What is the recommended treatment for psychosis, specifically schizophrenia?

Treatment of Psychosis in Schizophrenia

All patients with schizophrenia should be treated with antipsychotic medication combined with psychosocial interventions, starting immediately when psychotic symptoms have been present for ≥1 week with associated distress or functional impairment. 1

Initial Assessment Requirements

Before initiating treatment, conduct a comprehensive evaluation that includes: 1

• Psychiatric symptoms including hallucinations, delusions, disorganized speech, and negative symptoms (blunted affect, avolition, asociality) 2
• Trauma history and substance use assessment, particularly cannabis and methamphetamine use, as these are strongly linked to psychosis 2, 3
• Suicide and aggression risk at every encounter, given the 10% lifetime suicide risk 4
• Quantitative symptom measures using standardized scales (PANSS, BPRS, or CGI) to establish baseline severity 1
• Physical health screening including metabolic parameters (BMI, waist circumference, blood pressure, HbA1c, lipid panel), liver function, renal function, complete blood count, and ECG 5
• Cognitive assessment and mental status examination 1

First-Line Pharmacotherapy

Initial Antipsychotic Selection

For first-episode psychosis, start with risperidone 1-2 mg/day or olanzapine 7.5-10 mg/day as first-line agents. 5 Second-generation antipsychotics are preferred over first-generation agents because they cause fewer extrapyramidal symptoms. 2

Alternative second-line options include: 5

• Quetiapine 100-300 mg/day
• Aripiprazole 15-30 mg/day

Critical Dosing Principles

First-episode patients are more sensitive to both therapeutic effects and side effects, requiring lower maximum doses than chronic patients. 5 Specifically:

• Risperidone: Target 2 mg/day, maximum 4 mg/day (not the higher doses used in chronic schizophrenia) 5
• Olanzapine: Target 7.5-10 mg/day, maximum 20 mg/day 5

For chronic schizophrenia, therapeutic doses should reach at least 600 mg chlorpromazine equivalents daily. 1 Risperidone efficacy was established at 2-16 mg/day in clinical trials, with the 6 mg dose showing the most consistently positive responses. 6

Duration of Adequate Trial

Each antipsychotic trial must be administered at therapeutic dose for at least 4-6 weeks before assessing efficacy. 1, 5 The consensus guidelines specify a minimum of 6 weeks per trial to avoid false positives. 1

Algorithm for Treatment Failure

After First Failed Trial

If inadequate response after 4-6 weeks at therapeutic dose, switch to a second antipsychotic with a different pharmacodynamic profile. 5 For example:

• If risperidone fails → switch to olanzapine, quetiapine, or aripiprazole 5
• Do not increase to excessive doses; switching is more effective than high-dose strategies 5

Defining Treatment-Resistant Schizophrenia

Treatment resistance is established after: 1

• Failure of at least two adequate antipsychotic trials (each at therapeutic dose for ≥6 weeks)
• Different antipsychotic agents (though they need not be from different "generations" given overlapping mechanisms) 1
• Persistent symptoms despite adequate adherence

Approximately 34% of patients with schizophrenia are treatment-resistant to non-clozapine antipsychotics. 5

Clozapine for Treatment-Resistant Schizophrenia

Patients with treatment-resistant schizophrenia must be treated with clozapine after two failed adequate antipsychotic trials. 1, 5 This is a Level 1B recommendation (strong evidence). 1

Clozapine should also be used when: 1

• Suicide risk remains substantial despite other treatments (Level 1B recommendation)
• Aggressive behavior remains substantial despite other treatments (Level 2C suggestion)

The evidence shows clozapine does not demonstrate clear superiority in non-treatment-resistant first-episode patients, so it should be reserved for the indications above. 1

Long-Acting Injectable Antipsychotics

Consider long-acting injectable (LAI) antipsychotics for patients with poor or uncertain adherence, or when patients prefer this route. 1 This is a Level 2B suggestion.

For defining treatment resistance with certainty, at least one failed trial should ideally include an LAI given for ≥6 weeks after achieving steady state (typically ≥4 months from initiation). 1 This eliminates "pseudo-resistance" due to non-adherence.

Mandatory Psychosocial Interventions

All patients require a comprehensive treatment plan combining pharmacotherapy with evidence-based psychosocial interventions. 1 The following are Level 1B recommendations (strong evidence):

• Coordinated specialty care programs for first-episode psychosis 1, 5
• Cognitive-behavioral therapy for psychosis (CBTp) 1, 5
• Psychoeducation 1, 5
• Supported employment services 1, 5
• Assertive community treatment for patients with poor engagement leading to frequent relapse, homelessness, or legal difficulties 1

Additional interventions with moderate evidence (Level 2B-2C): 1, 5

• Family interventions for patients with ongoing family contact
• Social skills training for enhanced social functioning
• Cognitive remediation
• Supportive psychotherapy

Maintenance Treatment

Patients whose symptoms have improved with an antipsychotic must continue treatment with that same antipsychotic medication. 1 This is a Level 1A recommendation for continuation and Level 2B suggestion for staying with the same agent.

For first-episode patients, maintain treatment for 1-2 years after the initial episode. 5

Metabolic and Safety Monitoring

Mandatory monitoring at baseline and regularly during treatment includes: 5

• BMI and waist circumference
• Blood pressure
• HbA1c or fasting glucose
• Lipid panel
• Prolactin level
• Liver function tests
• Renal function (urea and electrolytes)
• Complete blood count
• ECG

Consider prophylactic metformin when starting olanzapine or clozapine to prevent metabolic complications. 5

Patients treated with second-generation antipsychotics require at least annual metabolic screening and interventions for weight management and smoking cessation due to increased cardiovascular risk. 2

Management of Antipsychotic Side Effects

Acute Dystonia

Treat with anticholinergic medication. 1 This is a Level 1C recommendation.

Parkinsonism

Options include (Level 2C): 1

• Lower the antipsychotic dose
• Switch to another antipsychotic
• Add anticholinergic medication

Akathisia

Options include (Level 2C): 1

• Lower the antipsychotic dose
• Switch to another antipsychotic
• Add a benzodiazepine
• Add a beta-blocker

Tardive Dyskinesia

For moderate to severe or disabling tardive dyskinesia, treat with a VMAT2 inhibitor (valbenazine or deutetrabenazine). 1 This is a Level 1B recommendation.

Critical Pitfalls to Avoid

Do not start antipsychotics for personality traits or prodromal symptoms alone, as this exposes patients to metabolic and neurological side effects without established benefit for preventing schizophrenia onset. 7 Treatment should only begin when psychotic symptoms have been present for ≥1 week with distress or functional impairment. 7, 5

Do not use excessive doses or pursue high-dose strategies instead of switching medications. 5 First-episode patients particularly require lower maximum doses than chronic patients. 5

Do not delay clozapine after two adequate failed trials, as this prolongs unnecessary suffering in treatment-resistant patients. 5

Do not neglect psychosocial interventions, as medication alone is insufficient for optimal outcomes. 5 Coordinated specialty care programs significantly improve outcomes in first-episode psychosis. 1, 5

Do not switch medications too quickly before completing an adequate 4-6 week trial at therapeutic dose. 1, 5

Do not use antipsychotics in older adults with dementia-related psychosis without careful consideration, as they carry increased mortality risk. 3