A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.
Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.
“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.
“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.
The study was published online Nov. 9 in the Journal of Psychiatric Research.
A growing trend
Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.
Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.
Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.
“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.
There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.
“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.
To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.
They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.
They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”
The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.