What is the role of pregabalin (anticonvulsant) in treating bipolar disorder?

Pregabalin in Bipolar Disorder

Direct Recommendation

Pregabalin should NOT be used as a standard treatment for bipolar disorder due to lack of evidence for efficacy in treating core mood symptoms, and it carries potential safety concerns including emergence of suicidal ideation. 1, 2

Evidence-Based Rationale

Lack of Efficacy Evidence

• No double-blind randomized controlled trials of pregabalin for bipolar disorder have been conducted, making it impossible to establish efficacy for core mood symptoms 2
• The American Academy of Child and Adolescent Psychiatry recommends lithium, valproate, or atypical antipsychotics as first-line treatments for acute mania/mixed episodes, with no mention of pregabalin 1
• Pregabalin has no FDA indication for any psychiatric disorder in the USA 3

Limited Open-Label Data

• One small open-label study (n=58) showed 41% acute response rate when pregabalin was used as adjunctive treatment in treatment-resistant bipolar patients, but this was uncontrolled and manufacturer-independent 3
• In that same study, 79% of non-responders discontinued due to intolerable side effects, indicating poor tolerability 3
• Only 42% of initial responders continued pregabalin long-term (average 45 months), suggesting limited sustained benefit 3

Safety Concerns

• A case report documented emergence of suicidal ideation and self-harming behavior after adding pregabalin to quetiapine in a bipolar II patient, which resolved upon pregabalin discontinuation 4
• The literature shows disagreement about pregabalin's safety profile, with concerns about suicidal effects of anticonvulsants in affective disorders 4
• While the open-label study reported no abuse, this contradicts broader concerns about gabapentinoid misuse potential 3

When Pregabalin Might Be Considered

Comorbid Anxiety Disorders

• Pregabalin has moderate evidence for efficacy in anxiety states (SMD -0.55 for preoperative anxiety), which could be relevant for bipolar patients with comorbid anxiety 2
• The American Academy of Child and Adolescent Psychiatry notes that anticonvulsants used as mood stabilizers (particularly pregabalin or gabapentin) may provide anxiolytic effects 1
• However, pregabalin should only be used adjunctively after mood stabilization is achieved with first-line agents, never as monotherapy or before establishing adequate mood control 1, 5

Clinical Algorithm for Decision-Making

If considering pregabalin in bipolar disorder:

1. First, ensure adequate trial of first-line mood stabilizers (lithium, valproate, or atypical antipsychotics for 6-8 weeks at therapeutic doses) 1
2. Confirm mood stability before adding any adjunctive agent to avoid mood destabilization 1
3. Target specific comorbid symptoms (anxiety, not core mood symptoms) that persist despite adequate mood stabilization 1, 2
4. Monitor closely for emergence of suicidal ideation, particularly in the first few weeks after initiation 4
5. Discontinue immediately if suicidal thoughts, self-harm behaviors, or mood destabilization occur 4

Critical Pitfalls to Avoid

• Never use pregabalin as monotherapy for bipolar disorder - it should not replace established mood stabilizers or antipsychotics 5
• Avoid unnecessary polypharmacy - pregabalin adds medication burden without proven benefit for core bipolar symptoms 1
• Do not assume gabapentinoid class effects translate to bipolar efficacy - despite the attractive pharmacological rationale targeting voltage-gated calcium channels, clinical evidence is lacking 2
• Be cautious in depressive episodes - the case report of suicidal ideation occurred during a depressive episode with anxiety features 4

Preferred Alternatives

• For comorbid anxiety in bipolar disorder, cognitive-behavioral therapy is the primary non-pharmacological intervention 1
• Pharmacologically, optimize the mood stabilizer regimen first, as many mood stabilizers have inherent anxiolytic properties 1
• Buspirone (5mg twice daily, maximum 60mg/day) may be useful for mild-to-moderate anxiety, though it requires 2-4 weeks for effect 1
• Low-dose benzodiazepines (lorazepam 0.25-0.5mg PRN) can be used cautiously for acute anxiety with clear frequency limitations 1