Esquizofrenia resistente al tratamiento. I, concepto e impacto clínico / Treatment resistant schizophrenia. I, concept and clinical impact

La esquizofrenia es una psicosis crónica que se caracteriza por tres dominios sintomáticos: síntomas positivos, síntomas negativos y síntomas cognitivos. Se estima que afecta al 1 % de la población. El desarrollo de la psicofarmacología y del tratamiento de la esquizofrenia ha permitido distinguir genios evolutivos según la respuesta terapéutica. En este sentido es que se delinea el concepto de esquizofrenia resistente al tratamiento (ERT). Se estima ERT en un 30 % aproximadamente de los sujetos que padecen esquizofrenia. La identificación temprana y adecuada de este subgrupo de individuos se relaciona con una mejor respuesta. Este artículo es una narrativa sobre el concepto de ERT y su impacto clínico.

Schizophrenia is a chronic psychosis characterized by three symptom domains: positive symptoms, negative symptoms and cognitive symptoms. Its prevalence is about 1 % of the general population. The development of psychopharmacology and schizophrenia treatment have made possible the distinction between different clinical courses and outcomes according to treatment response. This is the basis for the concept of treatment resistant schizophrenia (TRS), which can be present in 30 % of schizophrenic patients. Early and adequate identification of this subgroup is related to better outcomes. Authors analyze the previously mentioned concept and its clinical impact.

Relationship between Clozapine-Induced Electroencephalogram Abnormalities and Serum Concentration of Clozapine in Japanese Patients with Treatment-Resistant Schizophrenia

OBJECTIVE: The objective of this study was to investigate the relationship between the serum concentration of clozapine (C-CLZ), N-desmethylclozapine (N-CLZ) and the daily dose of CLZ (D-CLZ), and the relationships among CLZ and electroencephalogram (EEG) abnormalities. METHODS: Twenty-eight patients were recruited to this study, but 8 patients were excluded because clozapine was discontinued before the post-treatment measurement of EEG or C-CLZ. Ultimately, 20 patients (6 men, 14 women) with an average age of 36 years were enrolled. The subjects were divided into EEG normal and abnormal groups. C-CLZ and N-CLZ were measured at 4, 12, 26, and 52 weeks after initiating CLZ administration. RESULTS: All patients had normal baseline EEG signals, and 8 patients showed EEG abnormalities later. There were significant correlations between C-CLZ and D-CLZ, and between N-CLZ and D-CLZ. The C-CLZ/D-CLZ, N-CLZ/D-CLZ, and C-CLZ/N-CLZ ratio were not significantly different between the EEG normal and EEG abnormal groups. The EEG abnormal group had significant higher proportion of patients with high intra-individual variability in their C-CLZ/D-CLZ ratio. CONCLUSION: There is no relationship between C-CLZ and EEG abnormalities. However, patients with high intra-individual variability in their C-CLZ/D-CLZ ratio had greater possibility of exhibiting EEG abnormalities.

An Observational Study Of Clinical Profile And Cognitive Insight In Patients Of Treatment Resistant Schizophrenia

Objectives -It has been estimated that 20-50% patients with Schizophrenia can develop treatment resistance. Treatment resistance is associated with increased morbidity in these patients and it also increases the burden for the caretakers. Very few Indian studies have tried to establish the factors associated with resistance in Schizophrenia. Hence, this study was conducted to identify the socio-demographic profile, illness variables, co-morbidities and cognitive insight in patients with Treatment Resistant Schizophrenia. Methodology: The study was conducted after permission from Institutional Ethics Committee. 50 consecutive patients of Treatment Resistant Schizophrenia (treated with 2 antipsychotics from different classes with adequate doses for 6 weeks each and currently satisfying the DSM IV TR criteria for Schizophrenia) were included in the study. Patients were administered a semi-structured questionnaire to obtain details about sociodemographic status, age of onset, family history, number of episodes and treatment received. DSM-IV-TR was used to identify psychiatric comorbidities. Becks cognitive insight scale was used to assess cognitive insight. Results: The mean age of patients in the study with Treatment Resistant Schizophrenia (TRS) was found to be 33.5yrs with M: F ratio of 1.77:1. It was found that 34% of patients had an onset before 20 yrs of age. Positive family history of mental illness was present in 48% of the TRS patients. Multiple episodes (>5) were present in 36% of patients. TRS was characterized by absence of affective symptoms in 90% of patients. On applying Beck's cognitive insight scale, patients of TRS were found to have higher Self-Certainty score as compared to Self-Reflection, indicating poor awareness into their illness and treatment. Conclusions: It is important to identify Schizophrenia patients with early age of onset, positive family history, absence of affective features and poor cognitive insight to improve the long-term course of Schizophrenia

Esquizofrenia resistente al tratamiento: ¿hemos tomado una decisión? / Treatment-resistant schizophrenia: have we made a decision?

