- ACRONYMS AND DEFINITIONS
- CrCl - Creatinine clearance
- PPD - Postpartum depression
- RCT - Randomized controlled trial
- DRUGS IN CLASS
- Neuroactive steroid GABAA receptor positive modulators
- Allopregnanolone is an endogenous neuroactive progesterone metabolite with positive GABAA receptor activity
- Zuranolone (Zurzuvae®) is an oral neuroactive steroid that mimics the action of allopregnanolone
- Brexanolone (Zulresso®) is a drug approved for PPD that is chemically identical to allopregnanolone. It is administered via continuous IV infusion over 60 hours. [Zulresso PI]
- MECHANISM OF ACTION
- Postpartum depression (PPD) affects 10 - 15% of new mothers and is marked by the onset of a major depressive episode within 4 weeks of delivery that lasts 2 or more weeks
- Studies suggest PPD may be related to postpartum decreases in allopregnanolone, a neuroactive progesterone metabolite with positive GABAA receptor activity. Zuranolone is a steroid GABAA receptor positive modulator that mimics allopregnanolone's action, theoretically improving symptoms of PPD.
- FDA-APPROVED INDICATIONS
- Zuranolone is indicated for the treatment of postpartum depression (PPD) in adults
- POSTPARTUM DEPRESSION
- Overview
- The effects of zuranolone on PPD were evaluated in the trial detailed below
- The trial enrolled 200 women with a major depressive episode beginning in the third trimester and up to 4 weeks after delivery
Main inclusion criteria
- Major depressive episode beginning in the 3rd trimester or up to 4 weeks postpartum
- Agree to stop breastfeeding during treatment and for 7 days after
- ≤ 12 months postpartum
Main exclusion criteria
- Suicidal
- Active psychosis
- History of seizure
- Bipolar or schizophrenia
- History of sleep apnea
Baseline characteristics
- Average age 30 years
- Baseline antidepressant use - 15%
- Baseline 17-item HAMD score - 28.7
Randomized treatment groups
- Group 1 (98 patients): Zuranolone 50 mg once daily for 14 days
- Group 2 (97 patients): Placebo
- Drug dose could be reduced to 40 mg based on tolerability
- Patients taking stable doses of oral antidepressants for at least 30 days were allowed to continue them
- Study medication was taken in the evening with fat-containing food
Primary outcome: Change from baseline in the 17-item Hamilton rating scale for depression (HAMD) total score at Day 15 (score ranges from 0 - 52 with higher scores indicating worse depression)
Results
| Duration: 45 days | |||
| Outcome | Zuranolone | Placebo | Comparisons |
|---|---|---|---|
| Primary outcome (Day 15) | -15.6 | -11.4 | p=0.0007 |
| Primary outcome (Day 3) | -9.5 | -6.3 | p=0.0008 |
| Primary outcome (Day 28) | -16.3 | -13.5 | p=0.0203 |
| Primary outcome (Day 45) | -17.7 | -14.8 | p=0.0067 |
| Somnolence | 26.5% | 5.1% | N/A |
| Dizziness | 13.3% | 10.2% | N/A |
| Sedation | 11.2% | 1% | N/A |
Findings: Zuranolone was superior to placebo for reducing depressive symptoms in women with PPD
- Summary
- In the study above, zuranolone was superior to placebo in improving PPD symptoms for up to 45 days. The absolute difference at Day 15 on the depression rating scale (HAMD) was about 8%. Zuranolone's mechanism is similar to benzodiazepines, which have obvious psychoactive effects. This raises the possibility that unblinding by treatment effect may have influenced the outcomes.
- SIDE EFFECTS
| Side effects reported in a 45-day trial | ||
|---|---|---|
| Side effect | Zuranolone 50 mg (N=98) |
Placebo (N=98) |
| Somnolence✝ | 36% | 6% |
| Dizziness or vertigo | 13% | 9% |
| Diarrhea | 6% | 2% |
| Fatigue | 5% | 2% |
| UTI | 5% | 4% |
| Memory impairment | 3% | 0% |
| Abdominal pain | 3% | 0% |
- Driving impairment
- Zuranolone causes CNS sedation that impairs the ability to drive and/or perform potentially hazardous activities. Patients should not drive or perform other dangerous activities for at least 12 hours after zuranolone administration for the duration of the 14-day treatment period.
