What causes treatment resistance in psychosis?

Causes of Treatment Resistance in Psychosis

Treatment resistance in psychosis can develop from illness onset in some patients (early-onset treatment resistance) or after an initial period of response (later-onset treatment resistance), with different underlying mechanisms potentially responsible for each pattern. 1

Temporal Development of Treatment Resistance

• Treatment resistance is present from illness onset in some patients, while in others the illness initially responds to treatment but subsequently develops resistance 1
• Treatment resistance can be categorized based on when it develops:
  • Early-onset treatment resistance: within the first year of treatment 1
  • Medium-term onset treatment resistance: during 1 to 5 years after treatment onset 1
  • Late-onset treatment resistance: later than 5 years after treatment onset 1

Biological and Clinical Predictors

• Lower premorbid functioning is associated with higher risk of treatment resistance 2
• Negative symptoms from the first psychotic episode predict poorer treatment response 2
• Younger age at illness onset correlates with increased likelihood of treatment resistance 2
• Male gender may be associated with higher rates of treatment resistance, though evidence remains controversial 2, 3

Neurobiological Factors

• Structural brain abnormalities, including ventricular enlargement, are more common in treatment-resistant patients 3
• More severe cognitive impairment is observed in treatment-resistant patients compared to treatment-responsive patients 3
• Neurobiological mechanisms likely differ between early-onset and later-onset treatment resistance 1

Treatment-Related Factors

• "Pseudo-resistance" must be ruled out before confirming true treatment resistance, including:
  • Inadequate medication adherence 4
  • Insufficient antipsychotic dose or duration 1
  • Inadequate plasma levels of medication 4
• Development of resistance following relapse may represent a distinct pathophysiological mechanism 1
• Longer duration of untreated psychosis contributes to poorer treatment response 2

Substance Use and Environmental Factors

• Comorbid substance use significantly increases the risk of treatment resistance 2
• Lower level of education is associated with poorer treatment outcomes 2

Clinical Implications

• Approximately 30% (range 10-45%) of schizophrenia patients meet criteria for treatment resistance 3
• Early identification of treatment resistance is crucial to minimize social disability and suicidality 3
• Clozapine is the most effective treatment for treatment-resistant psychosis, with greater efficacy when initiated earlier in the treatment course 5
• Therapeutic drug monitoring of clozapine is recommended, with greatest efficacy at plasma levels ≥350 μg/L 5

Practical Definition of Treatment Resistance

• Treatment resistance is defined as failure to respond to at least two adequate antipsychotic trials (each lasting at least 6 weeks at therapeutic doses) 1
• Each antipsychotic trial should use a minimum dose equivalent to 600mg of chlorpromazine per day 1
• Persistent moderate to severe positive, disorganized, or negative symptoms despite adequate treatment 3
• Significant functional impairment despite treatment 1