What are the treatment approaches for positive and negative symptoms in schizophrenia?

Understanding Positive and Negative Symptoms in Schizophrenia

Positive symptoms in schizophrenia include hallucinations, delusions, disorganized thoughts and behavior, and agitation, while negative symptoms comprise five core domains: avolition (lack of motivation), anhedonia (inability to experience pleasure), asociality (social withdrawal), blunted affect (reduced emotional expression), and alogia (poverty of speech). 1, 2

Positive Symptoms: The "Added" Experiences

Positive symptoms represent an excess or distortion of normal functions and include: 3, 2

• Hallucinations (most commonly auditory) 2
• Delusions (fixed false beliefs) 2
• Conceptual disorganization (disorganized thinking and speech) 3
• Suspiciousness and unusual thought content 3
• Disorganized behavior and agitation/aggression 4, 2

These symptoms respond well to dopamine D2 receptor antagonists and partial agonists, which form the cornerstone of antipsychotic treatment. 5

Negative Symptoms: The "Subtracted" Capacities

Negative symptoms reflect a diminution or absence of typical behaviors and internal experiences, clustering into two distinct factors: 1

Experiential Factor (Motivational Deficits)

• Avolition: Lack of motivation and goal-directed behavior 1, 2
• Anhedonia: Inability to experience pleasure 1, 2
• Asociality: Social withdrawal and reduced social engagement 1, 2

Expressive Factor (Cognitive-Related)

• Blunted affect: Reduced emotional expression 1, 2
• Alogia: Poverty of speech 1, 2

The two factors likely have different pathophysiological bases, with the Experiential factor more related to motivational deficits and the Expressive factor more related to cognition. 1

Clinical Significance and Prevalence

Up to 90% of patients experiencing first-episode psychosis present with at least one negative symptom, and these persist in 35-70% of patients after treatment. 1

Negative symptoms carry substantially greater functional burden than positive symptoms: 1, 4

• They are closely related to functional outcomes and quality of life 4
• They affect approximately 40% of people with schizophrenia prominently 4
• They are associated with low remission rates, impaired academic and occupational performance, and poor social functioning 1
• They often predate the onset of psychosis 1

Critical Distinction: Primary vs. Secondary Negative Symptoms

Primary negative symptoms are intrinsic to schizophrenia, while secondary negative symptoms result from other factors including persistent positive symptoms, depression, medication side effects (particularly extrapyramidal symptoms and sedation), environmental deprivation, or substance misuse. 1, 6

This distinction is clinically crucial because secondary negative symptoms may resolve when the underlying cause is addressed, whereas primary negative symptoms require targeted treatment strategies. 1, 6

Treatment Approaches: A Systematic Algorithm

For Positive Symptoms

Start with dopamine D2 receptor antagonist or partial agonist antipsychotic monotherapy, which effectively reduces positive symptoms in approximately 70-80% of patients. 5, 3

• Select agents with minimal anticholinergic properties to avoid cognitive blunting 5
• If first antipsychotic fails after adequate trial, switch to a second different antipsychotic as monotherapy 5
• If two adequate monotherapy trials fail, initiate clozapine (effective in 34% of treatment-resistant cases) 7, 5

For Negative Symptoms: Step-by-Step Approach

Step 1: Rule out and address secondary causes 6

• Evaluate for persistent positive symptoms, depression, substance misuse, social isolation, medical illness, and antipsychotic side effects 6
• If extrapyramidal symptoms or sedation present, consider dose reduction or medication switch 6

Step 2: Optimize antipsychotic selection 6

• For predominant negative symptoms with controlled positive symptoms, switch to cariprazine or aripiprazole (aripiprazole shows standardized mean difference of -0.41 for negative symptom improvement) 6, 7
• Consider low-dose amisulpride 50 mg twice daily for patients with minimal or absent positive symptoms, as it preferentially blocks presynaptic autoreceptors and enhances dopamine transmission in mesocortical pathways 6
• If positive symptoms are well controlled, gradually reduce antipsychotic dose while remaining within therapeutic range 6

Step 3: Implement psychosocial interventions 6

• Cognitive remediation therapy shows robust effect sizes and should be offered with 1B evidence rating 6, 5
• Exercise therapy demonstrates effect sizes ranging from -0.59 to -0.24 for negative symptom reduction 6
• Social skills training and cognitive behavioral therapy for psychosis (CBTp) have demonstrated modest but lasting positive effects 6, 5
• These interventions enrolled patients with milder negative symptoms and had lower dropout rates (9.7-14.5%) compared to pharmacological trials (25.5%) 1, 6

Step 4: Consider antidepressant augmentation 6

• Antidepressant augmentation may benefit negative symptoms even without diagnosed depression 6
• Benefits are modest, so weigh against potential drug interactions 6

Step 5: For treatment-resistant negative symptoms 6, 7

• Consider clozapine if not already prescribed (target plasma level ≥350 ng/mL, potentially up to 550 ng/mL) 7
• For patients on clozapine with persistent negative symptoms, augment with aripiprazole (reduces psychiatric hospitalization risk with HR 0.86,95% CI 0.79-0.94) 7
• Alternative augmentation options include amisulpride or antidepressants 6

Common Pitfalls to Avoid

Antipsychotics effectively reduce positive symptoms but have limited efficacy on negative symptoms, with the exception of cariprazine, aripiprazole, and low-dose amisulpride. 1, 5

• Clinicians tend to primarily notice positive symptoms and may underestimate negative symptom burden 1
• Patients often lack insight into the extent and impact of their negative symptoms 1
• Ensure adequate trial duration of at least 4-6 weeks before determining intervention efficacy 6
• Monitor for metabolic side effects, particularly with olanzapine and clozapine, which may require adjunctive metformin 6
• Be cautious with antipsychotic polypharmacy, though specific combinations (e.g., aripiprazole with clozapine) may be beneficial 6, 7

Monitoring Requirements

Assess symptom response at 6-8 weeks using structured assessment tools such as the Positive and Negative Syndrome Scale (PANSS) or Scale for Assessing Negative Symptoms (SANS). 7, 3

• Document baseline movement disorders before starting treatment 7
• Check metabolic parameters (BMI, waist circumference, blood pressure, HbA1c, lipids, liver function) at baseline and repeat at 3 months 7
• Assess akathisia weekly during dose escalation 7
• Monitor for worsening agitation or activation, which may indicate excessive dosing 7