November 2023 Newsletter: Gepirone for MDD, Parasomnias Triggered by Antidepressant Medication, and Psychodynamic Psychopharmacology

In this newsletter, we explore the antidepressant gepirone extended release (Exxua), which was recently approved by the FDA for treating major depressive disorder in adults.

We also discuss principles for assessing and managing parasomnias triggered by antidepressants, key points from a presentation on psychodynamic psychopharmacology, and our practical research summaries of adult, child, and adolescent psychiatry (Quick Takes and CAP Smart Takes).

Gepirone ER for Major Depressive Disorder

On September 28, 2023, the FDA approved gepirone extended release (Exxua)—an antidepressant that modulates serotonergic neurotransmission—for the treatment of major depressive disorder (MDD) in adults. It’s noteworthy to mention that prior to this, the drug had been rejected 3 times, in 2004, 2007, and 2015.

How does gepirone work?
- Gepirone selectively modulates serotonergic neurotransmission by acting as a partial agonist at the serotonin (5HT) 1A receptor.
What do we know about its efficacy?
- Its efficacy was confirmed via 2 RCTs conducted over 8 weeks.
  - The main point of assessment was change in the Hamilton Depression Rating Scale score at the end of week 8.
  - In both studies, patients treated with gepirone showed a statistically significant improvement in their depression scores compared with those who received placebo.
- In a year-long study, patients treated with gepirone had a significantly lower rate of relapse (24% vs 38.7%). Learn more here.
Which dose was proven to be effective?
- Participants initially received an 18.3 mg/day dosage of gepirone, gradually increasing to 54.5 mg–72.6 mg/day.
What are the recommendations for dosing?
- Administer it once daily.
- Start with a dosage of 18.2 mg/day.
- On the 4th day, increase the dosage to 36.3 mg/day if it is well-tolerated.
- On the 7th day, increase the dosage to 54.5 mg/day.
- By the second week, if it is still tolerated well and showing beneficial results, increase to 72.6 mg/day.
Why was gepirone’s approval previously rejected?
- Although 2 studies supported its efficacy, others either yielded negative results or failed to demonstrate any efficacy.
- However, it is still unclear whether gepirone is effective for a specific type of depression, which may explain why it does not elicit a response in some patients.
What are the most common side effects?
- Dizziness, nausea, insomnia, abdominal pain, and dyspepsia
What are the contraindications for using gepirone?
- QTc > 450 msec at baseline
- Severe hepatic impairment
- Congenital long QT syndrome
- Concomitant use of strong CYP34A inhibitors. Read more here.
How is gepirone different from existing antidepressants?
- Gepirone demonstrated a clear advantage over commonly used SSRIs—often linked with sexual dysfunction—by exhibiting no adverse impact on sexual function.
When will gepirone (Exxua) be available?
- It is expected to be available in early 2024.

In conclusion, a new treatment for MDD is anticipated to be available soon. This could provide an effective alternative for patients who suffer sexual side effects from SSRIs. However, patients at risk of QTc prolongation should exercise caution. Moreover, it may be advisable for the general population to undergo an electrocardiogram before starting this treatment.

Parasomnias Triggered by Antidepressant Medication With Carlos H. Schenck, M.D.

In this interview, Dr. Carlos Schenck discusses crucial principles for assessing and managing parasomnias triggered by antidepressants. He highlights common antidepressants that may cause these conditions and introduces differential diagnoses for patients exhibiting symptoms of REM sleep behavior disorder (RBD).

Interview highlights include the following:

Establish the diagnosis of RBD through polysomnography before initiating treatment.
Melatonin and clonazepam are the first-line treatments of choice in the management of RBD.

Learn more and earn 0.5 CME credits here.

Psychodynamic Psychopharmacology: From Biomedical Approaches to Patient Relationships

In this presentation, Dr. David Mintz introduces us to psychodynamic psychopharmacology, an approach that acknowledges the role of meaning and interpersonal factors in pharmacotherapy. He explores treatment resistance while presenting a patient-centered way of prescribing in an era in which a biomedical focus has been predominant.

Attending the Patient’s Ambivalence

Patients have conflicts that may complicate many aspects of their lives.
Ambivalence about medication, doctors, care, or health contributes to treatment refractoriness.
A simple way to attend to ambivalence early on is to ask the patient what their feelings are about taking medication.
Be on the lookout for ambivalence.

Learn more and earn 1.75 CME credits here.

Quick Takes: Research, Digested

Risk of Irreversible Post‑SSRI Sexual Dysfunction With Antidepressants

Most practitioners believe SSRIs-induced sexual dysfunction is reversible, but recent research from Israel found rare cases of persistent dysfunction.
The study’s validity is debated due to potential limitations in the diagnostic accuracy of their database.
Informing patients about potential irreversible side effects might impact their willingness to undergo treatment, highlighting the need for larger, more detailed studies. Learn more.

Listen to or read the full volume, and earn 0.5 CME credits here.

CAP Smart Takes: Research, Digested

Antipsychotics in the Treatment of Youth With Anorexia Nervosa

Although some studies suggest benefits from antipsychotics, such as olanzapine, the evidence is inconsistent and must be interpreted with caution.
Although SSRIs, like fluoxetine, are FDA approved for bulimia nervosa, their use in weight-depleted patients with anorexia nervosa is not recommended; however, they can be beneficial post–weight restoration, potentially reducing the risk of relapse. Learn more.