Can You Use Mirtazapine and Abilify (Aripiprazole) for Suspected Bipolar 2?
Yes, you can use mirtazapine and aripiprazole together for suspected bipolar 2 disorder, but only if aripiprazole (or another mood stabilizer) is started first or simultaneously—never use mirtazapine alone in bipolar disorder due to the risk of triggering mania. 1, 2
Critical Screening Before Starting Treatment
Before initiating any antidepressant in suspected bipolar 2, you must screen for:
- Previous episodes of elevated mood, decreased need for sleep, grandiosity, racing thoughts, or impulsive behavior 1
- Family history of bipolar disorder, which increases risk of undiagnosed bipolar disorder 1
- History of antidepressant-induced mood destabilization or activation 2
The FDA explicitly warns that treating a depressive episode with an antidepressant alone may increase the likelihood of precipitating a manic/mixed episode in patients at risk for bipolar disorder. 2
Recommended Treatment Approach
Step 1: Initiate Mood Stabilization First
- Start aripiprazole as your primary agent, as it is FDA-approved for bipolar disorder and has demonstrated efficacy in both acute mania and maintenance therapy 3
- The American Academy of Child and Adolescent Psychiatry recommends atypical antipsychotics like aripiprazole as first-line treatment for bipolar disorder 4
- Aripiprazole has shown effectiveness in bipolar depression when used as adjunctive therapy with mood stabilizers 5, 6
Step 2: Add Mirtazapine Only After Mood Stabilization
- Never use mirtazapine as monotherapy in bipolar disorder 1, 2
- Low doses of mirtazapine (used for sleep/sedation) appear safer than antidepressant doses when combined with mood stabilizers 7
- Research indicates mirtazapine has a low risk of switching to mania when: (1) used at low doses, (2) combined with a mood stabilizer, and (3) the patient has no other risk factors for switching 7
Step 3: Dosing Strategy
- Start aripiprazole at 10-15 mg/day 3, 5
- Once mood is stable on aripiprazole (typically 2-4 weeks), consider adding mirtazapine if depressive symptoms persist 7, 8
- Use the lowest effective dose of mirtazapine (15-30 mg) rather than full antidepressant doses (45 mg) to minimize switch risk 7
Evidence for This Combination
A 2007 study directly examined mirtazapine plus aripiprazole combination therapy and found it safe and well-tolerated, with accelerated onset of antidepressant action compared to mirtazapine alone. 8 The combination also reduced mirtazapine-induced weight gain and aripiprazole-induced akathisia 8.
Real-world data from European hospitals shows that combinations of antidepressants (including mirtazapine) with atypical antipsychotics are commonly used in bipolar depression, though many such combinations lack formal efficacy studies 9.
Critical Safety Warnings
Monitor for Manic Switch
The FDA warns that mirtazapine can cause manic episodes with symptoms including: 2
- Greatly increased energy
- Severe trouble sleeping
- Racing thoughts
- Reckless behavior
- Unusually grand ideas
- Excessive happiness or irritability
Other Serious Risks with Mirtazapine
- Agranulocytosis (severe neutropenia): Monitor for fever, sore throat, or signs of infection 2
- Serotonin syndrome: Particularly when combined with other serotonergic drugs 2
- Suicidal thoughts: Increased risk in young adults during initial treatment 2
Common Pitfalls to Avoid
- Starting mirtazapine before establishing mood stability is the most dangerous error—this dramatically increases switch risk 1, 2
- Using full antidepressant doses of mirtazapine (45 mg) instead of lower doses (15-30 mg) when sleep/sedation is the primary goal 7
- Inadequate monitoring during the first 4-8 weeks when switch risk is highest 2
- Failing to continue aripiprazole for at least 12-24 months, as premature discontinuation leads to relapse rates exceeding 90% 4
Alternative First-Line Options
If you want to avoid antidepressants entirely in suspected bipolar 2:
- Lithium remains the gold standard with superior evidence for preventing both manic and depressive episodes 1, 4
- Olanzapine-fluoxetine combination is FDA-approved specifically for bipolar depression 1, 4
- Lamotrigine is particularly effective for preventing depressive episodes in bipolar disorder 1, 4
- Quetiapine monotherapy has evidence for bipolar depression 4, 9
The safest approach is to establish the diagnosis definitively and initiate aripiprazole first, then reassess the need for mirtazapine after achieving mood stability. 1, 4, 7