|Year : 2013 | Volume
| Issue : 1 | Page : 51-60
Schizophrenia resistance ( is there a difference?)
Mamdoh ElGamal1, Maha ElTayebani2, Seham Fathi3
1 Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Psychiatry, Faculty of Medicine, Al Azhar University, Egypt
3 Department of Neuropsychiatry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||06-Oct-2010|
|Date of Acceptance||15-Mar-2011|
|Date of Web Publication||3-Jun-2014|
Source of Support: None, Conflict of Interest: None
Schizophrenia is a chronic disease of the body and mind that affects 1% of the population. About one-fifth to one-third of all patients with schizophrenia do not respond adequately to drug treatment and that have been consistent over time. Definitions of this group have long been hampered by a lack of consistency with confusion with chronicity. Clozapine has shown superior efficacy and this has been replicated consistently.
Aim and objectives
Because of the high prevalence, importance, and inconsistency of schizophrenia resistance, the current study aimed to (a) examine the differences between resistant and nonresistant schizophrenic groups in chronic long-stay patients, (b) study the clinical profile of the clozapine-resistant group in comparison with others, and finally (c) determine the predictors of resistant schizophrenia.
This was a retrospective and cross-sectional study of 95 patients with chronic schizophrenia or schizoaffective disorder, admitted in long-stay hospital wards at the Psychological Medicine Hospital (Kuwait). They were interviewed by Structured Clinical Interview for DSM-IV and diagnosed according to the Diagnostic and Statistical Manual of Mental Illness, 4th ed. criteria. Patients were assessed by the Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGIS) scale, and Mini-Mental State Examination. Sociodemographics, clinical characteristics, and the history of treatment were determined. Schizophrenia resistance was formulated according to modified Kane’s criteria, which include the following: BPRS score of at least 45; two or more of positive symptoms score of at least 4 (suspiciousness, hallucinatory behavior, conceptual disorganization, and unusual thoughts); CGIS score of at least 4 (moderate to extremely ill); previous failure on two antipsychotic trials of different categories of the full therapeutic range (≥1000 mg of chlorpromazine equivalent) and for at least 3–6 months’ duration; and finally, no preceding good function for at least 2.5 years in the last 5 years.
Thirty-six patients fulfilled the criteria of schizophrenia resistance (37.8%). There was a significant shift in the drug regimen prescribed, with the prescription of more atypical antipsychotics, especially clozapine, with repeated failure of previous drug trials. The only significant difference between the resistant and the nonresistant group was in the psychopathological severity, indicated by higher scores on PANSS, and CGIS scores. Age younger than 40 years and early onset age of schizophrenia (<20 years) were powerful predictors for schizophrenia resistance; other sociodemographic and clinical characteristics lacked significant predictive value.
Conclusion and recommendation
Younger age and early-onset schizophrenia are considered poor prognostic factors. Early aggressive management of schizophrenia may help eliminate chronicity as well as resistance. Research on the biological predisposition for schizophrenia resistance including the clozapine resistance group is required.
Keywords: clozapine, resistance to antipsychotics, schizophrenia
|How to cite this article:|
ElGamal M, ElTayebani M, Fathi S. Schizophrenia resistance ( is there a difference?). Egypt J Psychiatr 2013;34:51-60
| Introduction|| |
Schizophrenia is a chronic disease of the body and the mind that affects 1% of the population. Schizophrenia should be understood at least from two perspectives: first, considering the integration of the individual into the society and second, schizophrenia is a medical problem that can be treated with medications and psychotherapies (Quintero et al., 2011). There is a large group of patients with ‘treatment-resistant schizophrenia’ (TRS), that is cases in which the minimum degree of remission with conventional treatments is not achieved. This indicates that even today, we lack an integrative treatment model that combines specific interventions with variable effectiveness. The concept of TRS should have evolved with advancement in the currently available knowledge and therapeutic response (Quintero et al., 2011).
Between one-fifth and one-third of all patients with schizophrenia do not respond adequately to drug treatment. Reports of the proportion of patients with drug resistance have been consistent over time (Prien and Cole, 1968; Davis and Casper, 1977; Essock et al., 1996), and the treatment of these patients has remained a persistent public health problem. Treatment-resistant patient are often highly symptomatic and may require extensive periods of hospital care (McGlashan, 1988). This involves a disproportionately high cost (Revicki et al., 1990). These formed the basis for interest among clinicians following the demonstration of clozapine’s efficacy in inpatients with TRS (Kane et al., 1988).
