Journal Article Annotations
2021, 3rd Quarter

Suicide

Annotations by Liliya Gershengoren, MD, MPH and Sohail Mohammad, MD, MPH
September, 2021

Suicide Attempts in US Veterans with Chronic Headache Disorders: A 10-Year Retrospective Cohort Study.
Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis.

PUBLICATION #1 — Suicide

Suicide Attempts in US Veterans with Chronic Headache Disorders: A 10-Year Retrospective Cohort Study.

X Michelle Androulakis, Siyuan Guo, Jiajia Zhang, Jason Sico, Peter Warren, Alec Giakas, Xiaoming Li, B Lee Peterlin, Roy Mathew, Deborah Reyes

Abstract: J Pain Res. 2021 Aug 24;14:2629-2639. doi: 10.2147/JPR.S322432. eCollection 2021.

Objectives:
A large-scale retrospective analysis of veterans with chronic pain was conducted to examine (1) the annual incidence of suicide attempts (SA) in veterans with chronic headache and other chronic pain conditions, and (2) the risk of SA in men and women with chronic headache and chronic headache concurrent with traumatic brain injury (TBI) as compared to non-headache chronic pain.

Methods:
This retrospective study (N=3,247,621) analyzed National Veterans Affair Health Administrative data of patients diagnosed with chronic head, neck, back and other chronic pain from 2000 to 2010. Multivariable Poisson regression was used to explore the relative risks of SA in veterans with chronic headache and chronic headache concurrent with TBI as stratified by sex.

Results:
Veterans with chronic headaches had the highest annual incidence of SA (329 to 491 per 100,000) each year among all identified types of chronic pain conditions. Compared to other non-headache chronic pain, chronic headache is associated with increased risk of SA [men RR (1.48), CI (1.37,1.59); women RR (1.64), CI (1.28,2.09)], after adjusting for demographic factors, TBI, and psychiatric comorbidities. The risk increased further when chronic headache is comorbid with TBI [men RR (2.82), CI (2.60, 3.05); women RR (2.16, CI (1.67-2.78)].

Conclusion:
Veterans with chronic headache have a higher risk of SA than those with other chronic pain and women with chronic headache are at a higher risk than men with chronic headache. Chronic headache concurrent with TBI further heightened this risk, especially in men. Our data underscore the importance of identifying specific types of chronic pain in veterans with comorbid TBI and sex disparity associated with SA when targeting suicide prevention measures.

Annotation

The finding:
In a retrospective study using Veterans Affairs Health System administrative data, chronic headache disorders were associated with an increased risk of suicide attempts among veterans. This risk was further elevated for women veterans with chronic headache. Concurrent traumatic brain injury increased the risk of suicide attempts especially in men.

Strength and weaknesses:
This longitudinal retrospective study examined a large cohort of veterans which is a particular strength. Another strength is obtaining physician verification of variables in question rather than relying solely on questionnaire-based surveys. One significant limitation is the lack of specificity concerning the duration and severity of chronic headache, traumatic brain injury, and mental health conditions. Chronicity does not always reflect the main characteristics of pain duration. In addition, an overwhelming majority of the patients in the study were identified as white and male, which limits generalizability to other, non-Veteran patient populations.

Relevance:
CL psychiatrists are often asked to comment on the psychiatric comorbidities of patients with chronic pain. This article highlights the implications of chronic headache disorders—with or without traumatic brain injury—on the risk of suicide attempts. Veterans are known to have higher suicide rates compared with the general population and require unique consideration when being evaluated.

PUBLICATION #2 — Suicide

Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis.

Pavel Klein, Orrin Devinsky, Jacqueline French, Cynthia Harden, Gregory L Krauss, Robert McCarter, Michael R Sperling

Abstract: JAMA Neurol. 2021 Sep 1;78(9):1118-1127. doi: 10.1001/jamaneurol.2021.2480.

Importance:
Most antiseizure medications (ASMs) carry a US Food and Drug Administration-mandated class label warning of increased suicidality risk, based on a meta-analysis comparing suicidality between individuals treated with medications vs placebo in randomized clinical trials done before 2008. ASMs approved since then carry this warning although they were not similarly studied.

