Is valproate indicated for a patient with antisocial personality disorder and substance‑use disorder?

Valproate for Antisocial Personality Disorder with Substance Use

No, valproate is not indicated for antisocial personality disorder (AsPD), even in the presence of substance use disorder, as there is insufficient evidence to support its use for this condition.

Evidence Base for Valproate in AsPD

The most comprehensive and recent systematic review found no studies evaluating valproate specifically for AsPD 1. The 2020 Cochrane review examining pharmacological interventions for AsPD identified only 11 studies with 416 participants, but none of these studies tested valproate in patients with AsPD 1. The review concluded that "the evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder" 1.

When Valproate Might Be Considered (Off-Label)

While not indicated for AsPD itself, valproate may have a role in specific clinical scenarios:

For Aggression Management

• The American Academy of Child and Adolescent Psychiatry suggests valproate shows promise for treating aggressive behavior when used as part of a comprehensive treatment approach 2
• Valproate should only be considered after psychosocial interventions (functional family therapy, multi-systemic therapy) have been implemented first 2
• Consider valproate when aggression is severe, poses safety risks, or when comorbid bipolar features or mood instability are present 2

For Comorbid Conditions

• If the patient has a confirmed diagnosis of bipolar disorder (not just mood instability), valproate is a standard therapy alongside lithium and atypical antipsychotics 3
• Valproate is FDA-approved for acute mania in bipolar disorder, not for personality disorder symptoms 3

Critical Clinical Pitfalls

Lack of Evidence for Core AsPD Features

• A 2009 review noted that while valproate has been used in borderline personality disorder, "data are insufficient to recommend this" 4
• An older open trial in borderline personality disorder (not AsPD) showed modest effects in only 50% of completers, with highly variable individual responses 5
• Do not use valproate as monotherapy for emotional lability or impulsivity without a clear diagnosis of a condition for which it has demonstrated efficacy 3

Serious Safety Concerns

• Valproate is teratogenic and specifically associated with neural tube defects 4
• Preliminary evidence links in utero exposure to decreased verbal intelligence in offspring 4
• There is a probable increased risk of polycystic ovary syndrome, severely limiting use in women of childbearing potential 4
• Regular monitoring of liver function is necessary due to rare but serious hepatotoxicity risk 2
• Recent calls emphasize the need to re-evaluate risks and benefits, particularly for off-label use 6

Recommended Approach

First-Line Treatment

• Psychological interventions should be the primary treatment for AsPD 7
• The 2020 Cochrane review on psychological interventions found limited evidence for cognitive behavioral therapy, schema therapy, and dialectical behavior therapy, but these remain the standard of care over pharmacological approaches 7

If Medication Is Considered

• Medications should be considered adjunctive, palliative, and non-curative; they should not be the sole intervention 2
• Target specific comorbid syndromes (e.g., confirmed bipolar disorder, not just "mood instability") rather than AsPD itself 2
• Establish a strong treatment alliance before starting medication trials 2
• If valproate is tried off-label for aggression and fails, switch to another class (such as an atypical antipsychotic) rather than adding multiple medications 2

For Substance Use Disorder Component

• Address substance use disorder with evidence-based treatments for that condition specifically 1
• Note that most studies examining medications in AsPD recruited participants primarily with substance abuse problems, not AsPD as the primary diagnosis 1