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Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophrenia
Insomnia as a Predictor for Symptom Worsening Following Antipsychotic Withdrawal in Schizophrenia Eran Chemerinski, Beng-Choon Ho, Michael Flaum, Stephan Arndt, Frank Fleming, and Nancy C. Andreasen Sleep disturbances have been associated with schizophrenia, and are an especially prominent feature during the prodrome preceding psychotic relapse. In this study, we examined the changes in sleep quality following withdrawal of antipsychotic treatment, as well as the predictive value of sleep disturbances on symptom exacerbation. One hundred twenty-two patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder underwent a 3-week medication wash-out prior to neuroimaging studies. Sleep quality was rated using items on the Hamilton Rating Scale for Depression (HAM-D), while symptom severity was measured using the Scale for the Assessment of Negative Symptoms (SANS} and the Scale for the Assessment of Positive Symptoms (SAPS). Sleep
quality deteriorated progressively following antipsychotic discontinuation. Total insomnia score prior to antipsychotic withdrawal had a significant effect on the severity of psychotic symptoms at the last weekly assessment, while baseline terminal insomnia had a significant effect on disorganized symptoms at the end of the medication-free period. These findings were independent of baseline symptom severity. Our findings suggest that schizophrenia patients with sleep disturbances are at a greater risk for worsening of positive symptoms after antipsychotic discontinuation. The implications of these findings in research and clinical settings are discussed. Copyright 2002, Elsevier Science (USA). All rights reserved.
CHIZOPHRENIA is a chronic illness characterized by psychotic exacerbations alternating with periods of relative remission. Antipsychotics are the mainstay of treatment, and have proven efficacy both during acute treatment and in reducing relapse rates. 1 However, a substantial proportion of patients are noncompliant with antipsychotic treatment, and many will experience a relapse following noncompliance. 2 Despite maintenance antipsychotic treatment, as many as 40% of patients relapse within 1 year) An effective strategy to prevent relapse must not only include improving adherence to antipsychotic treatment, it must also involve early intervention with treatment measures that may abort an impending psychotic episode. Increased antipsychotic dose, increased level of psychological support, and modifying the patient's environment at the first signs of exacerbation may avoid the costly need for inpatient hospitalization. Previous research support that a prodrome phase often precedes psychotic relapses in most patients with schizophrenia. 4,5 Herz and Melville 6 found that insomnia ranked highly among the symptoms that appeared or worsened prior to psychotic exacerbation. A wide variety of sleep disturbances have been described in association with schizophrenia. Many schizophrenic patients subjectively report decreased amounts of sleep during psychotic exacerbations, while others have experienced hypersomnia. Sleep appears to worsen in the context of
psychosis and improves following antipsychotic treatment 7 or when psychosis remits. 8 Polysomnographic studies have revealed decreased rapid eye movement (REM) latency, decreased percentage of slow-wave sleep, and decreased rebound after sleep deprivation in patients with schizophrenia. 9 The relationships between sleep disturbances, psychotic exacerbation, and antipsychotic treatment are complex. A patient may not be sleeping because he is hypervigilant and afraid that harm may befall him if he sleeps. However, it is known that sleep deprivation can aggravate or even precipitate a psychotic state. 10-12 This study examines data collected in patients who were withdrawn from antipsychotic treatment in an inpatient research unit prior to neuroimaging studies. The aims of the current work are to describe the changes in sleep quality following antipsychotic discontinuation and to examine the predictive value of sleep disturbances on symptom exacerbation.
