Why do some prescribers use two different antipsychotics (anti-psychotics) at once?

Why Prescribers Use Two Antipsychotics Simultaneously

While clinical guidelines consistently recommend antipsychotic monotherapy as first-line treatment, prescribers use antipsychotic polypharmacy (APP) in 10-40% of patients primarily because certain patients—particularly those with treatment-resistant schizophrenia—fail to respond adequately to single-drug therapy, and approximately 20-33% of patients cannot tolerate switching back to monotherapy once established on combination treatment. 1

Guideline Positions vs. Clinical Reality

Major treatment guidelines generally oppose routine antipsychotic polypharmacy:

• The American Psychiatric Association (2021) endorses monotherapy exclusively and does not acknowledge situations warranting APP 1
• NICE guidelines (2019) advise against regular combined antipsychotic use, except briefly during medication transitions 1
• The World Federation of Societies of Biological Psychiatry recommends APP only for treatment-resistant cases 1

However, the Finnish Current Care Guideline acknowledges that some patients benefit from concurrent antipsychotics, particularly aripiprazole combinations for negative symptoms 1

Despite guideline recommendations, APP prevalence ranges from 16% in North America to 32% in Asia, with some studies reporting up to 57.5% of patients receiving APP for at least 90 days 1

Primary Clinical Reasons for Antipsychotic Polypharmacy

Treatment-Resistant Positive Symptoms

The most frequently cited reason is insufficient response to monotherapy for positive symptoms (hallucinations, delusions) 1

Negative Symptom Management

Prescribers add second antipsychotics to reduce negative symptoms (social withdrawal, flat affect, lack of motivation), with aripiprazole augmentation showing specific benefit (standardized mean difference −0.41,95% CI −0.79 to −0.03, p = 0.036) 1

Clozapine Augmentation

NICE guidelines specifically permit adding another antipsychotic to augment clozapine when clozapine monotherapy proves ineffective, recommending selection of drugs that don't compound clozapine's side effects 1

The combination of clozapine with another second-generation antipsychotic (possibly risperidone) may offer advantages over monotherapy 1

Side Effect Management

Prescribers use APP to:

• Reduce metabolic side effects: Aripiprazole augmentation reduces prolactin levels and body weight 1
• Lower individual drug doses to minimize side effects while maintaining efficacy 1
• Reduce extrapyramidal symptoms through strategic combinations 1

Targeting Comorbid Symptoms

APP addresses specific symptoms including anxiety, cognitive dysfunction, impulsive/violent behavior, and sleep disturbances as an alternative to benzodiazepines, which may produce better outcomes given benzodiazepines' negative effects on suicide risk, cognition, and anxiety 1

Evidence Quality: A Critical Caveat

The evidence supporting APP is problematic: A 2021 meta-analysis found antipsychotic augmentation superior to monotherapy for total symptom reduction (standardized mean difference −0.53,95% CI −0.87 to −0.19, p = 0.002), but this benefit appeared only in open-label low-quality trials, not in double-blinded or high-quality studies 1

Another meta-analysis of 42 antipsychotic combinations found no clear evidence recommending APP over monotherapy, with effect sizes inversely correlated with study quality 1

The Problem with Discontinuation

Switching from APP to monotherapy carries significant risks: A meta-analysis of 6 RCTs (341 patients) found switching associated with a 2.28-fold increased risk of treatment discontinuation (95% CI 1.50–3.46) 1

Real-world studies demonstrate:

• One-third of patients cannot tolerate switching from APP to monotherapy and must return to combination therapy 1, 2
• Patients switching to monotherapy experienced greater symptom increases and 42% discontinuation rates versus 13% in the APP group 1
• Approximately 20-33% of patients require continued APP despite attempts at simplification 2, 3

Risks of Antipsychotic Polypharmacy

APP is associated with:

• Increased global side effect burden: Higher rates of Parkinsonian effects, anticholinergic medication needs, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation, cognitive impairment, and diabetes 2
• Drug-drug interactions affecting metabolic pathways, potentially causing additive effects and increased side effect severity 2
• High-dose prescribing: APP is a major contributor to excessive total antipsychotic doses 4

When APP May Be Justified

Based on guideline allowances and evidence:

1. Clozapine augmentation after inadequate response to optimized clozapine monotherapy 1
2. Treatment-resistant schizophrenia after multiple failed monotherapy trials 1, 5
3. Brief cross-titration periods when switching medications 1
4. Patients who previously failed monotherapy simplification attempts 1

Practical Approach If APP Is Necessary

If combination therapy is unavoidable:

• Select antipsychotics with differing side-effect profiles to avoid compounding adverse effects 2
• Start with lower doses of each medication to minimize side effects 2
• Establish clear treatment goals and reassessment timelines 2
• Monitor regularly for adverse effects including metabolic parameters 2
• Consider aripiprazole specifically for negative symptom reduction or metabolic side effect mitigation 1

The bottom line: APP persists in clinical practice because a subset of patients genuinely requires it despite guideline recommendations against routine use, but prescribers should exhaust monotherapy options first and recognize that most APP lacks high-quality evidence supporting its efficacy.