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Revista Brasileira de Psiquiatria

Print version ISSN 1516-4446On-line version ISSN 1809-452X

Rev. Bras. Psiquiatr. vol.29 no.3 São Paulo Sept. 2007 



Refractory schizophrenia: a neglected clinical problem


Esquizofrenia refratária: um problema clínico negligenciado



Dear Editor,

Treatment refractoriness is an important and frequent problem among individuals with schizophrenia, causing enormous suffering and distress to patients and families.1-2 Although psychosocial interventions are fundamental, antipsychotic treatment is the mainstay of care for schizophrenia. However, about 30% of the schizophrenic patients do not respond adequately to adequate antipsychotic treatment.2 Treatment of refractory schizophrenia criteria were established based on Kane's studies with clozapine and modified by the IPAP algorithm:3 1) no period of good functioning in the previous 5 years; 2) prior non-response to at least 2 antipsychotic drugs of two different chemical classes for at least 4-6 weeks each at doses ³ 400 mg equivalents of chlorpromazine or 5 mg/day of risperidone; 3) moderate to severe psychopathology, especially positive symptoms. Several studies and metanalyses confirm clozapine's superior efficacy on treatment-refractory schizophrenia,2-3 and the psychopharmachologic mechanisms involved in this superiority are not clear yet.2,4 Clozapine is the best validated approach, but there are several other interesting approaches being developed.5 Although refractory schizophrenia represents a challenge to the clinicians, it is often underdiagnosed and undertreated.

We have performed a study investigating the detection of the refractory schizophrenia cases in an academic outpatient clinic (Schizophrenia Program - PROESQ). We have developed a screening questionnaire describing the clinical characteristics, previous treatments and possible causes of refractoriness, and assessed 198 outpatients with diagnosis of schizophrenia and schizoaffective disorder. All psychiatrists (n = 17) were asked to point out their possibly refractory outpatients, based on four criteria stated in the questionnaire: treatment non-responder, non-compliant, clozapine user, and concomitant use of two or more antipsychotic drugs. Seventy patients (35%) met criteria for treatment refractory schizophrenia after extensive clinical chart review. Forty-seven patients (67%) were males, mean age 36 y.o. (range 17-59), the age of onset of schizophrenia was 22 y.o. (range 12-44), disease duration 13.7 years (SD = 7.8), the number of psychiatric hospitalizations was 1.8 (0 to 10, SD = 2.1), and 34.3% were alcohol and/or drug abusers/dependents. The treatment-refractory patients had used on average 4.6 (SD = 1.7) antipsychotic drugs, however only 43% (15% of all patients) had used clozapine.

These results show a low rate of recognition and appropriate treatment of refractory schizophrenia patients in an academic service in Brazil. We presume that these rates are even lower in other centers in Brazil, being a large proportion of the psychiatrists tolerant to imperative residual symptoms and misdiagnosing clinical refractoriness. Improvement on current psychiatric training is necessary to educate clinicians to recognize treatment-refractory schizophrenia and to manage the related clinical issues, such as poor compliance to medication, alcohol and drug abuse/dependence, and comorbid depression. To properly treat refractory schizophrenia patients in the public sector in Brazil, the outpatient clinics specialized in severe mental illnesses, such as the Centers for Psychosocial Attention - Centros de Atenção Psico-Social (CAPS), need psychiatrists trained to prescribe clozapine and manage potentially serious adverse effects (such as neutropenia, seizures and arrhythmias) and the availability of medication and hematological exams.


João Guilherme Fiorani Borgio, Rodrigo A Bressan
Schizophrenia Program (PROESQ), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil
Interdisciplinary Laboratory of Clinical Neurosciences (LiNC), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil

Jair Borges Barbosa Neto
Schizophrenia Program (PROESQ), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil
Program for the Attention of Victims of Violence and Stress (PROVE), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil

Claudiane S Daltio
Schizophrenia Program (PROESQ), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil



1. Rosa MA, Marcolin MA, Elkis H. Avaliação dos fatores de aderência ao tratamento medicamentoso entre pacientes brasileiros com esquizofrenia. Rev Bras Psiquiatr. 2005;27(3):178-84.

2. Bressan RA, Pilowsky LS. Treatment Resistant Schizophrenia - improving social and daily function. London, UK: Harcourt Health Communication; 2000.

3. Kenneth O, Jobson MD. The International Psychopharmacology Algorithm Project (IPAP) - schizophrenia algorithm, schizophrenia algorithm nodes. (cited 27 mar 2006) Available at:

4. Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ, Pilowsky LS. Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo. Biol Psychiatry. 2005;58(1):41-6.

5. Brunstein MG, Ghisolfi ES, Ramos FL, Lara DR. A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. J Clin Psychiatry. 2005;66(2):213-9.



Financing: None
Conflict of interests: The authors are investigators and sub-investigators of clinical trials sponsored by Eli Lilly and Janssen pharmaceutical companies. RAB is a consultant, speaker or produced scientific material for Astra Zeneca, Bristol, Eli Lilly, and Janssen.

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