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BPRS symptom factors and sleep variables in schizophrenia
329 Schizophrenia Research, 4 (1991) 329 - 340 0 1991 Elsevier Science Publishers B.V. 0920~9964/91/$03.50
NEUROPHYSIOLOGY
Ten years of studies on P50 sensory gating: A review and considerations for future studies L.E. Adler*, M.C. Waldo, H.T. Nagamoto, N. Baker, R. Franks, P. Bickford-Wimer, G. Rose, G. Gerhardt, C. Drebing, R. Johnson, K. Stevens, M. Johnson, L. Hoffer, M. Pecevich, E. Pachtman, J. Alpert, V. Leybman, and R. Freedman Departments of Psychiatry and Pharmacology, E. 9th Ave., Denver, CO 80262, USA.
UCHSC and the Denver WMC,
Bx C268-14, Dept. Psych. U. Co. Health SC. Ctr., 4200
Gating of auditory sensory processing is defective in schizophrenic patients. One defect is illustrated by the failure to gate the P50 wave of the auditory evoked potential in a conditioning-testing paradigm. In this paradigm, paired clicks are presented to the subject with 10 sets between each pair of click stimuli. Normals suppress or gate the P50 response to the second stimulus of each pair (test stimulus), presented 500 msec after the first. Schizophrenics fail to suppress the test response. This defect has been related to the inability of schizophrenic patients to filter out noise in their environment. Schizophrenics demonstrate this defect in both unmedicated and medicated states. Patients with other psychotic illnesses, such as mania, may fail to suppress the test response when untreated or acutely psychotic, but regain relatively normal sensory gating with treatment. This deficit in P50 sensory gating appears to be inversely correlated with plasma MHPG in mania, but not in schizophrenia. One study in human subjects suggests that a moderately intense stress, such as caused by the cold-pressor test, causes a transient impairment in P50 auditory sensory gating. Preliminary data in ongoing studies also suggest that nicotine may briefly enhance P50 auditory gating in nongating first-degree relatives of schizophrenic patients. An animal model has been developed using the N40 waveform in the rat, which has been found to be homologous to the P50 waveform in human subjects. Studies in rats have demonstrated that amphetamine impairs N40 sensory gating; and that the amphetamine effect is ameliorated by post-treatment with haloperidol or pretreatment with DSP-4, which selectively depletes CNS norepinephrine. Neuroanatomical data suggest that the hippocampus is involved in N40 auditory sensory gating in the rat, and that nicotinic receptors may also modulate N40 auditory gating. These data suggest that the auditory P50 conditioning-testing paradigm may serve as a useful tool in studies of psychosis in human subjects, and in parallel studies using single-unit or chronic recording techniques in animals, to permit more detailed neuroanatomic and neuropharmacologic studies.
BPRS symptom factors and sleep variables in schizophrenia K.L. Benson*, J.G. Csernansky,
V.P. Zarcone
Department of Psychiatry, TD 114, Stanford University School of Medicine, Stanford, C4 94305, USA.
The relationship of negative symptoms in schizophrenia to measures of slow wave sleep has been the subject of several previous reports. The dependent measures of slow wave sleep as well as the instruments for assessing negative symptoms have varied among studies. Although an inverse relationship between the level of negative symptoms and the amount of slow wave sleep was reported, the sample size in these studies was small. Consequently, we attempted to replicate these findings using a larger sample of schizophrenics. Also, sleep onset latency is often prolonged in schizophrenics relative to other psychiatric controls. We hypothesized that
330 this sleep onset insomnia would be directly related to the positive symptoms of schizophrenia rather than symptoms of anxiety and depression. We studied 1.5 schizophrenics and five schizoaffectives, mainly schizophrenic. Diagnoses were made using Research Diagnostic Criteria. All patients were male; their mean age was 33.8 years. They were neuroleptic free for at least two weeks before the three night sleep study. The first recording night was used for adaptation and to screen for the presence of sleep apnea or periodic leg movements. The sleep data were analyzed and averaged over recording nights 2 and 3. To enhance the reliability of symptom assessment, each item of the 18 item BPRS was averaged over two independent raters and was subsequently averaged over a second rating session conducted one week later. The first rating session was scheduled within 7 days of the sleep study and the second rating session within 14 days. We analyzed 3 higher-order factors of the BPRS: a positive symptom factor; a negative symptom factor; and an anxiety/depression factor. In this sample of 20, we found no correlation between negative symptom factor and measures of stage 3 or stage 4 sleep, and consequently we did not replicate the finding that slow wave sleep is inversely correlated with negative symptoms. We did, however, demonstrate a marked sleep onset insomnia that was significantly correlated (r = 0.60, p < 0.005) with the BPRS positive symptom factor. Sleep onset latency was not correlated with the BPRS anxiety/depression factor. (Research supported by the Medical Research Service of the Veterans Administration and by MH37252 & MH30854.)
