PARIS (FRONTLINE MEDICAL NEWS) – What’s the most effective medication for preventing rehospitalization in patients previously admitted for severe unipolar depression?

The answer, based upon a study of all 123,712 patients hospitalized for severe unipolar depression in Finland during 1987-2012, might come as a surprise. The medication that most effectively kept patients from returning to the hospital wasn’t a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or an atypical antipsychotic. It was lithium, Markku Lahteenvuo, MD, reported at the annual congress of the European College of Neuropsychopharmacology.

“We were actually surprised to find that SSRIs and other antidepressants aren’t really very effective at keeping depressed patients out of hospital. It seems like lithium is a lot more effective than any antidepressant. And funnily enough, it seems that lithium is a lot more effective when used without antidepressants than when used with them. Also, antipsychotics seem to be more effective than SSRIs,” Dr. Lahteenvuo said in an interview.

Using comprehensive nationwide databases, he and his coinvestigators followed these 123,712 hospitalized patients for a mean of 7.9 years, during which 49,146 of them had a total of 153,784 rehospitalizations for mental disorders. The investigators analyzed what psychotropic drugs the patients were taking when rehospitalized, as well as the drugs they were taking when they were out of hospital. Individuals served as their own controls in order to eliminate selection bias.

In an analysis adjusted for time since diagnosis of unipolar depression, the temporal order of prescribed drugs, and other concomitant medications, the use of lithium was associated with a 53% reduction in the risk of readmission, compared with nonuse.

Patients using lithium as monotherapy for their depression were 69% less likely to be rehospitalized than if they were not, whereas patients on lithium with antidepressants had a more modest 50% reduction in rehospitalization risk, reported Dr. Lahteenvuo, a forensic psychiatrist at Niuvanniemi Hospital and the University of Eastern Finland in Kuopio.

After lithium, clozapine was the drug associated with the next lowest risk of rehospitalization for a mental disorder. Patients on that drug were 35% less likely to be rehospitalized; however, clozapine wasn’t widely prescribed in patients with severe unipolar depression.

Antidepressants as a broad class were associated with a statistically significant 10% increase in risk of rehospitalization for a mental disorder. But within that category there were a couple of exceptions: Amitriptyline, which was widely prescribed, particularly in the early years of the study period, was associated with a 25% reduction in rehospitalization, compared with no use. And doxepin was associated with a 15% reduction.

Antipsychotics were associated with an overall 16% increased risk of rehospitalization, compared with no use. But there were some notable exceptions within this class of drugs. Both quetiapine and aripiprazole were associated with an 18% risk reduction.

The investigators also analyzed all-cause rehospitalizations, including acute myocardial infarction and all other somatic diseases, as well as mental disorders. During follow-up, 98,662 patients who had been hospitalized for severe unipolar depression had a collective total of 592,926 all-cause rehospitalizations.

Dr. Lahteenvuo said he had expected that lithium’s strong showing in preventing psychiatric rehospitalization might be offset by an increased risk of hospitalization for other conditions, because of the drug’s well-established association with thyroid, renal, and other toxicities. But that was not the case. Patients on lithium without antidepressants were 49% less likely to have an all-cause hospitalization than when they were not using the drug, and patients on lithium with antidepressants had a 42% reduction in risk.

”It seems that lithium also shielded the patients from going to the hospital for any somatic reason. So lithium seems to be safe and prevents various somatic hospitalizations as well. Whether that’s due to the drug’s enhancement of your ability to live your life, eat healthy, exercise, and give you energy to have good lifestyle habits, or it actually has an anti-inflammatory effect or other disease-modifying effect, we do not know,” Dr. Lahteenvuo said.

Lithium has traditionally been prescribed mainly as third-line therapy in treatment-refractory patients for severe unipolar depression. The Finnish data suggest it’s time to reconsider that strategy.

“We think lithium should be considered for a wider audience, keeping in mind of course that it can cause thyroid and kidney toxicity,” Dr. Lahteenvuo said.

Patients taking clozapine were 30% less likely to have an all-cause hospitalization than nonusers. Aripiprazole was associated with a 21% reduction in risk, quetiapine had a 12% risk reduction, amitriptyline had an 11% risk reduction, and doxepin had a 12% risk reduction.

In contrast, all-cause hospitalization was 12% more likely when patients were taking chronic benzodiazepines and 8% more likely while on hypnotics.

The full study results were published in the Lancet Psychiatry ( 2017 Jul;4[7]:547-53 ).

Dr. Lahteenvuo reported having no financial conflicts of interest related to the study, which was funded by the Finnish Ministry of Health.