Electroencephalographic sleep abnormalities in schizophrenia. Relationship to positive/negative symptoms and prior neuroleptic treatment.

Polysomnographic abnormalities in schizophrenia are not well characterized and their associations with schizophrenic symptomatology have not been adequately assessed. To address these issues, we recorded electroencephalographic sleep in 20 drug-naive schizophrenics, 20 drug-free but previously medicated schizophrenics, and 15 normal controls. Drug-naive and previously medicated patients had significantly greater impairment of sleep continuity and shorter rapid eye movement latency when compared with controls. In the previously medicated group, findings were significantly influenced by duration of drug-free status. Rapid eye movement latency was inversely correlated with the severity of negative symptoms (r = -.52) but was unrelated to depressive symptoms. Slow-wave sleep did not differ between schizophrenic patients and normal controls and was unrelated to any clinical parameter. Mechanisms underlying the observed associations between rapid eye movement sleep abnormalities and negative symptoms in the acute phase of schizophrenic illness need to be explored.

Utility of an oral diffusion sink (ODS) device for quantification of saliva corticosteroids in human subjects.

Measurement of cortisol by assay of single blood or saliva samples is inherently imprecise due to the episodic secretion of cortisol. In addition, assay of blood usually quantifies total cortisol, rather than separating free hormone, which is proportionately the much smaller fraction. Furthermore, the free fraction may be disproportionately higher in hypercortisolism. Urinary free cortisol is one measure that provides both a time integral and a focus on the free fraction, but it is inconvenient and prone to collection error in unsupervised ambulatory subjects. The Oral Diffusion Sink (ODS) apparatus takes up corticosteroids from saliva according to first-order kinetics and may provide a practical alternative. We assessed the utility of the ODS in a study of seven healthy volunteers admitted to the CRC for three days. Data on day two from 0700-1100 h and 1100-1500 h were compared between the ODS and three other means of assessing cortisol: urinary free cortisol (UFC), blood, and saliva. The subjects all tolerated wearing the ODS device without any complaint. High correlations were observed between ODS values vs. data for UFC, plasma, and saliva determinations. In summary, the ODS device was well tolerated and collected reliable corticosteroid data, and thus provides a new, non-invasive methodology for studies of HPA function in health and disease.

Neuropsychological function and REM sleep in schizophrenic patients.

To test the hypothesis that rapid eye movement (REM) sleep in schizophrenic patients is associated with cognitive function, we studied 18 schizophrenic inpatients by means of electroencephalograms taken during sleep in their own hospital beds after a minimum 2-wk medication withdrawal period. Patients underwent neuropsychological tests to measure memory function and other aspects of cognitive performance. REM sleep measures demonstrated positive and negative correlations with cognition and memory measures, depending on when REM occurred after sleep onset. Minutes of REM sleep and REM density in the first period correlated negatively with performance, while REM minutes occurring after the first REM period correlated positively with neuropsychological performance. Further work should test whether phasic REM sleep regulation at the beginning of the night plays a compensatory role for neuropsychological dysfunction in schizophrenics.

Effect of neuroleptic treatment on polysomnographic measures in schizophrenia.

To study the effects of neuroleptic therapy on sleep EEG variables in schizophrenia, as well as the clinical correlates of these variables, we performed polysomnographic (PSG) studies on 14 schizophrenic inpatients before and during neuroleptic therapy. Sleep continuity measures improved after 3 weeks of neuroleptic therapy, showing decreased sleep latency and improved sleep efficiency. REM latency increased with treatment, although half the patients continued to exhibit REM latencies less than 60 min. Other sleep stages and measures of REM sleep (density, activity, number of periods) did not appear to change with neuroleptic treatment. At baseline, REM latency had strong negative correlations with BPRS and SANS scores, but with 3 weeks of such treatment, this association disappeared. Further work is needed to distinguish direct medication effects from the effects of the changing clinical state on PSG measures.

Schizophrenia, narcolepsy, and HLA-DR15, DQ6.

A strong association between HLA-DR2, DQ1 and narcolepsy-cataplexy has been known since 1986. In 1990 a subdivision (HLA-DR15, DQ6) was shown to be equally associated. Narcolepsy symptoms include rapid eye movement (REM)-sleep intrusion hallucinations during the day. Some narcoleptics may be so hallucinated that they become delusional and receive a diagnosis of schizophrenia. Fifty-six inpatient schizophrenics and 56 normal controls were compared to see if there was an excess of the narcolepsy-associated antigens (NAA) among schizophrenics. Patients had frequency of the NAA 3.89 times higher than controls. After a subset was studied by night (n = 9) and day (n = 7) polysomnography, two patients were found to be true narcoleptics. Their psychosis improved with treatment for narcolepsy. When NAA(+) and NAA(-) schizophrenics were compared, the NAA(+) subgroup had significantly higher Brief Psychiatric Rating Scale (BPRS) scores and more hospitalizations. There were no effects attributable only to gender or race. We conclude that narcolepsy can simulate schizophrenia in some cases, and that even in nonnarcoleptic patients, the HLA-DR15,DQ6 antigens mark a group of severe schizophrenics that merits further study.

