Sensorimotor Gating and Habituation of the Startle Response in Schizophrenic Patients Randomly Treated With Amisulpride or Olanzapine

doi:10.1016/j.biopsych.2005.07.012

Biological Psychiatry

Volume 59, Issue 6, 15 March 2006, Pages 536-545

https://doi.org/10.1016/j.biopsych.2005.07.012 Get rights and content

Background

Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT_2A/D₂ and a pure D₂/D₃ antagonist on PPI and habituation of ASR in patients with schizophrenia.

Methods

The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise.

Results

Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect.

Conclusions

Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D₂ receptor blockade.

Section snippets

Participants

Twenty healthy participants and 37 acute schizophrenic patients participated in this study. Patients admitted to the Psychiatric Hospital of the University of Bonn after exacerbation of illness for inpatient treatment were considered eligible for the study if the following criteria were met: a diagnosis of schizophrenia according to DSM-IV, age: 18–65 years, Positive and Negative Symptom Scale (PANSS) ≥ 61, and no clozapine treatment within 3 months before inclusion. Furthermore, subjects were

Demographic Data and Clinical Data

Healthy control subjects and patients groups receiving study medication did not differ with regard to proportion of gender, age, years of education, smoking status, age at illness onset, and duration of illness, number of previous episodes, treatment days at first ASR assessment, or number of weeks in study (see Table 1). Seven patients dropped out between week 4 and week 8 (amisulpride: four, olanzapine: three): two were non-compliant (one and one, respectively), three were lost to follow-up

Discussion

The present study is the first to investigate the effects of two atypical antipsychotics with different receptor affinities on PPI, startle reactivity, and habituation of ASR in a randomized, double-blind, and controlled longitudinal design. There are six major findings of this study: First, we could confirm PPI deficits in schizophrenic patients. Second, schizophrenic patients did not differ in PPI from healthy control subjects after a treatment with either amisulpride or olanzapine. The

