Evidence-Based Reviews

Optimizing benzodiazepine treatment of anxiety disorders

Current Psychiatry. 2023 June;22(6):22-33,39 | doi: 10.12788/cp.0365

References

1. Rickels K, Moeller HJ. Benzodiazepines in anxiety disorders: reassessment of usefulness and safety. World J Biol Psychiatry. 2019;20(7):514-518. doi:10.1080/15622975.2018.1500031

2. Stevens JC, Pollack MH. Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents. J Clin Psychiatry. 2005;66(Suppl 2):21-27.

3. Pollack MH, van Ameringen M, Simon NM, et al. A double-blind randomized controlled trial of augmentation and switch strategies for refractory social anxiety disorder. Am J Psychiatry. 2014;171(1):44-53. doi:10.1176/appi.ajp.2013.12101353

4. Strawn JR, Geracioti L, Rajdev N, et al. Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review. Expert Opin Pharmacother. 2018;19(10):1057-1070. doi:10.1080/14656566.2018.1491966

5. Karaca-Mandic P, Meara E, Morden NE. The growing problem of co-treatment with opioids and benzodiazepines. BMJ. 2017;356:j1224. doi:10.1136/bmj.j1224

6. Bachhuber MA, Hennessy S, Cunningham CO, et al. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996-2013. Am J Public Health. 2016;106(4):686-688. doi:10.2105/AJPH.2016.303061

7. Bentué-Ferrer D, Akwa Y. Benzodiazepines: Effects on memory functioning. In: Pandi-Perumal SR, Verster J, Monti J, et al, eds. Sleep Disorders: Diagnosis and Therapeutics. CRC Press; 2008:104-114. doi:10.3109/9780203091715-15

8. Pomara N, Facelle TM, Roth AE, et al. Dose-dependent retrograde facilitation of verbal memory in healthy elderly after acute oral lorazepam administration.Psychopharmacology (Berl). 2006;185(4):487-494. doi:10.1007/s00213-006-0336-0

9. Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016;352:i90. doi:10.1136/bmj.i90

10. Biétry FA, Pfeil AM, Reich O, et al. Benzodiazepine use and risk of developing Alzheimer’s disease: a case-control study based on Swiss claims data. CNS Drugs. 2017;31(3):245-251. doi:10.1007/s40263-016-0404-x

11. de Gage SB, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease: case-control study. BMJ. 2014;349g5205. doi:10.1136/bmj.g5205

12. Shah R, Raji MA, Westra J, et al. Association of co-prescribing of opioid and benzodiazepine substitutes with incident falls and fractures among older adults: a cohort study. BMJ Open. 2021;11(12):e052057. doi:10.1136/bmjopen-2021-052057

13. Guina J, Rossetter SR, DeRhodes BJ, et al. Benzodiazepines for PTSD: a systematic review and meta-analysis. J Psychiatr Pract. 2015;21(4):281-303.

14. Ekström MP, Bornefalk-Hermansson A, Abernethy AP, et al. Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. BMJ. 2014;348:g445. doi:10.1136/bmj.g445

15. Donovan LM, Malte CA, Spece LJ, et al. Center predictors of long-term benzodiazepine use in chronic obstructive pulmonary disease and post-traumatic stress disorder. Ann Am Thorac Soc. 2019;16(9):1151-1157. doi:10.1513/AnnalsATS.201901-048OC

16. Sheehy O, Zhao JP, Bérard A. Association between incident exposure to benzodiazepines in early pregnancy and risk of spontaneous abortion. JAMA Psychiatry. 2019;76(9):948-957. doi:10.1001/jamapsychiatry.2019.0963

17. Kelly LE, Poon S, Madadi P, et al. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr. 2012;161(3):448-451. doi:10.1016/j.jpeds.2012.03.003

18. Agarwal SD, Landon BE. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw Open. 2019;2(1):e187399. doi:10.1001/jamanetworkopen.2018.7399

19. Hirschtritt ME, Olfson M, Kroenke K. Balancing the risks and benefits of benzodiazepines. JAMA. 2021;325(4):347-348. doi:10.1001/jama.2020.22106

20. Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. McGraw-Hill Education; 2018.

21. Nutt DJ, Malizia AL. New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder. British J Psychiatry. 2001;179:390-396. doi:10.1192/bjp.179.5.390

22. Sigel E. Mapping of the benzodiazepine recognition site on GABA(A) receptors. Curr Top Med Chem. 2002;2(8):833-839. doi:10.2174/1568026023393444

23. Savic´ MM, Huang S, Furtmüller R, et al. Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists? Neuropsychopharmacology. 2008;33(2):332-339. doi:10.1038/sj.npp.1301403

24. Smith TA. Type A gamma-aminobutyric acid (GABAA) receptor subunits and benzodiazepine binding: significance to clinical syndromes and their treatment. Br J Biomed Sci. 2001;58(2):111-121.