Sleep-onset rapid eye movement after electroconvulsive therapy is more frequent in patients who respond less well to electroconvulsive therapy.

The response to electroconvulsive therapy (ECT) was monitored with sleep polysomnography studies (SPS) performed pre- and post-ECT, in 25 patients with major depressive disorder (MDD). Patients included in this study met research diagnostic criteria for MDD and had been free of psychotropic medication for at least 10 days before SPS were performed. We compared ECT responders and nonresponders on SPS, demographic, and clinical parameters. Many SPS parameters, regardless of the clinical response, changed significantly with ECT. The presence of delusions was significantly associated with SOREM post-ECT. The presence of sleep-onset REM periods post-ECT was associated with poor response to ECT. SPS performed during a course of ECT may help identify patients at risk of responding less well to this modality of treatment.

Shortened REM latency PostECT is associated with rapid recurrence of depressive symptomatology.

Electroconvulsive therapy (ECT) is highly effective in the treatment of major depressive disorder (MDD). The 1-year relapse rates are reported to be high and in the 30%-60% range, however. To test whether polysomnography (PS) can identify patients with a propensity for relapse we studied 20 patients, responders to a course of ECT, with PS studies. All patients met baseline diagnostic criteria for MDD, were treated with ECT following standardized protocols, had PS studies performed after the course of ECT in a medication-free state, received maintenance antidepressants postECT, and were followed periodically with phone interviews. The recurrence of depressive symptoms was determined at 3 months and 6 months after discharge. Fifty-five percent of the patients were symptomatic when evaluated 6 months after the ECT. Sleep Onset rapid eye movement (REM) periods were identified in 55% of the patients. As a group, patients who had experienced a recurrence of depressive symptoms by 6 months after discharge, had significantly shorter REM latencies after the course of ECT. A shorter REM latency after ECT identified patients who at six months demonstrated significant depressive symptomatology. Shortened REM latency after ECT in patients with MDD appears to be a correlate of vulnerability for relapse.

Neuropsychological assessment and EEG sleep in affective disorders.

The neuropsychological test performance of 76 hospitalized, depressed patients meeting RDC for the presence of affective disorder was assessed as part of a protocol involving amitryptyline (n = 53) or placebo (n = 23). Tests included the Trail-making Test (TMT), the Benton Visual Retention Test, and the Shipley-Hartford Scale. Clinical ratings and data concerning the characteristics of EEG sleep were also obtained. Analysis of data collected after a drug-free period of 2 weeks and again at the end of the protocol yielded the following conclusions. Base-line performance was inferior to norms for these tests, but for the TMT, scores were not as poor as that expected for brain-damaged patients. Poor performance was often associated with older age, the presence of psychotic features, and prolonged sleep latencies. Baseline Hamilton Rating Scale (HRS) was predicted best by TMT part B. However, this association was not as strong as that between HRS and poor sleep efficiency. Treatment with drug or placebo had little differential effect upon test performance over the course of the protocol. It is suggested that further research should utilize tests which have specificity in localizing cerebral lesions, so that any focal deficits in brain function in depression might be identified.

EEG sleep in Cushing's disease and Cushing's syndrome: comparison with patients with major depressive disorder.

Because patients with Cushing' syndrome (CS) and Major depressive disorder (MDD) share features of hypercortisolism and the depressive syndrome, we compared electro-encephalographic (EEG) sleep in patients with pituitary-ACTH-dependent Cushing's syndrome (Cushing's disease, CD), patients with ACTH-independent Cushing's syndrome (AICS), patients with major depressive disorder (MDD), and normal subjects. There were substantial similarities in the abnormal polysomnography profiles of patients with CD, AICS, and MDD. All three patient groups demonstrated poorer sleep continuity, shortened rapid eye movement (REM) latency, and increased first REM period density compared with normal subjects. In addition, AICS patients and MDD patients had elevated REM activity and density. These findings are discussed in terms of models of pathophysiology that relate abnormalities in sleep, mood, and hypothalamic-pituitary-adrenal function.

Differential effects of amitriptyline and of zimelidine on the sleep electroencephalogram of depressed patients.

The effects of amitriptyline (n = 14) or zimelidine (n = 13) on the sleep electroencephalogram of hospitalized depressed patients were assessed in a double-blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings, and lighter non-rapid eye movement (REM) sleep than before taking the drug. Zimelidine did, however, induce a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first two nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM-suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these two drugs.

Effects of continuous positive airway pressure on phasic events of REM sleep in patients with obstructive sleep apnea.