S
From the Mental Health Clinical Research Center, Department of Psychiatry, The University of lowa College of Medicine, Iowa City, IA. Supported by National Institute of Mental Health Grants No. MH19113, MH43271, and MH40856. Address reprint requests to Beng-Choon Ho, M.R.C.Psych., Department of Psychiatry, 2939 JPP,, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. Copyright 2002, Elsevier Science (USA). All rights reserved. 0010-440)(/02/4305-0002535. 00/0 doi: 10.1053/comp.2002.34627
Comprehensive Psychiatry, Vol. 43, No. 5 (September/October), 2002: pp 393-396
393
394
CHEMERINSKI ET AL
METHODS
Sample Since 1988, as part of our single photon emission computer tomography (SPECT) and 015-positron emission tomography (PET) neuroimaging study protocols, 167 subjects with DSMIII or DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder, and who have substantial antipsychotic exposure (operationalized as more than 20 mg haloperidol-equivalent during the previous 3 weeks) were admitted to our inpatient research unit to undergo a 3-week medication-free period. In order to be enrolled in these neuroimaging studies, all subjects must sign an informed consent, approved by our institutional review board detailing the potential risks associated with antipsychotic withdrawal. Using standard ethical guidelines, our research staff assessed each subject's capacity to give informed consent for medication withdrawal. Only subjects capable of giving informed consent were allowed to begin these studies. On admission to our inpatient research unit, all psychotropic medications were tapered and discontinued. In addition to 24hour nursing supervision, a psychiatrist evaluated the subject's mental status daily. Antipsychotic treatment was reinstituted if the subject or his family withdrew consent, if the subject became dangerous to himself/herself or others, or if the research team felt that the subject was suffering due to exacerbation of symptoms. At the end of the medication-free period, the subjects underwent the respective brain scans, and antipsychotic treatment was reinitiated. Of the 167 subjects, 45 were excluded from subsequent analyses either because they did not have a baseline rating (n = 34) or did not have at least one set of weekly ratings during the 3-week medication-free period (n = 11). Of the available 122 subjects, 70 subjects were able to complete the full 3 weeks without antipsychotics. Twelve subjects (9.8%) terminated the drug wash-out prematurely during the second week, and another 40 subjects (32.7%) after the second week. The reasons for early termination were either withdrawal of consent by the subject and/or family, or because of worsening psychosis that led the research team to reinitiate antipsychotic treatment. The majority of subjects, i.e., 111 (90.9%), had DSM-III or DSM-IV schizophrenia, while two (1.6%) subjects had schizophreniform disorder, and nine (7.3%) schizoaffective disorder. Ninety-three (76.2%) subjects were male. The mean age for our sample was 32.8 years (SD = 10), while the mean number of years of illness was 12.2 years (SD - 8.9), and the mean number of hospitalizations was 6.8 (SD = 10.6). None of the subjects had major depressive disorder, bipolar affective disorder, or a primary sleep disorder.
Assessment The Scale for the Assessment of Negative Symptoms (SANS), 13 Scale for the Assessment of Positive Symptoms (SAPS), 14 and Hamilton Rating Scale for Depression (HAMD) 15 were administered upon admission, and then weekly during the subjects' stay on the inpatient research unit. Baseline ratings refer to the level of symptoms during the week prior to the initiation of medication withdrawal. Weekly ratings during the medication-free period were obtained at the end of each week to assess the worst level of symptoms during that week. Three symptom dimensions (i.e., psychotic, disorganized, and negative) were used to summarize symptom severity, based
on previous factor analytic studies.16,J7 The psychotic symptom dimension was defined as the sum of the global ratings of delusions and hallucinations (range, 0 to 10). The disorganized symptom dimension was defined as the sum of the global ratings of bizarre (disorganized) behavior, positive thought disorder, and inappropriate affect (range, 0 to 15). The negative symptom dimension was defined as the sum of the global ratings of alogia, anhedonia, avolition, and affective flattening (range, 0 to 20). Sleep quality at baseline and during antipsychotic withdrawal was rated using items on the 24-item HAM-D: item 8 (i.e., early insomnia) assessed the difficulty in falling asleep; item 9 (i.e. middle insomnia) assessed the presence of restlessness and sleep disturbance during the night; and item 10 (i.e., terminal insomnia) assessed the presence of wakefulness in early hours of the morning. Each item uses an ordinal scale (0, 1, and 2) with the latter representing worsening insomnia. A total insomnia score was derived from summing these three items.
