Suicide remains a critical global public health issue, significantly contributing to disability and mortality worldwide. Each year, more than 700,000 individuals die by suicide, with an estimated 25 suicide attempts for every death (World Health Organization, 2022). Research consistently highlights a strong link between elevated suicide rates and mental disorders, particularly depression and alcohol use disorders (World Health Organization, 2021).
Selective serotonin reuptake inhibitors (SSRIs) represent a newer class of antidepressants widely prescribed for treating various mental health conditions, including depression, anxiety, and other mood disorders. While SSRIs are generally effective and associated with relatively mild side effects, concerns have been raised about their potential to induce suicidality (e.g. see this blog). However, research exploring this connection has produced mixed findings. Some studies indicate a significant increase in suicide-related outcomes among SSRI users compared to those on placebo, while others suggest a protective effect or no significant impact on suicide risk (Emslie et al, 2006; Kasper 1997, Cooper et al., 2014; Montgomery et al., 1995).
Given these conflicting results, a recent network meta-analysis (Yuling et al, 2024) aims to address two key objectives:
- To synthesise the evidence regarding the efficacy of specific SSRIs in individuals with suicidal ideation, as measured by various suicide-related scales
- To evaluate the impact of SSRIs on suicide behaviour outcomes.
Do antidepressants protect against suicide, or can they actually increase our risk of suicide?
Methods
Six electronic databases were comprehensively searched.
The inclusion criteria for this analysis were:
- Studies addressing a range of mental disorders, not limited exclusively to major depressive disorder (MDD).
- Intervention groups consisting of patients treated with SSRIs, either alone or in combination with non-SSRIs, while control groups received either placebo or active placebo.
- Randomized controlled trials (RCTs) reporting mean scores, changes (with standard deviation) on relevant suicide scales, or the number (percentage) of suicide-related behaviours.
- Outcome data collected within 10 weeks of starting treatment.
- Studies had a randomized, double-blind design.
Exclusion criteria: studies with sample size less than ten or those only focused on the side effects of drug dose reduction.
The primary outcome was suicidal ideation assessed using the standardised mean difference (SMD) derived from the mean or mean change of suicide-related-scales. The secondary outcome encompassed the full range of suicidal behaviours from preparatory acts to death by suicide.
The risk of bias was independently assessed by two authors using the RoB 2 tool (Sterne et al., 2019).
Network meta-analysis (NMA) was performed using a frequentist approach. The authors assessed the impact of SSRIs on suicidal ideation at weeks 2 and 8, examining both short- and long-term effects, and analysed the occurrence of suicidal behaviour from weeks 1 to 10 due to the limited number of studies.
Results
29 double-blind randomised controlled trials (RCTs) involving 6,603 patients, comparing 12 different antidepressants with a placebo were included.
The overall risk of bias was rated as low in 13.8 %, unclear in 34.5%, and high in 51.7 % of the studies. The SSRIs in these RCTs were escitalopram, citalopram, paroxetine, fluoxetine, and sertraline.
Suicidal ideation
All RCTs targeted adults or the elderly for the week 2 outcome, whereas two RCTs included children and adolescents for the week 8 outcome.
Seven studies provided data for week 2 outcomes. When compared to placebo, an overall protective effect of most antidepressants, except sertraline, was observed. Among the SSRIs, paroxetine (SMD = -2.26, 95 % CI -3.27 to -1.25), fluoxetine (SMD = -1.96, 95 % CI -2.65 to -1.26), and escitalopram (SMD = -1.18, 95 % CI -2.01 to -0.34) were associated with a lower risk of suicidality. However, sertraline (SMD = -0.04, 95 % CI -0.36 to 0.29) did not show a significant decreasing or increasing suicidality risk. Non-SSRIs (SMD = -2.01, 95 % CI -2.95 to -1.07), including amitriptyline and bupropion, also showed a significant protective effect.
Nine RCTs provided data for week 8 outcomes, the results showed a lack of evidence for a protective or risky effect of specific SSRIs or non-SSRIs which included desipramine, imipramine, and bupropion.
Sensitivity analyses focusing on studies that only recruited adult patients, excluded imputed data, had low or some risk of bias, were industry-sponsored, targeted patients with MDD, and excluded baseline suicidality showed no relationship between SSRI or non-SSRI use and suicidal ideation at week 8. In sensitivity analyses when only those studies with a high risk of bias were analysed, fluoxetine appeared to limit suicidal ideation. However this finding was also found when non-industry sponsored studies were analysed, leading the authors to suggest that some studies without sponsorship were of lower quality and tending to report a beneficial effect of fluoxetine.
Suicidal behaviour
There were no significant effects of any one SSRI over the others at weeks 1–10 on suicidal behaviours. Thus, there was a lack of evidence supporting the preventive or risk-increasing effect of SSRIs on suicidal behaviour. When compared to placebo, the differences between antidepressants and placebo was uncertain. For SSRIs, the OR and 95 % CI were as follows: escitalopram (OR = 0.98, 95 % CI 0.25 to 3.84), sertraline (OR = 0.99, 95 % CI 0.14 to 7.10), citalopram (OR = 1.08, 95 % CI 0.16 to 7.37), and fluoxetine (OR = 2.30, 95 % CI 0.77 to 6.86). Non-SSRI (OR = 1.43, 95 % CI 0.33 to 6.26) included milnacipran, clomipramine, tianeptine, and bupropion. Given that the 95% confidence interval of all odds ratios included 1, there was no significant difference between drug and placebo in each case.