Studies of TRS have long been hampered by a lack of consistency in definition. Commonly, TRS was considered roughly equivalent to chronic or frequent hospitalization (Holden et al., 1968; Small et al., 1975; Ruskin et al., 1979; Carman et al., 1981; Wolkowitz et al., 1986). However, chronic hospitalization can occur despite a low level of symptoms (McGlashan, 1988). Current and persistent positive symptoms of psychosis and at least a moderate overall severity of current illness should also be used to define nonresponsiveness (Meltzer, 1990). Chronicity alone cannot predict the likelihood of response to a treatment regimen with antipsychotics (Brenner et al., 1990; Christison et al., 1991).
Using parameters to define poor outcome, some authors have used the number of rehospitalizations or chronic hospitalizations to define TRS. However, factors such as poor compliance, weak social support programs, or a history of violence may also result in long-term hospitalization of patients who do not have TRS (Elkis and Meltzer, 2010). For most researchers, the concept of TRS has a precise meaning. It is the persistence of positive symptoms, which are moderate or severe, after a correct biological treatment (Peuskens, 1999). Recent publications have used the following expressions: ultraresistant schizophrenia (Mouaffak et al., 2006), clozapine-resistant schizophrenia (Havaki-Kontaxaki et al., 2006), Pharmacological TRS (Enguix and Fernández, 2006), and neuroleptic-nonresponsive schizophrenia (Meltzer, 1992).
In accordance with these close definitions, it would be erroneous to classify a patient who does not follow the treatment as TRS, stating that resistance would be then due to the patient and not to the schizophrenic disease (Elkis and Meltzer, 2007). This statement is useful to investigate the efficacy of the drugs.
The landmark trial of Kane et al. (1988) showed superior efficacy of clozapine over other antipsychotic agents, a finding that has been replicated consistently (Chakos et al., 2001; Lewis et al., 2006; McEvoy et al., 2006) in studies that examined the subgroups of medication-resistant patients. Although clozapine is considered the most efficient antipsychotic agent in refractory patients, as many as 40–70% of these patients show only a poor or a partial response, even with adequate blood levels of clozapine (Kane et al., 1988; Meltzer et al., 1989; Lieberman et al., 1994; Tollefson et al., 2001).
| Methods|| |
The current study was carried out at the psychological medicine hospital, the only psychiatric hospital in the State of Kuwait. The researchers examined 127 patients who had been hospitalized for a long time (≥6 months) in the chronic wards of the hospital. All patients were examined after oral/written consent was obtained from the patients and/or their families. Approval from the local research ethical committee was obtained.
Patients at least 18 years of age, those with schizophrenia and schizoaffective disorder, both sexes, and treatment-resistant and nonresistant patients were included.
All patients were subjected to a Structured Clinical Interview using SCID (First et al., 1995) and were diagnosed according to the Diagnostic and Statistical Manual of Mental Illness, 4th ed. to confirm the diagnosis. Only 95 patients were found to have schizophrenia or schizoaffective disorder.
The study was carried out in two phases:
In this phase, the files of the patients were reviewed to collect data on all clinical data socio demographic and treatment characteristics of patients with schizophrenia or schizoaffective disorder.
Patients were subjected to the following psychometric ratings, carried out by two different raters for more reliability: the Positive and Negative Syndrome Scale (PANSS), which includes 30 items on three subscales: seven items covering positive symptoms, seven items covering negative symptoms, and 16 items covering general psychopathology. Each item was scored on a seven-point item-specific scale ranging from 1 to 7; thus, the positive and negative subscales each ranged from 7 to 49, and the general psychopathology scale ranged from 16 to 112. It is a standard tool for assessment of clinical outcome in treatment studies of psychotic disorders and useful for the assessment of severity in clinical practice (Kay et al., 1986). The Brief Psychiatric Rating Scale was used, which is a short scale for measuring the severity of psychiatric symptomatology. It includes 18 items that are rated on a seven-point item-specific scale from 0 to 6, with the total score ranging from 0 to 108 (Overall and Gorham, 1962). The Clinical Global Impression Severity (CGIS) scale was used, which is rated on a seven-point scale, measuring the severity of illness using a range of responses from 1 (normal) to 7 (the most severely ill) (Guy and Bonato, 1970). Finally, the Mini-Mental State Examination (MMSE) was used, which is a 30-point cognitive test developed for the bedside assessment of cognitive functions including orientation, memory, attention, construction, and language (Folstein et al., 1975).
