Commentary CONTROVERSIES IN PSYCHIATRY

Benzodiazepines for anxious depression

These agents should be more frequently considered as monotherapy for this indication

enzodiazepines’ potential antidepressant properties and their role in the treatment of depression were fairly Bextensively examined during the 1980s and early 1990s. There were various reasons for this investigation—from the adverse effects of available antidepressants (tricyclic antide- pressants [TCAs] and monoamine oxidase inhibitors) to the delay of action of the existing antidepressants and treatment resistance of a significant portion of depressed patients. Benzodiazepines had already been used in the treatment of depressive disorders for decades, but not as monotherapy or main treatment agents, but rather in combination with exist- ing antidepressants to alleviate initial or persistent anxiety, and to help with insomnia. Some authors1 felt that specific AYELET-KESHET/SHUTTERSTOCK benzodiazepines, such as alprazolam, were effective in mild and moderate depression, although not as effective as TCAs Richard Balon, MD for patients with endogenous or melancholic depression. Professor of Psychiatry and Anesthesiology Others2 proposed that benzodiazepines, particularly alpra- Departments of Psychiatry and Behavioral Neurosciences and Anesthesiology zolam, may be a useful treatment option for patients for Wayne State University School of Medicine whom antidepressants are contraindicated, poorly tolerated, Detroit, Michigan or ineffective. Petty et al2 suggested that the antidepressant efficacy of benzodiazepines was consistent with the then- entertained γ-aminobutyric acid theory of depression.

A shift from benzodiazepines to antidepressants The evidence for using benzodiazepines in anxious depres- sion was based on results of several studies, but it has not