Medication at Baseline and During Wash-Out At baseline, 102 subjects had been receiving typical antipsychotics, two clozapine, 11 risperidone, and two olanzapine. Five subjects had been medicated with a combination of both typical and atypical antipsychotics. The mean chlorpromazine equivalent dose for subjects who had received typical antipsychotics was 1,152.9 mg/d (SD = 104.2). Mean clozapine, risperidone, and olanzapine doses were 250 (SD = 70.7), 5.3 (SD = 3.6), and 13.7 (SD = 4.7) rag/d, respectively. Forty-four subjects did not require any psychotropic medications during the medication wash-out period. However, six subjects needed diphenhydramine, 59 subjects benzodiazepines, and 13 subjects required both diphenhydramine and benzodiazepines. These hypnotic agents were most often given to reduce anxiety and agitation associated with worsening psychosis.
Statistical Analysis The effects of baseline sleep quality on subsequent symptom severity were assessed using general linear model analysis of covariance (ANCOVA), with baseline sleep quality measures as independent variables, and symptom dimension scores at the last weekly assessment as dependent variables. The respective baseline symptom dimension score was entered as the covariate in each model. This is to control for the effects baseline symptom severity may have on baseline insomnia or on the last weekly symptom severity. Treatment with diphenhydramine and benzodiazepines during the antipsychotic-free period was not entered as a covariate since we did not observe any preferential use of hypnotics as a result of baseline sleep disturbances.
RESULTS The mean S A N S / S A P S scores for the negative, psychotic, and disorganized symptom items at baseline were 10.7 (SD = 3.3), 4.9 (SD = 2.9), and 3.4 (SD = 3.1), respectively. At the last weekly medication-free assessment, the mean S A N S / S A P S scores for the negative, psychotic, and disorganized symptom items were 12 (SD = 4.2), 5 (SD = 3.3), and 5.1 (SD = 3.9), respectively. Compared to baseline assessment, there was
INSOMNIA FOLLOWING ANTIPSYCHOTIC WITHDRAWAL
395
[] Baseline [] Week 1 Week 2
1.5
II Week 3
0 EL (D
_¢ O9 Fig 1. Quality of sleep during the course of the medicationfree period. Early, middle, and late insomnia were all moderately severe by the end of the medication wash-out.
0.5
early insomnia
significant worsening in negative and disorganized symptoms by the end of the medication free period (t = 4.04, df = 121, P < .0001 and t = 6.0, df = 121, P < .0001, respectively). However, psychotic symptoms at the last weekly assessment were not significantly different from baseline (t = 0.6, df = 121, P = .75). The mean baseline total HAM-D score for the sample was 18.2 (SD = 10.6) (out of a maximum score of 78). This is consistent with the clinical assessment that none of the subjects had a depressive illness. Sleep quality progressively worsened during the course of the medication-free period (Fig 1). Early, middle, and late insomnia were all moderately severe by the end of the medication wash-out. There was significant worsening of early, late and total insomnia at ~lhe last weekly assessment compared to the baseline assessment (t = 9.1, df = 121, P < .0001; t = 6.5, df = 121, P = .005 and t = 8.8, df = 121, P < .0001, respectively), but not of middle insomnia (t = 6.1, df = 121, P = .2). Total insomnia score at baseline had a significant effect on the severity of psychotic symptoms at the last weekly assessment, independent of baseline SAPS psychotic scores (F = 3.9 df = 1,122. P = .05). Poor sleep quality before antipsychotic discontinuation was associated with exacerbation of psychotic symptoms (Pearson's r = 0.25, df = 120, P = .006). Similarly, baseline terminal insomnia had a significant effect on disorganized symptoms at the end of the medication-free period after controlling for baseline SAPS disorganized symptoms score (F = 4.3 df = 1,122, P = .03). Again. poor sleep quality' at baseline was associated with worsening disorganized symptoms (Pearson's r =
middle insomnia
late insomnia
0.20, df = 120, P = .03). Baseline terminal insomnia also had a significant effect on positive symptoms (i.e., psychotic plus disorganized symptoms) at the end of the medication-free period after controlling for baseline SAPS positive symptoms score (F = 6.8, df = 1,122, P = .009; Pearson's r = 0.22, df = 120, P = .02). None of the baseline insomnia ratings had a significant effect on negative symptoms at the last weekly assessment. DISCUSSION
