Modulation of the startle response and startle laterality in relatives of schizophrenic patients and in subjects with schizotypal personality disorder: evidence of inhibitory deficits

OBJECTIVE: Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits. METHOD: Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm. The eye-blink component of the startle response was assessed bilaterally by using electromyographic recordings of orbicularis oculi. RESULTS: The patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had reduced prepulse inhibition relative to comparison subjects, and these deficits were more evident in measures of right eye-blink prepulse inhibition. Comparison subjects demonstrated greater right versus left eye-blink prepulse inhibition, whereas the probands, their relatives, and subjects with schizotypal personality disorder showed less asymmetry of prepulse inhibition. CONCLUSIONS: These data suggest a genetically transmitted deficit in prepulse inhibition (sensorimotor gating) in patients with schizophrenia spectrum disorders, including subjects with schizotypal personality disorder and relatives of patients with schizophrenia.     

Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype?

OBJECTIVE: Subjects with schizotypal personality disorder demonstrate deficits in inhibition when assessed on prepulse inhibition, P50 suppression, and antisaccade paradigms. This study determined if distinct subgroups of subjects with schizotypal personality disorder could be identified on the basis of performance on these measures and whether endophenotypes could be defined for future genetic study by using measures of inhibitory function. METHOD: Prepulse inhibition, P50 suppression, and antisaccade paradigms were assessed in 21 subjects with schizotypal personality disorder. RESULTS: Seven subjects with schizotypal personality disorder had deficits on each paradigm; seven had no deficits on any paradigm. P50 and antisaccade deficits were present in five of the same subjects and significantly correlated. CONCLUSIONS: These results suggest that P50 and antisaccade performance reflects a common endophenotype and that prepulse inhibition identifies a separate endophenotype reflecting different neurobiological substrate(s) in subjects with schizotypal personality disorder. This pattern may generalize to schizophrenia spectrum disorder patients.     

首发精神分裂症患者及其一级亲属感觉门控P50研究

目的探讨首发精神分裂症患者及其未患病的一级亲属感觉门控电位P50的特征。方法采用条件-测试听觉刺激模式对50例首发精神分裂症患者(患者组)、40名未患病的一级亲属(亲属组)和50名正常人(正常对照组)进行P50检测,比较3组P50各成分之间的差异。结果患者组、亲属组和正常对照组3组之间P50潜伏期比较,差异无统计学意义(P>0.05);患者组和亲属组测试刺激所诱发的P50(S2-P50)波幅(中位数1.69uV和1.39uV)高于正常对照组(0.92uV),而2组条件与测试刺激P50波幅的差值(中位数0.16uV和0.44uV)与P50抑制率(中位数10.23%和19.10%)低于正常对照组(1.32uV与62.29%),差异均有统计学意义(P<0.01);正常对照组内男女性别组间P50各项指标比较差异无统计学意义(P>0.05)。结论精神分裂症患者及其未患病的一级亲属均存在P50感觉门控功能异常,提示P50可能是精神分裂症的遗传素质指标。     

EEG synchronization to modulated auditory tones in schizophrenia, schizoaffective disorder, and schizotypal personality disorder

OBJECTIVE: The authors tested whether neural synchronization deficits were present in subjects with schizophrenia and schizotypal personality disorder. METHOD: Amplitude-modulated tones were used to evaluate auditory steady-state evoked potential entrainment in a combined group of 21 subjects with schizophrenia or schizoaffective disorder, 11 subjects with schizotypal personality disorder, and 22 nonpsychiatric comparison subjects. RESULTS: The schizophrenia or schizoaffective disorder group exhibited decreased power compared to the schizotypal personality disorder and nonpsychiatric comparison groups. There were no differences between groups in N100 amplitude. CONCLUSIONS: Subjects with schizophrenia but not subjects with schizotypal personality disorder have deficits in steady-state responses to periodic stimuli, despite an intact response to sensory-evoked potentials (N100). These deficits reflect aberrant neural synchronization or resolution and may contribute to disturbed perceptual and cognitive integration in schizophrenia.     

