Treatment-Resistant Schizophrenia

Since the introduction of chlorpromazine(Drug information on chlorpromazine), the first antipsychotic drug, it has been evident that a large number of patients have schizophrenia that is treatment resistant. It is estimated that between 20% and 60% of patients have schizophrenia that is resistant to treatment.^1,2

The relationship between treatment-resistant and treatment-responsive schizophrenia is not strictly black and white. No particular psychopathology of schizophrenia specifically suggests treatment-resistant disease. Brenner and Merlo³ proposed that treatment-resistant schizophrenia be considered at one end of a spectrum of antipsychotic drug response rather than being clearly differentiated from treatment-responsive schizophrenia. However, patients with treatment-resistant schizophrenia do tend to have prominent negative and cognitive symptoms and more severe psychopathology than patients whose condition responds to antipsychotic drugs.

Chronicity has often been confused with treatment-resistant schizophrenia. Schizophrenia is a chronic disorder that progresses to various levels of clinical deterioration without sustained remission or full recovery. In contrast with treatment-resistant schizophrenia, chronicity is associated with a favorable response to drug treatment, in which schizophrenic features are largely under control for 6 months or longer or there is partial recovery to the premorbid level of functioning.^4,5

Identifying treatment resistance

Although there are no universally accepted criteria, a common convention is that adequate drug treatment requires a duration of 4 to 10 weeks, a dosage equivalent to 1000 mg/d of chlorpromazine, and trials of 2 to 3 different classes of antipsychotic drugs.⁶ Table 1 presents suggested doses of atypical antipsychotics based on recent comparisons of efficacy.⁷

The guidelines of the American Psychiatric Association,⁸ the Schizophrenia Patient Outcomes Research Team,⁹ and the Texas Medication Algorithm Project¹⁰ have suggested that management of treatment-resistant schizophrenia is relevant to clinical practice. The current treatment guidelines recommend 2 or more treatment trials of atypical antipsychotics at adequate dosages. Typical antipsychotics can be used for 4 to 6 weeks to screen for treatment-resistant schizophrenia, after which treatment with clozapine(Drug information on clozapine) may be considered.

The International Psychopharmacology Algorithm Project (IPAP; http://www.ipap.org) proposes a practical clinical assessment-based screen for treatment-resistant schizophrenia (Table 2).

Adequate response to treatment has been defined as at least a 20% reduction in symptoms as measured by rating scales. Kane and colleagues⁶ narrowly defined treatment-resistant schizophrenia to identify more homogeneous clusters of patients (Table 3). Their study showed that clozapine is most effective for treatment-resistant schizophrenia.

Variations on the Kane criteria have been used in research and practice for the past 2 decades. All include 3 common elements:

• A history of treatment resistance

• Severe current symptoms

• Treatment resistance to current antipsychotic drugs

Various factors are responsible for “apparent” treatment resistance, which can be confused with true treatment resistance.⁸ A large number of patients have schizophrenia that does not respond because pharmacological, psychological, and psychosocial treatments are inadequate. Factors that cause “apparent” treatment resistance—most of which are treatable—need to be aggressively identified and actively corrected to enhance therapeutic effectiveness.

Poor treatment adherence is the most critical factor.⁹ Poor adherence is consistently associated with adverse effects, poor insight, and a poor therapeutic alliance. Comorbid psychiatric and physical disorders and inadequate social support are also crucial factors that can lead to inadequate treatment.