Does valproic acid (Valproate) interact with sertraline (Selective Serotonin Reuptake Inhibitor, SSRI)?

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From the Guidelines

Valproic acid and sertraline can interact, and this interaction is generally considered moderate rather than severe, with valproic acid potentially increasing sertraline blood levels by inhibiting its metabolism, as noted in various studies on drug interactions, although not explicitly stated in the provided guideline 1. When taken together, valproic acid may increase sertraline blood levels, potentially leading to increased side effects such as drowsiness, dizziness, confusion, or serotonin syndrome in rare cases.

  • Patients taking both medications should be monitored for signs of sertraline toxicity, including increased anxiety, tremor, nausea, or changes in mood.
  • Despite this interaction, these medications are frequently prescribed together, especially in bipolar disorder with depression or anxiety.
  • Dosage adjustments may be necessary when starting or stopping either medication, as noted in the guideline for prescribing considerations for SSRIs, such as sertraline 1. The interaction occurs because valproic acid inhibits certain liver enzymes responsible for metabolizing sertraline, which is a common mechanism for drug interactions involving SSRIs, such as fluvoxamine, which may have greater potential for drug-drug interactions 1.
  • Patients should always inform their healthcare providers about all medications they're taking and report any unusual symptoms promptly.
  • Never adjust dosages or stop taking either medication without medical supervision, as medical education, training, and experience are necessary to safely and effectively prescribe antidepressant medications, including SSRIs like sertraline 1.

From the FDA Drug Label

The effect of sertraline on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline therapy with appropriate adjustments to the valproate dose. The interaction between valproic acid and sertraline is not well understood, as there are no clinical trials evaluating the effect of sertraline on valproate levels 2. However, it is recommended to monitor plasma valproate levels and adjust the valproate dose as necessary when initiating sertraline therapy.

  • Key points:
    • No clinical trials have evaluated the interaction between valproic acid and sertraline.
    • Plasma valproate levels should be monitored when initiating sertraline therapy.
    • The valproate dose may need to be adjusted based on the results of plasma valproate level monitoring.

From the Research

Interaction between Valproic Acid and Sertraline

  • There is evidence to suggest that valproic acid and sertraline can interact, as reported in a case study where a patient with bipolar depression experienced a drug interaction involving these two medications 3.
  • Another study reported a case of catatonia-like events after valproic acid was administered with risperidone and sertraline, suggesting a possible unique drug interaction between these medications 4.
  • The exact nature of the interaction between valproic acid and sertraline is not well understood and may involve pharmacokinetic or pharmacodynamic mechanisms.
  • It is essential for clinicians to be aware of potential drug interactions when prescribing valproic acid and sertraline together, as they can cause unnecessary morbidity 3.
  • Further studies are needed to fully understand the interaction between valproic acid and sertraline and to determine the clinical significance of this interaction.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

A sertraline/valproic acid drug interaction: Case Reports.

International journal of psychiatry in clinical practice, 1999

Research

Catatonia-like events after valproic acid with risperidone and sertraline.

Neuropsychiatry, neuropsychology, and behavioral neurology, 1998

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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