What defines treatment resistance in psychosis?

Definition of Treatment Resistance in Psychosis

Treatment resistance in psychosis is defined as the failure to respond to at least two adequate trials with different antipsychotic drugs, each lasting at least 6 weeks at therapeutic doses, despite adherence to medication. 1

Core Diagnostic Criteria for Treatment Resistance

• Treatment resistance requires failure of at least two adequate antipsychotic trials with different medications, with each trial lasting at least 6 weeks at therapeutic doses 1
• Therapeutic doses should be at the target dose or mid-point of the target dose range as specified in the manufacturer's summary of product characteristics, or equivalent to at least 600mg of chlorpromazine per day 1
• Persistent symptoms of at least moderate severity must be present for a minimum of 12 weeks despite adequate treatment 1
• Symptoms should be assessed using validated instruments such as PANSS (Positive and Negative Syndrome Scale) or BPRS (Brief Psychiatric Rating Scale) 1, 2
• Functional impairment should be documented using validated measures such as the Role Functioning Scale or SOFAS (Social and Occupational Functioning Assessment Scale) 1

Temporal Patterns of Treatment Resistance

• Treatment resistance can be categorized based on when it develops 1:
  • Early-onset treatment resistance: develops within the first year of treatment 1, 3
  • Medium-term onset treatment resistance: develops during 1-5 years after treatment onset 1
  • Late-onset treatment resistance: develops more than 5 years after treatment onset 1
• Research shows that approximately 84% of treatment-resistant patients are resistant from illness onset (early-onset resistance) 3
• Factors associated with early treatment resistance include diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis 3

Ruling Out Pseudo-Resistance

• To rule out "pseudo-resistance," the following factors should be excluded 1, 4:
  • Inadequate treatment adherence (optimally, at least one failed trial should include a long-acting injectable antipsychotic) 1, 2
  • Inadequate dosing (doses should be equivalent to at least 600mg of chlorpromazine per day) 1
  • Insufficient treatment duration (each trial should last at least 6 weeks) 1
  • Incorrect diagnosis or unaddressed comorbidities 5, 4

Clozapine Resistance

• Clozapine resistance is a subspecifier of treatment resistance and refers to failure to respond to an adequate trial of clozapine 1
• An adequate clozapine trial requires:
  • Therapeutic blood levels of clozapine (≥350 ng/ml) measured on at least two occasions separated by at least a week at a stable dose 1, 2
  • If blood levels cannot be obtained, a minimum dose of 500mg/day is recommended, unless limited by tolerability 1, 2

Predictors of Treatment Resistance

• Several factors have been identified as predictors of treatment resistance 5, 3:
  • Lower premorbid functioning 5
  • Negative symptoms from first psychotic episode 5, 3
  • Younger age at onset 5, 3
  • Longer duration of untreated psychosis 5, 3
  • Non-adherence to treatment 5
  • Comorbid substance use 5

Clinical Implications

• Once treatment resistance is established, clozapine is the treatment of choice 2, 6
• The FDA has approved clozapine specifically for treatment-resistant schizophrenia, defined as failure to respond adequately to standard antipsychotic treatment 6
• Clinical trials have demonstrated clozapine's superior efficacy compared to other antipsychotics in treatment-resistant patients 6
• For patients who do not respond to clozapine (clozapine-resistant schizophrenia), augmentation strategies may be considered, though evidence for these approaches is limited 2, 4

Common Pitfalls to Avoid

• Premature discontinuation of antipsychotic trials before the minimum 6-week duration 1, 4
• Inadequate dosing that fails to reach therapeutic levels 1, 4
• Failure to assess and address medication adherence issues 1, 2
• Not considering a trial of clozapine after two failed antipsychotic trials 2, 6
• Overlooking the importance of functional outcomes in addition to symptom reduction 1