Criteria for treatment-resistant schizophrenia according to Kane et al. (1988)
In the current study, the researchers used the Kane et al.’s (1988) criteria to define resistant cases. According to Kane, for the classification of a schizophrenic patient as treatment resistant, he/she should fulfill the following criteria:
- Historical: at least three drug trials of different chemical classes with doses equivalent to 1000 mg/day chlorpromazine for a period of 6 weeks, without significant relief.
- No period of good function in the preceding 5 years (≥2.5 years)
- A score of at least 45 in the Brief Psychiatric Rating Scale (1–7 degree of severity), with scores of at least 4 in two of the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, or unusual thought content.
- CGIS more than or equal to 4 (moderately ill).
For practical reasons according to the clinical characteristics of our sample, modified criteria were applied as follows: (a) previous two drug trials with nonresponsiveness and (b) Previous treatment for at least 3–6 months with doses equivalent to 400–1000 mg/day chlorpromazine.
Data were collected and coded, and then entered into an IBM compatible computer, using the SPSS version 17 (International Business Machine Company, Armork, NewYork, USA); the data entered were checked for accuracy and then for normality using the Kolmogorov–Smirnov test. Qualitative variables were expressed as number and percentage, whereas quantitative variables were expressed as the mean (x¯) and SD. The arithmetic mean (x¯) was used as a measure of central tendency, whereas SD was used as a measure of dispersion.
The following statistical tests were used:
Independent-samples t-test was used as a parametric test of significance for comparison between two sample means after performing the Levene’s test for equality of variances.
The χ2-test (or likelihood ratio) was used as a nonparametric test of significance for comparison between the distribution of two qualitative variables.
Fisher’s exact test was used as a nonparametric test of significance for comparison between the distributions of two qualitative variables whenever the χ2-test was not appropriate; it yields the P-value directly.
Paired-sample t-test was used as a parametric test of significance for comparison between before and after values of quantitative variables.
One-way analysis of variance (F-test) was used as a parametric test of significance for comparison between more than two sample means using either Scheffe’s or Tauhane’s post-hoc tests for results of homogeneity testing.
The Pearson correlation coefficient (r) was used as a parametric measure of the mutual relationship between two normally distributed quantitative variables.
The Cochran test was used for comparison between categories and differential types of antipsychotics used in the three phases of treatment.
Logistic regression analysis was used to detect significant predictors of resistant schizophrenia according to Kane’s criteria.
A 5% level was chosen as a level of significance in all the tests used.
| Results|| |
On studying the 127 patients who were in the long-stay wards of the hospital, only 95 patients were found to have the diagnosis of schizophrenia or schizoaffective disorder. Those who were not diagnosed with schizophrenia (23 patients had mental subnormality, eight patients had nonschizophrenic psychosis, and one had personality disorder) were excluded. On the basis of Kane et al.’s criteria for the identification of patients with TRS after modification, only 59 patients (62.10%) were considered to be nonresistant, whereas 36 patients (37.89%) were found to be treatment resistant.
Sociodemographics and clinical characteristics (morbidity profile)
The sociodemographic data indicated that 84.21% of the patients were men, 32.6% were not working, 71.6% were single, and only 21% had a high level of education. Most of the patients (90%) were of very low or low socioeconomic standard, around 25% had no available private house, 50.5% of the studied sample had a positive family history of psychiatric illness, and only 31.7% had a family history of medical illness, that is diabetes mellitus, hypertension, or dyslipidemia [Table 1] and [Table 2].
|Table 1: Sociodemographic characteristics of definite resistant and non resistant patients (n=95)|
Click here to view
|Table 2: Clinical characteristics of definite resistant and nonresistant schizophrenic patients (n=95)|
Click here to view
Positive psychiatric symptoms were found in 72 patients (75.8%) at the onset of illness and undifferentiated schizophrenia or paranoia were the most common diagnoses (43.2 and 29.2%), respectively [Table 2].
In terms of medical comorbidities, 28 patients (29.47%) had diabetes, 29 patients (30.5%) had hypertension, and 46 patients (48.42%) had dyslipidemia. Half of the patients (n=49, 51.57%) were obese, with a BMI of at least 30. No significant difference was found between the resistant and the nonresistant groups of patients in any of the above-mentioned items (P>0.05).
