Lithium, injectable psychotropics most effective for relapse prevention in patients with bipolar disease

By Naveed Saleh, MD, MS, for MDLinx
Published April 10, 2018

Key Takeaways

To prevent rehospitalization secondary to bipolar disease relapse, lithium may be the most effective mood stabilizer and long-acting injectable antipsychotics the most effect antipsychotics, according to a recent study published in JAMA Psychiatry.

Bipolar disorder results in a greater loss of disability-adjusted life years than do all causes of cancer combined and, according to the World Health Organization, is the sixth most common cause of disability worldwide.1

In this study, Jari Tiihonen, MD, PhD, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, and colleagues compared the long-term effectiveness of psychiatric medications in preventing rehospitalization secondary to relapse of bipolar disease.

“Some meta-analyses have shown clinically meaningful differences between pharmacotherapies in their comparative effectiveness of acute treatment,” write the authors, “but treatment guidelines until recently did not recognize such differences.”

To date, studies examining the efficacy of drugs in the prevention of relapse of bipolar disorder have been limited to a few agents, and none had assessed the efficacy of long-acting antipsychotic injections vs their oral counterparts.  

In this cohort study, Dr. Tiihonen and colleagues used national databases to identify all patients hospitalized in Finland between January 1, 1987, and December 31, 2012 with bipolar disorder. They prospectively gathered information about hospitalizations, including the incidence, duration, and cause of rehospitalization; dispensed medications; and deaths.

Researchers included 18,018 patients (average age: 46.6 years; 9,558 women) with a mean follow-up of 7.2 years (128,353 person-years for the entire cohort), of whom 54.0% experienced at least one psychiatric rehospitalization.

To limit selection bias, subjects served as their own controls (ie, within-individual analysis). Study results were adjusted for other psychiatric medications, illness duration, and arrangement in time of exposure and nonexposure periods. To limit bias, sensitivity analyses were performed.

According to the researchers, the current study’s most important finding is that long-acting injections of antipsychotics resulted in better clinical outcomes than did identical oral antipsychotics. Patients who are administered long-acting injections of antipsychotics are at a 30% lower risk of psychiatric and all-cause hospitalization as compared with when these patients take the corresponding oral antipsychotics.

Use of the following specific drugs was associated with the lowest risk of relapse and psychiatric rehospitalization:

  • Risperidone long-acting injection (LAI) (HR: 0.58; 95% CI: 0.34-1.00)
  • Gabapentin (HR: 0.58; 95% CI: 0.44-0.77)
  • Perphenazine LAI (HR: 0.60; 95% CI: 0.41-0.88)
  • Lithium carbonate (HR: 0.67; 95% CI: 0.60-0.73)

However, according to the researchers, upon multivariate adjustment risperidone LAI did not remain statistically significant. Moreover, gabapentin did not clear sensitivity analysis. Taken as a whole, the researchers suggest that results for these specific drugs should be considered gingerly.

Dr. Tiihonen and colleagues also found the following:

  • Lithium was associated with the lowest risk of all-cause hospitalization, as well as a substantial reduced risk for psychiatric hospitalization (HR: 0.71; 95% CI: 0.66-0.76).
  • Quetiapine, the most widely used specific agent documented in this study, resulted in only an 8% risk reduction in relapse, making it unsuitable for this indication.
  • Benzodiazepine use was associated with an increase risk of both psychiatric and all-cause hospitalization. Nevertheless, the researchers write that “we cannot rule out that some of the observed association with an increased risk for hospitalization with benzodiazepines comes from patients with an acutely worsened state of comorbid anxiety or a substance abuse disorder.”
  • LAI formulations reduced risks of relapse leading to psychiatric hospitalization and all-cause hospitalizations due to mental or somatic illness by 30% compared to that achieved with identical oral antipsychotics.

“Although more research is needed to support the notion, LAIs might offer a safe and effective option for relapse prevention in bipolar disorder for patients for whom lithium is not suitable,” noted Dr. Tiihonen and fellow researchers.

They concluded with the recommendation that lithium “should remain as the first line of treatment for bipolar disorder, after decades of underprescription,” and suggest that “LAIs might offer a safe and effective option for relapse prevention in bipolar disorder for patients for whom lithium is not suitable.”

This study was supported by the Finnish Ministry of Social Affairs and Health.


  1. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743-800.
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