You lack the season of all natures, sleep

“You lack the season of all natures, sleep.”

—Shakespeare, William. Macbeth. 3-4-141

More than 48,000 deaths by suicide were reported per year in the United States and this number is probably underreported.¹ Innumerable studies have validated that insomnia is linked to suicidal ideation,^2–4 suicide attempts,^5–7 and death by suicide.^8–10 A nationwide cohort study from China that was published in 2018 remarked that suicide risk in patients with insomnia was 3.533-fold that of patients without insomnia.¹¹ Finding interventions to reduce insomnia targeted in populations with a high risk of suicide has been challenging and a controversial debate.

Among antipsychotic agents, clozapine and lithium have been proven to have anti-suicidal properties, yet their mechanism remains unclear.¹² Clozapine is the only antipsychotic that was approved by the U.S. Food & Drug Administration (FDA) in the United States, Finland, and Sweden to prevent suicide risk in schizophrenia.^13,14 A Danish cohort study came to the conclusion that clozapine decreased the suicide rate during current use, yet also found that the suicide rate associated with cumulative clozapine use was higher than that for cumulative use of other antipsychotics.¹⁵ Lithium was associated with reducing the risk of suicide death in bipolar disorder (Finnish cohort study¹⁶) and in randomized controlled trials in mood disorders (Cipriani et al¹⁷). A narrative review of more than 20 years of evidence from the suicide-prevention effect of lithium provided strong support that lithium-treated patients have a reduced risk of suicide as well as a reduced risk of mortality from other causes when compared with other drugs (eg, valproate) and placebo.¹⁸ However, there is limited evidence to conclude whether patients on clozapine and lithium would have a decreased risk of suicidal ideation and attempts once their insomnia improves. Interestingly, the University of Toronto used a mining approach to potentially generate a greater understanding of clozapine side effects in the real world and found that insomnia was significantly reported, in addition to other common side effects.¹⁹ Whether insomnia and suicide risk coexist as potential side effects of second-generation antipsychotics and mood stabilizers remains unknown.

In this issue of the Journal of Clinical Sleep Medicine, Miller and McCall²⁰ performed a systematic review with resources obtained from the FDA Adverse Event Reporting System (FAERS) from inception in 1968 through February 2021 to investigate the prevalence and reported odds of spontaneously reported psychiatric adverse drug reactions of insomnia and suicide ideation/behavior/death (SIB) in adults for second-generation antipsychotics (SGA) and mood stabilizers as opposed to clozapine and lithium, respectively. FAERS is a publicly available database that contains adverse-event medication error reports and product quality complaints, which are submitted by both health care professionals and consumers. The authors used 10 different SGAs and 5 different mood stabilizers in this review. Miller and McCall included all data on adults aged 18 to 64 years on SGAs or mood stabilizers during those periods of time. Data from “psychiatric disorders” were obtained from FAERS as a primary reaction group, with “insomnia” as the specific reaction, as well as “suicidal ideation,” “suicide attempts,” and “completed suicide” as SIB adverse effects. The results are impressive, with a large amount of data including 74,577 and 25,724 psychiatric adverse events for SGAs and mood stabilizers, respectively. Clozapine had a lower prevalence of both insomnia (3%) and SIB (16%). Lithium showed similar results for both insomnia (5.6%) and SIB (27%). For the second aim of this study, a bivariate correlation coefficient (Pearson’s r) was applied. Compared with clozapine, all other SGAs were associated with significantly increased reported odds of insomnia (reporting odds ratio (rOR) = 2.41–9.70) and SIB (r odds ratio [rOR] = 1.18–2.72). Compared with lithium, all other SGAs were associated with significantly increased reported odds of insomnia (rOR = 1.06–1.66), yet the latter finding was only significant for lamotrigine.

This paper is the first study to systematically review insomnia and SIB adverse effects for several SGAs and mood stabilizers. Using FAERS to obtain potential adverse events from the inception date until now is a wise way to capture the majority of reported events and probably leaves underreported events that makes it unique and reliable enough. These results were consistent with previous studies that clozapine and lithium continue to be associated with significantly reduced risk of SIB. Besides, no previous studies have shown whether improvement in insomnia in adults who use clozapine or lithium would decrease SIB. Miller and McCall successfully presented significant rORs between insomnia and SIB to show a positive correlation. This is a promising approach to shine a light on explicating the pathway of potential beneficial effects on sleep for clozapine and lithium. The article also provided several theories on mechanisms by which clozapine and lithium were associated with reduced risk of suicide, such as glycogen synthase kinase-3 and histamine H1 receptor antagonists. They proposed a next step which is measuring changes in insomnia, SIB, hyperarousal, and a pupillary light reflex test upon initiating clozapine and lithium to uncover potential underlying biological mechanisms to provide more hope for populations at high risk of suicide.

DISCLOSURE STATEMENT

The author reports no conflicts of interest.