Following the discontinuation of antipsychotics, we found that insomnia progressively worsened at each weekly assessment. More severe insomnia (total and terminal) prior to antipsychotic discontinuation had a significant effect on psychotic and disorganized symptom exacerbation, independent of baseline symptom severity. This indicates that in patients who already had insomnia in the beginning, one can anticipate substantial worsening in psychotic and disorganized symptoms after antipsychotic discontinuation. Although this is probably the largest study to examine sleep disturbances in schizophrenia, our study has several limitations. Our subjects had not been specifically recruited for the study of insomnia. They had been participants in neuroimaging protocols, and were being withdrawn from antipsychotic treatment in the controlled environment of an inpatient research unit. We were only able to examine the qualitative aspects of sleep during the medication-free period. We were unable to systematically quantify the number of sleep hours per day due to changes in nursing documentation over the
396
CHEMERINSKI E'F AL
years. Data on sleep hours obtained from inpatient medical records were too inconsistent to be useful for analysis. W h i l e standardized instruments for the assessment of i n s o m n i a have been d e \ e l oped, ~8,j9 m a n y studies of sleep disorders in clinical settings use questionnaires and sleep diaries, and have stressed the i m p o r t a n c e of assessing sleep quality. Furthermore, the Association of Sleep Disorders Centers ~ classification guidelines for the diagnosis of i n s o m n i a 2° also highlight the need to evaluate sleep quality using the patient's subjective assessment. 21 Nevertheless, future studies shottld e x a m i n e the relationship b e t w e e n s y m p t o m exacerbation and quantitative measures of sleep. Our findings are similar to those of D e n c k e r et al. 22 In their study of 32 schizophrenia patients who had been symptom-free for at least 2 years, middle i n s o m n i a was associated with increased risk of psychotic relapse following self-discominuation of antipsychotic medications. Sleep distarbances have also b e e n associated with increased
risk of developing depression. Results from a prospective study i n v o l v i n g a c o m m u n i t y sample found that sleep complaints predicted the developm e n t of depression 1 year later. 23 Our findings have implications for research, and m a y also be generalized to clinical settings as well. In research studies that require a medication-free period, i n s o m n i a m a y be a harbinger of psychotic exacerbation. Thus, investigators m a y want to be even more vigilant in m o n i t o r i n g such subjects during the medication-free period. In clinical practice, the emergence of i n s o m n i a in the patient following antipsychotic discontinuation, be it through n o n c o m p l i a n c e or on the r e c o m m e n d a t i o n by the clinician (e.g., after a period of improvem e n t and s y m p t o m resolution), m a y act as an early w a r n i n g sign of i m m i n e n t relapse. T i m e l y interv e n t i o n (such as reinitiation of antipsychotic treatment) w h e n sleep b e c o m e s disrupted m a y abort an i m p e n d i n g psychotic episode, and even avoid the need for inpatient treatment.
REFERENCES 1. Gilbert PL, ttarris MJ, McAdams LA, Jeste DV. Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Geu Psychiatry 1995;52:173-188. 2. Kane JM. Problems of compliance in the outpatient treatment of schizophrenia. J Clin Psychiatry 1983;44:3-6. 3. Hogarty GE. Prevention of relapse in chronic schizophrenic patients. J Clin Psychiatry 1993;54:18-23. 4. Donlon PT, Blacker KH. Clinical recognition of e~lrly schizophrenic dec~,mpensation. Dis Nerv Syst 1975;36:323327. 5. Docherty JP, Van Kammen DR Siris SG, Marder SR. Stages of onset of schizophrenic psychosis. Am J Psychi~ry 1978;135:420-426. 6. Herz MI, Melville C. Relapse in schizophrenia. An~ J Psychiatry 1980;137:801-805. 7. Taylor SF, Tandon R, Shipley JE, Eiser AS. Effect of neuroleptic treatment on polysomnographic measures in schi/~ophrenia. Biol Psychiatry 1991;30:904-912. 8. Kupfer DJ, Wyatt RJ, Scott J. Sleep disturbance in acate schizophrenic patients. Am J Psychiatry 1970;126:1213-1223. 9. Keshavan MS, Reynolds CF, Kupfer DJ. Electro-encephalographic sleep in schizophrenia: a critical review. Compr Psychiatry 1990;30:3447. 10. Tyler DB. Psychological changes during experimeiatal sleep deprivation. I)is Nerv Syst 1955;16:293-299. 11. West JL, Jenzen HH, Lester BK. The psychosis of sleep deprivation. Ann NY Acad Sci 1962;96:66-70. 12. Bliss EL. Review of disorders of sleep in schizophrenia and depression. In: Dement W (ed). Sleep and Altered States of Consciousness. Baltimore, MD: William & Wilkins, 1967:456469.
13. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City, IA: University of Iowa, 1983. 14. Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: University of Iowa, 1983. 15. Hamilton M. Development of a scale for primary depressive illness. Br J Soc Clin Psychol 1960;6:278-296. 16. Bilder RM, Mukherjee S, Rieder RO, Panduragi AK. Symptomatic and neuropsychological components of defect states. Schizophr Bull 1985;11:409-419. 17. Liddle PF. The symptoms of chronic schizophrenia. A re-examination of the positive-negative dichotomy. Br J Psychiatry 1987;151:145-151. 18. Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28:193-213. 19. Ellis BW, Johns MW, Lancaster R, Raptopoulos P, Angelopoulos N, Priest RG. The St. Mary's Hospital Sleep Questionnaire: a study of reliability. Sleep 1981;4:93-97. 20. Association of Sleep Disorders Centers. Diagnostic classification of sleep and arousal disorders. Sleep 1979;2:1-137. 21. Soldatos CR, Dikeos DG, Paparrigopoulos TJ. Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria. J Psychosom Res 2000;48:555-560. 22. Dencker SJ, Malm U, Lepp M. Schizophrenic relapse after drug withdrawal is predictable. Acta Psychiatr Scand 1986;73:181-185. 23. Roberts RE, Shema SJ, Kaplan GA, Strawbridge WJ. Sleep complaints and depression in an aging cohort: a prospective perspective. Am J Psychiatry 2000;157:81-88.
quality deteriorated progressively following antipsychotic discontinuation. Total insomnia score prior to antipsychotic withdrawal had a significant effect on the severity of psychotic symptoms at the last weekly assessment, while baseline terminal insomnia had a significant effect on disorganized symptoms at the end of the medication-free period. These findings were independent of baseline symptom severity. Our findings suggest that schizophrenia patients with sleep disturbances are at a greater risk for worsening of positive symptoms after antipsychotic discontinuation. The implications of these findings in research and clinical settings are discussed. Copyright 2002, Elsevier Science (USA). All rights reserved.
CHIZOPHRENIA is a chronic illness characterized by psychotic exacerbations alternating with periods of relative remission. Antipsychotics are the mainstay of treatment, and have proven efficacy both during acute treatment and in reducing relapse rates. 1 However, a substantial proportion of patients are noncompliant with antipsychotic treatment, and many will experience a relapse following noncompliance. 2 Despite maintenance antipsychotic treatment, as many as 40% of patients relapse within 1 year) An effective strategy to prevent relapse must not only include improving adherence to antipsychotic treatment, it must also involve early intervention with treatment measures that may abort an impending psychotic episode. Increased antipsychotic dose, increased level of psychological support, and modifying the patient's environment at the first signs of exacerbation may avoid the costly need for inpatient hospitalization. Previous research support that a prodrome phase often precedes psychotic relapses in most patients with schizophrenia. 4,5 Herz and Melville 6 found that insomnia ranked highly among the symptoms that appeared or worsened prior to psychotic exacerbation. A wide variety of sleep disturbances have been described in association with schizophrenia. Many schizophrenic patients subjectively report decreased amounts of sleep during psychotic exacerbations, while others have experienced hypersomnia. Sleep appears to worsen in the context of
psychosis and improves following antipsychotic treatment 7 or when psychosis remits. 8 Polysomnographic studies have revealed decreased rapid eye movement (REM) latency, decreased percentage of slow-wave sleep, and decreased rebound after sleep deprivation in patients with schizophrenia. 9 The relationships between sleep disturbances, psychotic exacerbation, and antipsychotic treatment are complex. A patient may not be sleeping because he is hypervigilant and afraid that harm may befall him if he sleeps. However, it is known that sleep deprivation can aggravate or even precipitate a psychotic state. 10-12 This study examines data collected in patients who were withdrawn from antipsychotic treatment in an inpatient research unit prior to neuroimaging studies. The aims of the current work are to describe the changes in sleep quality following antipsychotic discontinuation and to examine the predictive value of sleep disturbances on symptom exacerbation.
