Year : 2005 | Volume
: 47 | Issue : 3 | Page : 133--138
REM sleep latency and neurocognitive dysfunction in schizophrenia
Mrinmay Das, Ruchika Das, Udayan Khastgir, Utpal Goswami
Department of Psychiatry and Drug De-addiction Centre, Lady Hardinge Medical College and Associated Hospitals, New Delhi 110001, India
Consultant Psychiatrist, Culverhay CMHC Paignton, TQ 45 BD, Devon, UK
Background: Cognitive deficits-the hallmark of schizophrenic deterioration-still remain elusive as far as their pathophysiology is concerned. Various neurotransmitter systems have been implicated to explain these deficits. Abnormalities in cholinergic neurotransmission in the brain are one of the postulations; acetylcholine has also been postulated to regulate rapid eye movement (REM) sleep, especially REM latency. Thus, REM latency in patients with schizophrenia might provide a non-invasive window to look into the cholinergic functions of the brain.
Aim: To study REM sleep measures and neurocognitive function in schizophrenia, and the changes occurring in these parameters following pharmacological treatment.
Methods: Thirty subjects (15 with schizophrenia and 15 normal non-relative controls) were evaluated in this study. Most patients with schizophrenia had prominent negative symptoms and deficits in the performance in neurocognitive tests battery. They were treated with antipsychotics for a variable period of time and post-treatment evaluation was done using the same battery of neurocognitive tests and polysomnography. Patients were either drug-naive or kept drug-free for at least two weeks both at baseline as well as at the post-treatment stage.
Results: A positive correlation between the severity of negative symptoms and neurocognitive deficits (especially on the Wisconsin Card Sorting), and a negative correlation between these two parameters and REM latency was observed.
Conclusion: It can be hypothesized that the acetylcholine deficit model of dementia cannot be applied to schizophrenic dementia, rather a hypercholinergic state results. This state warrants anticholinergic medication as a treatment option for negative symptoms of schizophrenia.
|How to cite this article:|
Das M, Das R, Khastgir U, Goswami U. REM sleep latency and neurocognitive dysfunction in schizophrenia.Indian J Psychiatry 2005;47:133-138
|How to cite this URL:|
Das M, Das R, Khastgir U, Goswami U. REM sleep latency and neurocognitive dysfunction in schizophrenia. Indian J Psychiatry [serial online] 2005 [cited 2019 Dec 14 ];47:133-138
Available from: http://www.indianjpsychiatry.org/text.asp?2005/47/3/133/55934
Cognitive impairment is a central manifestation of schizophrenia. , It impacts on the quality of life of patients and on the cost of illness to society.  In recent years, researchers have attempted to identify and quantify the deficits through neuropsychological, neurophysiological and imaging studies of the brain; they have tried to identify specific regional brain abnormalities corresponding to these deficits. Using neuropsychological tests, some investigators have reported relatively greater left hemispheric deficits among patients with schizophrenia. , Others have found a more generalized and non-specific pattern of neurocognitive dysfunction.  Many investigators have focused on neuropsychological evidence of frontal lobe dysfunction in schizophrenia, and some supportive evidence has been reported. , Cerebral blood flow studies  and positron emission tomographic investigations  have provided further evidence of frontal lobe dysfunction in schizophrenia. More recently, neuroradiological metabolic studies have hypothesized abnormal connectivity between the frontal lobe and temporal areas, and have suggested an association between these functional abnormalities and cognitive impairment.  Despite these attempts, defining neurocognitive deficits along biological lines have remained elusive. 
As the pathophysiology of cognitive impairment in schizophrenia is unknown, no rational pharmacotherapy for this condition can be devised. Despite the fact that patients with schizophrenia do not show cholinergic deficits, drawing a similarity between Alzheimer disease and neurocognitive deterioration in schizophrenia, cholinomimetics might be tried to improve cognitive dysfunction in schizophrenia. 
