Treatment-refractory Schizophrenia Patients Research Articles

Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals

BackgroundBenign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 109 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment.MethodsThis was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again.ResultsThe study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation.ConclusionsCurrent evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

P.027 Relation between functional and cognitive impairments in remitted patients with bipolar disorder and suggestions for trials targeting cognition

Targeted cognitive training (TCT) has been reported to improve verbal learning deficits in patients with schizophrenia (SZ). Despite positive findings, it is not clear whether demographic factors and clinical characteristics contribute to the success of TCT on an individual basis. Medication-associated anticholinergic burden has been shown to impact TCT-associated verbal learning gains in SZ outpatients, but the role of anticholinergic medication burden on TCT gains in treatment refractory SZ patients has not been described. In this study, SZ patients mandated to a locked residential rehabilitation center were randomized to treatment as usual (TAU; n = 22) or a course of TAU augmented with TCT (n = 24). Anticholinergic medication burden was calculated from medication data at baseline and follow-up using the Anticholinergic Cognitive Burden (ACB) Scale. MATRICS Consensus Cognitive Battery Verbal Learning domain scores were used as the primary outcome variable. The TAU and TCT groups were matched in ACB at baseline and follow-up. While baseline ACB was not associated with verbal learning in either group, increases in ACB over the course of the study were significantly associated with deterioration of verbal learning in the TAU group (r = −0.51, p = 0.02). This was not seen in subjects randomized to TCT (r = −0.13, p = 0.62). Our results suggest that TCT may blunt anticholinergic medication burden associated reduction in verbal learning in severely disabled SZ inpatients.

Oscillatory biomarkers of early auditory information processing predict cognitive gains following targeted cognitive training in schizophrenia patients

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by “bottom-up” enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Verbal learning deficits associated with increased anticholinergic burden are attenuated with targeted cognitive training in treatment refractory schizophrenia patients

Targeted cognitive training (TCT) has been reported to improve verbal learning deficits in patients with schizophrenia (SZ). Despite positive findings, it is not clear whether demographic factors and clinical characteristics contribute to the success of TCT on an individual basis. Medication-associated anticholinergic burden has been shown to impact TCT-associated verbal learning gains in SZ outpatients, but the role of anticholinergic medication burden on TCT gains in treatment refractory SZ patients has not been described. In this study, SZ patients mandated to a locked residential rehabilitation center were randomized to treatment as usual (TAU; n=22) or a course of TAU augmented with TCT (n=24). Anticholinergic medication burden was calculated from medication data at baseline and follow-up using the Anticholinergic Cognitive Burden (ACB) Scale. MATRICS Consensus Cognitive Battery Verbal Learning domain scores were used as the primary outcome variable. The TAU and TCT groups were matched in ACB at baseline and follow-up. While baseline ACB was not associated with verbal learning in either group, increases in ACB over the course of the study were significantly associated with deterioration of verbal learning in the TAU group (r=−0.51, p=0.02). This was not seen in subjects randomized to TCT (r=−0.13, p=0.62). Our results suggest that TCT may blunt anticholinergic medication burden associated reduction in verbal learning in severely disabled SZ inpatients.

Targeted cognitive training improves auditory and verbal outcomes among treatment refractory schizophrenia patients mandated to residential care

Computerized targeted cognitive training (TCT) of auditory processing has been shown to improve verbal learning in several clinical trials of schizophrenia outpatients. Less is known, however, about the effectiveness of this promising intervention in more chronic, treatment-refractory patients who are treated in non-academic settings. This study aimed to determine whether TCT improves auditory processing, verbal learning, and clinical symptoms in SZ patients mandated to receive care at a locked residential rehabilitation center. Secondarily, potential factors that moderate TCT's effectiveness including age, symptom severity, antipsychotic medication load, and duration of illness were examined. Schizophrenia patients were randomized to treatment as usual (TAU; n = 22) or TAU augmented with TCT (TAU + TCT; n = 24). Outcomes included a measure of auditory perception (Word-In-Noise test, WIN), verbal learning domain scores from the MATRICS Consensus Cognitive Battery (MCCB), and clinical symptoms (Scale for the Assessment of Positive Symptoms, SAPS; Scale for the Assessment of Negative Symptoms, SANS). TCT produced significant improvements in auditory perception (d = 0.67) and verbal learning (d = 0.65); exploratory analyses revealed a statistically significant reduction in auditory hallucinations (d = −0.64). TCT's effects were only weakly, and mostly non-significantly, moderated by age, clinical symptoms, medication, and illness duration. These findings indicate that even highly symptomatic, functionally disabled patients with chronic illness benefit from this emerging treatment. Ongoing studies will examine the predictive utility of neurophysiological biomarkers and other characteristics assessed at baseline.