25. Althaus AL, Ackley MA, Belfort GM, et al. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology. 2020;181:108333. doi:10.1016/j.neuropharm.2020.108333

26. Jacob TC, Michels G, Silayeva L, et al. Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition. Proc Natl Acad Sci U S A. 2012;109(45):18595-18600. doi:10.1073/pnas.1204994109

27. Nicholson MW, Sweeney A, Pekle E, et al. Diazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca2+/calcineurin signalling downstream of GABAA receptors. Mol Psychiatry. 2018;23(9):1851-1867. doi:10.1038/s41380-018-0100-y

28. Dobson ET, Bloch MH, Strawn JR. Efficacy and tolerability of pharmacotherapy for pediatric anxiety disorders: a network meta-analysis. J Clin Psychiatry. 2019;80(1):17r12064. doi:10.4088/JCP.17r12064

29. Kuang H, Johnson JA, Mulqueen JM, et al. The efficacy of benzodiazepines as acute anxiolytics in children: a meta-analysis. Depress Anxiety. 2017;34(10):888-896. doi:10.1002/da.22643

30. Chugani DC, Muzik O, Juhász C, et al. Postnatal maturation of human GABAA receptors measured with positron emission tomography. Ann Neurol. 2001;49(5):618-626. doi:10.1002/ana.1003

31. Jochemsen R, Breimer DD. Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles. Curr Med Res Opin. 1984;8(Suppl 4):60-79. doi:10.1185/03007998409109545

32. Greenblatt DJ, Harmatz JS, Dorsey C, et al. Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo. Clin Pharmacol Ther. 1988;44(3)326-334. doi:10.1038/clpt.1988.158

33. Shader RI, Georgotas A, Greenblatt DJ, et al. Impaired absorption of desmethydiazepam from clorazepate by magnesium aluminum hydroxide. Clin Pharmacol Ther. 1978;24(3):308-315. doi:10.1002/cpt1978243308

34. Greenblatt DJ, Allen MD, MacLaughlin DS, et al. Diazepam absorption: effect of antacids and food. Clin Pharmacol Ther. 1978;24(5):600-609. doi:10.1002/cpt1978245600

35. Yamazaki A, Kumagai Y, Fujita T, et al. Different effects of light food on pharmacokinetics and pharmacodynamics of three benzodiazepines, quazepam, nitrazepam and diazepam. J Clin Pharm Ther. 2007;32(1):31-39. doi:10.1111/j.1365-2710.2007.00795.x

36. Stimpfl J, Mills JA, Strawn JR. Pharmacologic predictors of benzodiazepine response trajectory in anxiety disorders: a Bayesian hierarchical modeling meta-analysis. CNS Spectr. 2023;28(1):53-60. doi:10.1017/S1092852921000870

37. Griffin CE 3rd, Kaye AM, Bueno FR, et al. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214-223.

38. Buffett-Jerrott SE, Stewart SH. Cognitive and sedative effects of benzodiazepine use. Curr Pharm Des. 2005;8(1):45-58. doi:10.2174/1381612023396654

39. Fukasawa T, Suzuki A, Otani K. Effects of genetic polymorphism of cytochrome P450 enzymes on the pharmacokinetics of benzodiazepines. J Clin Pharm Ther. 2007;32(4):333-341. doi:10.1111/j.1365-2710.2007.00829.x

40. Kraus JW, Desmond PV, Marshall JP, et al. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther. 1978;24(4):411-419. doi:10.1002/cpt1978244411

41. Greenblatt DJ. Clinical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet. 1981;6(2):89-105. doi:10.2165/00003088-198106020-00001

42. Walkenstein SS, Wiser R, Gudmundsen CH, et al. Absorption, metabolism, and excretion of oxazepam and its succinate half‐ester. J Pharm Sci. 1964;53(10):1181-1186. doi:10.1002/jps.2600531010

43. Shull HJ, Wilkinson GR, Johnson R, et al. Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med. 1976;84(4):420-425. doi:10.7326/0003-4819-84-4-420

44. Abernethy DR, Greenblatt DJ, Ochs HR, et al. Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther. 1983;33(5):628-632. doi:10.1038/clpt.1983.85

45. Greenblatt DJ, Allen MD, Harmatz JS, et al. Diazepam disposition determinants. Clin Pharmacol Ther. 1980;27(3):301-312. doi:10.1038/clpt.1980.40

46. Ochs HR, Greenblatt DJ, Knüchel M. Kinetics of diazepam, midazolam, and lorazepam, in cigarette smokers. Chest. 1985;87(2):223-226. doi:10.1378/chest.87.2.223

47. Smith RB, Gwilt PR, Wright CE 3rd. Single- and multiple-dose pharmacokinetics of oral alprazolam in healthy smoking and nonsmoking men. Clin Pharm. 1983;2(2):139-143.