Introduction: For decades, the term refractory psychosis has been widely used, but not clearly defined. Although the exact mechanisms by which treatment-resistance is developed are unknown, some factors will lead to bigger vulnerability to present it. It remains unclear if it is just a severe extreme at the end of the psychosis spectrum, or a subtype of schizophrenia. Objective: To determine if there is current consensus in the concept of refractory psychosis. Methods: Review of different guidelines about it (EMEA, SIGN, NICE, BPA, APA, CPA and WFSBP) and comparison of their definitions and approach designs. Results: Consulted guidelines show differences in the way they define refractory psychosis, but uniformity in their management proposal. Conclusion: There is no consensus in the operational definition of treatment resistant psychosis.

Introducción: Por décadas, el término de esquizofrenia refractaria ha sido ampliamente usado, pero no adecuadamente definido. Aunque no se conocen los mecanismos exactos por los cuales se desarrolla resistencia a la terapia antipsicótica, algunos factores condicionarán mayor probabilidad de fallo terapéutico. No se sabe, a punto fijo, si el cuadro se trata sólo de un extremo severo al final del continuum del espectro psicótico, o si es un subtipo de esquizofrenia. Objetivo: Determinar si existe consenso actual sobre el concepto de esquizofrenia refractaria. Metodología: Revisión de distintas guías clínicas sobre el tema (EMEA, SIGN, NICE, BPA, APA, CPA y WFSBP) y comparación de sus definiciones y sus diseños de abordaje. Resultados: Las guías consultadas muestran diferencias respecto al modo en que definen esquizofrenia refractaria, pero uniformidad en su planteamiento de manejo. Conclusión: No existe consenso en la definición operacional de esquizofrenia resistente al tratamiento.

Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study

Objective: To investigate whether inpatients with disorganized schizophrenia are more resistant to treatment. Method: Eighty-five inpatients were assessed at admission and at discharge for schizophrenia subtype, symptom severity, and treatment resistance criteria. Results: Disorganized patients were significantly more treatment-resistant than paranoid patients (60%, p = 0.001), and presented worse scores on the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI-S), and the Global Assessment of Functioning Scale (GAF) (p < 0.001). Although the difference was not significant, 80% of treatment-resistant patients with disorganized schizophrenia responded to clozapine. Conclusion: Patients with the disorganized subtype of schizophrenia should benefit from clozapine as a second-line agent. .

Electroconvulsive Therapy for Patients with Treatment-Resistant Schizophrenia Patients : A Retrospective Study / 신경정신의학

OBJECTIVES: This study analyzes the effect of electroconvulsive therapy (ECT) by predicting the factors contributing to the effectiveness of ECT and evaluating the persistency of ECT effect in patients with treatment-resistant schizophrenia. METHODS: Using retrospective review of the charts of 24 schizophrenic inpatients who were admitted to Busan Paik Hospital between March 1, 2005 and December 31, 2009. We compared the pre-ECT Clinical Global Impression (CGI) scores and post-ECT CGI scores among these patients. We evaluated the differences in the ECT responses by sex, age, duration of illness and dose of antipsychotic agents, and investigated the rate of continuation of out-patient treatment and readmission, and the change of the CGI score for 12 months after the ECT. RESULTS: ECT resulted in an overall clinical improvement as measured on the CGI scale. 15 (62.50%) patients were good responders, while 9 (37.50%) were poor responders. There was no significant difference between sex, age, duration of the illness, and dose of antipsychotics taken by the patient before the ECT. 21 (87.50%) patients continuously visited the outpatient department for 12 month, and 14 (66.67%) of them maintained the ECT effect with medical treatment only and without readmission. CONCLUSION: This study showed that the ECT could be a useful treatment option for schizophrenic patients who are resistant to antipsychotics.

