An early career researcher discusses issues with blinding and diversity in peer review, and ultimately whether including non-peer-reviewed preprints in science publishing can have beneficial effects…
Worldwide, suicide is considered one of the most leading causes of mortality, accounting for around one million deaths every year, i.e., twice the number of deaths from homicide. Of note, young individuals and older adults are the most common vulnerable groups to suicidal ideation and self-harm. The lifetime prevalence of suicidal ideation among people with epilepsy is found to be around 25%. Although suicidal behaviour in epilepsy is a complex phenomenon, evidence suggests that suicide rates are higher among individuals with epilepsy than the general population. Yet, it has been a decade since the Food and Drug Administration (FDA) has passed a warning with anti-seizure medications (ASMs) and risk of suicide, the scientific community is still far from a final answer to this association. Since the available data are not methodologically strong enough to support or reject the claimed increased risk of suicide using ASMs, the dilemma continues. Through this blog post, author sought to list certain important issues that the past studies often over-looked, which play a vital role in determining the true relationship between the use of ASMs and the risk of suicide.
ASMs and Suicidal Behaviour
ASMs, often also called anticonvulsants, are used to treat seizure disorders; however, they are also widely used for other health indications such as psychiatric disorders like anxiety, bipolar disorder, depression and alcohol withdrawal and migraine, including neuropathic pain. In early 2008, the US FDA has passed an alert based upon a meta-analysis that found a significantly increased risk for suicide associated with the ASMs. However, several concerns have been raised with the methodological aspects of the meta-analysis, mostly related to the collected data, studies that were included, the grouping of different ASMs under a single class, statistical significance and issues pertaining to risk-benefit balance. In recent times, ASMs have been receiving increasing attention for a possible association with suicidal behaviour, including suicidal thoughts and behaviour. Individuals with epilepsy and/or psychiatric illness exhibit an increased risk of suicide; however, it is unclear whether the relationship between these conditions and suicidal behaviour is due to the baseline neurological condition or whether ASMs have a role as a contributing risk factor.
The question of whether ASMs are linked with the increased risk of suicide has been a matter of discussion in the scientific community for more than a decade. Recent studies have proved that among individuals with epilepsy, heightened suicide risk is also attributable to comorbid psychiatric conditions. However, most of these studies lack the statistical power to adjust for comorbid conditions associated with suicidal behaviour. Although the speculations on this possible association have been growing day-by-day, evidence suggests certain equal contradictory findings on this association. Thus, unfortunately, these studies did not answer the question as they were methodologically weak, with significant limitations being in the retrospective design and the failure to adjust for past suicidal behaviour.
In practice, none of the studies have demonstrated a clear association of whether ASMs increase or not linked with the risk of suicide in people with epilepsy. On the other hand, there is evidence stating that suicide attempts are associated with epilepsy, even before epilepsy manifests. In support of this, findings from a recent study inferred that both incident and recurrent suicide attempts are associated with epilepsy in the absence of ASMs. Similarly, a study that compared the number of suicidal attempts among patients on ASMs with epilepsy with the number of suicidal attempts among those who were not treated with ASMs resulted in no association. Hence, there is a lot to be studied whether ASMs have a role in modifying the risk of suicide or the disease by itself (i.e., epilepsy) lead to such ideations. Interestingly, studies observed that suicide itself could lead to an increased risk of developing epilepsy, a bi-directional relationship. Besides, to support the evidence of no relationship between ASM use and the risk of suicide, studies have proved that psychiatric disorders could increase the risk of completed suicide among people with epilepsy. Indeed, this is when the comorbidities should be recognized and considered while planning and delivery of care. Nevertheless, risks associated with stopping or not initiating the ASMs in epilepsy might lead to an excess risk of suicide in epilepsy.
Challenges, Pitfalls and Uncertainties
Alongside solely considering the etiological pathways of epilepsy and the pharmacological mechanisms of ASMs that trigger suicidal behaviour, certain other factors could be focussed, which could account for most of the differences in observing unclear or contradictory findings in the literature. Firstly, one of the significant challenges with the ASMs is their off-label use. Most of the previously conducted studies lack information about the actual therapeutic indication of the ASMs that were prescribed among their study population. Additionally, a substantial proportion of patients were on ASMs for other indications than epilepsy, such as psychological conditions or for treating pain, where these conditions themselves pose a risk for suicide or increase the suicidal risk associated with ASMs due to confounding by indication. Secondly, although there is limited evidence that suggests suicidal behaviour is not associated with the type or severity of epilepsy, studies lack the details on the classification or type of epilepsy. Thirdly, most of the studies used administrative databases, where it is highly impossible to identify suicidal behaviour since this information is usually not recorded. Also, being an important predictor, the previous history of suicide attempts are not captured using databases. Next, some studies had a smaller sample size, which could generate unreliable results that lack statistical power. Thus, most of the studies did not stratify the suicides based upon the dose of ASMs (i.e., treatment intensity) due to their limited sample size and difficulty in capturing this information using databases.
