Why can't individuals with a history of substance abuse use zuranolone (antidepressant medication)?

Why Individuals with Substance Use Disorder History Face Restrictions with Zuranolone

Zuranolone is a Schedule IV controlled substance with demonstrated abuse potential comparable to alprazolam, and individuals with a history of substance use disorders are at significantly greater risk of misuse, abuse, and development of substance use disorder including addiction when prescribed this medication. 1

Pharmacological Basis for Abuse Risk

Zuranolone functions as a positive allosteric modulator of GABAA receptors, producing CNS depressant effects similar to benzodiazepines and other sedative-hypnotics. 1, 2 In a human abuse potential study, single doses of zuranolone demonstrated dose-dependent abuse potential comparable to alprazolam on positive subjective measures including "drug liking," "overall drug liking," "take drug again," "high," and "good drug effects." 1 The study specifically documented abuse-related adverse reactions including euphoric mood, feeling drunk, and somnolence. 1

Heightened Risk in Substance Use Disorder Populations

Individuals with a history of drug abuse or substance use disorders are at substantially greater risk of misuse, abuse, and addiction with zuranolone. 1 This elevated risk stems from:

• Neurobiological vulnerability: Prior substance use disorders create lasting changes in reward pathways and impulse control mechanisms that increase susceptibility to developing new substance dependencies. 3

• Cross-sensitization effects: History of CNS depressant abuse (alcohol, benzodiazepines, opioids) particularly increases risk given zuranolone's similar mechanism of action on GABA receptors. 3, 1

• Behavioral patterns: Patients with substance use history demonstrate higher rates of aberrant drug-related behaviors including dose escalation, seeking prescriptions from multiple providers, and non-oral routes of administration. 3, 4

Physical Dependence and Withdrawal Concerns

Zuranolone produces physical dependence even with short-term use. 1 Adverse reactions documented upon discontinuation after only 5-7 days of use included insomnia, palpitations, decreased appetite, nightmares, nausea, hyperhidrosis, and paranoia. 1 In animal studies, convulsions occurred upon abrupt discontinuation after 14 days of administration. 1 Patients with substance use disorder history are more likely to use higher-than-recommended doses and for longer durations, substantially increasing withdrawal severity and risk of seizures. 1

Clinical Risk Stratification

While a history of substance use disorder is not an absolute contraindication to controlled substances, it requires careful risk-benefit assessment. 3 For zuranolone specifically:

• Active substance use disorder: Represents a strong relative contraindication given the 14-day treatment course provides ample opportunity for misuse and the medication's demonstrated abuse liability. 1

• Recent substance use disorder (within past year): Requires extreme caution, as relapse risk remains elevated and zuranolone could trigger return to active addiction. 3

• Remote substance use disorder (>1 year in sustained remission): May be considered only with intensive monitoring, but alternative treatments should be prioritized first. 3

Specific Contraindications from Stimulant Guidelines

Although zuranolone is not a stimulant, the principle from stimulant prescribing guidelines applies: A history of recent drug abuse or dependence of the same class represents a strong contraindication, while history of other substance classes requires enhanced monitoring but may not be absolute. 3 Given zuranolone's CNS depressant profile, particular caution is warranted in patients with history of alcohol, benzodiazepine, or sedative-hypnotic abuse. 3

Risk Mitigation When Prescribing Is Considered

If zuranolone is prescribed despite substance use disorder history, mandatory safeguards include:

• Validated risk assessment tools: Use the Opioid Risk Tool (ORT) or Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) to stratify risk, though these were developed for opioids, the principles apply to all controlled substances. 3

• Prescription drug monitoring program (PDMP) review: Check for concurrent controlled substance prescriptions and patterns of doctor shopping before initiating treatment. 3

• Controlled substance agreement: Document informed consent regarding risks, storage requirements, and consequences of misuse. 3

• Frequent monitoring: Assess for signs of misuse including requests for early refills, lost prescriptions, or behavioral changes suggesting intoxication. 3

• Coordination with addiction treatment providers: Obtain signed release and maintain communication with substance use disorder treatment team. 3

Alternative Treatment Considerations

For patients with substance use disorder history requiring treatment for major depressive disorder or postpartum depression, non-controlled substance alternatives should be prioritized first. 5 These include:

• Standard SSRIs and SNRIs, which carry minimal abuse potential despite rare case reports of misuse in vulnerable populations. 4
• Non-stimulant medications such as bupropion (with caution regarding seizure risk, particularly in patients with alcohol use disorder). 6
• Psychotherapy approaches including cognitive-behavioral therapy and interpersonal therapy. 3

The 14-day treatment course of zuranolone, while brief, provides sufficient exposure for individuals with substance use vulnerability to develop problematic use patterns, experience withdrawal upon discontinuation, and potentially trigger relapse to their primary substance of abuse. 1, 4