Swell in Off-Label Antipsychotic Prescribing 'Not Harmless'

Batya Swift Yasgur, MA, LSW

November 23, 2021

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 patient's life span," study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, told Medscape Medical News.

"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 November 9 in the Journal of Psychiatric Research.

A Growing Trend

Using low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has "surged in popularity," the authors write.

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 add.

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."

"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," Berge said.

In fact, 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 note.

"In order 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," 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 with ≥1 psychiatric visits (inpatient or outpatient) between July 1, 2006, and December 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 (ie, 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.

"Weak" Association

The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.

Of the cohort, 4.3% (n = 18,317) had ≥2 prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).

By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one fifth (19.5%) were from cardiometabolic-specific causes.

On the whole, treatment status (ie, treated vs untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% CI, 0.64 – 1.15]; P = .307).

Interestingly, compared to no treatment, treatment with olanzapine or quetiapine for <6 months actually was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6 – 12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22 – 2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.

"In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6% – 99%; P = .019) for every year exposed to an average 5 mg/day," the authors report.

The authors conclude that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but "weak."

The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03 – 1.50]; P = .026).

Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03 – 1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.

"The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but the results are somewhat divergent and not conclusive, so more research is needed," Berge commented.

Seek Alternatives

Commenting on the study for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, and head of the Mood Disorders Psychopharmacology Unit, called it a "timely paper" and "an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses]."

McIntyre, who is also the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said that this "important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label."

He advised clinicians to "seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances."

This work was supported by the South Region Board ALF, Sweden. Berge and coauthors have disclosed no relevant financial relationships. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. McIntyre is also CEO of AltMed.

J Psychiatr Res. Published online November 9, 2021. Abstract

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