On the other hand, it has been shown that shortened rapid eye movement (REM) latency is a non-specific finding, is present in depressive illness, and correlates negatively with the severity of negative symptoms of schizophrenia. , Cholinomimetic drugs have been used to show their REM latency-reducing property, with the hypothesis that increased cholinergic function or decreased aminergic function or both might be responsible for shortened REM latency. Here lies the paradox that cognitive impairment (hypocholinergic state), shortened REM latency and increased severity of negative symptoms (hypercholinergic state) are present in the same patient and at the same time. To understand the paradox, we measured the REM latency vis-a-vis negative symptoms and cognitive function.
We studied REM sleep measures and neurocognitive functions in schizophrenia. The changes occurring in these parameters following pharmacological treatment were also studied.
There were a total of 30 subjects (15 cases with schizophrenia and 15 normal controls) in the current investigation. All the patients with schizophrenia were recruited from among those seeking treatment at the OPD and inpatient services of the Department of Psychiatry, Lady Hardinge Medical College and Associated Hospitals, New Delhi. The clinical staff of the department had been told that the investigators were seeking previously unmedicated (drug-naive) or currently medication-free (for at least two weeks) patients with schizophrenia and were asked to contact the investigators. Given the rarity of such subjects, continuous surveillance of inpatient admissions was also maintained.
The patients being considered for this study were interviewed to determine whether they met the DSM-IIIR  criteria for chronic schizophrenia, as confirmed by the Structured Clinical Interview for DSM-IIR, Patient version (SCID-P).  The interview was supplemented by a review of the patients' records and an interview of family members. Patients who did not meet the inclusion criteria or met the exclusion criteria (Box 1) - [SUPPORTING:1] were kept out of the study. The patients we studied were chronically disabled but did not need acute hospitalization.
Informed consent was taken from the subjects who were able and willing; alternatively, if the subjects were judged to be incompetent to give written informed consent, the same was obtained from significant relatives.
A battery of relevant investigations was done to rule out any other medical, surgical or neurological disorder. A semistructured proforma devised for the study was used to collect sociodemographic information and historical data, with special reference to clinico-symptomatological, course-related and treatment outcome variables, including data on standard physical and detailed mental status examination.
Over a period of 13 months, a total of 23 drug-naive or psychoactive medication-free (for at least two weeks) patients were approached to participate in this study. Two patients refused. Four patients required medication to control agitation before they could be studied and hence were excluded. A seventh patient was excluded as his illness turned out to be schizoaffective disorder. Thus, of the original cohort of 23, 15 patients fulfilled the inclusion and exclusion criteria and were included in the study.
Subjects in the control group were selected from the clinical/paraclinical staff members of the department as well as healthy attendants who were not biologically related to the inpatients. The age, sex and educational status of the control group were matched as closely as possible with that of the index group [Table 1].
The mean age of the patient group was 32.1±6.7 years (range: 22-46 years) and that of the control group 31.0±8.1 years (range: 19-45 years). The majority of the subjects (both cases and controls) were educated till higher secondary (10+2), without any skew between the grouping, and the groups were comparable.
The average duration of illness was 4.6±4.1 years; 60% of the cases were diagnosed with paranoid, and 20% each with residual and undifferentiated schizophrenia. Of the 15 cases, 3 patients were drug-naive, 2 had been medicated for 1 year, 2 for 6 months, 2 for 3 months, 3 for 5 weeks and 3 for 2 weeks. Therefore, the mean duration of medication was 6.3±2.4 months.
The Positive and Negative Syndrome Scale (PANSS), 1 Montgomery-Asberg Depression Rating Scale (MADRS),  Abnormal Involuntary Movement Scale (AIMS),  Simpson- Angus rating scale (to measure extrapyramidal side-effects)  were administered to each subject to obtain a set of baseline measures in keeping with the aim of the study. The Global Assessment of Functioning (GAF) Scale of DSM-IV  was applied to assess the current level of global functioning.
REM sleep study procedure
Polysomnography was conducted on two consecutive nights in the sleep laboratory. Recording on the first night allowed acclimatization of the subject to the sleep laboratory environment. The polygraphic data of only the second night were used in the analysis.
