What are the key drug-drug interactions for antidepressants, mood stabilizers, and benzodiazepines (BZDs)?

From the Guidelines

Key drug-drug interactions for antidepressants, mood stabilizers, and benzodiazepines involve primarily cytochrome P450 enzyme interactions, serotonin syndrome risk, and additive central nervous system depression, and clinicians should prioritize caution when prescribing these medications together, especially considering the risk of fatal overdose and serotonin syndrome, as highlighted in the most recent guideline from 2020 1.

Key Interactions

• Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and paroxetine inhibit CYP2D6, potentially increasing levels of medications metabolized by this enzyme, including certain antipsychotics and beta-blockers.
• Combining SSRIs or SNRIs with MAOIs, tramadol, or triptans can cause potentially fatal serotonin syndrome, emphasizing the need for careful medication reconciliation when prescribing multiple agents, as noted in the 2020 guideline 1.
• Mood stabilizers like carbamazepine and phenytoin induce liver enzymes, reducing the effectiveness of many medications including oral contraceptives, while valproate inhibits enzymes and can increase levels of lamotrigine, requiring dose adjustments.
• Lithium toxicity risk increases when combined with NSAIDs, diuretics, or ACE inhibitors.
• Benzodiazepines combined with opioids, alcohol, or other CNS depressants can cause dangerous respiratory depression, with a near quadrupling of risk for overdose death compared with opioid prescription alone, as reported in a case-cohort study 1.

Clinical Considerations

• Clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible, and consider involving pharmacists and pain specialists as part of the management team when opioids are co-prescribed with other central nervous system depressants.
• A commonly used tapering schedule for benzodiazepines is a reduction of the dose by 25% every 1–2 weeks, with CBT increasing tapering success rates and potentially being helpful for patients struggling with a benzodiazepine taper, as suggested in the 2016 guideline 1.
• Experts emphasize the importance of communicating with mental health professionals managing the patient to discuss the patient’s needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care, highlighting the need for a multidisciplinary approach to managing these complex medication interactions, as noted in the most recent guideline from 2020 1.

From the Research

Key Drug-Drug Interactions for Antidepressants, Mood Stabilization, and Benzodiazepines

• Antidepressants, particularly monoamine oxidase inhibitors (MAOIs), can interact with certain foods and medications, leading to adverse reactions such as life-threatening blood pressure elevations 2.
• MAOIs can negatively interact with sympathomimetic and serotonergic drugs, and patients should avoid medications that can elevate blood pressure or increase serotonin levels 2.
• COVID-19 treatments, such as hydroxychloroquine and chloroquine, can interact with antidepressants and mood stabilizers, increasing the risk of QT prolongation and requiring ECG monitoring 3.
• Certain antidepressants, such as agomelatine and desvenlafaxine, may be safer to use with COVID-19 treatments, while others, such as lithium, are contraindicated with certain COVID-19 medications 3.
• Benzodiazepines do not typically interact with COVID-19 treatments, except for lopinavir/ritonavir, which requires caution 3.
• Gabapentinoids and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), can be used as substitutes for opioids and benzodiazepines, but their toxicities and combinations are not well understood 4.
• The combination of SSRIs and monoamine oxidase B (MAO-B) inhibitors, such as selegiline and rasagiline, can result in increased serotonergic effects, leading to serotonin syndrome, although this occurs rarely 5.
• Mood stabilizers, such as lithium and valproic acid, have safety and tolerability profiles that require monitoring and evidence-based strategies to manage adverse events 6.