Is Rexulti (brexpiprazole) effective for treating negative symptoms in patients with schizophrenia?

Rexulti (Brexpiprazole) for Negative Symptoms in Schizophrenia

Brexpiprazole is NOT a first-line agent for negative symptoms in schizophrenia—cariprazine and aripiprazole are preferred, with low-dose amisulpride as an alternative when positive symptoms are minimal. 1, 2

Current Evidence for Brexpiprazole and Negative Symptoms

FDA-Approved Indications

• Brexpiprazole is FDA-approved for schizophrenia based on improvement in total PANSS scores, not specifically for negative symptoms 3
• The PANSS includes 7 items measuring negative symptoms, but the pivotal trials (Studies 3 and 4) used total PANSS as the primary endpoint, which predominantly reflects positive symptoms and general psychopathology 3
• No antipsychotic medication currently has official FDA indication specifically for treating negative symptoms 4

Clinical Trial Data

• In the two pivotal 6-week trials, brexpiprazole 2-4 mg/day demonstrated placebo-subtracted differences in total PANSS scores ranging from -3.1 to -8.7 points 3
• While these studies showed overall symptom improvement, they were not designed or powered to specifically evaluate negative symptom efficacy 3
• The drug was generally well tolerated with relatively low incidence of activating and sedating adverse effects 5, 6

Recommended Treatment Algorithm for Negative Symptoms

Step 1: Rule Out Secondary Causes

• Evaluate for persistent positive symptoms, depressive symptoms, substance misuse, social isolation, medical illness, and antipsychotic side effects (particularly extrapyramidal symptoms and sedation) 1, 2

Step 2: First-Line Pharmacological Options

• Switch to cariprazine as the first-line option for predominant negative symptoms when positive symptoms are well-controlled 1, 2
• Aripiprazole is the second preferred option, with augmentation showing standardized mean difference of -0.41 (95% CI -0.79 to -0.03, p=0.036) for negative symptom improvement 1, 2
• Low-dose amisulpride (50 mg twice daily) should be considered when positive symptoms are minimal or absent, as it preferentially blocks presynaptic autoreceptors and enhances dopamine transmission in mesocortical pathways 1, 2

Step 3: Why Brexpiprazole Is Not Prioritized

• Despite being structurally similar to aripiprazole with partial D2 agonist activity, brexpiprazole has less intrinsic activity at D2 receptors than aripiprazole 5
• Current international guidelines from 2025 do not list brexpiprazole among recommended agents for negative symptoms, while specifically endorsing cariprazine, aripiprazole, and amisulpride 1, 2, 4
• The evidence base for brexpiprazole's efficacy on negative symptoms specifically is limited to post-hoc analyses of total PANSS scores rather than dedicated negative symptom trials 3

Clinical Considerations

When Brexpiprazole Might Be Considered

• If a patient has failed or cannot tolerate cariprazine, aripiprazole, and amisulpride 1, 2
• When a patient requires treatment for overall schizophrenia symptoms with a favorable metabolic and tolerability profile, though negative symptoms are not the primary target 5, 6
• As maintenance treatment after stabilization, where it has demonstrated efficacy in preventing relapse 3

Important Caveats

• Negative symptoms are often underdiagnosed because clinicians focus on positive symptoms, and patients may lack insight into their negative symptoms 4
• Distinguishing primary from secondary negative symptoms is crucial but challenging—ensure adequate treatment duration (at least 4-6 weeks) before determining efficacy 1
• Standard dopamine D2 antagonists and partial agonists have limited efficacy for negative symptoms despite managing positive symptoms effectively 4

Augmentation for Treatment-Resistant Cases

• If negative symptoms persist despite optimizing first-line agents, consider clozapine if not already prescribed 1, 2
• For patients already on clozapine with persistent negative symptoms, aripiprazole augmentation (5-15 mg/day) shows the most robust data 1, 2
• Antidepressant augmentation may provide modest benefit for negative symptoms even without depression diagnosis 1, 2

Psychosocial Interventions

• Cognitive remediation therapy shows robust effect sizes and represents the most strongly supported psychosocial intervention 1
• Exercise therapy demonstrates effect sizes ranging from -0.59 to -0.24 for negative symptom reduction 1
• Psychosocial interventions enrolled patients with milder negative symptoms and had lower dropout rates with the longest follow-up periods, suggesting durability of effects 7