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Prepulse Inhibition of the Startle Response in Men with Schizophrenia Effects of Age of Onset of Illness, Symptoms, and Medication

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Prepulse Inhibition of the Startle Response in Men with Schizophrenia Effects of Age of Onset of Illness, Symptoms, and Medication ORIGINAL ARTICLE Prepulse Inhibition of the Startle Response in Men With Schizophrenia Effects of Age of Onset of Illness, Symptoms, and Medication Veena Kumari, MA, PhD; William Soni, MB, BS, MSc; Vallakalil M. Mathew, MB, BS, MRCPsych; Tonmoy Sharma, MSc, MRCPsych Background: Prepulse inhibition of the startle reflex re- Methods: Thirty-eight male schizophrenic patients and sponse refers to the ability of a weak prestimulus to tran- 20 healthy male controls underwent testing for pre- siently inhibit the response to a closely following strong pulse inhibition of the acoustic startle response. sensory stimulus. This effect represents an operational index of sensorimotor gating and is found to be defi- Results: Earlier onset of illness was associated with re- cient in schizophrenia. Prepulse inhibition deficits in duced prepulse inhibition, while adult onset of illness was schizophrenia seem to be partially normalized by typi- not. No significant relationships occurred between cur- cal antipsychotics and more fully by some atypical anti- rent symptoms and prepulse inhibition. Patients given psychotics. Early onset of schizophrenia, particularly in typical, but not atypical, antipsychotics exhibited less men, has been associated with abnormal brain matura- prepulse inhibition compared with healthy controls. tion, profound neuropsychological deficits, and less re- sponsiveness to antipsychotic medication. We evalu- Conclusion: Early onset of illness is associated with pro- ated the effects of the age of onset of illness, current found deficits in prepulse inhibition of the startle re- positive and negative symptoms, and the type of medi- sponse in men with schizophrenia. cation (typical vs atypical) on prepulse inhibition of the startle response in schizophrenia. Arch Gen Psychiatry. 2000;57:609-614 REPULSE inhibition (PPI) of play a severe form of disease,10 more struc- the startle response repre- tural brain abnormalities,11,12 poor prog- sents an operational index of nosis,10,13 less favorable outcome with sensorimotor gating and is re- antipsychotic medication (especially with liably demonstrable in both onset at age #20 years),14 and poor neu- Phumans1 and animals.2 Prepulse inhibi- ropsychological functioning,15 compared tion provides a unique opportunity to char- with those with a relatively later onset. The acterize the attention and information pro- findings of greater PPI deficits in men than cessing deficits in schizophrenia that are core women with schizophrenia could also be features of this illness.3 It refers to a reduc- because of their younger age at the onset tion in response to an intense, startling of illness.16 Numerous changes are thought stimulus (the pulse) if this is preceded by to occur in the neuronal substrates for 30 to 150 milliseconds by a nonstartling thought and behavior during adoles- stimulus of subthreshold intensity (the cence, and the absence or failure of these prepulse).1 The inhibitory mechanisms ac- maturational processes may lead to the on- tivated by the prepulse are thought to re- set of schizophrenia and associated cog- duce the impact of any further stimulation nitive abnormalities.17 Furthermore, there until the processing of the prepulse is com- is evidence for an association between ear- plete and thus prevent the organism from lier onset of illness and larger lenticular receiving an overload of information. In line nuclei in schizophrenia18; PPI deficits in with postulated deficits in early stages of in- this population are thought to involve ab- formation processing, several studies have normalities of cortico-striato-pallido- demonstrated deficient PPI of the startle re- thalamic circuitry, including lenticular flex in schizophrenic patients,4-6 although structures.19 From the Section of Cognitive Psychopharmacology, Division some studies observed subnormal PPI in this Recent studies have examined the of Psychological Medicine, population only when active attention to the relationship of deficient PPI with symp- 7,8 Institute of Psychiatry, prepulse was required. toms and other cognitive deficits in schizo- University of London, Individuals with an early onset of phrenia. Prepulse inhibition deficits have London, England. schizophrenia, predominantly men,9 dis- been found to be strongly associated with (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, JUNE 2000 WWW.ARCHGENPSYCHIATRY.COM 609 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SUBJECTS AND METHODS Twenty healthy male controls (age range, 20-50 years), screened for thyroid dysfunction; heart disease; hypoten- sion