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Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia
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Citation Excerpt :
The reason for this discrepancy is unclear but likely related to differences in demographics and ascertainment methods between the COGS-2 case-control cohort and the COGS-1 family study reported in the current manuscript. In most prior studies reporting startle magnitude, schizophrenia subjects did not differ from controls (Braff et al., 1992; Braff et al., 2005; Cadenhead et al., 2000; Hasenkamp et al., 2010; Ludewig et al., 2002; Parwani et al., 2000; Perry et al., 2002; Storozheva et al., 2016; Swerdlow et al., 2006; Takahashi et al., 2008; Wynn et al., 2004) but in other studies, magnitude was lower in schizophrenia than control subjects (Kumari et al., 2005; Matsuo et al., 2016; Minassian et al., 2007; Quednow et al., 2006). Furthermore, psychosis-prone young adults had lower startle magnitude than controls (Simons and Giardina, 1992).
Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.
Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.
980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34–41% for latency and 45–59% for magnitude.
Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.
Deep brain stimulation and sensorimotor gating in tourette syndrome and obsessive-compulsive disorder
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Recent translational data suggest that deep brain stimulation (DBS) of the cortico-striato-thalamo-cortical (CSTC) loops improves sensorimotor gating in psychiatric disorders that show deficient prepulse inhibition (PPI), a robust operational measure of sensorimotor gating. To our knowledge we are the first to investigate this effect in patients with Tourette syndrome (TS). We measured PPI of the acoustic startle reflex in patients with TS (N = 10) or Obsessive-Compulsive Disorder (OCD) (N = 8) treated with DBS of the centromedian and ventro-oral internal thalamic nucleus and the anterior limb of internal capsule–nucleus accumbens area respectively, and aged- and gender-matched healthy controls (HC). PPI of the DBS groups was measured in randomized order in the ON and OFF stimulation condition. Statistical analysis revealed no significant difference in PPI (%) of patients with TS between ON (M = 20.5, SD = 14.9) and OFF (M = 25.2, SD = 29.7) condition. There were significantly reduced PPI levels in patients with TS in the ON condition compared to HC (M = 49.2, SD = 10.7), but no significant difference in PPI between TS in the OFF condition and HC. Furthermore, we found no significant stimulation or group effect for OCD and HC (OCD ON: M = 57.0, SD = 8.3; OCD OFF: 67.8, SD = 19.6; HC: M = 63.0, SD = 24.3). Our study has a number of limitations. Sample sizes are small due to the restricted patient collective. The study was not controlled for use of psychoactive medication or nicotine. Furthermore, we were not able to assess presurgical PPI measurements. In conclusion, we were able to show that PPI is impaired in patients with TS. This finding is in line with recent translational work. With respect to the OCD cohort we were not able to replicate our previously published data. A disability in sensorimotor gating plays a pivotal role in many psychiatric disorders therefore more research should be conducted to disentangle the potential and limitations of modulating sensorimotor gating via brain stimulation techniques.
Serotonin and schizophrenia
2020, Handbook of Behavioral Neuroscience
Citation Excerpt :
Patients with schizophrenia are often unable to filter out extraneous stimuli, leading to distractibility, sensory flooding, and impaired cognition (McGhie & Chapman, 1961). Several studies have found that schizophrenic patients show deficits of startle reflex habituation, potentially contributing to the sensory overload and disorganized cognitive processes that occur in the disorder (e.g., Bolino et al., 1994; Geyer & Braff, 1982, 1987; Ludewig, Geyer, & Vollenweider, 2003; Parwani et al., 2000; Quednow et al., 2006). An advantage of using habituation as a behavioral model is that similar testing procedures can be used to assess habituation in experimental animals and humans.
Although the serotonin hypothesis of schizophrenia is one of the oldest neurochemical hypotheses on the pathogenesis of the disease, it is still topical. The concept of how the serotonin system is involved in the origin and progress of schizophrenia has changed considerably over the past decades. Therefore, this chapter gives an overview about the development and the current directions of the serotonin hypothesis of schizophrenia. In this regard, we discuss the phenomenology of hallucinogenic drug action, model psychosis and translational research, postmortem studies on receptors and transporters, imaging studies, antipsychotic drug action, neuroendocrine challenge studies, platelet and cerebrospinal fluid data, genetic association studies, developmental aspects, and the cross-talk between the glutamate and the serotonin system. In sum, there are several lines of evidence suggesting that the serotonin system plays a role in the pathogenesis of at least a subpopulation of schizophrenia patients. Further studies are still needed to better characterize patients whose psychotic symptoms are suspected to have a serotonergic origin.
Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response
2018, Schizophrenia Research
Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P < 5 ∗ 10^− 8). These results imply that PPI might be modulated by four genotypes – COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 – indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is – like the disease phenotype – highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.
The effect of antipsychotic medications on acoustic startle latency in schizophrenia
2018, Schizophrenia Research
Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p = 0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p = 0.04) and the SGA subjects (p = 0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p = 0.03), the SGA group (p = 0.02) and the FGA group (p = 0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON.
Sensorimotor gating characteristics of violent men with comorbid psychosis and dissocial personality disorder: Relationship with antisocial traits and psychosocial deprivation
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Evidence suggests violence amongst those with psychosis is not aetiologically homogeneous, and that a large proportion of those who engage in violent behaviour have a comorbid antisocial personality disorder. Initial investigations indicate that this subgroup has distinct historical and neuropsychological characteristics, which may indicate diverse treatment needs. This study investigated sensorimotor gating characteristics of violent men with diagnoses of both psychosis and dissocial personality disorder (DPD) (n = 21) relative to violent men with psychosis alone (n = 12), DPD alone (n = 14) and healthy, non-violent male controls (n = 27), using the prepulse inhibition (PPI) paradigm. The results indicated that, relative to the psychosis alone and healthy control groups, the comorbid group had lower PPI, especially at 60-ms prepulse-to-pulse interval. The DPD group took an intermediary position and did not differ from any group. Antisocial personality traits (factor two scores of the Psychopathy Checklist - Revised), and greater severity of childhood psychosocial deprivation (including physical and sexual abuse), were significantly correlated with poor PPI across the clinical sample. The findings suggest diverse sensorimotor gating profiles amongst subgroups of violent offenders, with comorbid psychosis and DPD showing most impairment. This is consistent with a ‘double dose’ of deficit explanation amongst those with both diagnoses, explained at least in part by presence of antisocial personality traits and childhood psychosocial deprivation.

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Original articleSensorimotor Gating and Habituation of the Startle Response in Schizophrenic Patients Randomly Treated With Amisulpride or Olanzapine

Background

Methods

Results

Conclusions

Section snippets

Participants

Demographic Data and Clinical Data

Discussion

Schizophr Res

Neuropsychopharmacology

Biol Psychol

Neurosci Lett

Schizophr Res

Trends Neurosci

Biol Psychiatry

Psychiatry Res

Psychiatry Res

Biol Psychiatry

Schizophr Res

Schizophr Res

Biol Psychiatry

Biol Psychol

Biol Psychol

Schizophr Res

Biol Psychiatry

Biol Psychiatry

Psychiatry Res

Neuropsychopharmacology

Biol Psychol

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Repeated testing of prepulse inhibition and habituation of the startle reflexA study in healthy human controls

J Psychopharmacol

Improvement of negative symptomsconcepts, definition and assessment

Int Clin Psychopharmacol

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers

J Psychopharmacol

Neuropsychology of first-episode schizophreniaInitial characterization and clinical correlates

Am J Psychiatry

A comparative review of new antipsychotics

Can J Psychiatry

Habituation deficits, serotonergic function, and schizophreniaNew animal model data

Psychopharmacol Bull

Gating and habituation of the startle reflex in schizophrenic patients

Arch Gen Psychiatry

Prestimulus effects of human startle reflex in normals and schizophrenics

Psychophysiology

Symptom correlates of prepulse inhibition deficits in male schizophrenic patients

Am J Psychiatry

National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome

Arch Gen Psychiatry

Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder

Am J Psychiatry

Original article
Sensorimotor Gating and Habituation of the Startle Response in Schizophrenic Patients Randomly Treated With Amisulpride or Olanzapine