Common Drug-Drug Interactions in Psychiatry

Polypharmacy refers to the use of multiple medications in one individual. Medications, whether for blood pressure or depression, do not work in a vacuum. When we swallow, inhale, or inject medications they make their way through our bodies in complex ways. Most medications are transported in blood attached to proteins, but many others are transported unattached in their free form. As medications make their way to their target organs, they come in contact with all kinds of tissues, cells, and fluids before they are metabolized and/or eliminated from the body.

Prescribing multiple medications for one individual increases the risk for adverse drug interactions. Some medications might displace a medicine from transport proteins while others might alter the activity of enzymes, such as CYP450 enzymes, that metabolize other drugs. Alternatively, some medications might compete with other drugs at their receptor sites and alter their effects.

While the variety of mechanisms are beyond the scope of this post, we review some of the most common drug interactions for medications used to treat mental health disorders. 

Valproic acid (VPA) + Lamotrigine:

  • Valproic acid (VPA) increases lamotrigine levels

  • Increases risk of Steven-Johnson’s Syndrome (SJS/TEN)

  • When using both, decrease the dose of lamotrigine by 50%

Carbamazepine (CBZ) is an inducer of CYP3A4:

  • CBZ induces its own metabolism

  • CBZ induces the metabolism of numerous other medications including oral contraceptives, clozapine, alprazolam, buspirone, and clonazepam

Lithium + NSAIDs (not aspirin), ACE Inhibitors, Thiazide diuretics, low sodium diet:

  • Increases lithium levels

Lithium + caffeine, theophylline, high sodium diet:

  • Decreases lithium levels

Grapefruit Juice

  • Grapefruit juice is a potent inhibitor of CYP3A4 and P-glycoprotein

  • Grapefruit juice increases blood levels of many medications metabolized by CYP3A4

Smoking Tobacco cigarettes:

  • Induces activity of CYP1A2

  • The induction does not appear to be from the nicotine, but from the hydrocarbons in smoke

  • Decreases blood levels of medications metabolized by CYP1A2 (Olanzapine, Clozapine, Caffeine)


  • Increased risk of hypertensive crisis when eating tyramine containing foods while taking MAOIs, SSRIs, TCAs, Pseudoephedrine, and Stimulants

  • Tyramine-rich foods include banana peel, beer, fava beans, aged cheese, sauerkraut, sausage, soy sauce, concentrated yeast extract.

Fluoxetine, Paroxetine, and Bupropion are potent inhibitors of CYP2D6:

  • They can raise blood levels of medications metabolized by CYP2D6.

  • Tamoxifen and Codeine are prodrugs requiring metabolism by CYP2D6. Efficacy of these drugs may be decreased when used with inhibitors of CYP2D6.

Antimicrobial-Psychotropic Drug Interactions:

  • Antimalarials: Increase phenothiazine (e.g. chlorpromazine) levels

  • Azoles: Increase alprazolam, midazolam, and buspirone levels

  • Clarithromycin, Erythromycin: Increase alprazolam, midazolam, carbamazepine, clozapine, and buspirone levels

  • Quinolones: Increase clozapine and benzodiazepine levels but decreases benzodiazepine effects

  • Isoniazid: Increases haloperidol and carbamazepine levels. Isoniazid + disulfiram can cause ataxia

  • Linezolid: Serotonin syndrome if used with serotonergic drugs

Other Interactions/Adverse Reactions:

  • Erythromycin, Clarithromycin, and Ketoconazole: QT prolongation and ventricular arrythmias with TCAs and antipsychotics

  • Linezolid is an irreversible MAO-A inhibitor: Serotonin syndrome and Hypertensive crisis

  • Isoniazid is a weaker MAO inhibitor: Reports of Serotonin syndrome and hypertensive crisis

Common Side Effects of Antiretroviral Drugs

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Neuropsychiatric Side Effects
AbacavirDepression, Mania, Suicidal ideation, Anxiety
Psychosis, Insomnia, Nightmares, Fatigue
DidanosineNervousness, Agitation, Mania, Lethargy
EmtricitabineDepression, Odd dreams, Insomnia, Confusion, Irritability
Interferon-a-2aDepression, Suicidal ideation, anxiety, mania, psychosis, insomnia, delirium, altered cognition
LamivudineDepression, Insomnia, Dizziness, dystonia
ZidovudineAnxiety, Agitation, Restlessness, Insomnia, Mania, Psychosis
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
DelavirdineAnxiety, Agitation, Amnesia,
EfavirenzAnxiety, Insomnia, Irritability, Depression
Suicidal ideation, psychosis, Nightmares, Vivid dreams
NevirapineVivid dreams, Nightmares, Visual hallucinations
Delusions, Mood Instability
EtravirineInsomnia, lightheadedness/dizziness
RilpivirineOdd Dreams, Insomnia, lightheadedness/dizziness
Protease Inhibitors
AtazanavirDepression, Insomnia
IndinavirAnxiety, Agitation, Insomnia
Lopinavir and RitonavirInsomnia
NelfinavirDepression, Anxiety, Insomnia
RitonavirAnxiety, Agitation, Euphoria
Hallucinations, Taste changes
Decreased libido
SaquinavirAnxiety, Agitation, Euphoria
Depression, Hallucinations
Excessive dreaming
Integrase Inhibitors
RaltegravirDepression, suicidal ideation, psychosis
Vivid dreams, nightmares, vertigo,
ElvitegravirDepression, Insomnia, Suicidal ideation
DolutegravirInsomnia, Fatigue
Fusion Inhibitors
EnfuvirtideDepression, Insomnia

Drug Interaction Tables


  1. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  2. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  3. McCarron, Robert M., et al. Lippincotts Primary Care Psychiatry: for Primary Care Clinicians and Trainees, Medical Specialists, Neurologists, Emergency Medical Professionals, Mental Health Providers, and Trainees. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.
  4. Focus Psychiatry Review, Dsm-5: Dsm-5 Revised Edition by Deborah J. Hales (Author, Editor), Mark Hyman Rapaport (Author, Editor)
  5. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  6. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  7. Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
  8. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  9. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  10. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  11. Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
  12. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  13. Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th
  14. Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st 2012. APP.
  15. Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
  16. Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
  17. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  18. Meyer, Jerrold, and Quenzer, Linda. Psychopharmacology: Drugs, the Brain, and Behavior. Sinauer Associates. 2018.
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