What medications are used for mood stabilization in schizophrenia?

Mood Stabilization in Schizophrenia

Mood stabilizers—including lithium, valproate, carbamazepine, and lamotrigine—are used as adjunctive agents (not monotherapy) in schizophrenia to address specific symptom domains: agitation, mood instability, dysphoria, explosive outbursts, and aggression. 1

Primary Treatment Framework

Antipsychotic medications remain the cornerstone of schizophrenia treatment, targeting psychotic symptoms. 1 Mood stabilizers serve as adjunctive agents only, never as sole therapy, since they have no documented beneficial effect as monotherapy in schizophrenia. 2

Evidence-Based Adjunctive Mood Stabilizers

Lithium

• Best evidence exists for anti-aggressive effects when combined with antipsychotics. 2
• Also demonstrates efficacy for affective symptoms (mood instability, dysphoria) in schizophrenia. 2
• Reduces suicide attempts 8.6-fold and completed suicides 9-fold, an effect independent of mood stabilization. 3
• Most commonly prescribed mood stabilizer historically (13.2% of patients in 1994), though usage has declined. 4

Valproate (Divalproex)

• Most commonly prescribed mood stabilizer currently (35% of patients by 1998, nearly tripling from 12.3% in 1994). 4
• Average dosing: 1,520 mg/day for approximately two-thirds of hospital stay. 4
• Shows faster improvement in psychopathology when combined with risperidone or olanzapine compared to antipsychotic monotherapy in a 28-day trial of 249 patients. 5
• Positive effects on aggression demonstrated in single small study (n=30). 6
• Critical caveat: Despite widespread use, valproate has not shown consistently positive effects across studies and evidence remains sparse. 2, 6

Carbamazepine

• Anti-aggressive effects described, though less robust evidence than lithium. 2
• Less commonly used than lithium or valproate. 4

Lamotrigine

• Demonstrated beneficial effect in placebo-controlled study, but requires verification before establishing its role. 2
• Case reports suggest efficacy in schizoaffective disorder at doses of 400 mg/day (serum concentrations >10 mg/l), with partial effectiveness at lower doses. 7
• Evidence remains preliminary and insufficient for routine recommendation. 2

Gabapentin

• Emerging usage documented (increased from minimal use in 1994 to measurable prescribing by 1998), but no robust efficacy data. 4

Clinical Algorithm for Mood Stabilizer Selection

When aggression is the primary target symptom:

• First choice: Lithium (strongest evidence for anti-aggressive effects). 2
• Alternative: Valproate or carbamazepine. 2, 6

When affective symptoms (mood instability, dysphoria) predominate:

• First choice: Lithium (documented effects on affective symptoms). 2
• Alternative: Valproate (though evidence is inconsistent). 2, 6

When rapid symptom control is needed:

• Consider valproate combined with risperidone or olanzapine (faster onset demonstrated in controlled trial). 5

When tardive dyskinesia is present:

• Valproate showed significant reduction in single small study (n=30, WMD -3.3). 6

Monitoring Requirements

For valproate: 8

• Baseline: liver function tests, complete blood count, pregnancy test in females
• Ongoing: serum drug levels, hepatic function, hematological indices every 3-6 months
• Target serum concentration: 50-125 μg/mL

For lithium: 3

• Baseline: complete blood count, thyroid function, urinalysis, BUN, creatinine, serum calcium, pregnancy test
• Ongoing: lithium levels, renal and thyroid function, urinalysis every 3-6 months
• Target level: 0.8-1.2 mEq/L for acute treatment

Critical Pitfalls to Avoid

• Never use mood stabilizers as monotherapy in schizophrenia—they are ineffective without concurrent antipsychotic medication. 2
• Avoid premature conclusions about ineffectiveness—adequate therapeutic trials require 4-6 weeks at sufficient dosages. 1
• Do not overlook drug interactions, particularly with carbapenem antibiotics (which dramatically reduce valproate levels and may cause loss of seizure control). 8
• Recognize the evidence gap—despite widespread use (43.4% of schizophrenia inpatients receiving mood stabilizers by 1998), controlled clinical trials remain sparse. 4, 6
• Monitor for sedation with valproate, as this side effect occurs more frequently than with placebo. 6

Important Clinical Context

The adjunctive use of mood stabilizers in schizophrenia addresses associated symptomatology rather than core psychotic symptoms. 1 While commonly used in clinical practice, systematic studies addressing their use are lacking, particularly in juvenile populations. 1 The dramatic increase in valproate prescribing (nearly tripling from 1994-1998) occurred despite limited evidence for efficacy, highlighting the need for large, well-designed controlled trials. 4, 6