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Original Investigation
April 2018

Real-world Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder

Author Affiliations
  • 1Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital, Kuopio, Finland
  • 2Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 3Impact Assessment Unit, National Institute for Health and Welfare, Helsinki, Finland
  • 4Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland
  • 5School of Pharmacy, University of Eastern Finland, Kuopio, Finland
  • 6EPID Research Oy, Espoo, Finland
  • 7Hospital Clinic, Institute of Neuroscience, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Catalonia, Spain
JAMA Psychiatry. 2018;75(4):347-355. doi:10.1001/jamapsychiatry.2017.4711
Key Points

Question  What is the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in bipolar disorder?

Findings  In this Finnish nationwide cohort study of 18 018 patients, lithium use was associated with the lowest risk of rehospitalization because of mental or somatic disorder. The risk of rehospitalization was about 30% lower during treatment with long-acting injections compared with treatment with their oral counterparts.

Meaning  In bipolar disorder, lithium should remain the first line of treatment, and long-acting injections might offer a safe, effective option for patients in whom lithium is not suitable.


Importance  Mood stabilizers and antipsychotics are the main maintenance treatments for bipolar disorder. Lithium is considered to be the most effective mood stabilizer, but very little is known about overall health outcomes associated with specific treatments and the comparative long-term effectiveness of specific psychotropics or routes of administration in the prevention of rehospitalizations.

Objective  To study the comparative effectiveness of pharmacologic treatments in the prevention of rehospitalization in a nationwide cohort of patients with bipolar disorder.

Design, Setting, and Participants  This cohort study examined the risk of psychiatric, cardiovascular, and all-cause hospitalization from January 1, 1987, to December 31, 2012, among all patients in Finland who had been hospitalized for bipolar disorder (N = 18 018; mean follow-up time, 7.2 years) using prospectively gathered nationwide databases for hospitalization and dispensed medications. The primary analysis was within-individual analysis, in which each individual was used as his or her own control to eliminate selection bias. The study adjusted for the effect of concomitant psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods. Statistical analysis was conducted from January 1, 1996, to December 31, 2012.

Main Outcomes and Measures  Adjusted hazard ratios (HRs) for rehospitalization were calculated.

Results  Among the cohort (9558 women and 8460 men; mean [SD] age, 46.6 [17.0] years), 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. In comparison between use and no use among specific agents reaching nominal statistical significance, risperidone long-acting injection (HR, 0.58 [95% CI, 0.34-1.00]), gabapentin (HR, 0.58 [95% CI, 0.44-0.77]), perphenazine long-acting injection (HR, 0.60 [95% CI, 0.41-0.88]), and lithium carbonate (HR, 0.67 [95% CI, 0.60-0.73]) were associated with the lowest risk of psychiatric rehospitalization. Concerning all-cause hospitalization, lithium (HR, 0.71 [95% CI, 0.66-0.76]) was associated with the lowest risk. The most frequently used antipsychotic treatment, quetiapine fumarate, showed only modest effectiveness (risk of psychiatric rehospitalization: HR, 0.92 [95% CI, 0.85-0.98]; risk of all-cause hospitalization: HR, 0.93 [95% CI, 0.88-0.98]). Long-acting injections were associated with substantially better outcomes compared with identical oral antipsychotics (risk of psychiatric rehospitalization: HR, 0.70 [95% CI, 0.55-0.90]; risk of all-cause hospitalization: HR, 0.70 [95% CI, 0.57-0.86]). Results from sensitivity analyses showed consistent beneficial effects only for lithium and for long-acting injections compared with their oral counterparts.

Conclusions and Relevance  Lithium was the most effective mood stabilizer, and long-acting injections the most effective antipsychotics, in preventing hospitalization due to mental or physical illness.