Alteration in Plasma BDNF Level after Repetitive Transcranial Magnetic Stimulation(rTMS) in Treatment-Resistant Schizophrenia: A Pilot Study

OBJECTIVES: To assess clinical improvement and change in plasma brain-derived neurotrophic factor(BDNF) level after repetitive transcranial magnetic stimulation(rTMS) in patients with treatment-resistant schizophrenia. METHODS: Seven patients with DSM-IV schizophrenia, who were proven to be treatment-resistant, were treated with 15 sessions of rTMS for three weeks as an adjuvant therapy to antipsychotic treatment. Clinical improvement and change in plasma BDNF level were measured after the treatment period. The symptom severity was assessed with the Positive and Negative Syndrome Scale(PANSS) and the Korean Version of Calgary Depression Scale for Schizophrenia(K-CDSS) at baseline and 7 days after the treatment. Plasma BDNF level was measured by enzyme-linked immunosorbent assay(ELISA) at baseline and 7 days after the treatment. RESULTS: After the rTMS treatment, there was no significant improvement in PANSS total score(Z=-1.693, p=0.090) and no significant change in plasma BDNF was found(Z=-1.183, p=0.237). Negative correlations were found between percentage change in PANSS positive subscale score and duration of illness(rho=-0.991, N=7, p<0.0005, two-tailed), and PANSS negative subscale score at baseline and percentage change in plasma BDNF level(rho=-0.821, N=7, p=0.023, two-tailed). CONCLUSION: This preliminary study suggests that rTMS didn't make a significant change in clinical symptoms nor in plasma BDNF level in treatment-resistant schizophrenia. Percentage change in plasma BDNF, however, might be correlated with treatment resistance in schizophrenic patients. This is a pilot study with a small sample size, therefore, a further study with a larger sample size is needed.

The Efficacy and Safety of Concurrent Administration of Clozapine and Electroconvulsive Therapy: A Case Report / 대한정신약물학회지

To assess the efficacy and safety of combining electroconvulsive therapy(ECT) and clozapine in patients with treatment-resistant schizophrenia, the authors reviewed use of this combination in one treatment-resistant schizophrenic inpatient and to explain the mechanism of this combination, we measured the blood level of clozapine and its metabolite with high performance liquid chromatography(HPLC) before, during and after this combination. The combination of clozapine and bilateral ECT was mildly effective and the authors saw no adverse effects during combined treatment. The blood levels of clozapine and its metabolite did not significant change before, during and afyer this combination. Combining ECT and clozapine appears to be safe and is effective without significant change of the blood levels of clozapine and its metabolites in some patients with treatment-resistant schizophrenia.

Effect of Clozapine on the Quality of Life in Treatment-Resistant Schizophrenic Patients / 신경정신의학

OBJECTIVES: This prospective study was performed to determine effects of clozapine treatment on the quality of life of treatment-resistant schizophrenic patients. METHOD: Subjects were 18 patients with treatment-resistant schizophrenia. Patient's PANSS, BPRS and Simpson-Angus Rating Scale was assessed at 9 time points: baseline, the 2th, 4th, 6th, 8th, 10th, 12th, 16th, and 20th weeks of treatment. We chose to use the Quality of Life Scale (QLS) developed by Heinrichs and associates to evaluate the effect on the quality of life. The QLS was scaled at every month of treatment. RESULTS: Eighteen of twenty-three patients completed the five months trial of clozapine. Three PANSS factors (positive, negative, general) and BPRS total scores showed a significant improvement at the fifth month of clozapine treatment. The adverse effects of clozapine did not show a significant improvement. After five months of clozapine treatment, there were an increase of 52.69% in the total QLS score and a significant improvement of two QLS factors (interpersonal relations, intrapsychic foundation). Particularly two PANSS factors(negative, general) had a significant correlation with the QLS score. CONCLUSIONS: This study suggests that clozapine treatment has a positive effect on quality of life of treatment-resistant schizophrenic patients.