Exploration of somatosensory P50 gating in schizophrenia spectrum patients: reduced P50 amplitude correlates to social anhedonia

Originally, the hypothesis of a sensory gating defect in schizophrenia evolved from studies of somatosensory evoked potentials (SEP), although the idea has primarily been pursued in the auditory modality. Gating is the relative attenuation of amplitude following the second stimulus in a stimulus pair. Recently, SEP P50 gating was seen when recording the SEP P50 in a paradigm similar to the one used for auditory P50 gating. Hypothetically, abnormality of somatosensory information processing could be related to anhedonia, which is considered a core feature of schizophrenia. Twelve unmedicated, male, schizophrenia spectrum patients (seven schizophrenic and five schizotypal personality disorder patients) and 14 age-matched healthy men participated in recordings of pair-wise presented auditory and median nerve stimuli. The patients had smaller amplitudes of the SEP P50 at the first stimulus, but no gating defect. The reduced amplitude was particularly evident in subjects with high scores on the Revised Social Anhedonia Scale. Early somatosensory information processing seems abnormal in schizophrenia spectrum patients. This could be in agreement with the theory of loss of the benefit of regularity in schizophrenia, while the results are in-conclusive regarding sensory gating theory.     

Visual perception and working memory in schizotypal personality disorder

OBJECTIVE: Patients affected by schizophrenia show deficits in both visual perception and working memory. The authors tested early-stage vision and working memory in subjects with schizotypal personality disorder, which has been biologically associated with schizophrenia. METHOD: Eleven subjects who met DSM-III-R criteria for schizotypal personality disorder and 12 normal comparison subjects were evaluated. Performance thresholds were obtained for tests of visual discrimination and working memory. Both form and trajectory processing were evaluated for each task. RESULTS: Subjects with schizotypal personality disorder showed intact discrimination of form and trajectory but were impaired on working memory tasks. CONCLUSIONS: These data suggest that subjects with schizotypal personality disorder, unlike patients affected by schizophrenia, have relatively intact visual perception. Subjects with schizotypal personality disorder do show specific deficits on tasks of comparable difficulty when working memory demands are imposed. Schizotypal personality disorder may be associated with a more specific visual processing deficit than schizophrenia, possibly reflecting disruption of frontal lobe systems subserving visual working memory operations.     

Human and animal studies of schizophrenia-related gating deficits

Prepulse Inhibition (PPI) of the startle response and the P50 auditory-evoked potential suppression are used to assess impairments in the regulation of the neural substrates and to determine the clinical significance of inhibitory deficits in schizophrenia. The study of gating deficits in schizophrenia and in related animal model studies have already advanced our understanding of the neural substrates of information processing abnormalities in patients with schizophrenia. Individuals with schizotypal personality disorder as well as clinically unaffected family members of patients with schizophrenia show PPI and P50 suppression deficits. These "schizophrenic spectrum" populations are not grossly psychotic, nor are they receiving antipsychotic medications. Therefore, the gating deficits are presumed to reflect core (eg, intermediate phenotypic) schizophrenialinked information processing abnormalities. Several studies have reported that gating deficits are associated with clinical ratings of psychiatric symptoms, thought disorder, and neuropsychologic deficits in patients with schizophrenia. In addition, recent human pharmacologic studies have indicated that gating deficits can be reversed by rationallyselected compounds. Animal model studies have generally shown convergence with the human studies and may lead to improved identification of efficacious new antipsychotic medications for patients with schizophrenia.     