S
From the Mental Health Clinical Research Center, Department of Psychiatry, The University of lowa College of Medicine, Iowa City, IA. Supported by National Institute of Mental Health Grants No. MH19113, MH43271, and MH40856. Address reprint requests to Beng-Choon Ho, M.R.C.Psych., Department of Psychiatry, 2939 JPP,, University of Iowa College of Medicine, 200 Hawkins Dr, Iowa City, IA 52242. Copyright 2002, Elsevier Science (USA). All rights reserved. 0010-440)(/02/4305-0002535. 00/0 doi: 10.1053/comp.2002.34627
Comprehensive Psychiatry, Vol. 43, No. 5 (September/October), 2002: pp 393-396
393
394
CHEMERINSKI ET AL
METHODS
Sample Since 1988, as part of our single photon emission computer tomography (SPECT) and 015-positron emission tomography (PET) neuroimaging study protocols, 167 subjects with DSMIII or DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder, and who have substantial antipsychotic exposure (operationalized as more than 20 mg haloperidol-equivalent during the previous 3 weeks) were admitted to our inpatient research unit to undergo a 3-week medication-free period. In order to be enrolled in these neuroimaging studies, all subjects must sign an informed consent, approved by our institutional review board detailing the potential risks associated with antipsychotic withdrawal. Using standard ethical guidelines, our research staff assessed each subject's capacity to give informed consent for medication withdrawal. Only subjects capable of giving informed consent were allowed to begin these studies. On admission to our inpatient research unit, all psychotropic medications were tapered and discontinued. In addition to 24hour nursing supervision, a psychiatrist evaluated the subject's mental status daily. Antipsychotic treatment was reinstituted if the subject or his family withdrew consent, if the subject became dangerous to himself/herself or others, or if the research team felt that the subject was suffering due to exacerbation of symptoms. At the end of the medication-free period, the subjects underwent the respective brain scans, and antipsychotic treatment was reinitiated. Of the 167 subjects, 45 were excluded from subsequent analyses either because they did not have a baseline rating (n = 34) or did not have at least one set of weekly ratings during the 3-week medication-free period (n = 11). Of the available 122 subjects, 70 subjects were able to complete the full 3 weeks without antipsychotics. Twelve subjects (9.8%) terminated the drug wash-out prematurely during the second week, and another 40 subjects (32.7%) after the second week. The reasons for early termination were either withdrawal of consent by the subject and/or family, or because of worsening psychosis that led the research team to reinitiate antipsychotic treatment. The majority of subjects, i.e., 111 (90.9%), had DSM-III or DSM-IV schizophrenia, while two (1.6%) subjects had schizophreniform disorder, and nine (7.3%) schizoaffective disorder. Ninety-three (76.2%) subjects were male. The mean age for our sample was 32.8 years (SD = 10), while the mean number of years of illness was 12.2 years (SD - 8.9), and the mean number of hospitalizations was 6.8 (SD = 10.6). None of the subjects had major depressive disorder, bipolar affective disorder, or a primary sleep disorder.