The effect of ritanserin K.L. Benson*, J.G. Csernansky,
on slow wave sleep deficits in schizophrenia
V.P. Zarcone,
Jr.
Department of Psychiatry, TD114, Stanford University School of Medicine, Stanford CA 94305, U.S.A.
Slow wave sleep deficits are a prominent feature of sleep in schizophrenia as well as other psychiatric disorders. The degree to which slow wave sleep deficits in schizophrenia are stable over time and stable in response to experimental intervention is largely unknown. The purpose of the present study was to determine if slow wave sleep deficits in schizophrenia can respond to a pharmacological challenge. We chose ritanserin as the pharmacological probe because it, like other serotonin-2 antagonists, has produced large increases in the slow wave sleep of healthy controls. We have previously reported a positive correlation between spinal fluid levels of the serotonin metabolite, S-HIAA and slow wave sleep measures in schizophrenia. We conducted a pilot, open-label study of ritanserin in 10 inpatients who met DSM-III-R criteria for schizophrenia. All were male; their mean age was 37.9 years. They were neuroleptic free for at least 14 days before the start of the study which consisted of 6 nights of polysomnography. Night 1 was an adaptation night and was also used to screen patients for sleep disorders such as apnea and periodic leg movements. Baseline sleep data were derived from the average of nights 2 and 3. Ritanserin (10 mg) was administered at 8:00 AM on days 4 and 5. Medicated sleep data were therefore derived from the average of nights 4 and 5. We conducted an additional polysomnogram on night 6 to evaluate any withdrawal effect. We observed a virtual absence of stage 4 sleep at baseline and no increase in stage 4 sleep following treatment with ritanserin. Ritanserin was associated with a modest but insignificant increase in the stage 3 component of slow wave sleep. Computer-based measures may demonstrate more subtle effects of ritanserin such as an increase in delta wave frequency or amplitude. Ritanserin was associated with an increase in both state REM minutes and percent of total sleep. Finally, ritanserin appears to have a general sleep promoting effect; the amount of waking and the number of wakes after sleep onset were both reduced as was the amount of light, stage 1 sleep. (Research supported by the Medical Research Service of the Department of Veterans Affairs, by MH37252 and MH30854, and by a gift from the Janssen Research Foundation.)
NEUROPHYSIOLOGY
Ten years of studies on P50 sensory gating: A review and considerations for future studies L.E. Adler*, M.C. Waldo, H.T. Nagamoto, N. Baker, R. Franks, P. Bickford-Wimer, G. Rose, G. Gerhardt, C. Drebing, R. Johnson, K. Stevens, M. Johnson, L. Hoffer, M. Pecevich, E. Pachtman, J. Alpert, V. Leybman, and R. Freedman Departments of Psychiatry and Pharmacology, E. 9th Ave., Denver, CO 80262, USA.
UCHSC and the Denver WMC,
Bx C268-14, Dept. Psych. U. Co. Health SC. Ctr., 4200
Gating of auditory sensory processing is defective in schizophrenic patients. One defect is illustrated by the failure to gate the P50 wave of the auditory evoked potential in a conditioning-testing paradigm. In this paradigm, paired clicks are presented to the subject with 10 sets between each pair of click stimuli. Normals suppress or gate the P50 response to the second stimulus of each pair (test stimulus), presented 500 msec after the first. Schizophrenics fail to suppress the test response. This defect has been related to the inability of schizophrenic patients to filter out noise in their environment. Schizophrenics demonstrate this defect in both unmedicated and medicated states. Patients with other psychotic illnesses, such as mania, may fail to suppress the test response when untreated or acutely psychotic, but regain relatively normal sensory gating with treatment. This deficit in P50 sensory gating appears to be inversely correlated with plasma MHPG in mania, but not in schizophrenia. One study in human subjects suggests that a moderately intense stress, such as caused by the cold-pressor test, causes a transient impairment in P50 auditory sensory gating. Preliminary data in ongoing studies also suggest that nicotine may briefly enhance P50 auditory gating in nongating first-degree relatives of schizophrenic patients. An animal model has been developed using the N40 waveform in the rat, which has been found to be homologous to the P50 waveform in human subjects. Studies in rats have demonstrated that amphetamine impairs N40 sensory gating; and that the amphetamine effect is ameliorated by post-treatment with haloperidol or pretreatment with DSP-4, which selectively depletes CNS norepinephrine. Neuroanatomical data suggest that the hippocampus is involved in N40 auditory sensory gating in the rat, and that nicotinic receptors may also modulate N40 auditory gating. These data suggest that the auditory P50 conditioning-testing paradigm may serve as a useful tool in studies of psychosis in human subjects, and in parallel studies using single-unit or chronic recording techniques in animals, to permit more detailed neuroanatomic and neuropharmacologic studies.
