Are selective serotonin reuptake inhibitors (SSRIs) contraindicated in patients with bipolar II disorder?

Are SSRIs Contraindicated in Bipolar II Disorder?

SSRIs are not absolutely contraindicated in Bipolar II disorder, but they should be avoided as monotherapy and used only with extreme caution as adjuncts to mood stabilizers when depressive symptoms remain severe and refractory. 1

Primary Treatment Approach

The fundamental principle is that antidepressants should only be used as adjuncts for bipolar depression when the patient is already taking at least one mood stabilizer. 1 This is not a suggestion—it is the recommended standard of care.

Clinical Algorithm for Managing Depression in Bipolar II

1. First-line intervention: Optimize the current mood stabilizer dosage before considering any antidepressant 1

2. Second-line intervention: Switch to or add a different mood stabilizer rather than introducing an SSRI 1

3. Third-line intervention: Only after adequate mood stabilization should an SSRI be cautiously considered, and only if depressive symptoms remain severe and refractory 1

4. Preferred combination: If antidepressant therapy is deemed necessary, the FDA-approved combination for bipolar depression is olanzapine plus fluoxetine, not aripiprazole plus an SSRI 1

Key Risks and Contraindications

Mood Destabilization

SSRIs can destabilize mood and incite manic episodes in bipolar patients. 1 When a manic episode is precipitated by an SSRI, it is characterized as substance-induced, though it may represent unmasking of the underlying disorder or disinhibition. 1

Specific Contraindications

• Bipolar depression: Treatment with SSRIs should be avoided in patients with a history of bipolar depression due to risk of mania 2
• Concurrent use with MAO inhibitors: SSRIs are absolutely contraindicated 2
• Caution with stimulants: Combining SSRIs with stimulants (amphetamine class) requires extreme caution due to serotonin syndrome risk 1

Serotonin Syndrome Risk

When SSRIs are combined with other serotonergic agents, particularly stimulants, the risk of serotonin syndrome becomes significant. 1 Symptoms include:

• Mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 1
• Advanced symptoms: fever, seizures, arrhythmias, and unconsciousness that can be fatal 1

Evidence Nuances

There is contradictory evidence regarding SSRI use in Bipolar II specifically. Some smaller studies suggest that SSRI monotherapy may be effective for Bipolar II depression with low manic switch rates. 3, 4, 5 However, these studies had significant limitations including small sample sizes and short follow-up periods, and their findings should not override established guideline recommendations. 1

The distinction between Bipolar I and Bipolar II is important: Bipolar II patients may have lower manic switch rates with antidepressants compared to Bipolar I patients. 5 However, this does not justify routine SSRI monotherapy.

Common Pitfalls to Avoid

• Never prescribe SSRI monotherapy for Bipolar II depression without mood stabilizer coverage 1, 6
• Do not assume that absence of prior manic episodes means SSRIs are safe—unrecognized subsyndromal bipolarity is a frequent cause of treatment resistance 6
• Avoid abrupt discontinuation of SSRIs if they are being used, as this may precipitate SSRI withdrawal syndrome 2
• Monitor closely for new suicidal ideation, akathisia, or emerging hypomanic symptoms when SSRIs are used 2

Preferred Alternatives

For Bipolar II depression, prioritize:

• Lithium as a mood stabilizer with proven efficacy 2
• Lamotrigine as a mood stabilizer 6
• Quetiapine as an atypical antipsychotic with antidepressant properties that does not destabilize mood 7, 6

These agents provide antidepressant efficacy without the risk of mood destabilization inherent to SSRIs. 7