Next, using the administrative data, especially if the data is collected from the primary care, i.e., data based on prescriptions rather than dispensations, it is quite challenging to assess the adherence to ASMs. Some studies that looked at this association were cross-sectional, where it is not possible to study the causal relationship between ASMs and suicidal ideation. As discussed above, psychological disorders such as anxiety and depression are common among individuals with epilepsy, where both these conditions are identified as risk factors for suicide. Thus, epilepsy or ASMs could not be solely considered the cause for such suicidal thoughts or behaviour, where the comorbid diagnosis may add to the suicidal risk.Certain studies identified the cases only based upon medical codes due to the lack of access to the hospital or death records, which might likely be under-reporting suicidal attempts or deaths due to suicide. Lastly,at times, studies lack the information related to the time-varying covariates (such as, alcohol or substance drug use) and treatment discontinuation, which could potentially modify the association.
Since most of the studies lack enough sample size, further additional research with large samples that include all ages is necessary for confirming this specific relationship. Therefore, multi-centric, well-controlled prospective studies with robust methodology controlling for all kinds of bias are needed. In particular, studies that consider family or previous history of suicide and psychiatric comorbidity amongst individuals with epilepsy are warranted. The prior history of suicide attempts, especially preceding the onset of epilepsy, may address a key element in explaining that the ASMs might not have any definitive role in inducing such ideations. Ideally, clinical trials of ASMs should use specific instruments to self-screen and monitor behavioural problems like suicidal symptoms and should have detailed information on this particular problem before drugs are marketed. Furthermore, randomized-controlled trials should specifically focus on issues concerning psychological disorders such as depression and suicidal behaviour to elucidate the role of ASMs in suicidal behaviour and thereby should differentiate drug effects from illness-related effects.
In summary, people with epilepsy and psychiatric disorders are at increased risk for suicide, but just not ASMs use, which might further exacerbate the risk. Although the risk of suicidal ideation that has been observed due to ASMs is low, such risk needs to be weighed against the risk associated with discontinuing or not initiating the ASM treatment. Screening for suicide among individuals with epilepsy would be an appropriate approach, and well-designed observational studies are warranted to understand the possible role of ASMs pertaining to suicidal behaviour.
About the author: Dr. Sai Krishna Gudi is a Ph.D. student at the College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Canada. His research interests include studying medication use and its long-term effects in large populations; comparative effectiveness & medication-safety research; optimizing irrational drug-use & medication appropriateness (over-treatment), particularly among older adults; knowledge translation through evidence-based practice; pharmaceutical policy & health-services research; confounding & bias analysis; and systematic reviews, meta-analysis & network meta-analysis methods. Follow Dr. Gudi on Twitter @SaiKGudi
1. The World Health Organization (WHO). Mental Health Action Plan 2013-2020. 2014. https://apps.who.int/iris/bitstream/handle/10665/89966/9789241506021_eng.pdf;jsessionid=A5F5B3C6BEB895B2D286663846337A22?sequence=1
2. Raju Sagiraju HK, Wang CP, Amuan ME, Van Cott AC, Altalib HH, Pugh MJV. Antiepileptic drugs and suicide-related behavior: Is it the drug or comorbidity?. Neurol Clin Pract. 2018;8(4):331-339.
3. Caley CF, Perriello E, Golden J. Antiepileptic drugs and suicide-related outcomes in bipolar disorder: A descriptive review of published data. Ment Health Clin. 2018;8(3):138-147.
4. Williams Roberson S, Rehman R, Bucurescu G. Antiepileptic Drugs and Suicidality in Veterans with Seizures. Neurology. 2019;11(12) (In press).
5. Dreier JW, Pedersen CB, Gasse C, Christensen J. Antiepileptic Drugs and Suicide: Role of Prior Suicidal Behavior and Parental Psychiatric Disorder. Ann Neurol. 2019;86(6):951-961.
6. Mula M, Sander JW. Suicide and epilepsy: do antiepileptic drugs increase the risk? Expert Opin Drug Saf. 2015;14(4):553-8.
7. Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, Detyniecki K. Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy Behav. 2017;76:24-31.
8. Pompili M, Baldessarini RJ. Epilepsy: Risk of suicidal behavior with antiepileptic drugs. Nat Rev Neurol. 2010;6(12):651-3.
9. The United States Food and Drug Administration (US-FDA). Antiepileptic drugs and suicidality. 2008. https://www.fda.gov/files/drugs/published/Statistical-Review-and-Evaluation–Antiepileptic-Drugs-and-Suicidality.pdf.
10. Rissanen I, Jääskeläinen E, Isohanni M, et al. Use of antiepileptic or benzodiazepine medication and suicidal ideation-The Northern Finland Birth Cohort 1966. Epilepsy Behav. 2015;46:198-204.
11. Grimaldi-Bensouda L, Nordon C, Rossignol M, et al. Antiepileptic drugs and risk of suicide attempts: a case-control study exploring the impact of underlying medical conditions. Pharmacoepidemiol Drug Saf. 2017;26(3):239-247.
12. Molero Y, Larsson H, D’Onofrio BM, et al. Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden. BMJ. 2019;365:l2147.
13. Pompili M, Tatarelli R, Girardi P, Tondo L, Baldessarini RJ. Suicide risk during anticonvulsant treatment. Pharmacoepidemiol Drug Saf. 2010;19(5):525-8.