P50 sensory gating in multiplex schizophrenia families from a Pacific island isolate

OBJECTIVE: Multiplex schizophrenia families from Palau, Micronesia, were assessed with P50 sensory gating to 1) test for replication of the association between this inhibitory neurobiological trait and familial schizophrenia in non-Caucasian subjects and 2) evaluate the ability of the P50 trait to serve as an endophenotype in a genetic linkage study of these families. METHOD: A paired-stimulus auditory event- related potential paradigm was used to examine P50 sensory gating in 85 schizophrenia patients (56 medicated with typical antipsychotics and 29 unmedicated), 83 of their first-degree relatives (46 parents and 37 siblings), and 29 normal comparison subjects. RESULTS: Auditory sensory gating as measured by the P50 ratio was similarly impaired in medicated and unmedicated schizophrenia patients compared to the normal subjects, and medication dose had no significant effect on any P50 variable. This impairment extended to first-degree relatives, who also showed significantly higher P50 ratios than the normal subjects. Abnormal P50 ratios were found in 64.7% of the schizophrenia patients and 51.8% of their first-degree relatives but only 10.3% of the normal subjects. CONCLUSIONS: P50 sensory gating deficits were confirmed in Palauan schizophrenia families. Rates of abnormal P50 sensory gating in relatives versus normal subjects resulted in a risk ratio of 5.0. Impairment was independent of medication effects, indicating that the P50 paradigm measures a stable neurobiological trait unaffected by treatment with typical antipsychotics. These results suggest that this trait can fulfill the major criteria for an endophenotype for genetic liability to schizophrenia in these multiply affected Palauan families.     

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.     

Increased p50 gating but intact prepulse inhibition in borderline personality disorder

The authors explore sensory gating deficits in borderline personality disorder patients, such as those described in schizophrenia, in patients with borderline personality disorder. Gating of the P50, N100, and P200 auditory evoked potentials and prepulse inhibition of the startle response (PPI) were measured in borderline patients and a group of healthy comparison subjects. Borderline patients did not show lower sensory gating, but showed higher P50, N100, and P200 gating than comparison subjects. This was mainly due to the increased response after the first stimulus. There were no group differences in PPI. Unlike in other major psychiatric disorders, such as schizophrenia, sensory (motor) gating is intact in borderline personality disorder. The higher early preattentive and mid-latency evoked potentials suggest a higher response tendency in borderline personality disorder, but this needs further replication.     

Deficient attentional modulation of the startle response in patients with schizotypal personality disorder

OBJECTIVE: Attentional deficits have been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. The purpose of this study was to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated subjects with schizotypal personality disorder. METHOD: Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed in an acoustic attention-to-prepulse paradigm. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval. RESULTS: The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response. In contrast, the subjects with schizotypal personality disorder failed to show this pattern. CONCLUSIONS: Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.     

P50 sensory gating in adolescents from a pacific island isolate with elevated risk for schizophrenia.

BACKGROUND: Gating or inhibition of the P50 auditory evoked potential is a heritable neurobiological trait that has shown strong potential to serve as an endophenotype for schizophrenia. P50 sensory gating deficits have been found repeatedly in schizophrenic patients and in their unaffected first-degree relatives. P50 sensory gating has not yet been studied in high-risk (HR) offspring nor in prodromal adolescents. METHODS: A paired-stimulus auditory event-related potential paradigm was used to examine P50 sensory gating in 44 genetically HR adolescent offspring and 43 clinically HR prodromal adolescents with the same low genetic liability as a comparison group of 39 normal adolescents. RESULTS: Auditory sensory gating, as measured by the P50 ratio, was impaired in both genetically HR offspring and also in the clinically HR prodromal adolescents with no close affected relatives. In the genetically HR group, abnormal P50 sensory gating was found only in offspring who met criteria for the schizophrenia prodrome. CONCLUSIONS: Our findings suggest that P50 deficits are associated with the presence of prodromal symptoms, regardless of genetic risk. The results are consistent with the hypothesis that genetic liability in HR offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn, increase risk for impaired sensory gating.     

