Long-term use of benzodiazepines among patients with schizophrenia is common in Finland, the United States and other countries, “which suggests that benzodiazepine use may contribute to mortality among this patient population worldwide,” the Finnish team notes in a paper in Archives of General Psychiatry this month.
“I think that the important message for clinicians is that they (or some of them) should stop violating treatment guidelines which say that the chronic use (more than one month) of benzodiazepines should be avoided,” first author Dr. Jari Tiihonen, professor and chairman, Department of Forensic Psychiatry, University of Eastern Finland and Niuvanniemi Hospital, Kuopio, noted in an email to Reuters Health.
At present, its “unknown if the use of antidepressants or benzodiazepines has beneficial net effects in the treatment of schizophrenia; therefore, no conclusions on their use exist in treatment guidelines,” the authors note in their paper.
Using national databases of mortality and medication prescriptions, Dr. Tiihonen and colleagues examined antipsychotic, antidepressant and benzodiazepine polypharmacy and all-cause mortality in 2,588 adults hospitalized for the first time with a diagnosis of schizophrenia over eight years (2000-2007).
After adjusting for a variety of potentially confounding factors, current use of two or more antipsychotics (vs antipsychotic monotherapy) was not associated with increased mortality (HR 0.86), while no antipsychotic use was associated with a greater than twofold higher risk of mortality (HR 2.09), the researchers say. The HR was 0.41 for current use of two or more antipsychotics (vs no antipsychotic). Use of an antidepressant (vs no antidepressant) was also associated with a reduced risk of death (HR 0.57), mainly due to suicide. [
In contrast, the HR for death with current benzodiazepine use (vs no use) was 1.91; risk were elevated for suicide (HR 3.83) and nonsuicidal deaths (HR 1.60).
According to the researchers, more than 80% of all deaths occurred during treatment periods with prescriptions that included more than 28 defined daily doses of benzodiazepines, and more than 90% of patients used benzodiazepines on a long-term basis.
The researchers also looked at polypharmacy treatment patterns and total mortality. “In all combinations, current benzodiazepine use was associated with higher mortality compared with no benzodiazepine use, regardless of concomitant use or nonuse of antipsychotics or antidepressants,” they say. “Conversely, in all pairwise comparisons, current antidepressant use (vs no antidepressant use) and antipsychotic use (vs no antipsychotic use) was associated with lower mortality (ie, the effect of psychotropic drugs was similar in all combinations and no substantial interactions were observed).”
These results, the authors note, support other studies that suggest that antidepressants may enhance the therapeutic effects of antipsychotics, which may be relevant to reduce mortality risk.”
“It is interesting,” Dr. Tiihonen told Reuters Health, that a recent paper in BMJ Open reported increased risk of death among patients without schizophrenia during use of hypnotics (mainly benzodiazepines or benzodiazepine derivatives). “This implies that this finding applies also to other patients than those with schizophrenia,” the researcher said.
Reached for comment, Dr. Lone Baandrup, from University of Copenhagen, Denmark, said the Finnish study “replicates some of our earlier findings (J Clin Psychiatry 2010;71:103-108) increasing the scientific value of these findings.”
Furthermore, Dr. Baandrup said, “an important message from this article is that polypharmacy must be looked upon in a highly differentiated manner. Both the efficacy and as this study shows the safety must be addressed separately for the different types of combination treatment (i.e., antipsychotic + benzodiazepine, antipsychotic + antidepressant, antipsychotic + antipsychotic).”
Importantly, Dr. Baandrup added, “Possible concerns regarding the safety (especially regarding suicide) of combining antipsychotic and antidepressant are no longer valid due to this study showing substantial decrease in suicidal deaths.”
The study was supported by government subsidies from the Finnish Ministry of Social Affairs and Health and by Janssen-Cilag. Dr. Tiihonen has served as a consultant to Janssen-Cilag and received lecture fees from the company. A complete list of author disclosures is listed with the paper.