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#137 Benzodiazepines in Generalized Anxiety Disorder: Calm Your Nerves?

Are benzodiazepines effective in generalized anxiety disorder (GAD)?

In GAD, benzodiazepines are more effective than placebo and similar to antidepressants. They cause more withdrawals for adverse effects than placebo but less than antidepressants. They are recommended second-line generally due to concerns of dependence. The evidence quality is generally poor, trials are short-term, and none used benzodiazepines as adjunctive therapy. 

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Compared to placebo: 
  • Systematic review (23 Randomized Controlled Trials (RCTs), 2,326 patients) of diazepam, lorazepam, and alprazolam:1 
    • Fewer withdrawals for no efficacy with benzodiazepines: RR 0.29 (0.18-0.45). 
      • Number Needed to Treat=7 over 4-6 weeks.2,3 
    • More withdrawals for adverse effects: RR 1.54 (1.17-2.03). 
  • Other systematic reviews found benzodiazepines more effective than placebo.4,5 
Compared to tricyclic antidepressants: 
  • One systematic review (three RCTs, 617 participants):6 
    • Two RCTs found tricyclics better for psychiatric symptoms, while one found benzodiazepines better for somatic symptoms (another found no difference in somatic symptoms).   
      • Another RCT found no difference in efficacy.  
    • Two RCTs found benzodiazepines had fewer adverse effects (one no difference).  
Compared to paroxetine or venlafaxine:   
  • One systematic review (two RCTs, 709 participants):6 No difference in efficacy. 
    • Adverse Effects: Venlafaxine had more drop-outs for adverse effects than diazepam (9-13% versus 2%, Number Needed to Harm=9-14 over eight weeks).7 Adverse effects not reported in paroxetine study.8  
As adjunct to antidepressants: NRCTs found. 
  • Many studies conducted by manufacturers; small sample sizes, short-term (often ≤8weeks); data on randomization, blinding procedures and randomization concealment often not described; most studies involved middle-aged adults, limiting application to others.  
  • Rather than titrating to effect or as needed use, many studies used fixed doses of benzodiazepines with wide dosing ranges (example: alprazolam 2-6 mg/day in divided doses).1-3,6 
  • Benzodiazepines may have effects on cognition, performance and dependence,4 although the magnitude of these effects are not well understood. 
  • Adjunctive benzodiazepines use is supported by evidence in early panic disorders.9,10 
  • Onset of effect is more rapid with benzodiazepines than antidepressants.8 
  • Guidelines suggest benzodiazepines are second-line in GAD.11 

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  • Adrienne J Lindblad BSP ACPR PharmD
  • Jennifer P Young BScHon MD CCFP-EM

1. Martin JLR, Sainz-Pardo M, Furukawa TA, et al. J Psychopharmacol. 2007; 21(7):774-82.

2. Ansseau M, Olié JP, von Frenckell R, et al. Psychopharmacol. 1991; 104:439-43.

3. Enkelmann R. Psychopharmacol. 1991; 105:428-32.

4. Gale CK, Millichamp J. BMJ Clin Evid. 2011 Oct 27; 2011.pii:1002.

5. Mitte K, Noack P, Steil P, et al. J Clin Psychopharmacol. 2005; 25:141-50.

6. Offidani E, Guidi J, Tomba E, et al. Psychother Psychosom. 2013; 82(6):355-62.

7. Hackett D, Haudiquet V, Salinas E. Eur Psychiatry. 2003; 18:182-7.

8. Feltner DE, Harness J, Brock J, et al. CNS Neurosci Ther. 2009 Winter; 15(1):12-8.

9. Pollack MH, Simon NM, Worthington JJ, et al. J Psychopharmacol. 2003; 17(3):276-82.

10. Katzelnick DJ, Saidi J, Vanelli MR, et al. Psychiatry (Edgmont). 2006; 3:39-49.

11. Katzman MA, Bleau P, Blier P, et al. BMC Psychiatry. 2014; 14(Suppl 1):S1-83.

Authors do not have any conflicts to disclose.