Spectral decomposition of P50 suppression in schizophrenia during concurrent visual processing

Reduced suppression of the auditory P50 event-related potential has long been associated with schizophrenia, but the mechanisms associated with the generation and suppression of the P50 are not well understood. Recent investigations have used spectral decomposition of the electroencephalograph (EEG) signal to gain additional insight into the ongoing electrophysiological activity that may be reflected by the P50 suppression deficit. The present investigation extended this line of study by examining how both a traditional measure of sensory gating and the ongoing EEG from which it is extracted might be modified by the presence of concurrent visual stimulation - perhaps better characterizing gating deficits as they occur in a real-world, complex sensory environment. The EEG was obtained from 18 patients with schizophrenia and 17 healthy control subjects during the P50 suppression paradigm and while identical auditory paired-stimuli were presented concurrently with affectively neutral pictures. Consistent with prior research, schizophrenia patients differed from healthy subjects in gating of power in the theta range; theta activity also was modulated by visual stimulation. In addition, schizophrenia patients showed intact gating but overall increased power in the gamma range, consistent with a model of NMDA receptor dysfunction in the disorder. These results are in line with a model of schizophrenia in which impairments in neural synchrony are related to sensory demands and the processing of multimodal information.     

Increased hemodynamic response in the hippocampus, thalamus and prefrontal cortex during abnormal sensory gating in schizophrenia

OBJECTIVE: Deficits in sensory gating are a common feature of schizophrenia. Failure of inhibitory gating mechanisms, shown by poor suppression of evoked responses to repeated auditory stimuli, has been previously studied using EEG methods. These methods yield information about the temporal characteristics of sensory gating deficits, but do not identify brain regions involved in the process. Hence, the neuroanatomical substrates of poor sensory gating in schizophrenia remain largely unknown. This study used functional magnetic resonance imaging (fMRI) to investigate the functional neuroanatomy of sensory gating deficits in schizophrenia. METHODS: Twelve patients with schizophrenia and 12 healthy comparison subjects were scanned at 3 Tesla while performing a sensory gating task developed for fMRI. P50 EEG evoked potential recordings from a paired-stimulus conditioning-test paradigm were obtained from the same subjects. RESULTS: Compared to healthy comparison subjects, patients with schizophrenia exhibited greater activation in the hippocampus, thalamus, and dorsolateral prefrontal cortex (DLPFC) during the fMRI sensory gating task. No group difference was observed in the superior temporal gyrus. Schizophrenia subjects also showed decreased P50 suppression as measured with EEG. Hemodynamic response in the fMRI measure was positively correlated with test/conditioning ratios from the EEG sensory gating measure. CONCLUSIONS: Poor sensory gating in schizophrenia is associated with dysfunction of an apparent network of brain regions, including the hippocampus, thalamus and DLPFC. Greater activation of these regions is consistent with evidence for diminished inhibitory function in schizophrenia.     

The pathophysiology of schizophrenia disorders: perspectives from the spectrum

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.     

Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics.

Diminished gating of the P50 auditory evoked response to repeated stimuli is a psychophysiological feature of schizophrenia, that is also present in many relatives of patients. Animal models of auditory sensory gating indicate that nicotinic cholinergic neurotransmission is a critical neuronal substrate. The aim of this experiment was to determine if the deficit in sensory gating could be reversed by nicotine administration. Nonsmoking relatives of schizophrenics with abnormal sensory gating were selected as subjects for this initial double-blind trial, to avoid effects of psychotropic medications that might complicate trials in schizophrenic patients themselves. Nicotine-containing gum increased P50 sensory gating to near normal levels within 30 min of administration. The effect was transient; the gating of P50 returned to baseline levels within 1 hr. There was no change observed after placebo administration. In one of the subjects, the anticholinesterase inhibitor physostigmine similarly normalized P50 gating. The results are consistent with the hypothesis that nicotinic cholinergic neurotransmission may mediate a familial psychophysiological deficit in schizophrenia.     

Associations of P50 suppression and desensitization with perceptual and cognitive features of "unreality" in schizotypy.