- CNS depression
- In trials, up to 36% of zuranolone-treated patients reported CNS depressant effects, including somnolence, sedation, dizziness, hypersomnia, and confusion. Other CNS depressants, including alcohol, benzodiazepines, opioids, and tricyclic antidepressants, may potentiate these effects. If patients develop significant sedation, consider discontinuing zuranolone or reducing the dose. Use caution when prescribing with other CNS depressants and/or CYP3A4 inhibitors, which increase its exposure.
- Suicidal thoughts and behaviors
- In placebo-controlled trials, the incidence of suicidal thoughts and behaviors in patients ≤ 24 years old was higher in antidepressant-treated patients than in placebo-treated patients. In absolute terms, there were 14 additional cases of suicidality per 1000 patients treated among those younger than 18 years old and 5 additional cases per 1000 patients treated among 18- to 24-year-olds. There were no suicides in any of the pediatric trials.
- Drug abuse and dependence
- Zuranolone has positive GABAA receptor activity, which can cause a euphoric mood and/or drunk feeling, leading to abuse and dependence in some individuals. In studies, zuranolone had abuse potential similar to the benzodiazepine alprazolam. Physical dependence may also occur, as withdrawal symptoms, including insomnia, palpitations, decreased appetite, nightmares, nausea, hyperhidrosis, and paranoia, have been reported in patients who abruptly discontinued zuranolone.
- CONTRAINDICATIONS
- None known
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 60 ml/min: no dose adjustment necessary
- CrCl < 60 ml/min: recommended dose is 30 mg once daily
- Liver disease
- Child-Pugh A or B: no dose adjustment necessary
- Child-Pugh C: recommended dose is 30 mg once daily
- Pregnancy
- In rat studies, zuranolone caused fetal harm. Effects in humans are unknown. Women should avoid pregnancy during zuranolone use and for 7 days after discontinuation.
- Nursing
- The effects of zuranolone on breastfeeding infants and breastmilk production are unknown
- In PPD studies, women were not allowed to breastfeed during zuranolone treatment and for 7 days after discontinuation. Studies in lactating women taking 30 mg of zuranolone for 5 days showed that zuranolone is present in breast milk at levels equivalent to < 1% of the relative adult dose.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Zuranolone (Zurzuvae®)
- CNS depressants - concomitant CNS depressants, including alcohol, may potentiate the sedative effects of zuranolone. Avoid combined use when possible, or consider reducing the zuranolone dose.
- CYP3A4 strong inhibitors - zuranolone is a CYP3A4 sensitive substrate, and strong CYP3A4 inhibitors increase its exposure. Recommended dosing with strong CYP3A4 inhibitors is 30 mg once daily. Dose adjustments are not necessary with moderate inhibitors.
- CYP3A4 inducers - zuranolone is a CYP3A4 sensitive substrate, and CYP3A4 inducers reduce its exposure. Zuranolone is not recommended with CYP3A4 inducers.
- Metabolism and clearance
- CYP3A4 - sensitive substrate
- DOSING
- Dosage form
- 20 mg capsule | Comes in bottle of 14
- 25 mg capsule | Comes in bottle of 14 and blister pack of 28
- 30 mg capsule | Comes in bottle of 14
- Dosing
- Dosing: 50 mg once daily in the evening for 14 days. Take with fat-containing food (e.g. 400 to 1000 calories, 25% to 50% fat). Fat increases absorption.
- If patients experience CNS depressant effects, consider reducing the dosage to 40 mg once daily
- Missed doses: if a dose is missed, take the next dose at the regular time the following evening. Do not take extra capsules on the same day to make up for the missed dose.
- May be used alone or with antidepressant
- Safety beyond 14 days has not been established
- With CYP3A4 strong inhibitors
- Recommended dosing is 30 mg once daily. Dose adjustments are not necessary with moderate inhibitors.
- See CYP3A4 inhibitors and inducers
- With CYP3A4 inducers
- Not recommended
- Kidney disease
- CrCl ≥ 60 ml/min: no dose adjustment necessary
- CrCl < 60 ml/min: recommended dose is 30 mg once daily
- Liver disease
- Child-Pugh A or B: no dose adjustment necessary
- Child-Pugh C: recommended dose is 30 mg once daily
- LONG-TERM SAFETY
- Zuranolone was FDA-approved in 2023. No long-term safety data is available.
- BIBLIOGRAPHY
- 1 - Zurzuvae PI