BRIEF REPORT Effects of Clozapine on Perceptual Abnormalities and Sensory Gating A Preliminary Cross-Sectional Study in Schizophrenia Jean-Arthur Micoulaud-Franchi, MD, PhD,*†‡ Mitsuko Aramaki, PhD,§ Pierre Alexis Geoffroy, MD, PhD,k¶#** Raphaëlle Richieri, MD, PhD,*†† Michel Cermolacce, MD, PhD,*†‡ Catherine Faget, MD,*†† Sølvi Ystad, PhD,§ Richard Kronland-Martinet, PhD,§ Christophe Lancon, MD, PhD,*†† and Jean Vion-Dury, MD, PhD*†‡ Abstract: The aim of the present study was to investigate the effect of second-generation antipsychotics (clozapine or another second-generation antipsychotic) on perceptual abnormalities related to sensory gating deficit. Although clozapine is known to improve sensory gating assessed neurophysiologically, we hypothesized that patients with schizophrenia treated with clozapine would report less perceptual abnormalities related to sensory gating deficit than patients treated with other second-generation antipsychotics do. Forty patients with a diagnosis of schizophrenia were investigated (10 patients treated with clozapine and 30 patients treated with another second-generation antipsychotic drug). Perceptual abnormalities were assessed with the Sensory Gating Inventory. Sensory gating was assessed through electroencephalogram with the auditory eventrelated potential method by measuring P50 amplitude changes in a dual click conditioning-testing procedure. Patients treated with clozapine present normal sensory gating and report less perceptual abnormalities related to sensory gating than patients treated with other second-generation antipsychotics do. Although the cross-sectional design of this study is limited because causal inferences cannot be clearly concluded, the present study suggests clinical and neurophysiological advantages of clozapine compared with other second-generation antipsychotics and provides a basis for future investigations on the effect of this treatment on perceptual abnormalities related to sensory gating deficit in patients with schizophrenia. Key Words: schizophrenia, sensory gating, P50, perceptual abnormalities, clozapine (J Clin Psychopharmacol 2015;35: 184–187) A mong existing second-generation antipsychotics, clozapine has specific clinical and neurophysiological profiles.1 From From the *Pôle de Psychiatrie “Solaris,” and †Unité de Neurophysiologie et Psychophysiologie, Pôle de Psychiatrie Universitaire, Centre Hospitalier Universitaire de Sainte Marguerite; ‡Laboratoire de Neurosciences Cognitives, Unité Mixte de Recherche Centre National de la Recherche Scientifique 7291; §Laboratoire de Mécanique et d'Acoustique, Centre National de la Recherche Scientifique, Unité Propre de Recherche 7051, Aix Marseille Université, Centrale Marseille, Marseille; kInserm, Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale 1144, Paris; Fondation Fondamental, Créteil; ¶Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Saint Louis, Lariboisière, Fernand Widal, Pôle Neurosciences; #Université Paris Descartes; **Université Paris Diderot, Paris; and ††Laboratoire de Santé Publique Évaluation des Systèmes de Soins et Santé Perçue, Faculté de Médecine, Université de la Méditerranée, Equipe d'Accueil 3279, Marseille, France. Received July 6, 2014; accepted after revision October 31, 2014. Reprints: Jean-Arthur Micoulaud-Franchi, MD, PhD, Pôle de Psychiatrie “Solaris,” Centre Hospitalier Universitaire de Sainte Marguerite, 270 Bd de Sainte Marguerite, 13009 Marseille, France (e‐mail: jarthur.micoulaud@gmail.com). This study was funded by the Centre National de la Recherche Scientifique. The “Unité de Neurophysiologie et Psychophysiologie, Pôle de Psychiatrie Universitaire” belongs to the “Reseau Fondamental.” Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000270 184 www.psychopharmacology.com a clinical point of view, clozapine is more effective than other second-generation antipsychotics to treat positive and negative symptoms of schizophrenia,2,3 particularly in case of treatment resistance.4 From a neurophysiological point of view, clozapine is the most robust second-generation antipsychotics known to improve sensory gating deficit in schizophrenia.5–8 Sensory gating is classically assessed using electroencephalogram with the auditory event-related potential method by measuring P50 amplitude changes in a dual click conditioning-testing procedure.9 Sensory