This summary is a quick guide for clinicians on 2019 U.S. Food and Drug Administration (FDA) approvals.
Two new drugs with antidepressant effects were approved this year: Brexanolone and esketamine. These 2 drugs do not modulate the “classic” neurotransmitter system usually associated with antidepressant activity. Also, bremelatonide (a melanocortin receptor agonist) was approved for the treatment of hypoactive sexual desire disorder (HSDD).
Regarding antipsychotics, cariprazine is now approved for bipolar depression, and asenapine is approved as a transdermal patch for schizophrenia.
New Drugs Approved: Brexanolone, Bremelatonide, and Esketamine
Brexanolone (Zulresso) for PPD
- Brexanolone is the first drug to be FDA approved specifically for the treatment of PPD.
- It is available as an intravenous infusion.
- Mechanism of action:
- γ-Aminobutyric acid type A receptor modulator
- Exogenous formulation of allopregnanolone (an endogenous neurosteroid)
- Allopregnanolone levels rise during pregnancy, peak in the third trimester, and then drop sharply after parturition.
- The drop in allopregnanolone levels has been hypothesized as a factor in the pathophysiology of PPD.
- Efficacy: Modestly more efficacious than placebo in reducing postinfusion depressive symptom scores in women with moderate-to-severe PPD.
- Practical considerations:
- Brexanolone must be administered intravenously over a 60-hour infusion period.
- It must be administered in a certified healthcare setting.
- Cost for 1 treatment (5 vials) is $34,000 (US dollars) as of December 2019.
Bremelanotide (Vyleesi) for HSDD
- Bremelanotide is approved for the treatment of premenopausal women with acquired, generalized HSDD.
- Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire.
- Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation, or partner.
- HSDD is no longer included in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders. It has been replaced by sexual interest/arousal disorder.
- Bremelanotide is the second drug approved for HSDD. The first was flibanserin (Addyi), in 2015. There are no trials comparing them as of December 2019.
- Mechanism of action: Unknown; melanocortin receptor agonist
- Clinical comments:
- Bremelanotide needs to be administered subcutaneously at least 45 minutes before anticipated sexual activity.
- In clinical trials, bremelanotide was only modestly more effective than placebo in increasing sexual desire and decreasing distress associated with low sexual desire. It did not significantly increase the frequency of satisfying sexual events.
- Bremelanotide can cause nausea, increases in blood pressure, decreases in heart rate, and focal hyperpigmentation (it activates melanocortin receptors).
- Nausea often required antiemetic therapy in clinical trials.
Esketamine (Spravato) for Treatment-Resistant Depression
- Esketamine is approved for the treatment of treatment-resistant depression in adults, in conjunction with an oral antidepressant.
- Mechanism of action:
- Esketamine is the S-enantiomer of racemic ketamine. The precise mechanism of action is unknown.
- Esketamine is an N-Methyl-D-aspartate (NMDA) antagonist. The NMDA receptor is an ionotropic glutamate receptor.
- It has been suggested that its antidepressant effect could also be mediated in part through activation of mu-opioid receptors.
- Formulation: Nasal spray devices
- Efficacy:
- FDA approval was based on results from 4 clinical trials: 3 short-term (4-week) clinical trials and 1 longer-term maintenance-of-effect trial. Esketamine nasal spray was superior to placebo in 1 of the short-term trials and in the maintenance-of-effect trial.
- None of the available trials were designed to control for the dramatic subjective effect (“high”) the drug produces.
- Adverse effects:
- The most common side effects in clinical trials were disassociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity (hypoesthesia), anxiety, lethargy, increased blood pressure, vomiting, and feeling “drunk.”
- Esketamine increases blood pressure; the effect peaks 40 minutes after administration and lasts about 4 hours.
- It is contraindicated for use in patients with aneurysmal vascular disease, arteriovenous malformation, or a history of intracerebral hemorrhage.
- Risk Evaluation and Mitigation Strategy (REMS) program
- Nasal esketamine is available only through a restricted program called the SPRAVATO REMS.
- This is because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.
- Comments and practical aspects:
- Nasal esketamine must be administered under the direct supervision of a healthcare professional.
- The medication cannot be dispensed to the patient directly for use at home.
New Indications and Formulations
New Indication: Cariprazine (Vraylar) for Bipolar Depression
- In June 2019, FDA approved the supplemental new drug application for cariprazine (Vraylar, Allergan) for depression associated with bipolar I disorder in adults.
- Cariprazine is a D2 and 5-HT1A partial agonist (like aripiprazole and brexpiprazole). It also has 5-HT2A antagonist properties.
- The 4 FDA-approved medications now available for the treatment of bipolar disorder are:
- Olanzapine/fluoxetine combination (Symbyax).
- Quetiapine and quetiapine XR (Seroquel and Seroquel XR).
- Lurasidone (Latuda).
- Cariprazine (Vraylar).
New Formulation: Transdermal Asenapine (Secuado) for Schizophrenia
- In October 2019, FDA approved the first transdermal formulation for an antipsychotic: Asenapine for the treatment of adults with schizophrenia.
- The patch is applied once daily and provides sustained concentrations of asenapine over 24 hours.
- To date, there are no published trials directly comparing transdermal with sublingual asenapine.
- The systemic safety profile is consistent with what is known for sublingual asenapine.
- Comments:
- The manufacturer highlights the fact that a transdermal patch offers “visual confirmation” that a treatment is being utilized.
- Some clinicians wonder what would happen if the patient takes the patch off after visual confirmation or just leaves the first patch on.
- Currently, there are transdermal patches available for other drugs in psychiatry: Selegiline, nicotine, buprenorphine, methylphenidate, rotigotine, and rivastigmine.
In Memoriam: Donald Klein, “The Father of Psychopharmacology”
- Dr. Donald F. Klein, considered by many “the father of psychopharmacology”, died on August 7 in New York City. He was 90.
- Dr. Klein developed the concept of “pharmacologic dissection” of mental disorders. He showed that treatment response could be used to distinguish subgroups within a diagnostic category.
- He observed in the early 1960s that the so-called “major tranquilizers” (now known as antipsychotics) were not really tranquilizers and didn’t help anxious patients but rather patients with a psychotic illness.
References
- Actavis Pharma. (2019). Vraylar (Cariprazine): Prescribing Information. Parsippany, NJ.
- American Society of Clinical Psychopharmacology. (2019). Donald Klein Lifetime Achievement Award. Retrieved from https://ascpmeeting.org/awards/donald-klein-lifetime-achievement-award/
- Bremelanotide (Vyleesi) for hypoactive sexual desire disorder. (2019).The Medical Letter, 114–116.
- Brexanolone (Zulresso) for Postpartum Depression. (2019). Journal of the American Medical Association, 322(1), 73–74.
- Citrome, L., Zeni, C. M., & Correll, C. U. (2019). Patches: Established and Emerging Transdermal Treatments in Psychiatry. The Journal of Clinical Psychiatry, 80(4): pii: 18nr12554.
- Noven Therapeutics, LLC. (2019). Secuado: Prescribing Information. Miami, FL.
- Noven Therapeutics, LLC. (October 15, 2019). U.S. FDA Approves SECUADO® (asenapine) Transdermal System, the First-and-Only Transdermal Patch for the Treatment of Adults with Schizophrenia (Company press release). Retrieved from http://www.noven.com/PR101519.php
- U.S. Food and Drug Administration. (June 21, 2019). FDA Approves New Treatment For Hypoactive Sexual Desire Disorder in Premenopausal Women. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women