Case Report: Augmentation with Blonanserin for a Schizophrenia Patient with Insufficient Response to Clozapine

Background: Clozapine is the most efficacious among antipsychotics for patients with schizophrenia. Nevertheless, clozapine is not effective in more than about 50% of treatment refractory schizophrenia patients, and several pharmacological strategies are used to augment it. Several reviews including meta-analyses have been published, but the efficacy of augmentation therapy for clozapine-resistant patients is not adequately supported. Though there is a weak connection between the oral dose and plasma concentration of clozapine, there is no report of augmentation therapy considering the plasma concentration of clozapine. Blonanserin is reported to be effective in treatment of both positive and negative symptoms of schizophrenia and well tolerated. Methods: We obtained consent to evaluate clinical presentations and clozapine plasma concentrations at the Okayama Psychiatric Medical Center and had not identified the individual for ethical reasons. This is a case report. Results: This case fulfilled the diagnostic criteria of neuroleptic-induced dopamine supersensitivity psychosis. Monotherapy with blonanserin was not effective, but augmentation of blonanserin with clozapine was effective and well tolerated by a clozapine-resistant schizophrenia patient. Conclusion: Because clozapine may ameliorate dopamine supersensitivity psychosis, the addition of blonanserin to clozapine may be effective even if monotherapy with blonanserin was not.

Decrease of gray matter volume in treatment-refractory schizophrenia patients

Objective:To investigate the gray matter alterations in treatment-refractory schizophrenia (TRS) patients and to explore the correlations between gray matter alterations and clinical characteristics in these patients. Methods:Voxel based morphometry (VBM) in conjunction with statistical parametric mapping on the structural magnetic resonance images of TRS patients (n=24) and healthy controls (n=21) was performed to assess differences between the two groups in gray matter volume(GMV). Results: We found GMV decreased in the left olfactory, bilateral insula and right anterior cingulate of TRS patients compared to healthy controls (p<0.05, FWE corrected). However, we did not find any correlation between gray matter reduction and clinical characteristics in these patients. Conclusion:TRS patients have GMV decreased in the left olfactory, bilateral insula and right anterior cingulate

Is there a decline in cognitive functions after combined electroconvulsive therapy and antipsychotic therapy in treatment-refractory schizophrenia?

An analysis of literature shows that there is still little evidence concerning the efficacy of electroconvulsive therapy (ECT) combined with antipsychotic therapy in a group of treatment-resistant schizophrenia patients. More precisely, its influence on cognitive functions is still equivocal. The aim of this study was to assess the influence of ECT combined with antipsychotic therapy on working memory, attention, and executive functions in a group of treatment-refractory schizophrenia patients. Twenty-seven patients completed the study: 14 men and 13 women, aged 21 to 55 years (mean age, 32.8 years), diagnosed with treatment-resistant schizophrenia. Each patient underwent a course of ECT sessions and was treated with antipsychotic medications. Before the ECT and within 3 days after the last ECT session, the participants were assessed with the following neuropsychological tests: Trail Making Test (TMT) and Wisconsin Cart Sorting Test (WCST). There were no significant differences in the TMT and WCST results after combined ECT and antipsychotic therapy in treatment-refractory schizophrenia patients. According to the results of the neuropsychological tests, there was no decline in attention, executive functions, or working memory. The current study shows no significant difference in attention, working memory, or executive functions after treatment with a combination of electroconvulsive and antipsychotic therapy. This suggests that combined electroconvulsive therapy may not have a negative influence on the neuropsychological functioning of patients with treatment resistant schizophrenia.

Combined Clozapine and Electroconvulsive Therapy in Clozapine-Resistant Schizophrenia

For treatment-refractory schizophrenia, electroconvulsive therapy (ECT) remains controversial because of its cognitive adverse effects. We report here on clinical and cognitive outcomes of a treatment-resistant schizophrenia patient treated with clozapine and right unilateral ECT.The patient was administered 300 mg of clozapine and 12 right unilateral ECT sessions. Psychopathology was rated by means of the Positive and Negative Syndrome Scale. The neurocognitive test battery included the Wisconsin Card Sorting Test, the Münchner Gedächtnis Test, an attentional performance test, the Trail Making Test, and the Hamburger-Wechsler Intelligence Test.The Positive and Negative Syndrome Scale total score decreased, and all cognitive measures improved.Electroconvulsive therapy would seem to be a safe treatment option for treatment-refractory schizophrenia patients.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: The MOZART study

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score ≥ 80, and CGI-S score ≥ 4. Patients were randomized to ziprasidone (80–160 mg/day, n = 73) or clozapine (250–600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (− 25.0 ± 22.0, 95% CI − 30.2 to − 19.8) and clozapine (− 24.5 ± 22.5, 95% CI − 29.7 to − 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Long-Term Maintenance Electroconvulsive Therapy in the Treatment of Schizophrenia and Schizoaffective Disorder—A Case Series

