Are the benefits of benzodiazepines for anxiety disorders underestimated and their risks overestimated?

Benzodiazepines have been officially approved for use in the management of anxiety disorders since the 1960s. However, they have been gradually going out of favour in preference for medications such as quetiapine, an atypical antipsychotic. The reason for this shift is due to concerns regarding risk of abuse, dependence, tolerance, withdrawal, sedation, cognitive impairment, psychomotor impairment and suicide-related overdose (Hirschtritt et al., 2021). Benzodiazepine prescription rate in Australia has reduced by 25%, between 1992 (27.7 defined daily doses per 1000 population) and 2011 (20.8 defined daily doses per 1000 population) (Islam et al., 2013). Much of this reduction may be appropriate in the context of reducing long-term benzodiazepine use for chronic insomnia and for those who have benzodiazepine addiction. However, there is also likely to have been a reduction in benzodiazepine prescription for treatment-refractory anxiety disorders. On the contrary, the off-label prescription of atypical antipsychotics such as quetiapine for anxiety disorders have increased significantly, raising potential safety concerns (Malhi et al., 2019). In this commentary, we will briefly examine the risk/benefit profile of the use of benzodiazepines for treatment refractory anxiety disorders. This debate is especially important in the context of a recent United States Food and Drug Administration (US FDA) (September 2020) updated boxed warning for benzodiazepines (e.g. alprazolam, lorazepam, clonazepam, diazepam) particularly emphasising the risks of co-administration of opioids and benzodiazepines (Hirschtritt et al., 2021).

Quetiapine was first introduced in 1997 for the treatment of schizophrenia (Malhi et al., 2019). Since then, its use has gradually become increasingly broader, expanding to treating bipolar affective disorder, major depression and now to, more controversially, off-label use for anxiety disorders such as generalised anxiety disorder and primary insomnia (Malhi et al., 2019). In Australia Selective Serotonin Reuptake Inhibitors (SSRIs) and psychological therapies (e.g. Cognitive Behaviour Therapy (CBT)) remain the first-line treatments for anxiety disorders. However, many patients are unresponsive to these first-line interventions. This leads to considering augmentation or replacement with benzodiazepines or atypical antipsychotic medication like quetiapine.

There is no head-to-head clinical trial data directly comparing benzodiazepines with atypical antipsychotics for the treatment of anxiety disorders. However, a recent systematic review and network meta-analysis published in the Lancet showed that SSRI, Serotonin Noradrenaline Reuptake Inhibitors (SNRIs), quetiapine and benzodiazepine monotherapy had positive effect on reducing Hamilton Anxiety Rating Scales compared to placebo for the pharmacological treatment of generalised anxiety disorder. The mean difference compared to placebo is 3.6 for quetiapine and 2.29 for benzodiazepines (Slee et al., 2019). However, both quetiapine and benzodiazepines in this network meta-analysis had significantly higher side-effect profile when compared with placebo (odds ratio 1.44 and 1.43, respectively, in favour of placebo).

A well-known and particularly concerning adverse effect of quetiapine use is metabolic syndrome, which can lead to hypercholesterolaemia, diabetes and weight gain, associated with potentially increased overall morbidity and mortality. Given these significant long-term risks, quetiapine should only be considered for the carefully selected patient with treatment-refractory anxiety disorders.

Experts have opined that much of the contemporary bias against benzodiazepines may not be justified as the risks may have been overestimated (Silberman et al., 2020). For example, data suggests that abuse and misuse of benzodiazepines are in fact statistically rare in patients who do not already have a prior history of alcohol or substance abuse (Silberman et al., 2020). Furthermore, when taken alone, benzodiazepine overdose has been shown to have a relatively low lethality, but overdose risk increases significantly when used in conjunction with other substances, particularly opioids (Silberman et al., 2020). There is a widely held view that tolerance to the anxiolytic effects of benzodiazepines limits their long-term use for anxiety disorders. However, studies have demonstrated that long-term treatment is associated with maintenance of therapeutic benefit and no dose escalation for anxiety disorders (Silberman et al., 2020). Importantly, tolerance does develop for the sedating and psychomotor effects of benzodiazepines (Silberman et al., 2020).

The anxiolytic properties of benzodiazepines were their initial approved indication and evidence shows that they remain highly effective treatment (Hirschtritt et al., 2021). Therefore, we should retain this treatment option for patients non-responsive to first-line treatments (SSRI and CBT). The challenge lies in simultaneously considering the risk and benefits of benzodiazepines before initiation. Cautious assessment is required for patient-specific risk factors for benzodiazepine prescription. Important risk factors may include previous substance abuse (such as with alcohol or opioids), polypharmacy, older population and previous overdose attempts. After accounting for these patient-level risk factors, we believe benzodiazepines should be actively considered when SSRIs and CBT have initially failed for severe and disabling anxiety disorders.

Overall, both quetiapine and benzodiazepines may play a carefully balanced role in the treatment of refractory anxiety disorders. There is no trial evidence to directly suggest that quetiapine is superior to benzodiazepines for the treatment of refractory anxiety disorders, therefore benzodiazepines could be considered before initiating quetiapine. The population-level reduction of benzodiazepine use for treatment refractory anxiety disorders and its potential replacement with atypical antipsychotic medication require careful scrutiny and public health monitoring of outcomes such as population level of anxiety, overdose rates and cardio-metabolic effects.