Objective:
To review all placebo-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to evaluate the risk of suicidality of these drugs compared with placebo.

Data sources:
Primary publications and secondary safety analyses in PubMed of all phase 2 and 3 randomized placebo-controlled epilepsy trials of ASMs approved since 2008, using keywords epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation, and the names of individual drugs.

Study selection:
All phase 2 and 3 randomized clinical trials of adjunctive treatment of drug-resistant epilepsy and their secondary safety analyses.

Data extraction and synthesis:
Articles were reviewed for frequency of suicidality (ideation, attempts, and completed suicides). Mode of suicidality ascertainment included treatment-emergent adverse event reports, Standardized Medical Dictionary for Regulatory Activities queries for events in prespecified categories including suicidal ideation and behavior, prospective collection of suicidality data as a prespecified safety outcome using the Columbia-Suicide Severity Rating Scale, and retrospective evaluation by blinded review using the Columbia-Classification Algorithm of Suicide Assessment. A meta-analysis compared risk for drugs vs placebo of each outcome for all drugs overall and by individual drugs and trials.

Main outcomes and measures:
Suicidality (total and by ideation), attempts, and completed suicides.

Results:
Excluding studies that did not evaluate suicidality (everolimus and fenfluramine) or did not evaluate it prospectively (lacosamide, ezogabine, and clobazam), 5 drugs were analyzed: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Suicidality was evaluated in 17 randomized clinical trials of these drugs, involving 5996 patients, of whom 4000 patients were treated with ASMs and 1996 with placebo. There was no evidence of increased risk of suicidal ideation (drugs vs placebo overall risk ratio, 0.75; 95% CI, 0.35-1.60) or attempt (risk ratio, 0.75; 95% CI, 0.30-1.87) overall or for any individual drug. Suicidal ideation occurred in 12 of 4000 patients treated with ASMs (0.30%) vs 7 of 1996 patients treated with placebo (0.35%) (P = .74). Three patients treated with ASMs and no patients treated with placebo attempted suicide (P = .22). There were no completed suicides.

Conclusions and relevance:
There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.

Annotation

The finding:
In a meta-analysis of 17 randomized trials, 7of 4000 patients treated with antiseizure Medications (ASMs) (0.30%) had suicidal ideation, compared with 7 of 1996 patients treated with placebo (0.35%). There were no deaths by suicide. Overall, for the 5 ASMs in the study, there was no evidence of statistically significantly increased risk of suicidal ideation (risk ratio 0.75; 95% Confidence Interval: 0.35 to 1.60) or suicidal attempt (risk ratio 0.75; 95% Confidence Interval: 0.30 to 1.87). The 5 antiseizure medications reviewed were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate.

Strength and weaknesses:
The meta-analyses included 7 studies that conducted structured evaluation of suicidality using the validated Columbia Suicidality Severity Rating Scale (C-SSRS). The study followed the Preferred Reporting Items for Systemic Review and Meta-analyses (PRISMA) reporting guideline. The study limitations include a description limited to 5 ASMs and lack of use of standardized suicidality questionnaires in nearly 60% of the study population. Of the patients who had structured evaluation of suicidality using C-SSRS, 56% were from studies on only 2 Anti-Seizure Medications (ASMs), i.e., eslicarbazepine and brivaracetam. The meta-analysis did not include ASMs that are commonly used as mood stabilizers in patients with psychiatric disorders.

Relevance:
It is important to be aware of the potential adverse events of ASMs and their association to suicidality. Anti-Seizure Medications (ASMs) are commonly used as mood stabilizers in patients with psychiatric disorders. A structured evaluation of suicidality pre- and post-trial of ASMs may need to be considered using the validated Columbia Suicidality Severity Rating Scale (C-SSRS). Consultation-liaison psychiatrists should collaborate with neurologists to weigh the ASMs benefits versus the risks and their association to suicidality and support patients in informed and shared decision making.