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Clinically Significant Drug Interactions with Atypical Antipsychotics

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Abstract

Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications—most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug–drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events.

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Acknowledgments

Dr Kennedy has received grant funding for research from Johnson and Johnson and payment for lectures from Merck. Professor Jann has received research funding from Pfizer and Janssen, and is on the speaker’s bureau for Janssen. Dr Kutscher has no conflicts of interest that are directly relevant to the content of this review. No funds were received for the preparation of this article.

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Authors and Affiliations

  1. Department of Pharmacy Practice, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA, 76107, USA

    William Klugh Kennedy

  2. Department of Pharmacotherapy, University of North Texas System College of Pharmacy, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA

    Michael W. Jann

  3. Department of Psychiatry, School of Medicine, Mercer University, Savannah, GA, USA

    William Klugh Kennedy

  4. Department of Pharmacy Practice, College of Pharmacy Sioux Falls, South Dakota State University, Sioux Falls, SD, USA

    Eric C. Kutscher

  5. Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA

    Eric C. Kutscher

  6. Department of Behavioral Medicine, Memorial University Medical Center and Mercer University, 5002 Waters Avenue, Savannah, GA, 31404, USA

    William Klugh Kennedy

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  1. William Klugh Kennedy
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Correspondence to Michael W. Jann.

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Kennedy, W.K., Jann, M.W. & Kutscher, E.C. Clinically Significant Drug Interactions with Atypical Antipsychotics. CNS Drugs 27, 1021–1048 (2013). https://doi.org/10.1007/s40263-013-0114-6

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