Benzodiazepines’ potential antidepressant properties and their role in the treatment of depression were fairly extensively examined during the 1980s and early 1990s. There were various reasons for this investigation—from the adverse effects of available antidepressants (tricyclic antidepressants [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 existing antidepressants to alleviate initial or persistent anxiety, and to help with insomnia. Some authors1 felt that specific benzodiazepines, such as alprazolam, were effective in mild and moderate depression, although not as effective as TCAs for patients with endogenous or melancholic depression. Others2 proposed that benzodiazepines, particularly alprazolam, may be a useful treatment option for patients for whom antidepressants are contraindicated, poorly tolerated, 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 depression was based on results of several studies, but it has not been adequately analyzed, summarized, and promoted. Then, after the arrival of the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine arrived in the United States in 1987, and paroxetine and sertraline arrived in 1992), interest in benzodiazepines gradually waned. Within a few years, the SSRIs were also approved for various anxiety disorders. The SSRIs were heavily promoted not only for the treatment of depressive disorders, but also anxiety disorders, and were touted as well-tolerated medications without abuse potential. Benzodiazepines, on the other hand, were frequently described as less effective and having a substantial abuse potential.
Looking back, these claims were not properly substantiated. Berney et al3 concluded in a systematic review that comparative data of a high level of proof for using newer antidepressants in anxiety disorders rather that benzodiazepines were not available. Then, 5 years later, Offidani et al4 demonstrated in a systematic review and meta-analysis that benzodiazepines were more effective and better tolerated in the treatment of various anxiety disorders than TCAs. In addition, in a few studies comparing benzodiazepines with newer antidepressants such as paroxetine and venlafaxine, benzodiazepines were either comparable or showed greater improvement and fewer adverse effects that these antidepressants. Similarly to Berney et al,3 Offidani et al4 concluded that the change in the prescribing pattern favoring newer antidepressants over benzodiazepines for the treatment of anxiety disorders occurred without supporting evidence.
As far as abuse potential, the American Psychiatric Association Task Force on Benzodiazepine Dependency concluded that benzodiazepines do not strongly reinforce their own use and are not widely abused.5 When abuse occurs, it is almost always in the context of abusing other substances. The Task Force also noted that physiological dependence develops when benzodiazepines are used chronically; dependence being defined mostly in terms of symptoms of discontinuance.5 Thus, benzodiazepines need to be used appropriately, not in extremely high doses, and under medical supervision.
Nevertheless, the judgment, right or wrong, was out—benzodiazepines were deemed problematic and to be avoided. This has become, unfortunately, a pattern of many prescribing psychiatrists’ practice.
What about benzodiazepines for anxious depression?
Recently Benasi et al6 filled the void by investigating data from studies using benzodiazepines as monotherapy in depressive disorders (I was one of the co-authors of this study). They conducted a systematic review of 38 published randomized controlled trials that used benzodiazepines as a monotherapy vs placebo, antidepressants, or both. Patients in these trials were primarily diagnosed with depressive disorder or anxious depression. The majority of these studies used alprazolam as the benzodiazepine (other benzodiazepines used were adinazolam, bromazepam, chlordiazepoxide, and lorazepam) and imipramine or amitriptyline as the antidepressant comparator (other antidepressants used were desipramine, dothiepin, doxepin, and only one newer antidepressant, fluvoxamine, in one study). There was a lack of significant differences in response rate between benzodiazepines and placebo, and between benzodiazepines and TCAs.
In more than half of the studies comparing benzodiazepines with TCAs and/or placebo, benzodiazepines were significantly more effective than placebo and as effective as TCAs. In 11 studies, TCAs were better than benzodiazepines, while benzodiazepines were better than TCAs in one study. In 12 studies, benzodiazepines were associated with a faster onset of action than TCAs. Adverse effects occurred more frequently with TCAs, with the exception of drowsiness and cognitive impairment, which occurred more frequently with benzodiazepines. The findings of the meta-analysis (22 studies) confirmed the low response of anxious depression to psychotropic medications, whether TCAs or benzodiazepines. There was no demonstrated superiority of antidepressants over benzodiazepines for anxious depression. Thus, clearly, benzodiazepines are a bona fide therapeutic option for anxious depression and so far, there is no indication that antidepressants are preferable for this indication.
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