Brain Trust: Therapeutic Drug Monitoring and Adherence in Schizophrenia, With Jonathan M. Meyer, 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 Jonathan Meyer, MD, to discuss therapeutic drug monitoring of antipsychotics in schizophrenia spectrum disorders.

Plasma levels can replace guesswork about nonresponse in a population where nonadherence is common and exposure varied widely, even with long-acting injectables, Meyer said. Levels may be drawn 12 hours after dosing, and population dose-level relationships allow prediction; for example, the total active moiety of risperidone approximated 7 times the oral dose, so 4 mg at bedtime predicted a level near 28 ng/mL. Meyer highlighted that a level more than 50% below expectation most likely reflected nonadherence, whereas a consistently low level on repeat testing suggested ultrarapid metabolism in the absence of inducers.

Response thresholds were probabilistic population estimates. For clozapine, 350 ng/mL marked the level below which response was less likely, but exceeding it did not establish that a level was therapeutic; some patients might require 550 or 800 ng/mL, and 1000 ng/mL was the evidence-based ceiling if tolerated. Meyer noted, "Now you're in the ball game, but if there's inadequate response and you've managed the tolerability issues, you just need to keep moving along." For haloperidol, response began at 2 to 5 ng/mL, and levels beyond 18 ng/mL represented the point of futility, with less than 5% likelihood of converting a nonresponder to a tolerated response.

Upper limits Meyer provided aligned with the laboratory alert levels in a 2020 joint consensus statement on antipsychotic blood levels.¹ Laboratory ranges often lacked a documented basis; fluphenazine upper limits ranged from 2 to 10 ng/mL across laboratories. Meyer said, "It's probably the one instance where I say what you get from the lab is often grossly in error."

For a given oral dose, most benefit for positive symptoms emerged within 2 weeks, with little added after 4 weeks.² Unexpectedly high levels required patient assessment before dose changes, repeat testing, and documented reasoning, given clozapine assay error and falsely elevated lithium levels from tubes containing lithium heparin. In schizophrenia, levels every 6 months on oral antipsychotics established a baseline for interpreting later clinical change, Meyer concluded.

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 Meyer is a voluntary clinical professor of psychiatry at the University of California, San Diego.

References

1. Schoretsanitis G, Kane JM, Correll CU, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry. 2020;81(3):19cs13169.

2. Agid O, Kapur S, Arenovich T, et al. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60(12):1228-1235.