Another antidepressant has been linked in a clinical trial to increases in suicidal thoughts – specifically in male patients. This time, though, the antidepressant was one of the older tricyclic variety, while the comparator drug was one of the selective serotonin re-uptake inhibitors (SSRI) more commonly associated with suicidality.

The GENDEP (Genome-Based Therapeutic Drugs for Depression (GENDEP) trial compared suicidal ideation scores in 811 adults with moderate to severe unipolar depression who were allocated to flexible dosages of the tricyclic antidepressant (TCA) nortriptyline (Pamelor, Aventyl, Sensoval) or the SSRI escitalopram (Lundbeck/Forest Laboratories’ Lexapro/Cipralex) for a period of 12 weeks.

An international team led by Dr Nader Perroud from the Institute of Psychiatry at Kings College London in the UK conducted the multicentre, part-randomised, open-label study, results from which were published in the open-access journal BMC Medicine.

As the authors note, more than 100,000 men and women commit suicide every year in Europe. Mental disorders, particularly depression, are present in more than 90% of suicides and over 80% of these disorders are untreated at the time of death.

Recent randomised controlled trials in adults, however, have “left the verdict open” as to whether antidepressants actually reduce suicidal thoughts and behaviour, Perroud et al comment.

As they point out, reports of increased suicide-related adverse events during treatment with SSRIs and other antidepressants compared with placebo have prompted regulatory bodies in the US and Europe to issue warnings about the risk of suicide during the first weeks of drug therapy. These warnings “have had an impact on prescribing and may have paradoxically increased the risk of suicide in the population”.

Perhaps the most clinically relevant, “but as yet unanswered”, question is whether a specific type of antidepressant, such as the SSRIs, is associated with a higher risk of treatment emergent suicidal ideation (TESI), the authors write. A number of previous investigations have looked at the emergence of suicidal ideation in individuals who reported no such symptoms at baseline.

While this approach “highlights the relatively rare cases with de novo treatment of emergent suicidal ideation, the potential for worsening of existing suicidal ideation during treatment remains relatively unexplored, thus risking ‘throwing the baby out with the bath water’ through removing a large portion of patients at risk”, Perroud et al say.

Composite score

Suicidal ideation in the GENDEP trial was assessed through a composite score based on the third item of the 17-item Hamilton Rating Scale for Depression (HRSD-17), the ninth item of the self-reported 19-item Beck Depression Inventory (BDI), and the 10th item of the clinician-rated 10-item Montgomery-Asberg Depression Rating Scale.

The item response theory (IRT) graded response model was then used to derive the best estimate of suicidal ideation from the suicidal items of the three rating scales. Increases in this score were classified as TESI or as treatment worsening suicidal ideation (TWOSI), according to the absence or presence of suicidal ideation at baseline.

Gender effect

The results showed that treatment with either antidepressant was associated with a significant reduction in suicidal ideation over time. The mean suicidal score was higher in the nortriptyline group throughout the study but the difference was not significant after adjustment for the baseline suicidal score, the authors reported.

Just over 17% or 57 of the trial participants with no baseline suicidal ideation qualified for the TESI definition at some point during follow-up. There was a significant gender-by-drug interaction, with a higher risk of TESI in men taking nortriptyline than in those taking escitalopram.

In all, 20.93% (nine out of 43) of the men on nortriptyline had TESI compared with 10.67% (eight out of 75) of the escitalopram group. This outcome just missed the threshold for statistical significance, though, after adjustment for baseline severity of depression and severity of depression during the study.

Of the 473 trial subjects who reported significant suicidal ideation at baseline, 42% or 197 qualified for the TWOSI definition at some point during treatment. Again, there was a drug-by-gender interaction, with 43.4% (33 out of 76) of the men on nortriptyline showing TWOSI symptoms compared with 33.7% of the men taking escitalopram.

This interaction remained significant after adjustment for baseline severity of depression and severity of depression during the study.

While both SSRIs and TCAs were linked to a significant reduction in suicidal ideation in the GENDEP trial, clinicians “should be aware that TCAs are associated with at least equal risk of treatment-related suicidal ideation as SSRIs”, Perroud et al stated.