Results revealed a lack of evidence to support the notion that antidepressants are either risk factors for, or protective factors against suicide, 8 weeks after starting medication.
Conclusions
- This paper shows that when compared to placebo, SSRIs (paroxetine, fluoxetine, and escitalopram) showed a beneficial effect in significantly reducing suicidality at week 2, but this effect had reduced by week 8.
- In contrast sertraline did not significantly decrease or increase suicidal ideation.
- This paper also suggests a protective effect of non-SSRI treatments (amitriptyline and bupropion) on suicidal ideation compared with placebo at week 2.
- In addition no significant effect (positive or negative) of SSRIs on suicidal behaviour was observed between weeks 1 and 10.
Some antidepressants reduced suicide ideation at week 2, but these effects had faded by week 8.
Strengths and limitations
This is the first study to draw conclusions relating to SSRIs, suicidal ideation and suicidal behaviours by combining standardised mean difference and odds ratio outcomes to interpret suicidal ideation and behaviour.
The main conclusion the authors draw is that SSRIs may reduce suicidal ideation in the short-term, but this is not sustained even to week 8 of treatment. However, they did not discuss the potential interplay of this short-term effect with SSRI-induced impulsivity in the early days after commencing treatment, especially in patients with high levels of guilt. Impulsivity might interact negatively with their emotional state, potentially complicating the initial phase of treatment making people more liable to suicidal behaviour. We know the interplay between initial improvements in ideation and the risk of impulsivity can have significant implications for how SSRIs are prescribed and monitored, particularly in vulnerable populations, such as adolescents and young adults who are often considered at higher risk for SSRI-induced impulsivity.
The study differentiated the effects of specific SSRIs, highlighting the efficacy of paroxetine, fluoxetine, and escitalopram in protection from suicidal ideation, while noting the lack of significant impact of sertraline. It also extended beyond SSRIs to assess non-SSRI antidepressants (e.g., amitriptyline, bupropion), offering a broader perspective on antidepressant efficacy in suicidality.
The effect of SSRIs on suicide-related outcomes may be mediated by their effect on depression relief and of course across the studies the severity of depression varied. The authors acknowledged that because there was a diverse range of scales used to measure baseline and endpoint disease severity, this hindered comparability limiting the ability to synthesise findings in meaningful ways.
Certain important subgroup analyses or meta-regressions could not be performed because of the different scales used to measure different types of suicide-related outcomes and because some studies failed to report suicide-related outcomes or prioritise them when recording adverse events. This under-reporting reduces the accuracy of the data and may lead to an underestimation of suicide risks, weakening the statistical effect of the findings.
Only a small percentage (13.8%) of the included studies were assessed as having a low risk of bias, which may have restricted the study’s ability to accurately detect suicide risk.
This network meta-analysis predominantly consisted of RCTs with short treatment durations, ranging from 6 to 10 weeks, which restricted the observation of the long-term effects of SSRIs.
Low Bias, High Stakes: Just 13.8% of Studies had low bias, potentially limiting this review’s ability to accurately detect suicide risks.
Implications for practice
These results suggest that SSRIs may alleviate suicidal ideation in the short term, but may not reduce the occurrence of suicidal behaviours. Paroxetine, fluoxetine and escitalopram may be preferrable over sertraline in this respect.
Analysis based on suicidal behaviour revealed a non-significant difference in the anti-suicidal effects between SSRIs and placebo, suggesting that SSRI treatment may not prevent suicidal behaviour. Alternative risk management options need to be carefully thought of rather than relying on medication management.
SSRIs were also found to be inconsequential in increasing or decreasing the risk of suicidal ideation and / or behaviours. For patients as well as relatives, carers and friends worried about SSRIs increasing suicide risk, this may be reassuring.
Further investigations are needed to strengthen this evidence and understand the underlying mechanisms responsible for the effects of SSRIs on suicidality.
These results are reassuring for patients and carers who are worried about antidepressants increasing suicide risk.
Statement of interests
No conflicts to declare.
Links
Primary paper
Yuling Li, Chengfeng Chen, Qinghua Chen, Shiqi Yuan, Wanyuan Liang, Yikang Zhu, Bin Zhang (2024) Effects of selective serotonin reuptake inhibitors (SSRIs) on suicide: A network meta-analysis of double-blind randomized trials. Psychiatry Research, Jun:336:115917. doi: 10.1016/j.psychres.2024.115917
Other references
Badenoch, D. In adults with major depression, antidepressants may increase the risk of suicide. The Mental Elf, September 2019.
Cooper W.O. et al. Antidepressants and suicide attempts in children. Pediatrics 2014
Emslie G. et al., Columbia Suicidality Classification Group; TADS Team. Treatment for Adolescents with Depression Study (TADS): safety results. J. Am. Acad. Child Adolesc. Psychiatry 2006
Kasper S. The place of milnacipran in the treatment of depression. Hum. Psychopharmacol.: Clin. Exper. 1997
Montgomery S. A. et al., Reduction of suicidal thoughts with paroxetine in comparison with reference antidepressants and placebo. Eur. Neuropsychopharmacol. 1995
Sterne J.A.C. et al., RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366, 14898. 2019.
World Health Organization, 2022. World Suicide Prevention Day 2022 – Creating hope Through Action.
World Health Organization, 2021. Suicide (who.int).
Photo credits
- Photo by Myriam Zilles on Unsplash
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