In terms of the history of treatment, the patients had been subjected to two previous trials of a full therapeutic dosage of at least 1000 mg of chlorpromazine for at least 3–6 months, with no satisfactory response. There was a highly significant shift in the treatment characteristics between the two previous treatment trials and the current trial towards the use of atypical antipsychotics (P=0.000; Cochran’s test) [Table 3] ([Figure 1]a and b), where conventional antipsychotics were used in 85.3% of patients in trial 1, 37.9% in trail 2, and only 24.2% in the current stage. However, the atypical group showed a reverse trend (14.7, 51.5, and 75.7%, respectively). Clozapine and risperidone were among the most frequently prescribed atypical drugs.
|Figure 1(a) Comparison between definite resistant (n=36) and nonresistant (n=59) schizophrenic groups according to their treatment history. (b) Comparison between categories and differential types of antipsychotics used in 95 patients with chronic schizophrenia through three phases of treatment (P=0.00).|
Click here to view
|Table 3: Comparison between categories and differential types of antipsychotics used to treat 95 patients with chronic schizophrenia through three phases of treatment|
Click here to view
The mean current age of the studied sample was 48.9±10.3 years, the mean age at onset of schizophrenia was 21.2±5.7, the mean duration of illness was 27.5±9.3 years, the mean number of relapses was 19.07±12.5 times, and the mean relapse duration was 3.3±3.9 months. They had a chronic continuous institutionalization period of 9.8±6.2 years, and the mean duration of hospital stay was 14.6±7.4 years [Table 4].
|Table 4: Comparison between definite resistant (n=36) and nonresistant (n=59) schizophrenic cases according to age and clinical data|
Click here to view
Psychometric study indicated that the mean scores of positive, negative, and general psychopathology subscales of PANSS were 17.8±7.0, 28.4±10.9, and 38.15±9.4, respectively; the mean MMSE score was 19.49±7.1 and 5.3±1.1 for the CGIS [Table 4].
Difference between the resistant and the nonresistant schizophrenia group
The results showed no significant difference between the resistant and the nonresistant schizophrenia groups in terms of the sociodemographic or medical characteristics, medical comorbidities, anthropometric measures, treatment history as well as the MMSE score.
Risperidone failure in trial II was significant in resistant patients (n=16), whereas sulpiride (n=14) and trifluoperazine (n=10) were among the most commonly prescribed medications used for nonresistant patients (P=0.02) [Figure 1]b.
The only significant difference between the two groups was in the PANSS scores; resistant patients had significantly higher scores (P<0.000) compared with nonresistant patients [Table 4].
In terms of the CGIS score, all resistant patients were significantly moderately to extremely ill (≥4), whereas the nonresistant group showed a reasonable distribution (13 cases) in scores (<4) (P=0.03) [Figure 2].
|Figure 2: Severity of illness of definite resistant (n=36) and nonresistant (n=59) schizophrenic patients according to the Clinical Global Impression Severity scale.|
Click here to view
Difference between clozapine-resistant schizophrenia, non-clozapine-resistant, and nonresistant groups
Treatment-resistant patients were further divided into clozapine-resistant (n=17) and non-clozapine-resistant (n=19) patients.
There was no significant difference between the clozapine-resistant schizophrenic group, non-clozapine-resistant cases as well as nonresistant cases, in terms of the sociodemographics, clinical characteristics, medical state [Table 5], [Table 6] and [Table 7], CGIS [Figure 3] as well as treatment history [Figure 4].
|Figure 3: Clinical Global Impression Severity (SGIS) scale scores among clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia.|
Click here to view
|Figure 4: Previous nonresponsive treatment trials in clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia.|
Click here to view
|Table 5: Sociodemographic data of clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia|
Click here to view
|Table 6: Clinical characteristics of clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia|
Click here to view
|Table 7: Comparison between clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia in terms of age and some important clinical durations related to illness|
Click here to view
In terms of the other psychometric scales, clozapine-resistant patients had significantly higher PANSS scores in all the three subscales compared with the nonresistant and non-clozapine-resistant patients (P=0.00; [Figure 5]). However, the mean MMSE scores (P=0.34) did not differ significantly between the three groups: 17.1±7.7; 20.0±6.8; and 20.0±7.7, respectively.
