An Emulation of Randomized Trials of Administrating Benzodiazepines in PTSD Patients for Outcomes of Suicide-Related Events

Abstract

Benzodiazepines is a class of medications frequently prescribed to patients with post-traumatic stress disorder. Patients with PTSD have a notable increased risk of suicide compared to the general population. These medications have been theorized to increase suicidality and pose a risk when used in this patient population. Previous research has found little utility of using benzodiazepines in the PTSD population. However, benzodiazepines are still commonly prescribed by some clinicians for their symptomatic benefit. This study aims to identify the comparative efficacy of commonly prescribed benzodiazepines including midazolam, lorazepam, alprazolam, clonazepam, diazepam and temazepam in relation to suicide-related behaviors (SRBs). A total of 38,807 patients who had an ICD9 or ICD10 diagnosis of PTSD from January 2004 to October 2019 were identified through an electronic medical record database. Inclusion criteria include patients that initiated one of the above benzodiazepines after PTSD diagnosis. Exclusion criteria include previous history of benzodiazepine usage or history of SRBs within the last year prior to enrollment. For patients enrolled in this study, other concomitant drugs were not limited. The primary outcome was onset of SRBs with each respective benzodiazepine. SRBs were identified as ideation, attempt, or death from suicide. We emulated clinical trials of head-to-head comparison between two drugs by pooled logistic regression methods with the Firth option adjusting for baseline characteristics and post-baseline confounders. A total of 5753 patients were eligible for this study, with an average follow up of 5.82 months. The overall incidence for SRB was 1.51% (87/5753). Head-to-head comparisons identified that patients who received alprazolam had fewer SRBs compared to clonazepam (p = 0.0351) and lorazepam (p = 0.0373), and patients taking midazolam experienced fewer relative incidences of SRBs when compared to lorazepam (p = 0.0021) and clonazepam (p = 0.0297). After adjusting for the false discovery rate (FDR), midazolam still had fewer SRBs compared to lorazepam (FDR-adjusted p value = 0.0315). Certain benzodiazepines may provide a reduced risk of development of SRBs, suggesting careful consideration when prescribing benzodiazepines to the PTSD population.

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

“…We retrieved 3133 unique records, of which 200 were included in the review (Figure 1). All reasons for excluding records after full-text review are given in eAppendix 6 in Supplement 1.…”

“… The included studies spanned 26 fields of medicine, predominately infectious disease (43 [22%]; 27 [14%] on COVID-19), cardiology (30 [15%]), and oncology (30 [15%]) . One hundred and thirty-one studies (66%)…”

“…One-hundred and fifteen studies (58%) completely reported how the target trial protocol was emulated. Eighty-seven studies (44%) provided both the protocol of the target trial and described how it was emulated (Table 2).…”

Trazodone Add-on in COVID-19-related Selective Serotonin Reuptake Inhibitor-resistant Post-traumatic Stress Disorder in Healthcare Workers: Two Case Reports

“…The treatment with a drug as TRZ that targets sleep disturbances might be crucial for better PTSD treatment outcomes. This action of TRZ is essential because several studies showed that benzodiazepines (BZDs) should be considered relatively contraindicated for patients with PTSD or recent trauma [ 30 , 31 ]. Moreover, persons with PTSD may quickly develop substance-related problems, particularly with BZDs and z-pills, and, therefore, their administration should be avoided [ 32 ].…”

Advances in the pathogenesis and pharmacotherapy of acute stress disorder

“…Benzodiazepines are widely used in clinical practice, but there is no evidence of effective treatment for PTSD [27]. One of the reason why some clinicians still use benzodiazepines is that these drugs can control patients' symptoms in time, such as their out-of-control emotions and behaviors [33]. At the same time, some studies show that benzodiazepines are not recommended for the treatment of stress disorder, because they are basically ineffective for stress disorder and even cause serious adverse reactions [34,35].…”