FDA approves esketamine nasal spray for refractory depression


  • The FDA has approved esketamine nasal spray, Spravato (Janssen Pharmaceuticals), for treatment-resistant depression.

Why this matters

Key highlights

  • Indication is for adults with depression for whom ≥2 other antidepressant medications have failed.
  • It is to be taken with an oral antidepressant.
  • A black box warning accompanies approval because of serious adverse event risk, including for sedation, abuse, and suicidal thoughts and behaviors.
  • The spray is also subject to restricted distribution under a Risk Evaluation and Mitigation Strategy (REMS):
    • REMS requirements include patient commitment not to drive or use heavy machinery on the day of administration.
    • Health care providers are to monitor patients for 2 hours after self-administration of the spray, which cannot be taken home.
  • Supporting evidence:
    • Short-term placebo-controlled trial: effect was detected within 2 days in some cases.
    • Results of 2 other short-term trials did not meet threshold for statistical effect.
    • Long-term trial suggested stable remission or response, latency to relapse with treatment.
  • Side-effects include dissociation, dizziness, increased BP, feeling inebriated.
  • Spray is contraindicated in pregnancy and with breastfeeding and may increase risk for vascular events in patients with existing disease.

Sleep Apnea Linked to Depression in Men

Obstructive sleep apnea (OSA) is associated with an increased risk of depression in men, a large Australian study found.

Among 1,875 men ages 35 to 83 who were assessed for depression at two time points about 5 years apart in the Men Androgen Inflammation Lifestyle Environment & Stress Study (MAILES), previously undiagnosed severe OSA was associated with depression (OR 2.1, 95% CI 1.1-4, P<0.05), reported Carol J. Lang, PhD, of the University of Adelaide, at theannual meeting of the American Thoracic Society here.

This statistical significance remained even after adjustment for age, waist circumference, smoking, relationship status, financial difficulties, erectile dysfunction, and nocturia, she noted.

“Depression is highly prevalent in OSA, reaching 39% in clinic studies. However, few population-based studies have been done and results have been mixed,” Lang said.

In one longitudinal study that included 1,400 men and women, a dose-dependent association between a sleep-related breathing disorder and depression was seen, with a 2.6-fold increased risk of depression and a moderate or severe sleep-related breathing disorder.

A cardinal symptom of OSA is excessive daytime sleepiness, although not all affected patients report this problem. It’s unclear whether daytime sleepiness is associated with depression in OSA, and in the longitudinal study, sleepiness was not found to be an explanatory factor for the observed relationship between the sleep-related breathing disorder and depression.

Further complicating this relationship was the finding in another study that residual sleepiness persisting after continuous positive airway pressure treatment was linked with refractory depression.

In an attempt to clarify the association of OSA and depression, in 2010 Lang and colleagues conducted telephone interviews asking men if they had ever been diagnosed with sleep apnea with a sleep study, and those answering in the negative were invited to participate. A total of 857 men then underwent at-home polysomnography testing.

Depression was assessed using the Center for Epidemiologic Studies Depression Scale/Beck’s Depression Inventory, and daytime sleepiness was evaluated according to the Epworth Sleepiness Scale.

OSA was defined as an apnea-hypopnea index higher than 10. Mild-to-moderate OSA was an index score of 10 to 29, and severe was 30 or higher.

Logistic regression analysis determined that, along with severe OSA, daytime sleepiness was associated with depression (OR 1.1, 95% CI 1-1.2, P<0.05).

Then, in a model that included both previously undiagnosed OSA and excessive daytime sleepiness, individuals with both had 4.2 times greater odds of depression than those with neither, and 3.5 times greater likelihood of depression than those with either alone.

“The message is that clinicians need to be aware of these risks and assess for the other if one is present,” Lang said.

The precise mechanisms underlying the link between these conditions are uncertain, but may involve low oxygen levels, arterial inflammatory responses, and neurologic changes in the brain, she said.

The press conference moderator, Mihaela Teodorescu, MD, of the department of pulmonary and critical care at the University of Wisconsin in Madison, agreed that this is an important clinical issue.

“Sleep apnea leads to more refractory depression and patients get more treatment, including with benzodiazepines, which can aggravate and further contribute to depression,” she said.