|Figure 5: Mean Positive and Negative Syndrome Scale (PANSS) score for clozapine-resistant (n=17), non-clozapine-resistant (n=19), and nonresistant (n=59) patients with schizophrenia (P=0.000) for the three subscales.|
Click here to view
Using the logistic regression model (χ2 model=11.807, significance=0.05, R2=0.159) [Table 8], it was found that young age (<40 years) and early onset of schizophrenia (<20 years) were powerful predictors for schizophrenia resistance. Other factors of sociodemographics and psychopathological severity lacked this predictive value.
|Table 8: Logistic regression model for significant predictors of resistant schizophrenia according to Kane’s criteria for 95 patients with schizophrenia|
Click here to view
| Discussion|| |
Prevalence of treatment-resistant schizophrenia
In the current study, 37.8% of patients with chronic schizophrenia had resistant schizophrenia according to the modified Kane et al.’s (1988) criteria.
The prevalence in the current study is concomitant with the range of resistant schizophrenia and treatment nonresponse cases in other studies. The range of nonresponsiveness was reported to be 20–30% and up to 60% cases were not responding to conventional antipsychotics (Itil et al., 1966; Kane et al., 1988; Meltzer and Kostacoglu, 2001; Miller et al., 2006).
This wide range of schizophrenia nonresponders may be because of methodological differences and definition defendant (Juarez-Reyes et al., 1995; Essock et al.,1996; Solanki et al., 2007). The large percentages reported by some investigators may have been because they did not differentiate cases with true resistance from those who had only received inadequate treatment, especially in terms of the dosage, compliance, and duration (Elkis and Meltzer, 2007), or may have used more restricted and less broad diagnostic criteria as in the study of Juarez-Reyes et al. (1995), who applied the American Psychiatric Association 1980 criteria, with a mean prevalence 42.9±5.9%, and this estimate reduced to 12.9±2.7% when the Kane et al.’s criteria were used, which are more restrictive. These estimates of the prevalence of treatment resistance are similar to those when clozapine was first marketed, extrapolating to a total of 2 00 000–5 00 000 patients with TRS currently living in USA (Terkelsen and Grosser, 1990).
Effect of antipsychotics
Since the demonstration of clozapine’s superior efficacy, attention has shifted to the use of new antipsychotics for TRS. To obtain approval for marketing in the USA, new antipsychotics must have a safety or an efficacy profile that is superior to conventional neuroleptics.
In the current study, there was a highly significant shift from the use of conventional antipsychotics (85.3-24.2%) to the use atypical group (14.7-75.7%), especially clozapine (n=37 (38.9%)). This is quite logic and expected as the practice of most of psychiatrist was dependant previously on the use of traditional drugs based on their availability and cost as well as the claim of equal efficacy compared with second-generation drugs. Most studies have concluded that there are no apparent consistent differences between antipsychotic agents with respect to their effect, but only in their tolerability and adverse effect profile (Geddes et al., 2000; Keefe et al., 2007; Davidson et al., 2009; Hill et al., 2010) or dropout rates (CATI study phase 1; Keefe et al., 2003).
The shift to newer agents, especially clozapine, is relevant and has been documented in open and controlled studies because of the superior effect of clozapine on positive and negative symptoms compared with previous treatment with typical (Pickar et al., 1992; Meltzer, 1997; Lehman et al., 2004a, 2004b; Miller et al., 2004) and even new atypical antipsychotics with twice effect size (0.44) than later one (0.29) (Davis et al., 2003; Stroup et al., 2003; Solanki et al., 2007; CATI study phase II; Lieberman et al., 2005; Lewis et al., 2006; Keefe et al., 2007 McEvoy et al., 2006).
There was no significant difference between resistant and nonresistant patients with schizophrenia in the treatment profile in the current study, except that resistant patients failed to respond to risperidone significantly more than nonresistant patients in trial II of treatment. This in general may indicate that some atypical antipsychotics are less effective, with a higher failure rate, in the treatment of schizophrenia resistance.
In some studies, risperidone has shown a lower efficacy profile (Chouinard et al., 1994; Cohen and Underwood, 1994; Cardoni, 1995; Keck et al., 1995; Klieser et al., 1995). However, reports on the effectiveness of risperidone, which was comparable with other second-generation agents including clozapine and first-generation agents including haloperidol (Smith et al., 1996; Bondolfi et al., 1998; Wirshing et al., 1999), are in agreement with our results. This may support the hypothesis that the response to treatment may be varied depending on several factors including the biological makeup of patients, especially those with resistant schizophrenia.
