Jeffrey R. Strawn, MD Professor of Psychiatry, Pediatrics, and Clinical Pharmacology Director, Anxiety Disorders Research Program
Julia Stimpfl, MD PGY-2 General Psychiatry Resident
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Department of Psychiatry and Behavioral Neuroscience University of Cincinnati College of Medicine Cincinnati, Ohio
Disclosures Dr. Strawn has received research support from Abbvie, the National Center for Advancing Translational Sciences, the National Institutes of Health (NIH), and the Patient-Centered Outcomes Research Institute. He has served as a consultant for Cerevel, the FDA, IntraCellular Therapies, Lundbeck, and Otsuka. He receives royalties from Springer Publishing and UpToDate and received material support from Myriad. He also received honoraria from the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, Medscape Live, and Neuroscience Education Institute. Dr. Strawn is Current Psychiatry’s Section Editor, Child and Adolescent Psychiatry. Dr. Stimpfl reports no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products. Views expressed within this article represent those of the authors and are not intended to represent the position of the NIH, the National Institute of Mental Health, or the Department of Health and Human Services.
Acknowledgments This work was supported by the Yung Family Foundation (Dr. Strawn).
Another aspect of the superiority of clonazepam in some research relates to its pharmacokinetic properties, particularly when compared with benzodiazepines that have very short half-lives. Short half-life benzodiazepines have been associated with rebound anxiety, which is defined as “the relative worsening of symptoms on discontinuation of treatment as compared to baseline symptoms” and is distinct from withdrawal.64 While it is difficult to assess this in clinical trials, Herman et al65 provided insight into the contribution of rebound anxiety in a study of patients with panic disorder treated with alprazolam who experienced “interdose anxiety symptoms.” Of the 48 patients in this study, 41 switched to clonazepam, and most who switched (82%) experienced improvement. The improvement was attributed to the decreased frequency of clonazepam (vs alprazolam) administration and lack of interdose anxiety. When selecting an oral benzodiazepine, consider the duration, onset of action, and differences in metabolism that produce varying levels of effectiveness for individual patients. In situations where rapid onset is desired, a short-acting benzodiazepine may be preferable, while a longer-acting benzodiazepine would be preferable in situations where the patient needs sustained effects.
Regarding lipophilicity, differences among benzodiazepines could contribute to differences in psychological dependence and differential utility in some situations. For example, alprazolam rapidly enters the CNS, producing an immediate anxiolytic effect. However, its egress from the CNS is equally rapid, and its anxiolytic effects disappear quickly. This may be desirable for addressing acute, predictable anxiety, but could have unintended consequences in treating chronic anxiety, where it could facilitate psychological dependence.
Practical considerations
When prescribing benzodiazepines, consider a myriad of patient- and medication-specific factors, as these have clinically relevant implications on treatment response. This information, taken together, supports the importance of an individualized approach to benzodiazepine use. Before selecting a benzodiazepine and during treatment, important elements of the patient’s history must be considered, including age, body weight, concomitant medication use (eg, antacids, CYP3A4 inhibitors, OCPs), smoking status, and history of hepatic or renal disease.
Patients age <18 are unlikely to have full expression of GABA receptors in the brain30 and therefore benzodiazepines may not be as efficacious for anxiolysis in this population. Moreover, compared to younger patients, older patients may experience higher steady-state concentrations of benzodiazepines, especially lipophilic agents, due to an increased volume of distribution and decreased clearance. In patients treated with OCPs, oxidatively metabolized benzodiazepines (lorazepam, oxazepam, and temazepam) may take longer to reach steady-state, and dose adjustments may need to be considered. In patients who smoke, clearance of oral benzodiazepines is also accelerated, potentially decreasing half-life by up to 50%.
When dosing and titrating benzodiazepines, consider the patient’s body weight, particularly if they are obese. The effects of obesity on benzodiazepine pharmacokinetics are complex. For glucuronidated benzodiazepines, clearance is increased in patients who are obese; however, the volume of distribution is also increased in such patients, meaning it will take longer for benzodiazepines to achieve steady-state in these individuals compared to patients who are not obese. These effects suggest it may take longer to achieve a response at a given dose in patients who are obese compared to individuals who are not obese.
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