1 Newer antidepressants have not been shown to be superior to benzodiazepines and, given their negative adverse effect profiles as well, should not be given priority over benzodiazepines in clinical practice guidelines

There is significant overlap in the six editorials making this claim (Balon Reference Balon, Chouinard and Cosci2018, Reference Balon, Starcevic and Silberman2020; Nardi Reference Nardi, Cosci and Balon2018, Reference Nardi and Quagliato2022; Silberman Reference Silberman, Balon and Starcevic2021; Starcevic Reference Starcevic2022) and advocating essentially that guidelines should be revised in order to ‘return to the evidence’ (Silberman Reference Silberman, Balon and Starcevic2021). One of the most compelling points made by the ITFB to support this claim is that there are few large head-to-head randomised controlled trials (RCTs) comparing benzodiazepines with newer antidepressants. Given that both drug classes have been shown to be efficacious in multiple pre-marketing placebo-controlled trials, it is their contention that the drug classes should be treated equally in guideline recommendation placements (i.e. first line versus second line).

Efficacy comparison in RCTs

A 2016 Cochrane evaluation (the third comparison in the full report – selective serotonin reuptake inhibitors (SSRIs) versus benzodiazepines; Bighelli Reference Bighelli, Trespidi and Castellazzi2016) found only one industry-sponsored RCT worthy of inclusion, comparing alprazolam with paroxetine in 226 people over a 10-week period. This trial (GSK-29060/1; Glaxo Smith Kline, no date) is unpublished and it is difficult to find information on it beyond that given in the Cochrane publication itself. Nonetheless, Bighelli et al found that the trial data showed no difference between alprazolam and paroxetine on all outcomes except depression (advantage to paroxetine).

Another direct comparison study that was not included by the Cochrane group because of the design limitation of it being open-label and of higher risk for bias was that of Nardi et al, comparing clonazepam and paroxetine (Nardi Reference Nardi, Freire and Mochcovitch2012). This study has been cited a number of times in support of the ITFB's arguments in their editorials (the lead author of the study is a member of the ITFB) to justify longer-term use and demonstrate, at minimum, non-inferiority in effectiveness and tolerability between antidepressants and benzodiazepines (Nardi Reference Nardi, Cosci and Balon2018, Reference Nardi and Quagliato2022; Starcevic Reference Starcevic2022). This study is important because of the long follow-up time and it does contribute to the evidence on the topic in spite of its lack of masking (‘blinding’). However, an important limitation that needs to be acknowledged is the drug selection in the trial. Clonazepam is a long half-life benzodiazepine with lesser potential for withdrawal symptoms than other benzodiazepines. In contrast, paroxetine is an SSRI with one of the shortest half-lives, thus making it more likely for withdrawal phenomena to emerge. Paroxetine has become a highly unpopular SSRI because of its higher frequency of withdrawal symptoms (Fava Reference Fava, Gatti and Belaise2015). Additionally, its higher antimuscarinic burden makes it a less acceptable option in older adults (American Geriatrics Society Beers Criteria^® Update Expert Panel 2019). It would seem that the decks were stacked in favour of the benzodiazepines in this trial in terms of drug selection. This does not invalidate the trial as an important contributor to the evidence base, but it is important to allow for the results to be read in the context of what is known about the relative differences between antidepressants and what would be a ‘fair’ comparator in a benzodiazepines versus antidepressant RCT if one were conducted today.

Although there is a limited number of direct head-to-head trials comparing benzodiazepines with standard first-line antidepressants, the abundance of placebo-controlled trials does enable some inferences from the overall evidence for these two medication classes via indirect comparison. It should be noted that the potential differences in trial populations and methodology between the drug classes overall warrants caution in interpretation. Nevertheless, I have compared the Cochrane systematic review of benzodiazepines versus placebo (Breilmann Reference Breilmann, Girlanda and Guaiana2019) with that of SSRIs versus placebo (Bighelli Reference Bighelli, Castellazzi and Cipriani2018), both in the context of panic disorder treatment, and reproduced their main meta-analytic findings along with their evidence appraisal ratings Table 1.

TABLE 1

Meta-analytic comparisons of outcomes against placebo for trials of benzodiazepines and selective serotonin reuptake inhibitors in panic disorder^a

SSRI, selective serotonin reuptake inhibitor; RCT, randomised controlled trial; GRADE, Grading of Recommendations Assessment, Development and Evaluation.

a Data derived from two Cochrane systematic reviews: Bighelli et al (Reference Bighelli, Castellazzi and Cipriani2018) and Breilmann et al (Reference Breilmann, Girlanda and Guaiana2019).

b Some RCTs comparing antidepressants other than SSRIs with placebo in panic disorder reported by Bighelli et al (Reference Bighelli, Castellazzi and Cipriani2018) lasted for up to 6 months. This table covers only SSRIs to reduce confounding and because of their continued representativeness as a subclass of first-line antidepressants in psychiatry.

