Updated October 2025
Bipolar Disorder Maintenance
Mood Stabilization and Maintenance Therapy in Bipolar Disorder
Long-term maintenance therapy in bipolar disorder centers on preventing manic and depressive recurrences, reducing suicide risk, and optimizing functioning. High-certainty evidence supports lithium, quetiapine, olanzapine, and select second-generation antipsychotics; lamotrigine is strongest for depressive relapse prevention. Combination strategies (e.g., lithium or valproate plus an atypical antipsychotic) benefit high-risk patients but increase adverse effects. Treatment choice is guided by prior episode polarity, tolerability, comorbidities, and patient preference.
Clinical question
What pharmacologic and adjunctive strategies most effectively maintain euthymia and prevent relapse in adults with bipolar disorder?
Bipolar DisorderMaintenanceLithiumLamotrigineQuetiapineOlanzapineValproateSecond-generation antipsychoticsRelapse prevention
Key points
Lithium as the anchor
Strongest global maintenance efficacy with anti-manic, anti-depressive, and anti-suicidal properties; monitor levels and renal/thyroid function. Evidence base is consistent across guidelines and reviews [2], [3].
Polarity-guided selection
For depression-prone trajectories, emphasize lamotrigine or quetiapine; for mania-prone courses, favor lithium, olanzapine, asenapine, or valproate. Network meta-analysis quantifies episode-specific relapse risk reductions [1].
Combination for high-risk patients
Augment lithium/valproate with an atypical antipsychotic after severe mania, psychosis, or rapid recurrences; combinations improve relapse prevention but raise metabolic and extrapyramidal risks [1], [2].
Maintenance is lifelong, individualized
Most patients require ongoing pharmacotherapy with periodic reassessment and integration of psychosocial interventions to sustain remission and functioning [4], [5], [6].
Evidence highlights
RR 0.27–0.79 across effective agents vs placebo [1]
Depressive relapse reduction
RR 0.21–0.64 across effective agents vs placebo [1]
Mania/mixed relapse reduction
Lithium for mania, depression, and suicide prevention [2], [3]
First-line anchor
Prioritize agents by polarity, past response, and risk
Select maintenance therapy using prior episode polarity, individual response/tolerability, comorbidities (renal, thyroid, metabolic), pregnancy plans, and suicide risk.
1
Start with lithium when feasible
Lithium prevents both manic and depressive relapses and reduces suicide risk. Typical target trough 0.6–0.8 mmol/L for maintenance; 0.8–1.0 for recent severe mania. Monitor renal, thyroid, calcium, and interactions [2], [3].
2
Match drug to predominant polarity
Depression-prone: lamotrigine (strong for depressive relapse), quetiapine (bipolar I maintenance), or lithium. Mania-prone: lithium, olanzapine, asenapine, or valproate, with attention to metabolic and hepatic profiles [1], [2].
3
Use combination therapy after severe or frequent recurrences
Add an atypical antipsychotic (e.g., quetiapine, olanzapine, asenapine) to lithium/valproate when single-agent prevention is insufficient. Combinations show larger effect sizes for mania prevention but require vigilant adverse effect monitoring [1], [2].
4
Embed psychosocial interventions
Psychoeducation, CBT, family-focused therapy, and regular lifestyle routines improve adherence and reduce relapse when added to pharmacotherapy [4], [5].
5
Reassess longitudinally
Maintenance is dynamic: adjust doses, simplify regimens, and deprescribe cautiously after extended stability. Monitor for medical comorbidities, metabolic syndrome, and iatrogenic depression or activation [5], [6].
Evidence signals for maintenance efficacy
Effect sizes from randomized trials and network meta-analyses inform drug selection. Below highlights recurrence/relapse prevention by episode type.
Depressive episode prevention
Aripiprazole + valproate: RR 0.27 (95% CI 0.08–0.99) vs placebo [1]
Lamotrigine: effective vs placebo; strongest for depressive polarity [1]
Lithium: RR 0.79 (95% CI 0.66–0.95) vs placebo [1]
Olanzapine, quetiapine: significant reductions vs placebo [1]
Mania/hypomania/mixed prevention
Asenapine: RR 0.21 (95% CI 0.08–0.53) vs placebo [1]
Valproate: RR 0.64 (95% CI 0.48–0.86) vs placebo [1]
Olanzapine, quetiapine, lithium: significantly reduce manic relapse [1]
First-line anchors
Lithium: broad-spectrum efficacy and suicide risk reduction [2], [3]
Quetiapine/olanzapine: robust across poles; weigh metabolic risks [1], [2]
Key safety considerations
Lithium: renal (eGFR), thyroid (TSH), calcium/hyperparathyroidism; drug–drug interactions (NSAIDs, ACEi/ARBs, thiazides) [2], [3]
Valproate: hepatic toxicity, thrombocytopenia, teratogenicity; avoid in pregnancy-capable patients when possible [2]
Atypical antipsychotics: weight gain, dyslipidemia, hyperglycemia; monitor metabolic panel and EPS [2], [6]
Lamotrigine: rash risk; follow slow titration and manage interactions (e.g., valproate increases levels) [2]
Duration and continuity
After a single severe episode or ≥2 episodes, maintain long-term therapy; many need lifelong treatment [5], [6], [3]
Taper changes slowly over weeks to reduce destabilization risk [6]
Use adherence supports: once-daily dosing, pillboxes, blood level feedback (lithium) [6]
Clinical pearls
Align maintenance agent with the index episode and prior best response [5]
Consider combination therapy during the first post-manic year, then attempt cautious simplification if stable [2]
Integrate psychoeducation and sleep–wake regularity to reduce triggers [4], [5]
Monitoring and follow-up
Structured monitoring mitigates preventable adverse effects and supports adherence.
Baseline and periodic labs
Lithium: BMP/eGFR, TSH, calcium; trough level 5–7 days after dose change; q3–6 months levels when stable [2], [3]
Valproate: LFTs, CBC/platelets; trough levels as indicated [2]
SGAs: weight/BMI, waist circumference, BP, fasting glucose/A1c, lipids at baseline, 3 months, then q6–12 months [2], [6]
Relapse prevention plan
Early warning signs checklist with patient/family
Sleep hygiene and regular routines; limit substances
Rapid access pathway for breakthrough symptoms; consider temporary dose adjustments per plan [4], [5]
References
Source material
Primary literature that informs this article.
Mood stabilizers and/or antipsychotics for bipolar disorder ...
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Long-term treatment of bipolar disorder - PMC
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Bipolar disorder
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Bipolar Disorder - StatPearls
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Maintenance treatment received by patients with bipolar I ...
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Bipolar disorder treatment according to illness trajectory
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Treatment of bipolar disorder: a systematic review of available ...
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Lithium treatment of Bipolar disorder in adults: A systematic ...
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