What are the risks of starting treatment with rapid-acting antidepressants?

The risks associated with starting treatment with rapid-acting antidepressants depend heavily on the specific class of medication being used, as these agents operate through different mechanisms than traditional monoamine-targeting drugs.

The rapid-acting antidepressants include NMDA receptor antagonists (ketamine, esketamine, dextromethorphan/bupropion) and GABA modulators (brexanolone, zuranolone). Stimulants are also noted for their rapid mood-lifting effects in certain populations, but carry specific risks.

Risks Associated with GABA Receptor Positive Modulators (Brexanolone and Zuranolone)

These agents are noted for their fast onset (within hours to days) in treating postpartum depression.

• Excessive Sedation and Loss of Consciousness: Brexanolone treatment carries the risk of serious harm resulting from excessive sedation or sudden loss of consciousness. Because of this risk, brexanolone is only available through a restrictive Risk Evaluation and Mitigation Strategy (REMS), requiring administration as a 60-hour continuous IV infusion under the direct, continuous supervision of a healthcare provider who must monitor the patient for excessive sedation and sudden loss of consciousness using continuous pulse oximetry monitoring.

• CNS Depression Interactions: Concomitant use of these modulators with other Central Nervous System (CNS) depressants, such as opioids, standard antidepressants, benzodiazepines, or alcohol, may increase the likelihood or severity of adverse reactions related to sedation.

• Suicidality: Patients taking zuranolone should be balanced for benefits versus risks and challenges, including potential suicidal thoughts or behavior. Patients are advised to report the emergence of suicidal thoughts and behaviors immediately.

• Dependence and Withdrawal: Zuranolone may produce physical dependence. Patients may experience withdrawal symptoms (such as insomnia, palpitations, decreased appetite, nightmares, nausea, hyperhidrosis, and paranoia) after abrupt discontinuation or significant dose reduction, with the risk being higher at greater doses or longer durations.

• Impaired Functioning: Zuranolone can cause sedation that precludes performing some activities of daily living like driving for 14 days.

• Fetal Risk: Based on animal studies, both brexanolone and zuranolone may cause fetal harm.
  

Risks Associated with NMDA Receptor Antagonists (Esketamine, Ketamine, and Dextromethorphan/Bupropion)

These agents target the glutamatergic system and have shown a rapid onset of effect, typically within one to two days.

• Dissociation and Sedation (Esketamine): Esketamine-related adverse events reported include dissociation (with a highly disproportionate risk ratio), sedation, and feeling drunk. Esketamine treatment must be administered under the direct supervision of a healthcare provider.

• Cognitive and Behavioral Effects: Esketamine can impair short-term cognitive performance.

• Suicidality: Esketamine has been associated with reports of suicidal ideation and suicidal and self-injurious ideation signals were observed when comparing esketamine to venlafaxine. Dextromethorphan/bupropion also requires monitoring for worsening depression and suicidal thinking.

• Seizure Risk: The dextromethorphan/bupropion combination can cause seizures.

• Specific Drug Interactions (Dextromethorphan/Bupropion): This combination is contraindicated in patients taking, or within 14 days of stopping, Monoamine Oxidase Inhibitors (MAOIs) due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome.

• Transient Efficacy: Ketamine's antidepressant effects are described as transient, lasting hours, with relapse reported within 3–21 days after single or multiple uses.

• Long-Term Safety: The long-term efficacy and safety profile of esketamine and ketamine are not well established, and the optimal treatment duration is currently unknown.
  

Risks Associated with Stimulants (Used for Rapid Mood Lift)

While not always classified as traditional rapid-acting antidepressants, stimulants (such as methylphenidate or dextroamphetamine) can rapidly lift mood and ameliorate fatigue in the medically ill.

• Cardiovascular Effects: Even at low therapeutic dosages, stimulants can produce modest increases in heart rate and blood pressure. They are labeled as contraindicated in patients with structural heart disease. High caution, informed consent, and consultation with a cardiologist are prudent before prescribing stimulants to patients with unstable coronary disease, arrhythmias, rapid heart rate, hypertension, or heart failure.

• Psychiatric/Behavioral Effects: Stimulants may precipitate manic or hypomanic symptoms in patients with undiagnosed bipolar disorder, or exacerbate psychotic symptoms. They can also cause agitation, anxiety, tension, and restlessness.

• Abuse and Dependence: Amphetamines have a rapid onset of action (within 1 hour orally), and tolerance develops quickly. Chronic abuse can lead to tolerance and psychic dependence. Stimulant misuse can precipitate behaviors that place an individual at increased risk of harm by violence or accidental injury.

• Serotonin Syndrome Risk: Every single stimulant drug (including amphetamine, ecstasy, meth, Adderall, and cocaine) can precipitate serotonin syndrome, especially if used concurrently with other serotonergic medications like MAOIs.