BPRS symptom factors and sleep variables in schizophrenia K.L. Benson*, J.G. Csernansky,
V.P. Zarcone
Department of Psychiatry, TD 114, Stanford University School of Medicine, Stanford, C4 94305, USA.
The relationship of negative symptoms in schizophrenia to measures of slow wave sleep has been the subject of several previous reports. The dependent measures of slow wave sleep as well as the instruments for assessing negative symptoms have varied among studies. Although an inverse relationship between the level of negative symptoms and the amount of slow wave sleep was reported, the sample size in these studies was small. Consequently, we attempted to replicate these findings using a larger sample of schizophrenics. Also, sleep onset latency is often prolonged in schizophrenics relative to other psychiatric controls. We hypothesized that
330 this sleep onset insomnia would be directly related to the positive symptoms of schizophrenia rather than symptoms of anxiety and depression. We studied 1.5 schizophrenics and five schizoaffectives, mainly schizophrenic. Diagnoses were made using Research Diagnostic Criteria. All patients were male; their mean age was 33.8 years. They were neuroleptic free for at least two weeks before the three night sleep study. The first recording night was used for adaptation and to screen for the presence of sleep apnea or periodic leg movements. The sleep data were analyzed and averaged over recording nights 2 and 3. To enhance the reliability of symptom assessment, each item of the 18 item BPRS was averaged over two independent raters and was subsequently averaged over a second rating session conducted one week later. The first rating session was scheduled within 7 days of the sleep study and the second rating session within 14 days. We analyzed 3 higher-order factors of the BPRS: a positive symptom factor; a negative symptom factor; and an anxiety/depression factor. In this sample of 20, we found no correlation between negative symptom factor and measures of stage 3 or stage 4 sleep, and consequently we did not replicate the finding that slow wave sleep is inversely correlated with negative symptoms. We did, however, demonstrate a marked sleep onset insomnia that was significantly correlated (r = 0.60, p < 0.005) with the BPRS positive symptom factor. Sleep onset latency was not correlated with the BPRS anxiety/depression factor. (Research supported by the Medical Research Service of the Veterans Administration and by MH37252 & MH30854.)
The effect of ritanserin K.L. Benson*, J.G. Csernansky,
on slow wave sleep deficits in schizophrenia
V.P. Zarcone,
Jr.
Department of Psychiatry, TD114, Stanford University School of Medicine, Stanford CA 94305, U.S.A.
Slow wave sleep deficits are a prominent feature of sleep in schizophrenia as well as other psychiatric disorders. The degree to which slow wave sleep deficits in schizophrenia are stable over time and stable in response to experimental intervention is largely unknown. The purpose of the present study was to determine if slow wave sleep deficits in schizophrenia can respond to a pharmacological challenge. We chose ritanserin as the pharmacological probe because it, like other serotonin-2 antagonists, has produced large increases in the slow wave sleep of healthy controls. We have previously reported a positive correlation between spinal fluid levels of the serotonin metabolite, S-HIAA and slow wave sleep measures in schizophrenia. We conducted a pilot, open-label study of ritanserin in 10 inpatients who met DSM-III-R criteria for schizophrenia. All were male; their mean age was 37.9 years. They were neuroleptic free for at least 14 days before the start of the study which consisted of 6 nights of polysomnography. Night 1 was an adaptation night and was also used to screen patients for sleep disorders such as apnea and periodic leg movements. Baseline sleep data were derived from the average of nights 2 and 3. Ritanserin (10 mg) was administered at 8:00 AM on days 4 and 5. Medicated sleep data were therefore derived from the average of nights 4 and 5. We conducted an additional polysomnogram on night 6 to evaluate any withdrawal effect. We observed a virtual absence of stage 4 sleep at baseline and no increase in stage 4 sleep following treatment with ritanserin. Ritanserin was associated with a modest but insignificant increase in the stage 3 component of slow wave sleep. Computer-based measures may demonstrate more subtle effects of ritanserin such as an increase in delta wave frequency or amplitude. Ritanserin was associated with an increase in both state REM minutes and percent of total sleep. Finally, ritanserin appears to have a general sleep promoting effect; the amount of waking and the number of wakes after sleep onset were both reduced as was the amount of light, stage 1 sleep. (Research supported by the Medical Research Service of the Department of Veterans Affairs, by MH37252 and MH30854, and by a gift from the Janssen Research Foundation.)