Mood Stabilizers Potential Lifesavers in Bipolar Disorder

Mood stabilizers protect against suicide and all-cause mortality in patients with bipolar disorder (BD), including natural mortality, with lithium emerging as the most protective agent, new research suggests.

Investigators led by Pao-Huan Chen, MD, of the Department of Psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in over 25,000 patients. with BD and found that those with BD had higher mortality.

However, they also found that patients with BD had a significantly decreased 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.

“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.

“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological conditions of patients with bipolar disorder,” they add.

The study was published online November 11 in Acta Psychiatrica Scandinavica.

Research gap

Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.

Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”

To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.

The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”

Covariates included sex, age, employment status, comorbidities, and concomitant drugs.

Of the patients with BD, 4000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.

Cardioprotective Effects?

The standardized mortality ratios (SMRs) — the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population — were:

Cause of death

SMR (95% CI)


5.26 (5.10-5.43)


26.02 (24.20-27.93)

Natural causes

4.68 (4.51-4.85)

The cumulative mortality rate was higher among men vs women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios [HRs], .60 and .52, respectively; both Ps < .001).

The suicide risk peaked between the ages of 45 and 65 years, while the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.

Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.

Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).

Mood stabilizer

Mortality type

Adjusted HR (aHR)








Natural causes









Natural causes


Valproic acid



Valproic acid



Valproic acid

Natural causes


Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.

Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).

Mortality type

Duration aHR

Cumulative dose aHR

P value




< . 001




= .002

Natural causes



< . 001

Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.

The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health or patients with BD,” the investigators note.

The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.

Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.

The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyzes were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.

The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, due to the narrow therapeutic index.”

First-line treatment

Commenting for Medscape Medical NewsRoger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality suicide mortality and natural mortality.”

McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to the document.” the effect.”

But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potential especially in such a large sample.”

The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said McIntyre.

This research was supported by grants from the Ministry of Science and Technology, Taiwan, and Taipei City Hospital, Taipei City, Taiwan. The authors declare no relevant financial relationships. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai , Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, Atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

Acta Psychiatr Scand. Published online November 11, 2022. Abstract

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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