As can be seen by a meta-analytic comparison using a standard, rigorous methodology from an internationally respected clinical research collaborative, benzodiazepines do appear to have higher effect sizes and greater tolerability on the most broadly meaningful clinical measures. However, this can be at least partially accounted for by the following: (a) the rapid induction of anxiolysis compared with antidepressants would presumably result in a faster symptom reduction response, which would prevent fair comparison of the two drug classes because of early drop-outs resulting from patient-perceived ‘lack of efficacy’ (DeVane Reference DeVane, Jann, Penzak and Cohen2016); (b) a potentially lower standard of methodological rigour in trial design or reporting quality required for market approval in trials conducted before the advent of the modern antidepressant era might bias results towards positive outcomes; and (c) the smaller total sample sizes in the meta-analytic estimates (generally speaking, as trials accumulate, effect estimates tend to approach a smaller ‘true’ value).

Of importance aside from measures of effectiveness is the acknowledgement that antidepressants (at least for the SSRIs in Table 1) seem to have more trials with more participants, tend to be longer on average, have higher certainty of evidence on some measures and were conducted more recently (whether this last observation correlates with methodological rigour, however, is up for scrutiny).

2 There is an abundance of scientific bias and unjustifiable propaganda against benzodiazepines that has prevailed in influencing guidelines and clinical practice and that this has resulted in ‘fear’ of benzodiazepines and underuse in situations where they would be beneficial

I agree with the authors (Balon Reference Balon, Chouinard and Cosci2018, Reference Balon2022; Nardi Reference Nardi and Quagliato2022; Silberman Reference Silberman2022) that conflicts of interest, via the pharmaceutical industry, influencing the production of educational content, research and clinical guidelines is a real concern and threat to medical decision-making whereby the best available evidence becomes suppressed or distorted. However, the overwhelming degree of concordance between various national and international guidelines on the point of antidepressants having some precedence over benzodiazepines as a first-line maintenance treatment in anxiety conditions should not be simply dismissed as a grand conspiracy of conflict of interest. I contend that a full systematic review of the literature with the purpose of analysing claims about benzodiazepines should be conducted to firmly convince the clinical scientific community of indisputable, persisting bias that has distorted the scientific record. Ultimately, the burden of proof remains on the ITFB to demonstrate, in a compelling, methodologically rigorous way, that benzodiazepines deserve a place alongside modern antidepressants as a first-line maintenance treatment for common anxiety disorders. The group's call for new head-to-head RCTs is a good starting point.

I also wish to respectfully draw attention to the fact that six of the nine editorials (Balon Reference Balon, Chouinard and Cosci2018, Reference Balon, Sonino and Rafanelli2021, Reference Balon2022; Nardi Reference Nardi and Quagliato2022; Silberman Reference Silberman2022; Starcevic Reference Starcevic2022) are in the journal Psychotherapy and Psychosomatics, whose current editor-in-chief is a member of the ITFB. The current editor-in-chief and both associate editors of the journal are also from Italy, the country identified by the International Narcotics Control Board as being responsible for over 50% of global pharmaceutical production of benzodiazepines in 2020 (International Narcotics Control Board 2021). In good faith I expect this to be purely coincidental. However, a country that has an economic interest in the export and clinical use of millions of doses of benzodiazepines may produce a widespread clinical environment in which these medications are more favourably viewed than elsewhere in the world. I hope that at the minimum, a group rightfully drawing attention to industry bias as regards antidepressants shall itself set a higher future standard by publishing its opinion editorials in a peer-reviewed journal that is not associated with the ITFB. This would reduce the appearance of privileging particular perspectives or agendas. Such an approach is consistent with already well-established ethical publication standards for biomedical journals (Gottlieb Reference Gottlieb and Bressler2017; Stead Reference Stead2017).

3 The high rate of use of benzodiazepines is evidence that the guidelines should be changed to reflect real-world utilisation rates

I contest that pharmacoepidemiological data showing a rise in benzodiazepines use (Balon Reference Balon, Starcevic and Silberman2020, Reference Balon2022; Silberman Reference Silberman2022; Starcevic Reference Starcevic2022) is too complicated a matter to warrant a simple claim that the majority of real-world use ‘must be ahead of treatment guidelines in this realm’ (Starcevic Reference Starcevic2022). Although we might hope to have such faith in prescribers, it is clear that there are a number of reasons why guidelines may not be adhered to, some of which are described here.

First, adherence to practice guidelines is a problem in many fields of medicine and healthcare and is the daunting task of an entire domain of research and healthcare work: implementation science research and knowledge translation effort (Eccles Reference Eccles and Mittman2006; Straus Reference Straus, Tetroe and Graham2013). It does not follow that simply because real-world practice is very imperfect guidelines should ‘go backwards’ to match it. Indeed, research is currently ongoing to improve the success of de-prescribing in the context of long-term benzodiazepine use by using implementation science methods, theories and frameworks (Lynch Reference Lynch, Ryan and Cadogan2022).