gating deficit has been confirmed repeatedly in schizophrenia.10 Recently, it was found that sensory gating deficit is related to perceptual abnormalities in schizophrenia.11 Patients with high sensory gating deficit report the perception of being inundated and overwhelmed by external sensory stimuli.11,12 Although perceptual abnormalities are now known as core symptoms of schizophrenia,13,14 only a few studies investigated the effects of second-generation antipsychotics on these abnormalities. Thus, the aim of the present study was to investigate the effect of second-generation antipsychotics on perceptual abnormalities related to sensory gating deficit. For that purpose, we (1) excluded the analysis of patients treated with first-generation antipsychotics that are clearly known not to improve sensory gating deficit15 and (2) compared groups of patients treated with only 1 second-generation antipsychotics drug (clozapine or another second-generation antipsychotics drug). Clozapine is known to improve sensory gating assessed neurophysiologically,5,7 thus we hypothesized that patients with schizophrenia treated with clozapine would report less perceptual abnormalities related to sensory gating deficit than patients treated with other secondgeneration antipsychotics do. MATERIALS AND METHODS Participants Forty outpatients with a diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria based on Structured Clinical Interview were recruited from the Department of Psychiatry, Marseille University Hospital, France. Inclusion criteria were medication with only 1 secondgeneration antipsychotics drug during the enrollment of the experiment and written informed consent. Ten patients (9 men and 1 woman) were treated with clozapine. Thirty other patients (22 men and 8 women) were treated with aripiprazole (n = 14), quetiapine (n = 6), olanzapine (n = 4), risperidone (n = 3), or amisulpride (n = 3). Exclusion criteria were diagnoses other than schizophrenia on Axis I of the Diagnostic and Statistical Manual of Mental Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015 Disorders, Fourth Edition; auditory impairment; neurological illness; brain injury; and mental retardation. Data regarding age of onset, duration of disorder, and number of hospitalizations were collected. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression assessed the clinical severity of illness. The Global Assessment of Functioning assessed the severity of the handicap. Assessment of Perceptual Abnormalities Perceptual abnormalities related to sensory gating were assessed with the French version of the Sensory Gating Inventory (SGI), that is, a validated self-report perceptual scale composed of 36 items addressing a broad range of sensory gating–like subjective experiences that are rated by the patients on a 6-point Likert scale.16,17 The psychometric properties of the SGI indicate that it provides valuable information on 4 dimensions of perceptual abnormalities: perceptual modulation (linked to 16 items, eg, “My hearing is so sensitive that ordinary sounds become uncomfortable”), overinclusion (7 items, eg, “I notice background noises more than other people”), distractibility (8 items, eg, “There are times when I can't concentrate with even the slightest sounds going on”), and fatigue-stress modulation (5 items, eg, “It seems that sounds are more intense when I'm stressed”). Sensory Gating Measures P50 amplitude changes in a dual click conditioning-testing procedure were investigated to measure sensory gating neurophysiologically. The P50 component is a middle-latency positive event-related potential component occurring approximately 50 milliseconds after the onset of a brief auditory stimulus.9 In a conditioning-testing P50 procedure described previously in the study of Micoulaud-Franchi et al,11 the P50 amplitude was measured in response to an auditory-paired click stimulus: S1 (conditioning stimulus) and S2 (testing stimulus). The percentage of reduction of the P50 amplitudes is labeled P50 suppression (P50supp). The percentage of P50supp was calculated using the following formula: P50supp = [1 − (AS2/AS1)]