BACKGROUND: P50 suppression is an electrophysiologic index of early sensory gating and has consistently been found deficient in schizophrenic patients. This gating deficit is thought to lead to sensory overload and cognitive fragmentation, and correspondingly many symptoms of the disorder. However, the link between P50 suppression deficits and symptomatology is yet to be established, and so this study was designed to determine whether such a relation is present within a nonclinical population. METHODS: P50 suppression and schizotypy measures were obtained from 36 healthy volunteers, and correlation analyses determined whether measures of schizotypy were related to P50 suppression. RESULTS: Consistent with the view that P50 gating deficits are related to schizophrenic symptoms, subjects with poorer P50 suppression reported more perceptual anomalies and magical ideation--an unreality syndrome--in contrast to other positive symptoms and to withdrawal. This study also found a trend to P50 suppression desensitization, and that whereas subjects low on "unreality" demonstrated desensitization to the second of the paired clicks, subjects high on "unreality" demonstrated sensitization. CONCLUSIONS: It is concluded that early sensory gating deficits, in the form of poor P50 suppression, are related to unreality aspects of schizotypy. This supports the view that poor P50 suppression in schizophrenia is related to symptomatology.     

Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications

OBJECTIVE: Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression. METHOD: P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications. RESULTS: The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%). CONCLUSIONS: The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.     

Do self-reports of perceptual anomalies reflect gating deficits in schizophrenia patients?

Jin and colleagues presented an innovative study examining P50 suppression and patients' self-reported perceptual anomalies as two related operational measures of sensory gating deficits in schizophrenia patients. They found that those schizophrenia patients who endorsed experiences of sensory inundation had normal levels of P50 suppression, whereas patients who tended to endorse fewer complaints of perceptual anomalies had P50 suppression deficits. Jin et al's finding challenges the common belief that P50 suppression deficits are associated with cognitive and sensory anomalies reflecting poor gating in schizophrenia patients. This article comments on how the dissociation between phenomenological experiences of gating disturbances and P50 suppression might be explained by the limits of self-report in schizophrenia patients who have deficient insight and self-awareness. We hypothesize that the self-reported inability to screen out irrelevant stimuli reflects a voluntary, controlled process that is different from the involuntary, automatic process measured by P50 suppression.     

氯氮平与氯丙嗪对精神分裂症患者听觉感觉门控的比较：前瞻性病例对照研究

背景精神分裂症患者听觉感觉门控（以下简称感觉门控）P50受损,各种抗精神病药物对该P50的作用仍有争议。假设第二代抗精神病药物氯氮平治疗的精神分裂症患者比氯丙嗪治疗患者的感觉门控P50的改善明显。方法前瞻性对照研究纳入刚住院的精神分裂症患者,由治疗医师决定氯氮平治疗者26例（研究组）,氯丙嗪治疗者30例（对照组）。氯氮平组有23例完成8周研究纳入分析,氯丙嗪组为20例。检测P50的方法为双短声刺激[听觉条件（S1）-测试刺激（S2）范式],检测时点为基线、治疗第4周和第8周。临床症状用阳性与阴性综合征量表（Positive and Negative Syndrome Scale,PANSS）评定。结果两组年龄、性别、教育程度、病程和基线PANSS总分差异均无统计学意义。氯丙嗪组平均（标准差）治疗剂量为389（96）mg/d,氯氮平组为345（117）mg/d。重复测量的方差分析显示,氯氮平组颅顶中央脑区（central zone,Cz）P50比值（S2/S1）的下降比氯丙嗪组明显[基线为108%比106%,第4周94%比102%,第8周84%比95%,F=4.91,P=0.029],而S1和S2波幅差异无统计学意义。两组间S1和S2的波幅无明显差异。氯氮平组治疗后P50比值较治疗前下降（F=4.39,P=0.014）,氯丙嗪组治疗前后P50比值没有明显变化。结论氯氮平治疗可以减轻精神分裂症患者感觉门控的受损程度;与氯丙嗪治疗相比,氯氮平治疗者的改善程度较明显。