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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lähteenvuo reported being a major shareholder and board member at Genomi Solutions Ltd, a Finnish based bioinformatics company; receiving research grants or awards from Boehringer-Ingelheim; receiving travel grants from Sunovion Ltd; and working as a coordinator for a research project funded by the Stanley Foundation. Dr Tanskanen reported participating in research projects funded by Janssen Cilag and Eli Lilly with grants paid to the Karolinska Institutet and serving as a member of the advisory board for Janssen-Cilag. Dr Taipale reported participating in research projects funded by Janssen-Cilag and Eli Lilly, with grants paid to the Karolinska Institutet. Dr Hoti and Ms Vattulainen are employed by EPID Research, which is a contract research organization that performs commissioned pharmacoepidemiologic studies; thus, its employees have been and currently are working in collaboration with several pharmaceutical companies. Dr Vieta reported receiving grants and serving as consultant, advisor, or continuing medical education speaker for AB-Biotics, Aequus, Adamed, Alexza, Allergan, Almirall, AstraZeneca, Bial, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Elan, Eli Lilly, Esteve, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Pierre-Fabre, Rovi, Qualigen, Roche, Sanofi, Servier, Schering-Plough, Shire, Solvay, Sunovion, Takeda, Telefónica, Teva, the Spanish Ministry of Science and Innovation, the Seventh European Framework Programme, the Stanley Medical Research Institute, United Biosource Corporation, and Wyeth. Dr Tiihonen reported serving as a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, F. Hoffman–La Roche, Janssen-Cilag, Lundbeck, Organon, and Finnish Medicines Agency; receiving fees for giving expert testimony to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Otsuka, and Pfizer; receiving lecture fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Novartis, Otsuka, and Pfizer; receiving grants from Stanley Foundation and Sigrid Jusélius Foundation; serving as a member of advisory boards for AstraZeneca, Eli Lilly, Janssen-Cilag, and Otsuka; and having research collaboration with Lilly and Janssen-Cilag.

Figures

Figure 1.. Within-Individual Analysis of Psychiatric Hospitalization

Hazard ratios (HRs) for the risk of psychiatric hospitalization for different medications. Mood stabilizers are indicated with orange squares, antipsychotics with blue squares, and other psychotropics with gray squares. The last line describing pooled HRs for long-acting injections (LAIs) vs equivalent oral antipsychotic treatments was carried out in a separate analysis (eg, risperidone LAI vs risperidone oral). aSignificant P value after Benjamini-Hochberg correction for 5% false discovery rate (FDR).

Figure 2.. Within-Individual Analysis of All-Cause Hospitalization

Hazard ratios (HRs) for the risk of all-cause hospitalization for different medications. Mood stabilizers are indicated with orange squares, antipsychotics with blue squares, and other psychotropics with gray squares. The last line describing pooled HRs for long-acting injections (LAIs) vs similar oral antipsychotic treatments was carried out in a separate analysis (eg, risperidone LAI vs risperidone oral). aSignificant P value after Benjamini-Hochberg correction for 5% false discovery rate (FDR).

Figure 3.. Within-Individual Analysis of Cardiovascular Hospitalization

Hazard ratios (HRs) for risk of cardiovascular hospitalization for different medications. Mood stabilizers are indicated with orange squares, antipsychotics with blue squares, and other psychotropics with gray squares. LAI indicates long-acting injection. aSignificant P value after Benjamini-Hochberg correction for 5% false discovery rate (FDR).