100, where AS1 and AS2 are the P50 amplitudes of the conditioning and testing, respectively.18 A 50% threshold for the P50supp value is classically defined as the following: patients below this threshold have a sensory gating deficit.15 Statistics Data analyses were performed using Statistical Package for the Social Sciences software (version 18, Predictive Analytics Software Statistics). Data were compared using independentsample t tests. For each analysis, effects were considered as significant when the P value was equal to or less than 0.05. RESULTS Demographic, clinical, perceptual, and neurophysiological data are shown in Table 1. Concerning the demographic and clinical data, we found that the groups did not significantly differ from each other except for the positive symptom factor of the PANSS. The patients treated with clozapine presented a significantly higher score for this factor. The patients treated with clozapine reported less perceptual abnormalities related to the overinclusion factor and the fatiguestress modulation factor of the SGI than the patients treated with other second-generation antipsychotics did. These 2 factors are related to perceptual abnormalities of being overwhelmed by external sensory stimuli. More specifically, they seemed to assess © 2015 Wolters Kluwer Health, Inc. All rights reserved. Effects of Clozapine on Perceptual Abnormalities abnormalities as a result of hyperawareness of irrelevant stimuli and perceptual vulnerability during periods of fatigue and stress.16 Moreover, the patients treated with clozapine had a higher P50supp (no sensory gating deficit) than the patients treated with other second-generation antipsychotics had. This effect is mainly attributed to the amplitude differences measured at S1 for the 2 groups. The patients treated with clozapine presented larger P50 amplitudes (3.39 μV) than patients treated with other secondgeneration antipsychotics did (1.76 μV). DISCUSSION This study firstly revealed that the patients treated with clozapine reported less perceptual abnormalities related to sensory gating than the patients treated with other second-generation antipsychotics did and secondly confirmed that the patients treated with clozapine presented normal sensory gating (P50supp, >50%). These results are consistent with a cross-sectional study5 and a longitudinal study7 that showed that clozapine reduces sensory gating deficit in patients with schizophrenia and confirmed the relationship between sensory gating deficit and perceptual abnormalities found in schizophrenia.11 This study secondly found a sensory gating deficit (P50supp, <50%) in patients treated with non–clozapine second-generation antipsychotics drug. More specifically, the degrees of P50supp were 48.22%, 13.76%, 32.03%, 28.60%, and 36.92%, respectively, for the patients receiving aripiprazole, quetiapine, olanzapine, risperidone, and amisulpride. Up to date, the effects of non–clozapine second-generation antipsychotics on the P50supp are still a matter of debate. Indeed, 1 cross-sectional study found higher sensory gating with second-generation antipsychotics than with first-generation antipsychotics19 and 1 longitudinal study found a significant sensory gating improvement with quetiapine (n = 16).20 Patients in the cross-sectional study of Light et al19 were treated with clozapine (n = 5), olanzapine (n = 6), or risperidone (n = 2) and the P50supp were 82.55%, 74.95%, and 39.19%, respectively. However, other studies showed opposite results. Three cross-sectional studies did not find higher sensory gating with second-generation antipsychotics than first-generation antipsychotics.5,21,22 Patients in the study of Yee et al22 were treated with risperidone (n = 22) and the P50supp was 45%. Patients in the study of Adler et al5 were treated with olanzapine (n = 31), quetiapine (n = 9), and risperidone (n = 22), and the P50supp were 19.5%, −9.6%, and 25.0%, respectively. Patients in the study of Sanchez-Morla et al21 were treated with risperidone (n = 33), olanzapine (n = 21), aripiprazole (n = 11), and combinations of second-generation antipsychotics (n = 3), and the mean P50supp was 31.9% (data not available per molecules). Two recent longitudinal studies did not find significant improvement in P50supp with olanzapine (n = 12)23 as well as with sulpiride (n = 24) and risperidone (n = 24).24 Finally, we did not confirm the results of the study of Oranje et al20 by observing that the P50supp of the 6 patients treated with quetiapine in our study was lower than 50% and that the SGI overall score was high (94.17). Thus, our findings help to shed some light on this controversial literature and suggest that non–clozapine second-generation antipsychotics (ie, aripiprazole, quetiapine, olanzapine, risperidone, and amisulpride) do not improve sensory gating deficit and perceptual abnormalities in schizophrenia. Our results should be further validated with a longitudinal controlled study on a larger population. Indeed, although we conducted a cross-sectional study, the patients were not randomly assigned to the treatment groups and our study is prone to contain a selection bias. The perceptual and neurophysiological differences showed here could be related to clinical characteristic www.psychopharmacology.com Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. 185 Journal of Clinical Psychopharmacology • Volume 35, Number 2, April 2015 Micoulaud-Franchi et al TABLE 1. Demographic, Clinical, Perceptual, and Neurophysiological Characteristics as well as t Test Statistics for Patients With Schizophrenia Treated With Clozapine and With Other Second-Generation Antipsychotics Medications Patients With Schizophrenia (N = 40) Treated With Clozapine (n = 10) Sex: male, n (%) Age, y Education level, y Age of onset, y Duration of disorder, y No. hospitalizations PANSS Total Positive Negative Excited Depressive Cognitive Global Assessment of Functioning Clinical Global Impression SGI Overall score Perceptual modulation Overinclusion Distractibility Fatigue-stress modulation Stimulus S1 P50 amplitude, μV P50 latency, ms Stimulus S2 P50 amplitude, μV P50 latency, ms P50supp, % Treated With Other Second-Generation Antipsychotics (n = 30) t Tests Mean SD Mean SD t P 9 (90%) 32.80 10.50 19.90 12.90 5.90 — 7.19 2.95 4.56 7.35 5.30 22 (73%) 32.90 12.30 20.90 12 3.43 — 7.91 3.31 4,43 7.34 5.56 — 0.035 1.52 0.61 −0.34 −1.23 0.27* 0.97 0.14 0.54 0.74 0.23 83.50 19.40 22.70 10.30 10.30 18.00 53 4.10 31.68 9.72 7.30 3.65 3.65 9.63 15.81 1.19 69.97 13.50 19.67 10.43 9.60 16.77 61.33 3.60 19.81 6.24 7.59 4.31 3.70 6.68 15.81 1.19 −1.59 −2.24 −1.10 0.088 −0.55 −0.45 1.45 −1.15 0.12 0.03 0.27 0.93 0.58 0.65 0.15 0.25 56 21.30 10.20 16.80 7.70 32.88 16.24 7.22 6.79 6.22 81.60 31.73 16.83 21.10 11.93 37.19 18.11 8.23 9.60 5.63 1.93 1.61 2.27 1.31 2.05 0.06 0.11 0.02 0.19 0.05 3.39 60.88 2.27 14.12 1.76 59.09 1.39 13.64 2.71 0.01 −0.36 0.72 0.97 60.36 71.06 1.05 17.24 27.49 1.04 60.72 36.08 1.04 15.08 52.01 −0.17 0.86 0.063 0.72 −2.02 0.05 *The χ2 test for qualitative variables. differences, particularly positive symptom severity and treatment resistance that led to the selection of the treatment. Concerning positive symptom severity, the patients treated with clozapine presented more positive symptoms than the patients treated with other second-generation antipsychotics did. However, patients with positive symptoms are known to be more likely associated with perceptual abnormalities.25,26 Concerning treatment resistance, which was not assessed in our study, the patients treated with clozapine could be more treatment resistant than the patients treated with other second-generation antipsychotics. However, treatmentresistant patients with schizophrenia are known to be more likely associated with sensory gating deficit.5 Thus, according to these explanations, it is unlikely that positive symptom severity and possible treatment resistance differences could explain the perceptual and neurophysiological differences showed in our study. Although the cross-sectional design of this study is limited because causal inferences cannot be clearly concluded, the present study suggests the clinical and neurophysiological advantages of clozapine compared with other second-generation antipsychotics and provides a basis for future investigations on the effect of this treatment on perceptual abnormalities related to sensory gating deficit in patients with schizophrenia. 186 www.psychopharmacology.com ACKNOWLEDGMENTS The authors thank Mélanie Faugere, Adeline Surray, and Estelle Pierard-Labadie for their technical assistance in the event-related potential recordings. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. REFERENCES 1. Kinon BJ, Lieberman JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Berl). 1996;124:2–34. 2. Llorca PM, Lancon C, Farisse J, et al. Clozapine and negative symptoms. An open study. 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