literature and studying placebo responders, synthesizing his findings in a 2013 book, The Placebo Effect in Clinical Practice.

Joseph F. Goldberg, MD, in this installment of "Brain Trust: Conversations in Psychopharmacology," sat down with Michael Ostacher, MD, MPH, to discuss managing co-occurring mood and substance use disorders (SUDs), including patient engagement, the "self-medication" narrative, and underuse of evidence-based addiction pharmacotherapy. Ostacher traced his approach to mentor Ken Minkoff, who argued against a separate addiction specialty because all clinicians treat patients with addictions. Ostacher said a directive stance with patients who use substances rarely helped, since most already recognized the problem, as opposed to something like sleep hygiene counseling, where direct instruction worked well. On whether mood symptoms or substance use came first, Ostacher said the distinction mattered less than commonly assumed, since most patients presented with continuing symptoms of both. Patients who invoked self-medication were often "precontemplative" about change, he said. Counterintuitively, in studies including STEP-BD, "the people who have substance use disorders are much more likely to get better and to get better more quickly than the people who don't have a substance use disorder and bipolar disorder," likely because motivated patients reduced use upon seeking treatment. Ostacher did not recommend avoiding addiction pharmacotherapy for bipolar patients pending disorder-specific trials. He supported varenicline and nicotine replacement for smoking cessation, methadone or buprenorphine (including long-acting injectables) for opioid use disorder, and naltrexone or acamprosate for alcohol use disorder, noting these worked regardless of psychiatric comorbidity. He cited a Stanford study in which only about 2% of patients with alcohol use disorder were discharged on an indicated medication, and a STEP-BD finding that only 4.4% of eligible bipolar patients received SUD pharmacotherapy. Ostacher said, "if you have a patient who has an alcohol use disorder diagnosis, you should offer them medications for treatment. They're welcome to not take them, but you should offer them for treatment." He added that GLP-1 agonists are being studied for alcohol use disorder. Goldberg closed by underscoring that, rather than waiting to start treatment for one condition pending resolution of the other, clinicians must address both simultaneously.