Off-label prescribing of antipsychotics: Where's the evidence?

By Naveed Saleh, MD, MS | Medically reviewed by Kevin Kennedy, MD
Published October 19, 2022

Key Takeaways

  • The off-label use of second-generation (ie, atypical) antipsychotics is common for conditions such as insomnia, anxiety, and depression.

  • Off-label prescriptions of antipsychotics usually entail lower doses, but adverse events such as weight gain can still result.

  • Physicians should carefully monitor their patients for long-term effects of antipsychotics prescribed off-label and counsel patients on the potential risks.

Psychiatrists are increasingly prescribing second-generation antipsychotics for conditions including anxiety, depression, and insomnia, according to an article published in BMC Psychiatry.[]

But off-label prescriptions can come with risks. How can psychiatrists help prevent harm to patients from off-label medications?

Rationale for off-label prescribing

Off-label prescribing is common and considered justified in many settings.

It lets prescribers expose patients to the latest possible treatments, offer alternatives when other treatments have failed, and offer patients access to a drug of interest in a class approved for the indication. And in light of social/institutional pressures, off-label prescribing can yield quick control of a condition.

However, off-label prescribing can increase the risks of adverse effects and may be ineffective. Moreover, inappropriate off-label prescribing can open up physicians to legal consequences.

A lack of clinical trials in psychiatry makes off-label prescriptions an important option. Healthcare professionals have been shown to have some knowledge of the practice based on medical school and residency training. Additionally, peer-reviewed research articles on off-label uses are available for reference.[]

Off-label antipsychotics

Antipsychotics were originally indicated for the treatment of schizophrenia and manic episodes in bipolar disorder.

FDA indications of antipsychotics have grown over the years. For instance, risperidone and aripiprazole were greenlighted to treat behavioral disturbance related to autism spectrum disorders, and several second-generation antipsychotics have FDA indications for the adjunctive treatment of major depressive disorder and for bipolar depression.

Off-label prescribing is likely more common than on-label prescribing for second-generation antipsychotics. According to the BMC Psychiatry article, 60.7% of atypical antipsychotics are prescribed off-label. The following conditions are among those treated with off-label antipsychotics:

  • Behavioral/psychological symptoms of dementia

  • Anxiety disorders

  • Borderline personality disorder

  • Obsessive-compulsive disorder

  • PTSD

  • ADHD

  • Depression

  • Substance use disorders

  • Eating disorders

  • Insomnia

Research has shown that the prescription of antipsychotics has increased by sevenfold in the US between 1997 and 2005.

Results of a study published in Acta Psychiatrica Scandinavica indicated that, among individuals receiving off-label prescriptions of antipsychotics in a Finnish cohort, 70.1% had been diagnosed with depression and 40.1% had been diagnosed with anxiety.[]

Investigators found that individuals who were prescribed off-label antipsychotics tended to be of lower socioeconomic status, had lower levels of education, had higher rates of somatic and psychiatric comorbidities, and exhibited substance use disorder.

But in patients taking antipsychotics for indications such as schizophrenia and bipolar disorder, those taking off-label medications exhibited less comorbidity, higher socioeconomic status, and were more educated.

Risperidone, quetiapine, and olanzapine are the atypical antipsychotics most commonly prescribed off-label.[]

Clinical findings

The off-label use of antipsychotics usually involves lower doses and is common with disorders such as insomnia or anxiety.

But clinical studies have shown that adverse effects can still result from low doses.

Data from different trials show that even at quetiapine doses of about 100 mg per day, body weight rose after 6 and 12 months of use, in addition to increases in blood pressure, BMI, and blood-glucose levels.

Unlike selective serotonin reuptake inhibitors, however, low-dose quetiapine did not predict type 2 diabetes. Its long-term effects need to be further explored.

Because the use of off-label antipsychotic medications requires more research to establish effects, psychiatrists may want to approach the practice gingerly, according to the Acta Psychiatrica Scandinavica authors.

“The potentially harmful effects of even small doses of AP should be acknowledged in clinical practice,” they wrote, “and proper follow-up and monitoring of long-term effects and, for example, metabolic effects, should be done more systematically.”

What this means for you

Despite its widespread practice, the prescription of off-label antipsychotics requires further research. Even low doses can result in adverse effects such as weight gain and increased blood pressure. Physicians should counsel their patients on the potential risks and monitor them closely for long-term impact.

Read Next: Have you heard of these head-turning off-label prescriptions?
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