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).
The distribution of medications, including benzodiazepines, is altered in patients who are obese because of increased adipose tissue.53,54 This increase in the volume of distribution can attenuate the onset of action, increase medication accumulation in fat, and potentiate the duration of action.55,56
Obesity may also affect hepatic metabolism by induction of CYP1A2, CYP2C9, and CYP2C19, and inhibition of CYP3A4.57 Triazolam, which is metabolized by CYP3A4, is associated with a greater exposure (ie, plasma concentrations) in individuals who are obese.58 However, when considering differences in benzodiazepine pharmacokinetics in patients who are obese, clinicians must remember that elimination half-life depends on both volume of distribution and clearance. In patients who are obese (compared to patients who are not obese), the half-lives are increased for alprazolam (22 hours vs 11 hours, P < .001)59 and diazepam (82 hours vs 32 hours, P < .005).60 In a pharmacokinetic study of diazepam in individuals who were obese and individuals who were not obese, total metabolic clearance did not differ. Rather, the increased half-life was related to a tripling of thevolume of distribution in obese patients (228 liters vs 70 liters, P < .01). This indicates that patients who are obese may experience a much slower onset of maximal effect compared to patients who are not obese because the accumulation of the medication is delayed. Additionally, for benzodiazepines that are conjugated (lorazepam and oxazepam), clearance is significantly enhanced in patients who are obese. For example, lorazepam clearance is 102 mL/min in individuals who are obese compared to 63 mL/min in individuals who are not obese; for oxazepam, clearance is 181 mL/min in patients who are obese compared to 98 mL/min in individuals who are not obese.61 These differences are attributed to increased uridine diphosphate glucuronyl transferase in obesity and to increases in liver size in obesity.53
How quickly do benzodiazepines work?
Benzodiazepines act quickly. Meta-analyses36 suggest that improvement in anxiety symptoms compared to placebo is greatest initially and then the rate of improvement slows over successive weeks. Research on benzodiazepines reveals statistically significant differences between benzodiazepines and placebo within the first week of treatment, with >80% of the expected improvement by Week 8 of treatment emerging by Week 4 (Figure 336). The rapid reduction in anxiety symptoms seen with benzodiazepines has important treatment implications, given that traditional psychotherapeutic and antidepressant treatments are slow to produce improvements. Consistent data suggesting that benzodiazepines work faster than other treatments support that they may have a role during the initiation of other treatments.
What is the ‘best’ dose?
As seen with other classes of psychotropic medications,4 the relationship between benzodiazepine dose and response is complex. In a recent meta-analysis of 65 placebo-controlled trials of benzodiazepines in adults with anxiety disorders, there was a superior response over time for low-dose benzodiazepines (<3 mg/d in lorazepam equivalents) compared to a medium dose (3 to 6 mg/d; P = .042); high-dose benzodiazepines (>6 mg/d) yielded less improvement compared to medium doses (P = .001).36 A study of adults with panic disorder similarly found the greatest responses with alprazolam plasma concentrations of 20 to 40 ng/mL, with no additional benefit at <20 ng/mL or >40 ng/mL.49 As plasma concentrations increase, adverse effects such as sedation also increase, which may confound the observed loss of a dose-response relationship at higher doses and plasma concentrations.62 This may, in part, account for the observation that higher doses of benzodiazepines are associated with greater depressive symptoms and disrupted sleep.63 As such, low doses may represent a delicate equipoise between efficacy and tolerability, yielding the most optimal clinical response.
Which benzodiazepine should I prescribe?
Comparing benzodiazepines is difficult, given the differences in dosing and disorders studied and differences in how each individual clinical trial was conducted. A meta-analysis by Stimpfl et al36 that used Bayesian hierarchical modeling, which allowed some of this heterogeneity to be addressed, found that relative to the reference benzodiazepine (lorazepam), clonazepam had the greatest trajectory/magnitude of response (other specific benzodiazepines did not statistically differ from lorazepam) (Figure 436).