In patients with obstructive sleep apnea and associated rapid-eye-movement (REM) sleep deprivation and disruption, the first night of nasal continuous positive airway pressure (CPAP) is often associated with increases in REM sleep time and REM density (REM rebound). The amount of REM rebound, however, varies considerably. We sought to characterize the magnitude of REM rebound and to determine what factors determine individual differences in REM rebound with initial CPAP treatment. Twenty-six patients with sleep apnea had a baseline nocturnal polysomnogram and a second night with a trial of CPAP. REM sleep time increased by 69% with CPAP, REM density increased by 73%, and REM activity by 169%. REM density was highest in the second REM period. Improvement in respiratory disturbance index with CPAP correlated significantly with increased minutes of REM sleep with CPAP. Of polysomnographic measures on the baseline night, change in minutes of REM sleep with CPAP correlated best with minimum oxygen saturation and to a lesser degree with respiratory disturbance index, and minutes of Stage 1 sleep. One possible explanation for the effect of hypoxemia on subsequent REM rebound is that some physiological functions of REM sleep may fail when oxygen saturation falls below a certain level.

Sleep architecture and sleep apnea in patients with Cushing's disease.

Patients with Cushing's syndrome (CS) frequently have sleep complaints. We evaluated sleep polysomnographically in 22 patients, including 17 with pituitary-ACTH-dependent Cushing's disease (CD) and five with CS from an adrenal tumor. Data were compared to healthy controls of comparable age. Seven patients (32%) demonstrated at least mild sleep apnea (> or = 9.4 events/hour), and four of 22 (18%) had > or = 17.5 events/hour. The apneic CD and CS patients had a trend for a greater complaint of excessive daytime sleepiness. Both apneic and nonapneic groups had considerable snoring and obesity. The electroencephalographic (EEG) sleep of nonapneic patients was compared to that of normal subjects. Nonapneic CD patients differed strikingly from healthy volunteers in sleep continuity and architecture, demonstrating lighter, fragmented sleep. Rapid eye movement (REM) sleep in CD patients bore many similarities to the sleep of patients with major depression, with REM latency being significantly shortened and REM density significantly increased. Continued examination of EEG sleep in CD patients may shed light on similarities in pathophysiology between CD and major depression, disorders which are characterized by both a dysfunction of the hypothalamic-pituitary-adrenal axis and alterations in mood.

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients.

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n = 17) and amitriptyline (AT, n = 16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiles for uptake blockade and anticholinergic potency for these two compounds.

Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms.

Based on the implication of increased muscarinic ACh activity in the production of negative symptoms, the association of decreasing cholinergic activity with positive symptoms, and the covariance of positive and negative symptoms in the psychotic phase of schizophrenia, a model of (DA) dopaminergic/(ACh) cholinergic interactions in schizophrenia was recently formulated. It suggests that DA/ACh balance is of central importance in schizophrenic pathophysiology and that muscarinic ACh activity increases in an attempt to maintain this balance in the face of increasing DA activity that occurs in the psychotic phase of the illness. The model further suggests that the muscarinic system exerts a damping influence on the emergence of positive symptoms associated with DA hyperactivity, but that this compensatory increase in muscarinic activity is accompanied by an intensification of negative symptoms. In the present study, we tested two important postulates of this model. We tested the prediction that muscarinic activity is increased in schizophrenia by comparing the effect of biperiden, an antimuscarinic M-1 agent, on REM latency in 12 drug-free schizophrenic inpatients and matched normal controls. We found that biperiden caused a smaller increase in REM latency in schizophrenic patients, suggesting that muscarinic activity is increased in schizophrenia. We tested the prediction that an anticholinergic agent would increase positive symptoms and decrease negative symptoms by studying the effect of 8 mg of biperiden/day for 2 days on positive and negative symptoms (assessed by the BPRS) in 30 medication-free schizophrenic inpatients.(ABSTRACT TRUNCATED AT 250 WORDS)

Orbital or medial frontal cortical lesions have different effects on tail pressure-elicited oral behaviors in rats.

Three groups of rats were tested with daily tail pressure (TP) tests until reliable and stable baseline eating, gnawing or licking was observed. One group then received bilateral aspiration of the medial frontal cortex, a second group received orbital frontal cortical lesions, and a third group received control lesions of the motor cortex. Daily TP tests were continued postoperatively. There was no disruption of TP-elicited oral behaviors after medial frontal or motro cortex lesions. In contrast, orbital frontal lesions abolished TP behaviors on the first day postoperatively, and there was a slow recovery of TP until day 5 when the elicited behaviors were about 80% of preoperative levels. The time course of recovery of TP-elicited oral behavior closely paralleled the recovery of elective eating after orbital frontal lesions, both in the group given TP and in another group given orbital lesions but not TP. These data demonstrate a marked difference between the medial and orbital divisions of the prefrontal cortex in the mediation of stress-induced oral behavior, and we discuss our data in terms of the possible role of dopamine terminals in these regions.

Monitoring of antidepressant response to ECT with polysomnographic recordings and the dexamethasone suppression test.

Ten patients treated with electroconvulsive therapy (ECT) only were followed with serial sleep polysomnographic recordings and dexamethasone suppression tests (DSTs). Both biological correlates of depression showed improvement with ECT. The use of serial sleep measures and serial DSTs in monitoring the clinical response to ECT is discussed.