Efficacy of Long-term Treatment with Risperidone in Treatment-Resistant Patients with Schizophrenia / 대한정신약물학회지

OBJECTIVE: This open prospective study was performed to investigate the long-term efficacy and safety of risperidone in the treatment-resistant patient with chronic schizophrenia who had completed a 8-week short-term trial. METHOD: Fourteen patients with treatment-resistant chronic schizophrenia(DSM-IV), who had been previously treated with at least two different kinds of typical antipsychotic drugs but with insufficient clinical effects or who experienced distressing extrapyramidal side effects, were evaluated over a 48-week risperidone treatment period. Efficacy was assessed by the PANSS and the CGI, and its safety by the ESRS and the UKU side effect rating scale. Both were assessed at 8-week intervals. RESULT: Nine(four males and five females) of the fourteen patients completed the study. Overall, PANSS score for the entire period showed an improvement when compared with the baseline state. The pronounced improvement in CGI severity was seen between the 8th and 16th week, continued until endpoint. Of fourteen patients, eleven(78.6%) patients showed at least a 20% decrease in total PANSS scores on endpoint analysis. Transiently-observed extrapyramidal side effects following medication were akathisia(n=3), bradykinesia(n=3), and sialorrhea(n=2). Early UKU side effects included; increased dream activity, sedation, amenorrhea, and concentration difficulty. These were common but transient with the exception of amenorrhea. Three of the four patients with amenorrhea did not resume menses throughout the study. CONCLUSION: These results suggest that risperidone is a safe antipsychotic drug with long-term efficacy against both the positive and negative symptoms in the treatment of treatment-resistant schizophrenia.

The Therapeutic Effect of Sertraline in Treatment-resistant Schizophrenics / 대한정신약물학회지

OBJECT: This study was undertaken to know whether there is any therapeutic effecets of sertraline in treatment-resistant schizophrenics. METHOD: Seventy seven treatment-resistant schizophrenic patients, to whom the same antipsychotics as usual were administered, were randomly assigned to two groups; to the experimental group, sertraline was and to the controlled group, placebo was administered adjuntively for 6weeks in single blind design. We assessed psychopathology by BPRS, PANSS, YBOCS, HRSD, and SCL-90-R. RESULTS: BPRS, positive scale of PANSS, and HRSD were significantly decreased in experimental group and statistically siginificant differences between the experimental group and placebo group. Negative scale of PANSS and YBOCS were significantly decresed in experimental group but no statistically significant differences between the experimental group and placebo group. The therapeutic effect of sertraline was occurred within 3rd weeks. CONCLUSION: We suggested that sertraline may be useful in the treatment of schizophrenic symtom in treatment-resistent schizophrenia, especially in positive and depressive symptoms.

Efficacy of Risperidone in Treatment-Resistant Patients with Chronic Schizophrenia / 대한정신약물학회지

OBJECTS: This open study was designed to investigate the efficacy and safety of risperidone in the treatment-resistant patients with chronic schizophrenia. 24 patients were entered on the 8-week open trial. A total of 3 patients discontinued risperidone treatment before the end of the study. METHODS: We investigated risperidone's efficacy and its side effects in 21 patients with treatment-resistant chronic schizophrenia, who had previously been treated with different kinds of classical antipsychotic drugs but with insufficient clinical effect or distressing extrapyramidal side effects, over a 8-week period. After 3- 7 days of placebo wash-out period, patients were assigned to receive risperidone. The overall clinical efficacy was assessed at the 1st, 2nd, 4th, and 8th week of the treatment using the PANSS and the CGI. Safety and tolerability were assessed by the ESRS, the UKU side effect rating scale, the vital signs, and the laboratory tests including CBC, urinalysis, liver function test, and ECG. RESULTS: Clinically PANSS total score and CGI severity score on the end study point showed a significant improvement compared with baseline state. Significant improvements in both PANSS positive and negative subscale scores was as early as week 1 through week 8. Nine(43%) among of the 21 patients showed at least a 20% decrease in total PANSS scores. The tolerability of risperidone was geneally found to be good. Insomnia(52%), fatigue(52%), and sedation(52%) were the most common side effects. CONCLUSION: These results suggest that risperidone may be a effective antipsychotic agent in the treatment of refractory schizophrenia. However, double-blind comparative trial between risperidone and clozapine should be performed to further clarify the efficacy of risperidone in treatment-resistant patients with chronic schizophrenia.