Even with clozapine, 30% of patients are labeled ultraresistant, with a poor response to clozapine (Buckley et al., 2001; Chakos et al., 2001), indicating the inconsistency of the efficacy of antipsychotics and may be the biological basis for treatment response, especially in resistant or ultra resistant schizophrenic patients.
Predictors of treatment resistance
Younger age (<40 years) and early age at onset (<20 years) were powerful predictors of treatment resistance in our sample. These results were in agreement with those of Meltzer (1992), indicating that resistance and poor outcome are linked to younger age at onset (<20).
The lack of a significant association between schizophrenia resistance and the sociodemographics, clinical profile, treatment history, and medical state may indicate the presence of multiple factors behind resistance including intrinsic biological factors of the individual, psychological and behavioral characteristics, pharmacogenetic, biological comorbidities, family factor, social, and personal and noncompliance predispositions.
Some studies have indicated intrinsic biological factors such as ventricular enlargement and cortical atrophy predominance in resistant cases as well as low plasma homovanillic acid and alternatives of function and concentration of T cells and some interleukins (Lieberman et al., 1996; Elkis and Meltzer, 2007). Mouaffak et al. (2011) found that genetic factors have a significant association with ultraresistant schizophrenia.
In addition, Xiu et al. (2009) have reported lower levels of brain-derived neurotrophic factors in chronic patients with schizophrenia than in healthy control individuals, and this was observed in patients treated with risperidone (9.3±2.3 mg/ml) compared with those treated with clozapine (10.2±2.0 mg/ml, P<0.001) and atypical antipsychotics (10.0±2.1 mg/ml, P<0.01).
In summary: research studies on TRS can be the basis for the identification of a subgroup of schizophrenia patients, who have a unique etiology, possibly on genetic basis or gene–environment interactions. This may not only lead to the development of effective treatments for these individuals but may also reduce hetrogenicity and allow the study of the etiology of schizophrenia in those who respond adequately to current medications.
| Conclusion and recommendations|| |
- Treatment resistance-schizophrenia is quite common, especially among chronic patients.
- Some clinical factors such as younger age and early onset age of schizophrenia are predictors for nonresponsiveness.
- Focusing on intrinsic biological factors of illness and individuals through pharmacogenetic studies can aid the detection of the risk of schizophrenia resistance, poor response to treatment, and poor outcome.
- More studies for valuable, clinical guidelines as well as algorithms for treatment-resistant cases with recommended aggressive treatments of first-episode schizophrenia may eliminate subgroups of cases with suspected refractoriness.
| References|| |
|1.||Bondolfi G, Dufour H, Patris M, May JP, Billeter U, Eap CB, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. Am J Psychiatry. 1998;155:499–504 |
|2.||Brenner HD, Dencker S J, Goldstein MJ, Hubbard JW, Keegan DL, Kruger G, et al. Defining treatment refractoriness in schizophrenia. Schizophr Bull. 1990;16:551–561 |
|3.||Buckley PF, Krowinski AC, Miller DD, Friedman L, Eaton Y, Tronetti M. Clinical and biochemical correlates of ‘high-dose' clozapine therapy for treatment - refractory schizophrenia. Schizophr Res. 2001;49:225–227 |
|4.||Cardoni AA. Risperidone: review and assessment of its role in the treatment of schizophrenia. Ann Pharmacother. 1995;29:610–618 |
|5.||Carman JS, Bigelow LB, Wyatt RJ. Lithium combined with neuroleptics in chronic schizophrenic and schizoaffective patients. J Clin Psychiatry. 1981;42:124–128 |
|6.||Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001;158:518–526 |
|7.||Chouinard G, Vainer JL, Bélanger MC, Turnier L, Beaudry P, Roy JY, et al. Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis. Prog Neuroosychopharmacol Biol Psychiatry. 1994;18:1129–1141 |
