A new meta-analysis of modern lithium trials found no evidence that the drug prevents suicide or non-fatal suicidal behavior. The study included 12 randomized controlled trials ( RCTs ) comparing lithium with placebo or usual care for mood disorders, enrolling 2,578 participants. The researchers found that the difference between lithium and placebo for all suicide-related outcomes was not statistically significant.
The study was led by Joanna Moncrieff of University College London, who recently gained media attention for a review that debunked the low serotonin (“chemical imbalance”) theory of depression.
Reached for comment via email, Moncrieff said:
“The idea that lithium prevents suicide added to its mystique and helped propagate the idea that lithium is a highly specific and effective treatment. But that never made sense. Lithium is a sedative substance highly toxic.It dampens emotions, which could reduce suicidal thoughts, but we know that many psychiatric drugs have this emotional dampening effect and yet do not reduce suicidal behavior.
Previous studies have come to conflicting conclusions about the supposed anti-suicidal properties of lithium. For example, a recent large RCT on lithium for suicide prevention in veterans was prematurely terminated because the drug was found to be no better than a placebo. However, other analyzes showed that lithium was slightly better than a placebo.
For this reason, even some experts who acknowledge the weak evidence base for almost all psychiatric drugs – such as Nassir Ghaemi – believe that lithium has a stronger evidence base. Some have even called for adding lithium to drinking water.
According to the current researchers, one of the reasons for the inconsistent results is that previous meta-analyses used Peto’s method. In the Peto method, studies in which suicide deaths do not occur are discarded – only studies in which the event does occur are analyzed.
The researchers write: “Because suicide is so rare, many trials with relevant data were not included in these analyses, which may have inflated treatment effects.”
Another related problem is that since so few people die by suicide, results can be skewed by a single trial with poor methodology. The researchers write that previous meta-analyses may have been skewed by such a trial: a study by Lauterbach et al. in which the blind was broken, many participants did not adhere to treatment, and the lithium group received additional care.
In contrast, the current study used data from all relevant lithium trials for mood disorders (including depression and bipolar disorder) in adults since the year 2000. The researchers did not included only studies that lasted at least 12 weeks from the short-term studies. tend to artificially inflate the effects of treatment. The researchers followed the PRISMA guidelines for conducting a systematic review and pre-specified their outcome measures.
“A previous meta-analysis of lithium trials claimed to confirm it had anti-suicidal properties, and it was very influential, but it only included trials in which there had been suicide, excluding the majority of trials in which none occurred. Therefore, we wanted to perform an analysis including all data from randomized trials. We showed that if you did that, the claim that lithium reduces suicide is quite fanciful and not supported by evidence from randomized trials,” Moncrieff said.
Of the 2,578 participants, two died by suicide in the lithium group (0.2%), while five died by suicide in the placebo or usual care group (0.4%). This difference was not statistically significant, which means that such a difference is what one would expect by chance, given such small numbers.
Only seven trials included the outcome of non-fatal suicidal behavior. Of the 1975 participants in these trials, 81 (6.3%) in the lithium group versus 85 (6.5%) in the placebo group had non-fatal suicidal behavior. Again, this difference was not statistically significant.
It’s not just the modern studies either – in a further analysis the researchers included 15 other studies from before 2000. Their results were unchanged – the drug is no better than the placebo.
To see if this finding was due to the specific type of analysis used, the researchers reanalyzed their data using other meta-analytic methods. All of these tests found no difference between lithium and placebo.
“The idea that lithium helps prevent suicide really should be put to bed now. The latest, and by far the largest, trial of its anti-suicidal effects was even stopped early because it was so obvious that “there was no effect. Yet some psychiatrists are so enamored with lithium that it will likely persist. Amazingly, some still demand that lithium be added to drinking water and use arguments about its anti-suicidal properties like justification “God forbid!” said Moncrieff.
Nabi, Z., Stansfeld, J., Plöderl, M., Wood, L. and Moncrieff, J. (2022). Effects of lithium on suicide and suicidal behavior: systematic review and meta-analysis of randomized trials. Epidemiology and Psychiatric Sciences, 31(e65), 1–11. https://doi.org/10.1017/S204579602200049X (Full text)