Lithium, LAIs Best Bet for Preventing Bipolar Rehospitalization

Batya Swift Yasgur, MA, LSW

March 15, 2018

Lithium is the most effective mood stabilizer, and long-acting injectable (LAI) antipsychotic drugs are the most effective antipsychotics for preventing rehospitalization of patients with bipolar disorder, new research shows.

Investigators found that compared to no treatment, treatment with lithium was associated with a 30% reduction in the risk for rehospitalization for either mental or physical disorders among patients with bipolar disorder. LAI drugs also appeared to reduce the risk for rehospitalization by 30%, compared to the same antipsychotic drugs delivered orally.

"The take-home message is that lithium and long-acting antipsychotic injections are associated with the lowest risk of psychiatric and all-cause rehospitalization," senior study author Jari Tilhonen, MD, PhD, professor, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

The study was published online February 28 in JAMA Psychiatry.

Low Remission Rates

"Long-term medication is often required to attain remission and prevent relapses" in patients with bipolar disorder, "although, even with advanced treatment protocols, rates of remission remain low," the authors write.

Many randomized clinical trials (RCTs) and meta-analyses have investigated the most efficacious treatments for preventing relapse, but those trials may not accurately "reflect the real-world effectiveness of therapies in their actual clinical application," the investigators write. Moreover, such trials often have "stringent" inclusion and exclusion criteria and limited follow-up times, they note.

Observational studies are "the most efficient way to obtain a good estimate on the overall real-world effectiveness of therapies for bipolar disorder," but previous observational studies were limited by the small number of agents investigated.

"We wanted to study if there are any clinically meaningful differences in the real-world effectiveness of pharmacological treatments for bipolar disorder.... No study including all widely used medications had been done before," Tilhonen said.

Moreover, no previous studies have compared the effectiveness of LAIs to their corresponding oral agents.

The current study "aimed to overcome these shortcomings in the largest and most complete register-based, real-world effectiveness study of pharmacotherapies for bipolar disorder," the authors state.

To investigate, the authors combined prospective registry data from several Finnish nationwide databases to identify patients who had been hospitalized for bipolar disorder between January 1, 1987, and December 31, 2012.

The databases enabled them to examine the incidences, durations, and reasons for rehospitalizations; obtain information about reimbursed medications dispensed from pharmacies; and retrieve information on deaths.

The primary analysis used a within-individual model, in which each individual was used as his or her own control to eliminate selection bias.

The researchers also adjusted for the effect of concomitant use of psychotropic medications, duration of illness, and the temporal orders of exposure and nonexposure periods.

The study cohort consisted of 18,018 people (mean age, 46.6 years [SD, 17.0 years]; n = 9558 women and 8460 men). The total observation time was 128,353 person-years, and the mean observation (follow-up) time was 7.2 years (range, 1 day to 17.0 years).

A total of 9721 patients (54.0%) underwent one or more psychiatric rehospitalization.

During the study period, there were 82,858 hospitalizations for any cause (approximately 4.6 per individual). Of those, 36,131 were psychiatric hospitalizations (approximately 2.0 per individual), and 4862 were hospitalizations for cardiovascular reasons (approximately 0.3 per individual).

No Surprises

When the researchers compared use of specific agents with the absence of use for agents that reached nominal statistical significance, risperidone LAI, gabapentin, perphenazine LAI, and lithium carbonate were associated with the lowest risk for psychiatric rehospitalization (for risperidone LAI: hazard ratio [HR], 0.58; 95% confidence interval [95% CI], 0.34 -1.00]; for gabapentin: HR, 0.58; 95% CI, 0.44 - 0.77; for perphenazine LAI: HR, 0.60; 95% CI, 0.41 - 0.88]; for lithium carbonate: HR, 0.67; 95% CI, 0.60 - 0.73).

Lithium was also associated with the lowest risk of all-cause hospitalization (HR, 0.71; 95% CI, 0.66 - 0.76).

LAIs were associated with substantially better outcomes, compared with identical oral antipsychotics, in risk for psychiatric hospitalization and all-cause hospitalization (HR, 0.70; 95% CI, 0.55 - 0.90; and HR, 0.70; 95% CI, 0.57 - 0.86, respectively).

After sensitivity analyses were conducted, only lithium and LAIs (in contrast to their their oral counterparts) showed consistent beneficial effects.

Notably, quetiapine fumarate — the most frequently used antipsychotic — showed only "modest effectiveness" in risk for psychiatric and all-cause rehospitalization (HR, 0.92; 95% CI, 0.85 - 0.98; and HR, 0.93; 95% CI, 0.88 - 0.98, respectively).

Use of benzodiazepine was associated with an increased risk for psychiatric and all-cause rehospitalization.

As a therapeutic group, the mood stabilizers were associated with an increased risk for cardiovascular hospitalization, but once each individual mood stabilizer was examined, only valproic acid and carbamazepine were found to be associated with such risk.

When the three most frequently used medications were compared, lithium was found to be associated with the lowest incidence of hospitalization due to physical Illness, followed by valproate and quetiapine.

Tilhonen said that he was "not very surprised by the findings," because "there has been some information in previous studies on the superiority of lithium, although not for all-cause hospitalization."

However, "the results for LAIs vs orals had not been studied before," he pointed out.

The findings in the current study of bipolar disorder were similar to those from a previous study that he and his team conducted among patients with schizophrenia, he said.

Use Lithium With Caution

Commenting on the study for Medscape Medical News, Stefan Leucht, MD, professor of psychiatry, Technical University of Munich, Germany, who was not involved with the study, discussed the advantages and disadvantages of studies based on national registries.

He noted that such RCTs have "several problems" — for example, "the population of patients is not necessarily the same as those we find in routine care."

He said that although national registry studies have the advantage of covering the whole population, "the problem with this type of analysis is that it can't rule out confounders, although the colleagues have tried to control for confounders as best as they could."

Moreover, "the results might not be the same if the study had been conducted in another country where some medications may not be available, so we need replication in different countries that also have large registries," said Leucht, who is the coauthor of an accompanying editorial.

He noted that although lithium "comes out well in this analysis," its effects with respect to renal failure have "not been sufficiently examined."

He added that lithium is "not a mild drug, because it has been shown that if people take it for years, kidney function worsens, and sometimes people even reach end-stage renal failure, so the message to 'use lithium because it's benign' isn't correct, and antipsychotics also have side effects, such as weight gain."

He advised clinicians to "check the side effects of lithium and antipsychotics when choosing a drug for a given patient, even though lithium turned out well in terms of efficacy and reduction of hospitalizations."

Study coauthor Eduardo Vieta, MD, PhD, professor of psychiatry, University of Barcelona, Spain, added that, although "the results show that lithium and the long-acting injectable antipsychotics are the most effective treatments for preventing rehospitalization, this does not mean they should be the only drugs used in bipolar disorder."

He noted that hospitalization is "most often indicated in manic episodes, but the morbidity of bipolar disorder also involves depressive episodes, many of which are suffered silently at the patient's home."

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Full listings of the authors' and editorialists' relevant financial relationships are included in the original articles.

JAMA Psychiatry. Published online February 28, 2018. Abstract, Editorial

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