Clozapine and Haloperidol in Moderately Refractory Schizophrenia

Kane, John M.; Marder, Stephen R.; Schooler, Nina R.; Wirshing, William C.; Umbricht, Daniel; Baker, Robert W.; Wirshing, Donna A.; Safferman, Allan Z.; Ganguli, Rohan; McMeniman, Marjorie; Borenstein, Michael

doi:10.1001/archpsyc.58.10.965

Cited by 163 publications

(117 citation statements)

References 22 publications

(21 reference statements)

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“…This is opposed to the study of Kane et al who found that refractory patients had a better improvement with Clozapine than patients under haloperidol treatment. 27 In our study, the severity of illness was in fact associated with super-refractoriness, which is in accordance with some studies. 7 It is interesting to know that in terms of Quality of life measures although the super-refractory group had the lowest QoL scores, this group had an improvement of 2.5% in QoL scores but such improvement did not correlate with improvement in psychopathology.…”

Section: Discussionsupporting

confidence: 93%

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

Neto

Elkis

2007

Rev. Bras. Psiquiatr.

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Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study Aspetos clínicos da esquizofrenia super-refratária: estudo observacional de coorte com seguimento de seis meses A b s t r a c t Objective: Approximately 30% of treatment-resistant schizophrenic patients do not fully respond to Clozapine and such patients are termed Clozapine non-responders or super-refractory schizophrenics. The aim of this study was to characterize patients with super-refractory schizophrenia according to demographic and psychopathological variables, as compared with patients with refractory schizophrenia or non-refractory subjects. Method: One hundred and two outpatients meeting DSM-IV criteria for schizophrenia were followed-up for 6 months. Subjects were classified into 3 groups: non-refractory (n = 25), refractory (n = 43) and super-refractory (n = 34). Psychopathology was assessed by the Positive and Negative Syndrome Scale, the Schedule for Deficit Syndrome, the Calgary Depression Scale and the Quality of Life Scale. Patients were rated at 2-month intervals. Results: Higher levels of severity at the disease onset as well as higher severity of positive symptoms were found to be predictive of superrefractoriness.

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Section: Discussionsupporting

confidence: 93%

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

Neto

Elkis

2007

Rev. Bras. Psiquiatr.

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“…Subsequent studies have confirmed these results (Rosenheck et al, 1997;Buchanan et al, 1998;Pickar et al, 1992;Breier et al, 1994;Essock et al, 1996;Conley et al, 1999). The advantage of clozapine over a firstgeneration antipsychotic medication was also found in partially responsive, community-based, schizophrenic patients (Kane et al, 2001;Buchanan et al, 1998;Breier et al, 1994). There is now convincing evidence that the ACC is involved in a distributed neural network that mediates psychosis (Cleghorn et al, 1992;Silbersweig et al, 1995;Szechtman et al, 1998;Shergill et al, 2000).…”

Section: Discussionmentioning

confidence: 84%

“…Clozapine demonstrates a superior antipsychotic action in schizophrenia compared to other first-or second-generation antipsychotics (Kane et al, 1988;Conley et al, 1998;Breier et al, 1999;Wirshing et al, 1999;Kane et al, 2001). Moreover, in addition, it is not associated with Parkinsonism, akathisia, or tardive dyskinesia, and may improve cognitive function in schizophrenia (Buchanan and McKenna, 2000).…”

Section: Introductionmentioning

confidence: 99%

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Lahti

Holcomb

Weiler

et al. 2003

Neuropsychopharmacol

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Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with 15 O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n ¼ 6) and normal volunteers (NVs) (n ¼ 12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1) Rest, (2) sensory motor control (SMC) task, and (3) decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n ¼ 5) and/or clozapine (n ¼ 5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol-and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidoltreated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

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“…For example, in addition to sharing clinical properties with all other atypical antipsychotics, clozapine is also considered by many clinicians and investigators to be singular among antipsychotics in regards to efficacy (Taylor and DuncanMcConnell, 2000;Chakos et al, 2001;Conley and Kelly, 2001). This is particularly evident in the high success rates with clozapine among treatment-resistant patients with schizophrenia (Kane et al, 1988;Chakos et al, 2001;Kane et al, 2001). Thus, rather than due to mechanisms shared by all atypical antipsychotics (eg D2 and 5HT2 antagonism), clozapine's ability to abolish PPI deficits in BB rats may be due to a putative mechanism which distinguishes clozapine from all other currently available antipsychotics, and which is responsible for its unique efficacy profile.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Sensorimotor Gating Deficits in Brattleboro Rats by Acute Administration of Clozapine and a Neurotensin Agonist, but not Haloperidol: a Potential Predictive Model for Novel Antipsychotic Effects

Feifel

Melendez

Shilling

2004

Neuropsychopharmacol

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Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of haloperidol as well as the second-generation antipsychotic, clozapine, and the putative novel antipsychotic, PD149163, a neurotensin mimetic that crosses the blood-brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of clozapine and all the doses of PD149163 tested reversed the PPI deficits in BB rats. In addition, haloperidol, but not clozapine or PD149163 produced significant catalepsy in BB rats, supporting the notion that PD149163 has a profile consistent with atypical antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of antipsychotic efficacy and suggest that this model may differentiate between antipsychotics belonging to different therapeutic categories, for example, first-and second-generation agents.

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Clozapine and Haloperidol in Moderately Refractory Schizophrenia

Abstract: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Cited by 163 publications

References 22 publications

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

Clinical aspects of super-refractory schizophrenia: a 6-month cohort observational study

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Reversal of Sensorimotor Gating Deficits in Brattleboro Rats by Acute Administration of Clozapine and a Neurotensin Agonist, but not Haloperidol: a Potential Predictive Model for Novel Antipsychotic Effects

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