48. Figgitt DP, McClellan KJ. Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders. Drugs. 2000;60(4):925-954. doi:10.2165/00003495-200060040-00006

49. Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993;24(6):453-471. doi:10.2165/00003088-199324060-00003

50. Yasui N, Kondo T, Furukori H, et al. Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology (Berl). 2000;150(2):185-190. doi:10.1007/s002130000438

51. Özdemir M, Aktan Y, Boydagˇ BS, et al. Interaction between grapefruit juice and diazepam in humans. Eur J Drug Metab Pharmacokinet. 1998;23(1):55-59. doi:10.1007/BF03189827

52. Greenblatt DJ, Harmatz JS, Zhang Q, et al. Slow accumulation and elimination of diazepam and its active metabolite with extended treatment in the elderly. J Clin Pharmacol. 2021;61(2):193-203. doi:10.1002/jcph.1726

53. Abernethy DR, Greenblatt DJ. Drug disposition in obese humans: an update. Clin Pharmacokinet. 1986;11(3):199-213. doi:10.2165/00003088-198611030-00002

54. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71-87. doi:10.2165/11318100-000000000-00000

55. Bauer LA. Drug Dosing in special populations: renal and hepatic disease, dialysis, heart failure, obesity, and drug interactions. In: Weitz M, Thomas, CM, eds. Applied Clinical Pharmacokinetics. 3rd ed. McGraw-Hill Education; 2014. https://accesspharmacy.mhmedical.com/book.aspx?bookid=1374

56. Kendrick JG, Carr RR, Ensom MHH. Pharmacokinetics and drug dosing in obese children. J Pediatr Pharmacol Ther. 2010;15(2):94-109. doi:10.5863/1551-6776-15.2.94

57. Brill MJE, Diepstraten J, van Rongen A, et al. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51(5):277-304. doi:10.2165/11599410-000000000-00000

58. Derry CL, Kroboth PD, Pittenger AL, et al. Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men. J Clin Psychopharmacol. 1995;15(3):197-205. doi:10.1097/00004714-199506000-00008

59. Abernethy DR, Greenblatt DJ, Divoll M, et al. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet. 1984;9(2):177-183. doi:10.2165/00003088-198409020-00005

60. Abernethy DR, Greenblatt DJ, Divoll M, et al. Prolonged accumulation of diazepam in obesity. J Clin Pharmacol. 1983;23(8-9):369-376. doi:10.1002/j.1552-4604.1983.tb02750.x

61. Abernethy DR, Greenblatt DJ, Divoll M, et al. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med. 1983;101(6):873-880.

62. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry. 1993;54 Suppl:4-11.

63. Chen YT, Liu CY, Chang CM, et al. Perceptions, clinical characteristics, and other factors associated with prolonged and high daily dose of benzodiazepine use among patients with anxiety or depressive disorders. J Affect Disord. 2020;271:215-223. doi:10.1016/j.jad.2020.03.077

64. Herman JB, Brotman AW, Rosenbaum JF. Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry. 1987;48(Suppl):22-28.

65. Herman JB, Rosenbaum JF, Brotman AW. The alprazolam to clonazepam switch for the treatment of panic disorder. J Clin Psychopharmacol. 1987;7(3):175-178.

The properties of individual benzodiazepines should also be considered when selecting a benzodiazepine treatment. If circumstances necessitate rapid symptom relief, a lipophilic benzodiazepine, such as diazepam, may be preferred for quick onset and offset of action. Onset of action may also be hastened by taking the benzodiazepine without food; conversely, if peak adverse effects are problematic, concurrent consumption of a high-fat meal may help decrease peak concentration and prolonging absorption. In other circumstances, such as if sustained anxiolysis is desired, a clinician may opt for a less lipophilic benzodiazepine, such as clonazepam. Finally, in terms of general treatment response, benzodiazepines separate from placebo in the first week of treatment, which supports the idea they may be useful during the introduction of other medications (eg, SSRIs) that take a longer time to achieve clinical effect.

Bottom Line

The pharmacokinetics of benzodiazepines are intimately linked with the onset of action and duration of clinical effect and vary based on individual absorption and distribution/redistribution. Benzodiazepines’ clinical profile derives from their pharmacokinetic differences and is influenced by many factors, including age, body weight, concomitant medication use, smoking status, and hepatic or renal disease. Consider these factors to individualize the approach to using benzodiazepines and optimize tolerability and efficacy.

Related Resources

Weber SR, Duchemin AM. Benzodiazepines: sensible prescribing in light of the risks. Current Psychiatry. 2018;17(2):22-27.
Balon R. Benzodiazepines for anxious depression. Current Psychiatry. 2018;17(8):9-12.

Drug Brand Names

Alprazolam • Xanax
Chlordiazepoxide • Librium
Clobazam • Onfi
Clonazepam • Klonopin
Clorazepate • Gen-Xene
Diazepam • Valium
Diltiazem • Cardizem
Fluvoxamine • Luvox
Ganaxolone • Ztalmy
Ketoconazole • Nizoral
Lorazepam • Ativan
Midazolam • Versed
Temazepam • Restoril
Triazolam • Halcion
Verapamil • Calan