Sleep was recorded in the laboratory on a 24-channel polygraph (MPA-S Medilog instruments, Oxford). An electroencephalogram (EEG), an electro-oculogram (EOG) and a bipolar submental chin electromyogram (EMG) recorded the sleep state. The EEG consisted of a C4-scalp placement referenced to linked mastoids. The EOG consisted of electrode placement at the outer canthi of the eye with the derivation of each eye also referenced to the linked mastoids. All electrode impedances were determined to be less than 5000 ohms. The filter setting was 1-30 Hz for the EEG, 0.3- 30 Hz for the EOG and 10-90 Hz for the submental chin EMG.
All sleep recordings were scored in 30 second epochs following Rechtschaffen-Kales criteria.  Sleep onset was defined by the first minute of 10 consecutive minutes of stage II non-rapid eye movement (NREM) sleep, with no more than 2 intervening minutes of stage I sleep or awakening, following lights out.
REM sleep was defined as not less than 3 consecutive minutes of REM sleep, with no less than 20 minutes of NREM sleep (stages I through IV) subtending any two REM periods. Sleep architecture was defined in terms of percentage of sleep time spent in NREM stages I through IV and REM.
Assessment of cognitive functions
To test cognitive functions, a battery of tests was applied by means of a computer-assisted NeuroScan machine utilizing STIM software (Neurosoft Inc. 1990, STIM Audio system). The following tests were used: Card Sort, Visual Continuous Performance Task (VISCPT), Stroop and Spatial Task.
The Card Sort program has been modelled after the Wisconsin Card Sorting Test (WCST), , which was designed to test 'abstract behaviour' and 'shift of set'. The program presents the subjects with a set of four card-like stimuli with a different pattern on each. The patterns contain different shapes in different colours. A probe stimulus is presented in the lower portion of the screen. The subject was required to choose the card from among the original four that best matched the probe stimulus. There were three randomly varied response contingencies. First, the subjects might be required to respond on the basis of the colour of the image on the card. Second, the subjects might be required to respond on the basis of the pattern of the image. Third, the subjects might be required to respond on the basis of the number of images on the card. The patients were not informed of the correct principle but a feedback on whether they were correct or not was given after their matching of each card. Once the criterion of 10 correctly sorted cards is attained, the principle is changed; the patient is not informed of this change. The test proceeds until the patient has completed six sorting categories, each consisting of 10 consecutive cards. The types of errors that are elicited may vary, although the most sensitive response type with respect to frontal lobe dysfunction is the perseverative response, reflecting subjects' difficulty in shifting their strategies or cognitive sets.
The Visual Continuous Performance Task (VISCPT) was used to test the attention span. In this program, user-created visual stimuli which could be precisely timed at rates were presented on the computer screen. The subject had to press the left button of the mouse when a '0' appeared and the right button for all other digits that appeared on the screen.
Spatial Task was used to test spatial memory. In this test, the number of object locations, and the time between stimulus element presentation and response could be varied. The scoring percentage of right/wrong among the total number of stimuli presented tested the spatial memory.
Stroop Test  was used as a measure of reading fluency and frontal lobe dysfunction. This task required subjects to rapidly shift the perceptual set when viewing names of colours that appeared in matching or non-matching colours. The Stroop program allowed the presentation of up to four different words in four different colours (e.g. red, yellow, green and blue). The program randomly presented the words in congruent and incongruent colours.
The patients were first familiarized with the tests and were then helped to give the test on their own, after which the data were taken for analysis.
Following the baseline assessments, patients in the schizophrenic group were allocated to either the haloperidol or risperidone group. Seven patients were treated with haloperidol as the main antipsychotic and the remaining 8 with risperidone for a variable period, ranging from 4 weeks to 14 weeks.
Next, various measures including symptom profile, side-effects profile, level of functioning, sleep polygraph measures were repeated for the entire cohort of patients with schizophrenia keeping them off medications for two weeks before the test.
