Valproic Acid Can Cause Agitation in Some Patients
Valproic acid can cause agitation as an adverse effect, particularly in elderly patients with dementia and in some neuropsychiatric conditions. This side effect is documented in both drug labeling and clinical guidelines.
Evidence for Valproic Acid-Induced Agitation
FDA Drug Label Evidence
The FDA drug label for valproic acid 1 lists several neuropsychiatric adverse effects that can manifest as agitation:
- Emotional lability (6% of patients)
- Agitation (specifically noted in post-marketing experience)
- Psychomotor hyperactivity
- Hostility
- Disturbance in attention
- Behavioral deterioration
Clinical Guidelines Evidence
Multiple guidelines acknowledge the potential for valproic acid to cause behavioral disturbances:
The Alzheimer's disease management guidelines 2 list valproic acid as a mood-stabilizing agent for agitation, but note it has "problematic side effects" that require monitoring.
The 2021 SNO and EANO brain tumor guidelines 2 specifically mention that valproic acid use is "associated with complications" beyond just the commonly cited thrombocytopenia and hepatotoxicity.
Patient Populations at Higher Risk
Elderly and Dementia Patients
Cochrane systematic reviews 3, 4 have consistently found that:
- Valproic acid is ineffective for treating agitation in dementia
- It may actually worsen agitation in some patients
- The medication is associated with higher rates of adverse effects in elderly populations
Neurological Conditions
In patients with brain tumors or other neurological conditions, valproic acid may have paradoxical effects on behavior 2.
Monitoring and Management
If a patient develops agitation while on valproic acid:
- Assess for temporal relationship between medication initiation/dose changes and onset of agitation
- Rule out other causes of agitation (infection, pain, other medications)
- Consider dose reduction if clinically appropriate
- If agitation persists, consider alternative anticonvulsant therapy such as levetiracetam, which may have fewer behavioral side effects 2
- Monitor closely during medication changes, as abrupt discontinuation can worsen seizure control
Alternative Medications
For patients requiring anticonvulsant therapy who develop agitation on valproic acid:
- Levetiracetam may be better tolerated in terms of behavioral side effects according to brain tumor guidelines 2
- However, note that levetiracetam can also cause behavioral side effects in some patients
Clinical Perspective
While some studies have explored valproic acid as a treatment for agitation in specific settings like ICU delirium 5 or palliative care 6, the evidence for its benefit is limited and of low quality. In fact, the most rigorous evidence from Cochrane reviews 3, 4 indicates that valproic acid is ineffective for treating agitation and may worsen it in certain populations.
When evaluating a patient with new-onset agitation, always consider medication side effects as a potential cause, with valproic acid being a recognized contributor to such symptoms in susceptible individuals.