Assessment The Scale for the Assessment of Negative Symptoms (SANS), 13 Scale for the Assessment of Positive Symptoms (SAPS), 14 and Hamilton Rating Scale for Depression (HAMD) 15 were administered upon admission, and then weekly during the subjects' stay on the inpatient research unit. Baseline ratings refer to the level of symptoms during the week prior to the initiation of medication withdrawal. Weekly ratings during the medication-free period were obtained at the end of each week to assess the worst level of symptoms during that week. Three symptom dimensions (i.e., psychotic, disorganized, and negative) were used to summarize symptom severity, based
on previous factor analytic studies.16,J7 The psychotic symptom dimension was defined as the sum of the global ratings of delusions and hallucinations (range, 0 to 10). The disorganized symptom dimension was defined as the sum of the global ratings of bizarre (disorganized) behavior, positive thought disorder, and inappropriate affect (range, 0 to 15). The negative symptom dimension was defined as the sum of the global ratings of alogia, anhedonia, avolition, and affective flattening (range, 0 to 20). Sleep quality at baseline and during antipsychotic withdrawal was rated using items on the 24-item HAM-D: item 8 (i.e., early insomnia) assessed the difficulty in falling asleep; item 9 (i.e. middle insomnia) assessed the presence of restlessness and sleep disturbance during the night; and item 10 (i.e., terminal insomnia) assessed the presence of wakefulness in early hours of the morning. Each item uses an ordinal scale (0, 1, and 2) with the latter representing worsening insomnia. A total insomnia score was derived from summing these three items.
Medication at Baseline and During Wash-Out At baseline, 102 subjects had been receiving typical antipsychotics, two clozapine, 11 risperidone, and two olanzapine. Five subjects had been medicated with a combination of both typical and atypical antipsychotics. The mean chlorpromazine equivalent dose for subjects who had received typical antipsychotics was 1,152.9 mg/d (SD = 104.2). Mean clozapine, risperidone, and olanzapine doses were 250 (SD = 70.7), 5.3 (SD = 3.6), and 13.7 (SD = 4.7) rag/d, respectively. Forty-four subjects did not require any psychotropic medications during the medication wash-out period. However, six subjects needed diphenhydramine, 59 subjects benzodiazepines, and 13 subjects required both diphenhydramine and benzodiazepines. These hypnotic agents were most often given to reduce anxiety and agitation associated with worsening psychosis.
Statistical Analysis The effects of baseline sleep quality on subsequent symptom severity were assessed using general linear model analysis of covariance (ANCOVA), with baseline sleep quality measures as independent variables, and symptom dimension scores at the last weekly assessment as dependent variables. The respective baseline symptom dimension score was entered as the covariate in each model. This is to control for the effects baseline symptom severity may have on baseline insomnia or on the last weekly symptom severity. Treatment with diphenhydramine and benzodiazepines during the antipsychotic-free period was not entered as a covariate since we did not observe any preferential use of hypnotics as a result of baseline sleep disturbances.
RESULTS The mean S A N S / S A P S scores for the negative, psychotic, and disorganized symptom items at baseline were 10.7 (SD = 3.3), 4.9 (SD = 2.9), and 3.4 (SD = 3.1), respectively. At the last weekly medication-free assessment, the mean S A N S / S A P S scores for the negative, psychotic, and disorganized symptom items were 12 (SD = 4.2), 5 (SD = 3.3), and 5.1 (SD = 3.9), respectively. Compared to baseline assessment, there was
INSOMNIA FOLLOWING ANTIPSYCHOTIC WITHDRAWAL
395
[] Baseline [] Week 1 Week 2
1.5
II Week 3
0 EL (D
_¢ O9 Fig 1. Quality of sleep during the course of the medicationfree period. Early, middle, and late insomnia were all moderately severe by the end of the medication wash-out.