Second, in many instances the prescribing of benzodiazepines rather than antidepressants is more stressful for both patient and clinician. Many patients are worried about the significant withdrawal syndrome associated with benzodiazepines. Also, there are strict regulatory requirements in most jurisdictions for the prescribing and dispensing of benzodiazepines, which create a difficult situation for patients taking these drugs long-term who either lose their medication or who independently increase dosage or frequency beyond that prescribed. Their doctors must submit early dispensing authorisations to pharmacists for them to provide the medication for patients who have run out of their benzodiazepines earlier than expected. This is not an uncommon scenario in clinical practice and contributes to the reluctant long-term prescribing of benzodiazepines on the part of some treating clinicians. The imposition placed on busy prescribers by the urgent demand for ‘early release’ authorisations by patients and their pharmacists is made difficult by the inability to assess the patient in a timely manner to guide prescribing decisions. The stress placed on relationships between patients and clinicians because of both the nature of benzodiazepine dependence and the medication access restrictions is not to be underestimated (Sirdifield Reference Sirdifield, Anthierens and Creupelandt2013, Reference Sirdifield, Chipchase and Owen2016). It is unclear what the ITFB's position is on the scheduling or regulatory status of benzodiazepines and what changes, if any, it believes should be made. Overall, in this regard, I would argue that antidepressants are frequently less complex and socially concerning, in terms of patients’ medication behaviour, for the stability of the average prescriber–patient relationship, an important factor in and of itself for the quality provision of care.

Third, much out-patient benzodiazepine use is for insomnia, a condition where the benefit/risk ratio diminishes with long-term use, and benzodiazepines are not recommended over cognitive–behavioural therapy for chronic insomnia (Sateia Reference Sateia, Buysse and Krystal2016). Insomnia as an explanation or argument for greater benzodiazepine use is conveniently left out of these editorials, perhaps because some evidence has shown that benzodiazepines can diminish sleep quality (Bourgeois Reference Bourgeois, Elseviers and Van Bortel2013). A different type of study that conducted a qualitative evaluation of factors affecting patient preference found a significant association between patients using benzodiazepines for chronic insomnia and a later desire to taper off the medication (Sake Reference Sake, Wong and Bartlett2019). Furthermore, misuse of benzodiazepines by a patient struggling with insomnia may also then lead to subsequent confrontational encounters with care providers because of the regulatory requirements described in the previous point.

4 ‘The role of [benzodiazepines] in the management of various troublesome GI symptoms (e.g., aerophagia and GI pain), or some acute and chronic GI disorders (e.g., peptic ulcer disease, colitis and IBS), has not been fully appreciated. Their use should be expanded.’ (Balon Reference Balon, Sonino and Rafanelli2021)

Although Balon et al's (Reference Balon, Sonino and Rafanelli2021) editorial provides an interesting overview of potential pharmacological mechanisms, a review of the link between various gastrointestinal (GI) disorders and mental illness (especially somatic disorders such as irritable bowel syndrome (IBS)) and a short review of a few studies from the 1970s, the authors do not come close to justifying the above concluding statement. In a section just short of 500 words they cover the efficacy of benzodiazepines for various GI conditions. The section briefly reviews six studies from the 1970s, five of which are small and none of which have influenced recent gastroenterology clinical practice guidelines in support of benzodiazepines in routinely supplanting commonly used medication classes such as antispasmodics, antidepressants or proton pump inhibitors (Kamada Reference Kamada, Satoh, Itoh and Ito2021; Lacy Reference Lacy, Pimentel and Brenner2021). Although not specifically addressed, the unique but antiquated combination of chlordiazepoxide and clidinium bromide was recently evaluated with positive results as an add-on therapy for functional dyspepsia but it is unclear how much benefit is clearly derived from the antimuscarinic compared with the benzodiazepine, as they have not been evaluated separably (Puasripun Reference Puasripun, Thinrungroj and Pinyopornpanish2020). The authors of this trial recommend short-term use of this combination solely as an adjunct to standard pharmacotherapy such as proton pump inhibitors (Puasripun Reference Puasripun, Thinrungroj and Pinyopornpanish2020).

Before their concluding statement, Balon et al (Reference Balon, Sonino and Rafanelli2021) make quite reasonable points for preferring benzodiazepines over antidepressants based on their respective GI adverse effect profiles. It should be noted that benzodiazepines are not entirely devoid of GI concerns themselves, in particular oesophageal acid reflux (Tutuian Reference Tutuian2010), a point that was missed by the authors. Although their arguments here would be most relevant for the condition of IBS, a comparative review of the positive evidence for SSRIs in IBS is not mentioned and it is summarily concluded that benzodiazepines should therefore be preferred.