The normal healthy controls also underwent the same evaluations, including a polysomnography study and neurocognitive assessment, but only once.
Clinical profile of the patients
[Table 2] shows the mean psychopathology scores in the index group, both before and after treatment with antipsychotics. All the three subscale scores of the index group (positive, negative and general psychopathology subscales in PANSS) were significantly more than those of the control group (significant at p  In the study by Weinberger et al., long-term hospitalized patients with chronic schizophrenia who had not been taking medications for 4 weeks before testing, showed similar responses. Improvement in neuropsychological performance might be explained by the fact that antipsychotic medications have a stabilizing effect on the brain's mesolimbic frontal dopamine system. This hypothesis is consistent with the findings of previous studies ,, which have shown that initial deficits in information processing during the acute phase tend to normalize over time with appropriate medication. However, there have been arguments against this interpretation. Berman et al. ascribed the refractoriness of WCST deficits in patients with schizophrenia to intentional and medication factors. On comparing groups of neuroleptic-treated and neuroleptic-free patients with schizophrenia and normal controls on the WCST result, it was found that WCST results were not affected by the medication status of the groups. The authors concluded that 'state factors' such as attention, effort or global psychosis do not account for the observed pattern of results.
The most confusing result that we came across in our study is the significantly shortened REM latency, which apparently 'normalizes' after antipsychotic treatment and the positive correlation of this with the severity of negative symptoms and cognitive deficits. There have been studies ,, which hypothesized that cholinergic hyperactivity (muscarinic supersensitivity) might be responsible for the shortened REM latency. Similarly, a positive correlation found between the severity of negative symptoms and shortened REM latency in different studies, ,, prompted these authors to hypothesize the cholinergic mechanism of negative schizophrenic symptoms. Our study also showed a similar correlation between the severity of negative symptoms, REM latency and severity of cognitive deficits. So we can hypothesize that the acetylcholine deficit model of dementia cannot be applied to schizophrenic dementia, rather a hypercholinergic state results, which warrants anticholinergic medication as a treatment option for the negative symptoms of schizophrenia.Further evidence of the hypercholinergic state in chronic, predominantly negative, schizophrenia is evident from the abuse of anticholinergic medication in patients with schizophrenia.
|1||Kraepelin E. Dementia praecox and paraphrenia. Edinburgh: E& S Livingstone; 1919.|
|2||Levin S, Yurgelun-Todd D, Craft S. Contributions of clinical neuropsychology to the study of schizophrenia. J Abnorm Psychol 1989;98:341-56.|
|3||Sevy S, Davidson M. The cost of cognitive impairment in schizophrenia. Schizophr Res 1995;17:1-3.|
|4||Flor-Henry P. On certain aspects of the localization of the cerebral system regulation and determining emotion. Biological Psychiatry 1979;14:677-98.|
|5||Gruzelier J, Hammond N. Schizophrenia: A dominant hemisphere temporal-limbic disorder. Research in Community Psychology and Psychiatry 1976;1:33-72.|
|6||Goldstein G. The neuropsychology of schizophrenia. In: Adams KA, Grant I (eds). Neuropsychological assessment of neuropsychiatric disorders. New York: Oxford University Press Inc; 1986.|
|7||Kolb B, Whishaw IQ. Performance of schizophrenic patients on tests sensitive to left or right frontal, temporal, or parietal function in neurological patients. J Nerv Ment Dis 1983;171: 435-43.|
|8||Taylor MA, Abrams R. Cognitive impairment in schizophrenia. Am J Psychiatry 1984;141:196-201.|
|9||Ingvar DH, Franzen G. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatr Scand 1974;50:425-62.|