0.5
early insomnia
significant worsening in negative and disorganized symptoms by the end of the medication free period (t = 4.04, df = 121, P < .0001 and t = 6.0, df = 121, P < .0001, respectively). However, psychotic symptoms at the last weekly assessment were not significantly different from baseline (t = 0.6, df = 121, P = .75). The mean baseline total HAM-D score for the sample was 18.2 (SD = 10.6) (out of a maximum score of 78). This is consistent with the clinical assessment that none of the subjects had a depressive illness. Sleep quality progressively worsened during the course of the medication-free period (Fig 1). Early, middle, and late insomnia were all moderately severe by the end of the medication wash-out. There was significant worsening of early, late and total insomnia at ~lhe last weekly assessment compared to the baseline assessment (t = 9.1, df = 121, P < .0001; t = 6.5, df = 121, P = .005 and t = 8.8, df = 121, P < .0001, respectively), but not of middle insomnia (t = 6.1, df = 121, P = .2). Total insomnia score at baseline had a significant effect on the severity of psychotic symptoms at the last weekly assessment, independent of baseline SAPS psychotic scores (F = 3.9 df = 1,122. P = .05). Poor sleep quality before antipsychotic discontinuation was associated with exacerbation of psychotic symptoms (Pearson's r = 0.25, df = 120, P = .006). Similarly, baseline terminal insomnia had a significant effect on disorganized symptoms at the end of the medication-free period after controlling for baseline SAPS disorganized symptoms score (F = 4.3 df = 1,122, P = .03). Again. poor sleep quality' at baseline was associated with worsening disorganized symptoms (Pearson's r =
middle insomnia
late insomnia
0.20, df = 120, P = .03). Baseline terminal insomnia also had a significant effect on positive symptoms (i.e., psychotic plus disorganized symptoms) at the end of the medication-free period after controlling for baseline SAPS positive symptoms score (F = 6.8, df = 1,122, P = .009; Pearson's r = 0.22, df = 120, P = .02). None of the baseline insomnia ratings had a significant effect on negative symptoms at the last weekly assessment. DISCUSSION
Following the discontinuation of antipsychotics, we found that insomnia progressively worsened at each weekly assessment. More severe insomnia (total and terminal) prior to antipsychotic discontinuation had a significant effect on psychotic and disorganized symptom exacerbation, independent of baseline symptom severity. This indicates that in patients who already had insomnia in the beginning, one can anticipate substantial worsening in psychotic and disorganized symptoms after antipsychotic discontinuation. Although this is probably the largest study to examine sleep disturbances in schizophrenia, our study has several limitations. Our subjects had not been specifically recruited for the study of insomnia. They had been participants in neuroimaging protocols, and were being withdrawn from antipsychotic treatment in the controlled environment of an inpatient research unit. We were only able to examine the qualitative aspects of sleep during the medication-free period. We were unable to systematically quantify the number of sleep hours per day due to changes in nursing documentation over the
396
CHEMERINSKI E'F AL
years. Data on sleep hours obtained from inpatient medical records were too inconsistent to be useful for analysis. W h i l e standardized instruments for the assessment of i n s o m n i a have been d e \ e l oped, ~8,j9 m a n y studies of sleep disorders in clinical settings use questionnaires and sleep diaries, and have stressed the i m p o r t a n c e of assessing sleep quality. Furthermore, the Association of Sleep Disorders Centers ~ classification guidelines for the diagnosis of i n s o m n i a 2° also highlight the need to evaluate sleep quality using the patient's subjective assessment. 21 Nevertheless, future studies shottld e x a m i n e the relationship b e t w e e n s y m p t o m exacerbation and quantitative measures of sleep. Our findings are similar to those of D e n c k e r et al. 22 In their study of 32 schizophrenia patients who had been symptom-free for at least 2 years, middle i n s o m n i a was associated with increased risk of psychotic relapse following self-discominuation of antipsychotic medications. Sleep distarbances have also b e e n associated with increased
risk of developing depression. Results from a prospective study i n v o l v i n g a c o m m u n i t y sample found that sleep complaints predicted the developm e n t of depression 1 year later. 23 Our findings have implications for research, and m a y also be generalized to clinical settings as well. In research studies that require a medication-free period, i n s o m n i a m a y be a harbinger of psychotic exacerbation. Thus, investigators m a y want to be even more vigilant in m o n i t o r i n g such subjects during the medication-free period. In clinical practice, the emergence of i n s o m n i a in the patient following antipsychotic discontinuation, be it through n o n c o m p l i a n c e or on the r e c o m m e n d a t i o n by the clinician (e.g., after a period of improvem e n t and s y m p t o m resolution), m a y act as an early w a r n i n g sign of i m m i n e n t relapse. T i m e l y interv e n t i o n (such as reinitiation of antipsychotic treatment) w h e n sleep b e c o m e s disrupted m a y abort an i m p e n d i n g psychotic episode, and even avoid the need for inpatient treatment.
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