Disclosure The author reports no financial relationships with any company whose products are mentioned in Current Psychiatry this article, or with manufacturers of competing products. Vol. 17, No. 8 9 been adequately analyzed, summarized, not in extremely high doses, and under and promoted. Then, after the arrival of medical supervision. the selective serotonin reuptake inhibi- Nevertheless, the judgment, right or tors (SSRIs) (fluoxetine arrived in the wrong, was out—benzodiazepines were United States in 1987, and paroxetine and deemed problematic and to be avoided. sertraline arrived in 1992), interest in ben- This has become, unfortunately, a pattern zodiazepines gradually waned. Within a of many prescribing psychiatrists’ practice. Benzodiazepines few years, the SSRIs were also approved for depression for various anxiety disorders. The SSRIs were heavily promoted not only for the What about benzodiazepines for treatment of depressive disorders, but anxious depression? also anxiety disorders, and were touted as Recently Benasi et al6 filled the void by well-tolerated medications without abuse investigating data from studies using ben- potential. Benzodiazepines, on the other zodiazepines as monotherapy in depressive hand, were frequently described as less disorders (I was one of the co-authors of this effective and having a substantial abuse study). They conducted a systematic review Clinical Point potential. of 38 published randomized controlled trials When abuse of Looking back, these claims were not that used benzodiazepines as a monotherapy properly substantiated. Berney et al3 con- vs placebo, antidepressants, or both. Patients benzodiazepines cluded in a systematic review that com- in these trials were primarily diagnosed occurs, it is almost parative data of a high level of proof for with depressive disorder or anxious depres- always in the context using newer antidepressants in anxiety sion. The majority of these studies used of abusing other disorders rather that benzodiazepines were alprazolam as the benzodiazepine (other not available. Then, 5 years later, Offidani benzodiazepines used were adinazolam, substances et al4 demonstrated in a systematic review bromazepam, chlordiazepoxide, and loraz- and meta-analysis that benzodiazepines epam) and imipramine or amitriptyline as were more effective and better tolerated in the antidepressant comparator (other antide- the treatment of various anxiety disorders pressants used were desipramine, dothiepin, than TCAs. In addition, in a few studies doxepin, and only one newer antidepressant, comparing benzodiazepines with newer fluvoxamine, in one study). There was a lack antidepressants such as paroxetine and of significant differences in response rate venlafaxine, benzodiazepines were either between benzodiazepines and placebo, and comparable or showed greater improve- between benzodiazepines and TCAs. ment and fewer adverse effects that these In more than half of the studies compar- antidepressants. Similarly to Berney et al,3 ing benzodiazepines with TCAs and/or Offidani et al4 concluded that the change placebo, benzodiazepines were significantly in the prescribing pattern favoring newer more effective than placebo and as effective antidepressants over benzodiazepines for as TCAs. In 11 studies, TCAs were better the treatment of anxiety disorders occurred than benzodiazepines, while benzodiaze- without supporting evidence. pines were better than TCAs in one study. In As far as abuse potential, the American 12 studies, benzodiazepines were associ- Psychiatric Association Task Force on ated with a faster onset of action than TCAs. Benzodiazepine Dependency concluded Adverse effects occurred more frequently that benzodiazepines do not strongly rein- with TCAs, with the exception of drowsiness force their own use and are not widely and cognitive impairment, which occurred Discuss this article at abused.5 When abuse occurs, it is almost more frequently with benzodiazepines. www.facebook.com/ always in the context of abusing other The findings of the meta-analysis (22 stud- MDedgePsychiatry substances. The Task Force also noted that ies) confirmed the low response of anxious physiological dependence develops when depression to psychotropic medications, benzodiazepines are used chronically; whether TCAs or benzodiazepines. There dependence being defined mostly in terms was no demonstrated superiority of antide- of symptoms of discontinuance.5 Thus, ben- pressants over benzodiazepines for anxious Current Psychiatry 10 August 2018 zodiazepines need to be used appropriately, depression. Thus, clearly, benzodiazepines are a bona fide therapeutic option for anx- enough attention to anxiety and related ious depression and so far, there is no indi- issues in depressed patients. Interestingly, cation that antidepressants are preferable for anxiety has not been listed among symp- this indication. toms of major depression disorder (MDD) MDedge.com/psychiatry However, it is important to note that there in several editions of the Diagnostic and are almost no studies comparing benzodiaz- Statistical Manual of Mental Disorders (DSM). epines to newer antidepressants for anxious Only and finally did DSM-58 add a speci- depression. One double-blind 6-week study fier “with anxious distress” for both MDD of 112 patients7 compared fluvoxamine with and persistent depressive disorder (dys- lorazepam for mixed anxiety and depression thymia), although this specifier still avoids in general practice. There were no significant the word “anxiety” in the description of differences between treatments at any point its symptomatology. in the study. Lorazepam produced more It is difficult to disentangle whether the sedation, while fluvoxamine produced more anxiety is part of depressive disorder symp- nausea and vomiting. tomatology or whether it is a comorbid We clearly need randomized