Submitted: September 19, 2008; Revised: October 8, 2008; Accepted: October 30, 2008 Introduction Since the first days of electroconvulsive therapy (ECT) over seventy years ago when Cerletti first treated a schizophrenic patient, it has been established that ECT is an effective treatment for psychotic disorders (1). Electroconvulsive therapy was once the mainstay of biological treatments for psychotic disorders, but with the advent of neuroleptics, most schizophrenic and schizoaffective disorder patients were treated primarily with medications. For treatmentrefractory patients, however, or for those with acute exacerbations of psychoses, the addition of ECT to neuroleptics is effective in reducing psychotic and affective symptoms (2-4). Both acute and short-term maintenance ECT (mECT) have been utilized and are effective in this patient population (57). Chanpattana and colleagues have reported on the use of combined acute course neuroleptics in treatment-resistant schizophrenia, with fifty-five percent of patients showing clinical improvement in positive symptoms (8). Additionally, they reported sustained improvement in quality of life, psychopathology, and social functioning in the majority of treatment-refractory schizophrenia patients treated with mECT for one year (9). Schizophrenia and schizoaffective disorder are lifelong illnesses, typically beginning in the early decades of life, and Bruce Sutor , Keith G. Rasmussen 1

Weight Gain During a Double-Blind Multidosage Clozapine Study

Possible variables associated with weight gain during clozapine treatment include dosing, treatment duration, baseline body mass index (BMI), sex, and plasma norclozapine concentrations. Weight gains during a double-blind, randomized clozapine study using 100-, 300-, and 600-mg/d doses were analyzed. It was hypothesized that weight gain was associated with baseline BMI, clozapine dosing, and demographic factors. The possible contribution of plasma clozapine and norclozapine concentrations was explored. Fifty treatment-refractory schizophrenia patients were randomized to 100-, 300-, or 600-mg/d doses of clozapine for a 16-week, double-blind treatment in a research ward. Nonresponsive patients went onto a second and/or a third 16-week, double-blind treatment at the other doses. Weights of patients were measured every week. During the first clozapine treatment, weight gain varied across 3 baseline BMI categories (normal-weight patients [4.1 kg, P < 0.001], overweight patients [2.6 kg, P = 0.05], and obese patients [0.36 kg, not significant]) and according to dosing (600 mg/d [4.4 kg], 300 mg/d [2.6 kg], and 100 mg/d [1.3 kg]). Sex had no effect after controlling for baseline BMI and dose, but the African-American race had a strong significant effect despite the small number of African Americans (n = 6). At the end of the first clozapine treatment, plasma norclozapine concentration was not significantly correlated with weight gain in the total sample (r = 0.16, P = 0.32, n = 43), but seems to be strongly correlated in nonsmokers. Despite its limitations, this study indicates that baseline BMI, dosing, and, possibly, the African-American race may be major determinants of clozapine-induced weight gain.

Shaping attention span: an operant conditioning procedure to improve neurocognition and functioning in schizophrenia.

The high prevalence of neurocognitive deficits in schizophrenia, and their association with poorer outcomes, has created interest in treatments that can improve neurocognitive functioning in this illness. While a variety of rehabilitation interventions have been developed, many are not appropriate for the most severely ill patients, whose attention spans are so short that they cannot attend to the material being presented. For this population, the only neurocognitive rehabilitation methods with demonstrated effectiveness are those that involve the operant conditioning technique known as shaping. In this article, we review the rationale for the use of shaping-based methods as neurocognitive retraining techniques for treatment-refractory schizophrenia patients, review published reports using this intervention, and offer suggestions for the future development of this method from both clinical and research perspectives.

Heterogeneity of serotonergic response in treatment-refractory schizophrenia patients

Oral metachlorophenylpiperazine (m-CPP) as a direct-acting postsynaptic serotonergic agonist was used to study serotonergic dysfunction in treatment-refractory chronic schizophrenia based on the hypothesis that some patients may show central serotonergic hypersensitivity. Seventeen DSM-III-R chronic schizophrenic patients with a history of neuroleptic nonresponse underwent double-blind challenge with oral m-CPP (0.25 mg/kg body weight) and placebo after medication washout: m-CPP significantly elevated both prolactin and cortisol levels as compared to placebo. There was a significant relationship between change in cortisol level and change in psychopathology under m-CPP; a blunted cortisol response was associated with a decrease in total psychopathology, while an increase in cortisol response related to an increase in psychopathology. Similarly, decrease in severity of the activation factor and the hostility factor was associated with a smaller cortisol response in the m-CPP condition. These results point to heterogeneity in central serotonergic sensitivity within the context of different subpopulations of serotonergic receptors.