Slim Evidence for Off-Label Antidepressant Prescribing

Batya Swift Yasgur, MA, LSW

February 24, 2017

Off-label prescribing of antidepressants is common among primary care physicians, and most of this prescribing is not backed by strong scientific evidence, new research shows.

Investigators led by Jenna Wong, a PhD candidate in the Department of Epidemiology, Biostatistics, and Occupational Health at McGill University, Canada, used records of a Canadian indication-based electronic prescribing database to investigate 106,850 antidepressant prescriptions written by 174 physicians for 20,290 adult patients.

They found that nearly a third of all antidepressants were prescribed for an off-label indication. Of these, only 1 in 6 prescriptions were supported by strong scientific evidence.

"We found that most off-label prescriptions were not supported by strong scientific evidence, although often another antidepressant in the same class did have strong evidence for the indication," Wong told Medscape Medical News.

The study was published online February 21 in BMJ.

Wide Range of Indications

A previous study conducted by Wong's group investigated off-label antidepressant prescribing in Quebec between 2006 and 2015 and found that an estimated 29% of antidepressants were prescribed for off-label indications.

"We wanted to deepen our investigation to further examine these indications and see if these off-label uses were evidence-based or not," Wong said.

As in the previous study, the current research analyzed antidepressant treatments captured by an electronic prescription and drug management system used by primary care physicians. The analysis was expanded to include prescriptions of drugs approved for depression between January 1, 2003, and September 30, 2015.

Treatment indications were categorized according to ICD-10 criteria, and each prescription was then classified as on label or off label, depending on whether the drug had been approved for the indication by Health Canada or the US Food and Drug Administration as of September 2015.

Drugs with fewer than 150 prescriptions were excluded. This resulted in the exclusion of all monoamine oxidase inhibitors, nefazodone (Serzone, Bristol-Myers Squibb), maprotiline (Ludiomil, Novartis), and vortioxetine (Trintellix, Takeda).

Off-label prescriptions were further analyzed according to the level of scientific evidence supporting the drug's use for the particular off-label indication. The drugs were then classified as to whether there was strong evidence for the off-label use of the drug, no strong evidence for the off-label use of that particular drug but strong evidence for the use of another drug in the same class, or no strong evidence for that drug or any other drug in the same class.

Strength of evidence was determined on the basis of the Micromedex DrugDex compendium, which contains evaluations of drug efficacy, strength of recommendations, and strength of evidence for off-label drug indication pairs.

Overall, 29.3% (95% confidence interval [CI], 26.6% to 32.3%) of all antidepressant prescriptions were written for an off-label indication.

The prevalence of prescribing for an off-label indication was highest for the tricyclic antidepressants (TCAs) (81.4%; 95% CI, 77.3% to 85.5%), primarily because of the high off-label prescribing rate for amitriptyline (multiple brands) (93%; 95% CI, 89.6% to 95.7%). Amitriptyline was almost exclusively prescribed for off-label indications, most commonly pain (48.4%; 95% CI. 39.7% to 57.8%), insomnia (22.5%; 95% CI, 13.6% to 31.3%), and migraine (16.7%; 95% CI, 12.2% to 21.9%).

Other antidepressants (trazodone [multiple brands], bupropion [multiple brands], and mirtazapine [Remeron, Organon]; 42.4%; 95% CI, 37.1% to 47.7%) also had a high rate of off-label indications, largely because of trazodone, which was mostly prescribed for insomnia (82.5%; 95% CI, 74.5% to 88.1%), although it has not been approved for this indication.

Selective serotonin uptake inhibitors (SSRIs) had a high rate of off-label prescribing (21.8%; 95% CI, 19.0% to 25.0%), in contrast to serotonin-norepinephrine (noradrenaline) reuptake inhibitors (SNRIs) (6.1%; 95% CI, 4.8% to 7.5%).

Strong scientific evidence for an antidepressant's indication was found in only 15.9% (13.0% to 19.3%) of all off-label prescriptions. Most of such prescriptions for which there was strong evidence supporting an off-label use were for the TCA amitriptyline for the treatment of pain (87.1%; 95% CI, 80.9% to 92.1%). In addition, there was strong scientific evidence in support of the use of the SSRI escitalopram (Lexapro, Forest Labs) for the treatment of panic disorders and for the SNRI venlafaxine (multiple brands) for the treatment of obsessive-compulsive disorder.

There was strong evidence for another drug in the same class as the off-label antidepressant for the prescribed indication in only 39.6% (95% CI, 35.7% to 43.2%) of prescriptions. This proportion was highest among off-label SSRI prescriptions (92.0%; 95% CI, 89.2% to 94.4%); it was lower among off-label prescriptions for SNRIs (35.4%; 95% CI, 25.0% to 46.7%) and TCAs (28.3%; 95% CI, 20.5% to 36.6%).

"There may be a misconception that two drugs in the same class are about the same, but physicians should be cautious when thinking that these drugs are interchangeable," said Wong.

For the remaining 44.6% (95% CI, 40.2% to 49.0%) of off-label antidepressant prescriptions, "neither the prescribed drug nor any other drug in the same class had strong evidence for the indication," the researchers report.

One of the reasons for the prevalence of off-label antidepressant prescribing is that "according to feedback we received, it is difficult for physicians to keep informed about which antidepressants are and which are not backed by evidence for a given indication," Wong reported.

"If that is the reason for high rates of off-label antidepressant prescriptions, we should push out ways of informing physicians so they are aware of the evidence when making prescription decisions," she said.

A Cautionary Note

Daniel R. Morales, MBChB, PhD, general practitioner and Discovery Fellow, Population Health Sciences Division, University of Dundee Medical School, United Kingdom, who is a coauthor of an accompanying editorial, offered a cautionary note regarding the relevance of the scientific evidence base in prescription decisions.

"Even when we prescribe a drug on label, we assume that the risks and benefits are the same for our patients as for trial participants, but we do not know if this is really case," he told Medscape Medical News.

"Patients in everyday clinical practice are not subject to the exclusion criteria that apply to patients in clinical trials," said Dr Morales, who was not involved in the study.

Wong agreed, noting that each patient has individual needs that have a bearing on the physician's treatment decisions.

"A patient may have comorbidities or may not have responded well to a drug approved for a given indication," she said. "Or the patient's insurance may not cover approved agents for that indication, which is a systemic problem of the healthcare system."

It is important for physicians "to inform patients of the indication and evidence base in their dialogue with the patient," she emphasized.

This study was funded by the Canadian Institutes of Health Research. The authors of the study and of the editorial have disclosed no relevant financial relationships.

BMJ. Published online February 21, 2017. Full text, Editorial

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