|8.||Christison GW, Kirch DG, Wyat RJ. When symptoms persist: choosing among alternative somatic treatments for schizophrenia. Schizophr Bull. 1991;17:217–245 |
|9.||Cohen SA, Underwood MT. The use of clozapine in a mentally retarded and aggressive population. J Clin Psychiatry. 1994;55:440–444 |
|10.||Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker WW, Keefe RS, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am J Psychiatry. 2009;166:675–682 |
|11.||Davis JM, Casper R. Antipsychotic drugs: clinical pharmacology and therapeutic use. Drugs. 1977;14:260–282 |
|12.||Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60:553–564 |
|13.||Elkis H, Meltzer HY. Refractory schizophrenia. Rev Bras Psiquiatr. 2007;29(Suppl 2):S41–S47 |
|14.||Elkis H, Meltzer HY. Therapy-resistant schizophrenia. Adv Biol Psychiatry. 2010;26:1–8 |
|15.||Enguix SC, Fernández AS. Pharmacological treatment resistant schizophrenia. Acta Esp Psiquiatr. 2006;34:48–54 |
|16.||Essock SM, Hargreaves WA, Dohm FA, Goethe J, Carver L, Hipshman L. Clozapine eligibility among state hospital patients. Schizophr Bull. 1996;22:15–25 |
|17.||First MB, Spitzer RL, Gibbon M, Williams W Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). 1995 Washington American Psychiatric Pub |
|18.||Folstein MF, Folstein SE, McHugh PR. ‘Mini mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198 |
|19.||Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. Br Med J. 2000;321:1371–1376 |
|20.|| Guy W, Bonato RR (1970). Manual for the ECDEU assessment battery 2. Rev ed. Chevy Chase, Md: National institute of mental health (12–1)—(12–6) |
|21.||Havaki-Kontaxaki BJ, Ferentinos PP, Kontaxakis VP, Paplos KG, Soldatos CR. Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia. Clin Neuropharmacol. 2006;29:52–56 |
|22.||Hill SK, Bishop JR, Palumbo D, Sweeney JA. Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert RevNeurother. 2010;10:43–57 |
|23.||Holden JMC, Itil TM, Keskiner A, Fixk M. Thioridazine and chlordiazepoxide, alone and combined, in the treatment of chronic schizophrenia. Compr Psychiatry. 1968;9:633–643 |
|24.||Itil TM, Keskiner A, Fink M. Therapeutic studies in ‘therapy resistant’ schizophrenic patients. Compr Psychiatry. 1966;7:488–493 |
|25.||Juarez-Reyes MG, Shumway M, Battle C, Bacchetti P, Hansen MS, Hargreaves WA. Effects of stringent criteria on eligibility for clozapine among public mental health clients. Psychiatr Serv. 1995;46:801–806 |
|26.||Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796 |
|27.|| Kay SR, Opler LA, Fiszbein A (1986). Positive and Negative Syndrome Scale (PANSS) Rating Manual. New York: Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Centre and Schizophrenia Bullettin; 29: 757–69 |
|28.||Keck PE Jr, Wilson DR, Strakowski SM, McElroy SL, Kizer DL, Balistreri TM, et al. Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder and psychotic mood disorders. J Clin Psychiatry. 1995;56:466–470 |
|29.||Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry. 2007;64:633–647 |
|30.||Keefe RSE, Mohs RC, Bilder RM, Harvey PD, Green MF, Meltzer HY, et al. Neurocognitive assessment in the clinical antipsychotic trials of intervention effectiveness (CATIE) project schizophrenia trial: Development, methodology and rationale. Schizophr Bull. 2003;29:45–55 |
|31.||Klieser E, Lehmann E, Kinzler E, Wurthmann C, Heinrich K. Randomized, double-blind, controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol. 1995;15(Suppl 1):45S–51S |
|32.||Lehman AF, Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB, Goldberg R, et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2003. Schizophr Bull. 2004a;30:193–217 |
|33.||Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004b;161(Suppl):1–56 |
|34.||Lewis S W, Barnes TRE, Davies L, Murray RM, Dunn G, Hayhurst KP, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32:715–723 |
|35.||Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry. 1994;151:1744–1752 |
|36.||Lieberman JA, Alvir JM, Koreen A, Geisler S, Chakos M, Sheitman B, et al. Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology. 1996;14(Suppl):13S–21S |
|37.||Lieberman JA, Scott Stroup T, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223 |