|10||Buchsbaum MS, Ingvar DH, Kessler R, et al. Cerebral glucography with positron tomography. Use in normal subjects and in patients with schizophrenia. Arch Gen Psychiatry 1982;39:251-9.|
|11||Weinberger DR. A connectionist approach to the prefrontal cortex. J Neuropsychiatry Clin Neurosci 1993;5:241-53.|
|12||Davidson M, Haroutunian V. Cognitive impairment in geriatric schizophrenic patients: Clinical and postmortem characterization. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The fourth generation of progress. New York: Raven Press; 1995:1447-549.|
|13||Davidson RJ. Asymmetric brain function, affective style and psychopathology. The role of early experience and plasticity. Development and Psychopathology 1994;6:741-58.|
|14||Tandon R, Shipley JE, Greden JF, et al. Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms. Schizophr Res 1991;4:23-30.|
|15||Tandon R, DeQuardo JR, Goodson J, et al. Effect of anticholinergics on positive and negative symptoms in schizophrenia. Psychopharmacol Bull 1992;28:297-302.|
|16||American Psychiatric Association, Committee on Nomenclature and Statistics. Diagnostic and statistical manual of mental disorders. Revised third edition (DSM-IIIR). Washington, DC: APA; 1987.|
|17||Spitzer RL, Williams JB, Gibbon MSWM, et al. Structured Clinical Interview for DSM-III-R, Patient version (SCID-P). Washington, DC: American Psychiatric Press; 1987.|
|18||Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261-76.|
|19||Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-9.|
|20||Lane RD, Glazer WM, Hansen TE, et al. Assessment of tardive dyskinesia using the Abnormal Involuntary Movement Scale. J Nerv Ment Dis 1985;173:353-7.|
|21||Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970;46 (Suppl. 212):11.|
|22||American Psychiatric Association (APA). Global Assessment of Functioning Scale (GAF Scale). In: Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: APA; 1994.|
|23||Rechtschaffen A, Kales A. A manual of standardized terminology techniques and scoring system or sleep stages of human subjects. Publication No. 204. Washington, DC: National Institute of Health; 1968:204.|
|24||Braff DL, Heaton R, Kuck J, et al. The generalized pattern of neuropsychological deficits in outpatients with chronic schizophrenia with heterogeneous Wisconsin Card Sorting Test results. Arch Gen Psychiatry 1991;48:891-8.|
|25||Goldberg TE, Weinberger DR, Berman KF, et al. Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test. Arch Gen Psychiatry 1987;44:1008-14.|
|26||Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643-62.|
|27||Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 1986;43: 114-24.|
|28||Spohn HE, Lacoursiere RB, Thompson K, et al. Phenothiazine effects on psychological and psychophysiological dysfunction in chronic schizophrenics. Arch Gen Psychiatry 1977;34: 633-44.|
|29||Saccuzzo DP, Braff DL. Information-processing abnormalities: Trait- and state-dependent components. Schizophr Bull 1986;12:447-59.|
|30||Braff DL, Saccuzzo DP. Effect of antipsychotic medication on speed of information processing in schizophrenic patients. Am J Psychiatry 1982;139:1127-30.|
|31||Berman I, Viegner B, Merson A, et al. Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia. Schizophrenia Res 1997;25:1-10.|
|32||McCarley RW. REM sleep and depression: Common neurobiological control mechanisms. Am J Psychiatry 1982;139:565-70.|
|33||Gillin JC, Sitaram N, Mendelson WB, et al. Cholinergic modulation of sleep, growth hormone, and analgesia in normal volunteers. In: Jenden DJ (ed). Cholinergic mechanism and psychopharmacology. New York: Plenum Press; 1978:781-89.|
|34||Sitaram N, Moore AM, Gillin JC. Scopolamine-induced muscarinic supersensitivity in normal man: Changes in sleep. Psychiatry Res 1979;1:9-16.|
|35||Benson KL, Zarcone VP Jr. Testing the REM sleep phasic event intrusion hypothesis of schizophrenia. Psychiatry Res 1985;15:163-73.|
|36||Ganguli R, Reynolds CF 3rd, Kupfer DJ. Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls. Arch Gen Psychiatry 1987;44:36-44.|
|37||Tandon R, Greden JF. Cholinergic hyperactivity and negative schizophrenic symptoms. A model of cholinergic/dopaminergic interactions in schizophrenia. Arch Gen Psychiatry 1989;46: 745-53.|