Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome

Lieberman, Jeffrey A.; Safferman, Allan Z.; Pollack, Simcha; Szymanski, S.; Johns, Celeste A.; Howard, Alfreda; Kronig, Michael H.; Bookstein, Peter; Kane, John M.

doi:10.1176/ajp.151.12.1744

Cited by 332 publications

(44 citation statements)

References 36 publications

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“…These variables included employment status (dichotomous, e.g. employed vs. unemployed), age at onset of primary disorder [20,21,22], suicide attempt in lifetime (dichotomous), treatment with ECT in lifetime (dichotomous) [23,24], patient status (dichotomous, e.g. inpatient vs. outpatient), and the presence of a substance use disorder (dichotomous) [25,26,27,28].…”

Section: Methodsmentioning

confidence: 99%

Anxiety Disorder Comorbidity in Bipolar Disorder, Schizophrenia and Schizoaffective Disorder

et al. 2012

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Background: Reported rates of comorbid anxiety disorders in psychotic and mood disorders vary widely among studies. Sampling and Methods: We used the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, to examine rates of comorbid anxiety disorders in patients with schizoaffective disorder (SZA; n = 153), bipolar I disorder (BP; n = 304) and schizophrenia (SZ; n = 174). Results: The rates of anxiety disorders in participants with SZA (30.1%), BP (22.4%) and SZ (16.7%) differed significantly [χ²(2) = 8.368, p = 0.015]. Among anxiety disorders, this effect was most pronounced for panic disorder (PD). PD rates were significantly higher in participants with SZA (15.7%) as compared to participants with BP (6.9%) and SZ [6.9%; χ²(2) = 10.879, p = 0.004]. Logistic regression models controlling for demographic and clinical characteristics confirmed that primary diagnosis (SZA, BP or SZ) was a significant predictor of PD comorbidity and approached significance in predicting the comorbidity of any anxiety disorder. Conclusions: Our findings suggest that patients with SZA have high rates of anxiety disorders. Clinicians treating patients with SZA should evaluate for anxiety disorder comorbidity, especially as anxiety symptoms may not be reported at first presentation.

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Section: Methodsmentioning

confidence: 99%

Anxiety Disorder Comorbidity in Bipolar Disorder, Schizophrenia and Schizoaffective Disorder

et al. 2012

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“…Although there is still controversy over the higher rate of effectiveness of second-generation antipsychotics, the use of drugs such as clozapine and olanzapine has increased due to fewer side effects. In addition, clozapine proved to be beneficial in medical treatment-resistant patients; however, only 30-50% of patients experience clinically significant symptom improvement with clozapine treatment [9,10,11]. In addition, clozapine has proven to be beneficial in the treatment of patients who are resistant to medicine; however, only 30-50% of cases have a significant reduction in symptoms.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Follow-Up of MRI-Guided Bilateral Anterior Capsulotomy in Patients with Refractory Schizophrenia

Liu

Hao

Zhan

et al. 2014

Stereotact Funct Neurosurg

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Aim: To determine whether there is a long-term benefit of MRI-guided bilateral anterior capsulotomy in the treatment of refractory schizophrenia. Methods: 116 patients (16 patients did not complete the follow-up evaluation) with refractory schizophrenia who underwent capsulotomy were included. The treatment effect was evaluated using a series of international rating scales. Evaluations were performed at baseline, 3 weeks and 24 months after surgery. Results: The rate of effectiveness was 74% according to the Clinical Global Impression evaluation, and there was an obvious improvement based on the statistical analysis for Positive and Negative Symptom Scale (baseline vs. 24 months after surgery, 6.86 ± 8.12, 10.70 ± 8.70 vs. 26.65 ± 4.85, 21.66 ± 7.19), Brief Psychiatric Rating Scale (14.75 ± 13.21 vs. 44.97 ± 9.36), Activities of Daily Living Scale (18.06 ± 6.58 vs. 24.61 ± 8.95), Social Disability Screening Schedule (6.69 ± 6.12 vs. 15.06 ± 3.18) and Global Assessment Scale (74.35 ± 12.75 vs. 48.74 ± 9.18). Among all the symptoms of schizophrenia, aggressive behavior (82% response rate), hallucination, (71% response rate) and delusion (70% response rate) showed the best response. Conclusion: Our research indicates that capsulotomy is a relatively safe and effective intervention for patients with refractory schizophrenia. It could be an alternative therapy for those patients with chronic and severe schizophrenia. But there must be strict inclusion criteria considering the complications and irreversibility of this procedure.

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“…Individuals who quit prior to study completion invariably affect response rates and may confound the ability to identify genetic variants linked to treatment response. Unfortunately, rates for treatment discontinuation in AP drug trials are estimated to be in the range of 40%, with common reasons for discontinuation including noncompliance, lack of efficacy, and adverse side effects [18,75,76]. In certain patients, response to CLZ may take up to 5 months or longer, suggesting that some participants who discontinue treatment because of lack of efficacy most likely do so prematurely.…”

Section: Discussionmentioning

confidence: 99%

“…TRS was defined as failure to respond to 2 or more AP trials with drugs from at least 2 different chemical classes at doses of ≥1,000 mg/day chlorpromazine equivalents for 4-6 weeks, together with no period of good functioning in the preceding 5 years [7]. A smaller portion of patients (<15%) met criteria for treatment intolerance defined as the presence of moderate-to-severe tardive dyskinesia or extreme sensitivity to extrapyramidal symptoms [18]. …”

Section: Methodsmentioning

confidence: 99%

“…Response to CLZ is complex and thought to depend, at least in part, on genetic factors, as indicated by twin and family studies [11,12,13,14]. Like other APs, high interindividual variability is also observed with CLZ treatment [15,16,17], with up to 50% of eligible patients failing to respond [7,18]. Studies in pharmacogenetics aim to identify gene variants with the potential to predict dosing, response, and side effects prior to starting drug treatment [19].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

Taylor¹,

Tiwari²,

Lieberman

et al. 2016

Complex Psychiatry

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Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ² tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (p_uncorrected = 0.008, p_corrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

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Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome

Abstract: These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

Cited by 332 publications

References 36 publications

Anxiety Disorder Comorbidity in Bipolar Disorder, Schizophrenia and Schizoaffective Disorder

Anxiety Disorder Comorbidity in Bipolar Disorder, Schizophrenia and Schizoaffective Disorder

Long-Term Follow-Up of MRI-Guided Bilateral Anterior Capsulotomy in Patients with Refractory Schizophrenia

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine

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