|38.||McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry.. 2006;163:600–610 |
|39.||McGlashan TH. A selective review of recent North American long-term followup studies of schizophrenia. Schizophr Bull. 1988;14:515–542 |
|40.||Meltzer H, Kostacoglu ALieberman J, Murray R. Treatment-resistant schizophrenia. Comprehensive care of schizophrenia: a textbook of clinical management. 2001 London Martin Dunitz:181–203 |
|41.||Meltzer HY. Commentary: defining treatment refractoriness in schizophrenia. Schizophr Bull. 1990;16:563–565 |
|42.||Meltzer HY. Treatment of the neuroleptic-nonresponsive schizophrenic patient. Schizophr Bull. 1992;18:515–542 |
|43.||Meltzer HY. Treatment-resistant schizophrenia - the role of clozapine. Curr Med Res Opin. 1997;14:1–20 |
|44.||Meltzer HY, Bastani B, Kwon KY, Ramirez LF, Burnett S, Sharpe J. A prospective study of clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology. 1989;99(Suppl):S68–S72 |
|45.||Miller A, McEvoy J, Jeste D, Marder SLieberman J, Stroup TS, Perkins D. Treatment of chronic schizophrenia. Textbook of schizophrenia. 2006 Washington DC The American Psychiatric Publishing:365–381 |
|46.||Miller AL, Hall CS, Buchanan RW, Buckley PF, Chiles JA, Conley RR, et al. The Texas medication algorithm project antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry. 2004;65:500–508 |
|47.||Mouaffak F, Tranulis C, Gourevitch R, Poirier MF, Douki S, Olié JP, et al. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin Neuropharmacol. 2006;29:28–33 |
|48.||Mouaffak F, Kebir O, Chayet M, Tordjman S, Vacheron MN, Millet B, et al. Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia. Pharmacogenomics J. 2011;11:267–273 |
|49.||Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799–812 |
|50.||Peuskens J. The evolving definition of treatment resistance. J Clin Psychiatry. 1999;60(Suppl 12):4–8 |
|51.||Pickar D, Owen RR, Litman RE, Konicki PE, Gutierrez R, Rapaport MH. Clinical and biologic response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine. Arch Gen Psychiatry. 1992;49:345–353 |
|52.||Prien RF, Cole JO. High dose chlorpromazine therapy in chronic schizophrenia. Arch Gen Psychiatry. 1968;18:482–495 |
|53.||Quintero J, Del Cura EB, Lopez-Lbor MI, Lopez-lbor JJ. The evolving concept of treatment-resistant schizophrenia. Actas Esp Psiquiatr. 2011;39:236–250 |
|54.||Revicki DA, Luce BR, Weschler JM, Brown RE, Adler MA. Economic grand rounds: cost-effectiveness of clozapine for treatment-resistant schizophrenic patients. Hosp Community Psychiatry. 1990;41:850–854 |
|55.||Ruskin P, Averbukh I, Belrnaker RH, Dasberg H. Benzodiazepines in Chronic Schizophrenia. Biological Psychiatry. 1979;14:557–558 |
|56.||Small JG, Kellams JJ, Milstein V, Moore J. A placebo controlled study of lithium combined with neuroleptics in chronic schizophrenic patients. Am J Psychiatry. 1975;132:1315–1317 |
|57.||Smith RC, Chua JW, Lipetsker B, Bhattacharyya A. Efficacy of risperidone in reducing positive and negative symptoms in medication-refractory schizophrenia: an open prospective study. J Clin Psychiatry. 1996;57:460–466 |
|58.||Solanki RK, Singh P, Swami MK. Clozapine: current perspective. Indian J Psychiatry. 2007;49:271–276 |
|59.||Stroup TS, McEvoy JP, Swartz MS, Byerly MJ, Glick ID, Canive JM, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29:15–31 |
|60.||Terkelsen KG, Grosser RC. Estimating clozapine’s cost to the nation. Hosp Community Psychiatry. 1990;41:863–869 |
|61.||Tollefson GD, Birkett MA, Kiesler GM, Wood AJ. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry.. 2001;49:52–63 |
|62.||Wirshing DA, Marshall BD Jr, Green MF, Mintz J, Marder SR, Wirshing WC. Risperidone in treatment-refractory schizophrenia. Am J Psychiatry. 1999;156:1374–1379 |
|63.||Wolkowitz OM, Pickar D, Doran AR. Combination alprazolam-neuroleptic treatment of the positive and negative symptoms of schizophrenia. Am J Psychiatry. 1986;143:85–87 |
|64.||Xiu MH, Hui L, Dang YF, De Hou T, Zhang CX, Zheng YL, et al. Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuroosychopharmacol Biol Psychiatry. 2009;33:1508–1512 |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]