or hypertension; a history of mental illness, anorexia, SUBJECTS rapid mood changes, drug and alcohol abuse, or regular medical prescription; and presence of psychosis in their first- Forty-one male patients (age range, 20-59 years) with a degree relatives, were recruited via advertisements in lo- DSM-IV diagnosis of schizophrenia or schizoaffective dis- cal newspapers and tested for comparison purposes. Healthy order were recruited from the inpatient and outpatient ser- controls were paid for their time. vices at the Maudsley Hospital, London, England. All pa- The study was approved by the Ethical Committee of tients were diagnosed by an experienced psychiatrist using the Institute of Psychiatry, London. All subjects gave their the Structured Clinical Interview for DSM-IV.32 Of 41 pa- written informed consent. tients recruited, 3 were excluded, either because of being nonresponders in reaction to startle probes (n=2) or be- STARTLE RESPONSE MEASUREMENT cause there was no confirmation of the age of onset with documented records (n=1). Thus, the final sample was com- All subjects were tested for intact auditory abilities using posed of 38 patients. an audiometer (Kamplex KLD23 Advanced Lightweight Symptoms were rated on the day of testing using the Posi- Diagnostic Audiometer; PC Werth Ltd, London) at 40 tive and Negative Syndrome Scale.33 Age of onset was de- dB (A) (1000 Hz). No subject was excluded on this fined as the age at first appearance of psychotic symptoms account. Startle testing was carried out using a commer- (this definition has high reliability34 and been used in previ- cial computerized human startle response monitoring ous studies9) as reported retrospectively by patients them- system (Mark II; SRLab, San Diego, Calif). This was used selves, and confirmed by documented records in all cases. to deliver acoustic startle stimuli, and record and score All patients were receiving antipsychotics for a mini- the electromyographic (EMG) activity for 250 millisec- mum of 6 weeks prior to their participation in the study. Ten onds starting from the onset of the stimulus. Stimuli patients had illness onset in adolescence18 (age range, 13-20 were presented to subjects binaurally through head- years; 3 patients were given typical antipsychotics [2, flu- phones (TDH39P; Telephonics, SRLabs, San Diego). phenazine decanoate and 1, zuclopenthixol]; 7 patients were Electromyographic recordings were taken with subjects given atypical antipsychotics [3, risperidone; 2, olanzapine; sitting comfortably in a moderately lit soundproof labo- and 2, clozapine]; 5 patients [50%] were of low to lower-middle ratory. socioeconomic status as judged on the basis of parental occu- Eyeblink component of the startle response was pation; and 5 [50%] were of upper-middle socioeconomic indexed by recording EMG activity of the orbicularis oculi status). The remaining 28 patients had illness onset in adult- muscle directly beneath the right eye, by positioning 2 hood (age range, 21-35 years; 6 patients were given typical an- miniature silver/silver chloride electrodes filled with tipsychotics [1, fluphenazine decanoate; 2, haloperidol; Dracard electrolyte paste (SLE Ltd, Croydon, England). 1, chlorpromazine; and 2, flupenthixol]; 22 patients were given The ground electrode was attached behind the right ear on atypical antipsychotics [6, risperidone; 6, olanzapine; 9, cloza- the mastoid. pine;and1,quetiapine];13patients[46%]wereoflowtolower- The startle system recorded EMG activity for 250 mil- middle socioeconomic status; and 15 patients [54%] were of liseconds (sample interval, 1 millisecond) from the onset upper-middle to upper socioeconomic status). of the stimulus. The amplification gain control for the EMG thought disorder in schizophrenia.20,21 However, the re- more fully normalized by the atypical antipsychotic lationship of PPI with some other cognitive abnormali- clozapine.25,29 ties, such as poor performance on the Wisconsin Card The main aim of this study was to address the hy- Sorting Test, which correlates with tactile but not acous- pothesis that earlier onset of illness would be associated tic PPI,22,23 and high distractibility on the continuous per- with more impaired PPI in males with schizophrenia. The formance test,24 and with both positive and negative symp- secondary aims were to examine the influence of cur- toms of schizophrenia is rather weak.20,25,26 rent symptoms and medication (typical vs atypical) on Pharmacological agents with psychotic and antipsy- PPI in schizophrenia. We hypothesised that there would chotic properties for humans, can disrupt and potentiate be a greater degree of impairment of PPI in patients given PPI in animals.27 In the rat, the disruption of PPI by typical antipsychotics than in those given atypical anti- dopamine agonists is reversed by typical and atypical psychotics and healthy controls. Keeping in view the weak
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