controlled anxiety disorder. As I noted in a previous trials comparing benzodiazepines with article,9 psychiatric comorbidity is a con- Clinical Point newer antidepressants in anxious depression. fusing phenomenon. Nevertheless, anxiety A meta-analysis However, as in the case with anxiety disorders, and depression are highly comorbid or co- these types of trials are strikingly missing. symptomatologic. In a study by Kessler et found that for al,10 45.7% of survey responders with life- treating anxious time MDD had ≥1 lifetime anxiety disorder. depression, Any clinical wisdom? Similarly, in a STAR*D study,11 in Level 1, antidepressants Anxiety could be a serious clinical problem 53.2% of patients had anxious depression. were not superior in the treatment of patients with depres- Kessler et al10 raised an interesting ques- sive disorder(s). We have not always paid tion about the importance of temporally to benzodiazepines primary anxiety disorders as risk mark- benzodiazepines have been involved in ers vs causal risk factors for the onset and nearly one-third of overdose-related deaths persistence of subsequent MDD, includ- (either separately or in combination with ing the possibility that anxiety disorders opioids), and the FDA strongly warns against might primarily be risk markers for MDD co-prescribing benzodiazepines and opioids, onset and causal risk factors for MDD per- they need to be prescribed appropriately, sistence. As is well-known, mood disor- carefully weighing their risks and benefits.12 Benzodiazepines ders should be treated as soon as possible Because the analysis by Benasi et al6 for depression after they are diagnosed, and should be demonstrated that benzodiazepines seem treated vigorously, addressing the major comparably effective as antidepressants in symptomatology. anxious depression, we should be consider- These findings emphasize the need to ing using benzodiazepines as monotherapy pay more attention to anxiety in depressed for this indication more frequently and vig- patients (especially those newly diagnosed) orously, considering their similar efficacy, and for forceful treatment of anxious depres- faster onset of action, and better tolerability, sion. Importantly, in the STAR*D study,11 while also considering their risks. Clinicians Clinical Point remission in anxious Level 1 (treated with use them in combinations anyway. We also Benzodiazepines citalopram) depressed patients was signifi- need rigorous trials comparing benzodiaz- cantly less likely and took longer to occur epines with newer antidepressants for anx- need to be prescribed than in patients with nonanxious depression. ious depression. appropriately, carefully In addition, ratings of adverse effects fre- weighing their risks quency, intensity, and burden, as well as the References 1. Birkenhäger TK, Moleman P, Nolen WA. Benzodiazepines and benefits number of serious adverse events, were sig- for depression? A review of the literature. Int Clin nificantly greater in the anxious depression Psychopharmacol. 1995;10(3):181-195. 2. Petty F, Trivedi MH, Fulton M, et al. Benzodiazepines as group. Similarly, in Level 2 (either switched to antidepressants: does GABA play a role in depression? Biol bupropion, sertraline or venlafaxine, or cita- Psychiatry. 1995;38(9):578-591. 3. Berney P, Halperin D, Tango R, et al. A major change lopram augmented with bupropion or buspi- of prescribing pattern in absence of adequate evidence: rone), patients with anxious depression fared benzodiazepines versus newer antidepressants in anxiety disorders. Psychopharmacol Bull. 2008;41(3):39-47. significantly worse in both the switching 4. Offidani E, Guidi J, Tomba E, et al. Efficacy and tolerability and augmentation options. One wonders of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. if Level 1 patients treated with benzodiaz- Psychother Psychosom. 2013;82(6):355-362. epines, and Level 2 patients switched to 5. The American Psychiatric Association Task Force on Benzodiazepine Dependence. Benzodiazepine dependence, benzodiazepines or offered augmentation toxicity, and abuse. Washington, DC: American Psychiatric with them would not have fared better, espe- Association; 1990. 6. Benasi G, Guidi J, Offidani E, et al. Benzodiazepines as a cially in view of the fact that many old and monotherapy in depressive disorders: a systematic review. new antidepressants have significant adverse Psychother Psychosom. 2018;87(2):65-74. 7. Laws D, Ashford JJ, Anstee JA. A multicentre double-blind effects and are difficult to discontinue due to comparative trial of fluvoxamine versus lorazepam in mixed anxiety and depression treated in general practice. withdrawal symptoms such as dizziness, Acta Psychiatr Scand. 1990;81(2):185-189. vertigo, and, in case of newer antidepres- 8. Diagnostic and statistical manual of mental disorders, 5th ed. Washington, DC: American Psychiatric Association; sants, brain “zaps.” Benzodiazepines cer- 2013. tainly have serious withdrawal symptoms, 9. Balon R. The confusion of psychiatric comorbidity. Ann Clin including anxiety, rebound insomnia, and Psychiatry. 2016;28(3):153-154. 10. Kessler RC, Sampson NA, Berglund P, et al. Anxious and withdrawal seizures, especially when discon- non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys. Epidemiol tinued abruptly and when the dose was high. Psychiatr Sci. 2015;24(3):210-226. Thus, as is the case for many other medica- 11. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious tions (eg, steroids, anticoagulants, and some depression: a STAR*D report. Am J Psychiatry. antidepressants), benzodiazepines must 2008;165(3):342-351. be tapered carefully in order to avoid dis- 12. Salzman C, Shader RI. Not again: benzodiazepines once more under attack. J Clin Psychopharmacol. 2015;35(5): continuance signs and symptoms. Because 493-495.

Current Psychiatry 12 August 2018