A double-blind comparison of the effect of the antipsychotics haloperidol and olanzapine on sleep in...

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Braz J Med Biol Res 40(3) 2007

Effects of antipsychotics on sleep in mania

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Brazilian Journal of Medical and Biological Research (2007) 40: 357-366ISSN 0100-879X

A double-blind comparison of the effectof the antipsychotics haloperidol andolanzapine on sleep in mania

1Departamento de Psiquiatria, Grupo de Estudos de Doenças Afetivas,2Laboratório de Sono, Instituto de Psiquiatria, Hospital das Clínicas,Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil3Departamento de Psiquiatria, Faculdade de Medicina,Universidade de Santo Amaro, São Paulo, SP, Brasil

R.A. Moreno1,M.M. Hanna1,2,

S.M. Tavares2

and Y.P. Wang1,3

Abstract

The effects of haloperidol and olanzapine on polysomnographicmeasures made in bipolar patients during manic episodes were com-pared. Twelve DSM-IV mania patients were randomly assigned toreceive either haloperidol (mean ± SD final dosage: 5.8 ± 3.8 mg) orolanzapine (mean ± SD final dosage: 13.6 ± 6.9 mg) in a 6-week,double-blind, randomized, controlled clinical trial. One-night poly-somnographic evaluation was performed before and after the halo-peridol or olanzapine treatment. Psychopathology and illness severitywere rated respectively with the Young Mania Rating Scale (YMRS)and the Clinical Global Impressions - Bipolar version (CGI-BP).There was a significant improvement in the YMRS and CGI-BPscores at the end of the study for both groups. Mixed ANOVA used tocompare the polysomnographic measures of both drugs demonstratedsignificant improvement in sleep measures with olanzapine. In theolanzapine group, statistically significant time-drug interaction ef-fects on sleep continuity measures were observed: sleep efficiency(mean ± SEM pre-treatment value: 6.7 ± 20.3%; after-treatment: 85.7± 10.9%), total wake time (pre-treatment: 140.0 ± 92.5 min; after-treatment: 55.2 ± 44.2 min), and wake time after sleep onset (pre-treatment: 109.7 ± 70.8 min; after-treatment: 32.2 ± 20.7 min).Conversely, improvement of polysomnographic measures was notobserved for the haloperidol group (P > 0.05). These results suggestthat olanzapine is more effective than haloperidol in terms of sleep-promoting effects, although olanzapine is comparatively as effectiveas haloperidol in treating mania. Polysomnography records shouldprovide useful information on how manic states can be affected bypsychopharmacological agents.

CorrespondenceR.A. Moreno

Grupo de Estudos de Doenças Afetivas

Instituto de Psiquiatria, HC, FMUSP

Rua Dr. Ovídio Pires de Campos, 785

05403-010 São Paulo, SP

Brasil

Fax: +55-11-3069-6648

E-mail: [email protected]

Research supported by FAPESP

(No. 99/07290-5).

Received June 7, 2006

Accepted December 13, 2006

Key words• Olanzapine• Haloperidol• Sleep• Mania• Bipolar disorder• Polysomnographic

measurements

Introduction

Sleep disturbances are prominent clinicalfeatures of manic states. Although some dis-crepant findings have been reported (1-3),

polysomnographic (PSG) studies of manicpatients have consistently revealed a numberof abnormalities, including significantly de-creased total-recording period, decreasedtime spent asleep, decreased sleep efficiency,

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shortened rapid eye movement (REM) la-tency, and increased REM density comparedto their pre-morbid state (4-8) and comparedto controls (9,10).

Antipsychotic drugs have been prescribedfor bipolar disorder patients for several de-cades as the treatment for psychotic symp-toms or as an adjunctive therapy when otheralternatives have failed, such as lithium andother mood-stabilizing drugs. However, theuse of conventional antipsychotics in mooddisorder patients is limited because of theirside effects. Haloperidol is a well-knownexample of a high-potency dopamine D2

antagonist antipsychotic drug with floridextra-pyramidal side effects. Alternatively,some newer antipsychotics, e.g., olanzapine,risperidone, ziprasidone, quetiapine, andaripiprazole, have been tested to treat manicstates (11,12). The search for new drugs forthe treatment of bipolar disorder has identi-fied the novel atypical antipsychotic agentolanzapine, which has shown superior effi-cacy when compared with placebo in clini-cal trials (13) and seems to be as effective aslithium in treating acute mania (14). There isalso some evidence that olanzapine is effec-tive in some bipolar patients who are refrac-tory to other conventional treatments (15).The favorable tolerability profile of olanza-pine might be due to its affinity at dopamin-ergic D1-D4, serotonergic (5-HT2,3,6), mus-carinic (subtypes 1-5), adrenergic (α-1), andhistaminergic (H1) binding sites (11). Themain PSG finding for olanzapine tested onhealthy subjects is an increase of slow-wavesleep (16-18).

The lack of studies evaluating the effectsof antipsychotics on the sleep of manic pa-tients represents a major gap in the literature.A number of investigators have argued thatthe degree of sleep disturbance relates to theduration of manic episodes, and thereforetreating sleep disturbances may be useful foracutely manic patients by reducing the timeneeded for recovery (19-21). The aim of thepresent study was to compare the effects of

haloperidol and olanzapine on the PSG pro-file of bipolar manic patients.

Subjects and Methods

Subjects

The subjects included in the study metthe DSM-IV’s (22) criteria for bipolar disor-der, acute manic phase, with or without psy-chotic characteristics. All patients were in-terviewed by trained psychiatrists usingthe Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition, ver-sion 2.0 (SCID-I/P) (23). Patients were ac-cepted into the study if they had not switchedfrom a depression phase to mania, or from amania phase to depression, within 1 monthbefore or after the PSG procedure. Baselinepsychopathology, as rated by the YoungMania Rating Scale (YMRS) (24), had toscore higher than 20 on the occasion of bothvisits 1 and 2 for the patient to remain in thestudy.

Originally, 19 eligible patients were re-cruited from the Mood Disorder outpatientunit of the Institute of Psychiatry (Grupo deEstudos de Doenças Afetivas) to participatein the study. All recruited patients were hos-pitalized during the study. Seven patientswere subsequently excluded from the trialdue to the following reasons: 1 patient re-fused to be enrolled, 3 patients withdrewconsent, and 3 patients received non-allowedmedication. The final sample of 12 bipolarpatients comprised 9 females and 3 males,with a mean age of 38.8 years (range: 22 to62 years). Socio-demographic information,previous episode, and past mood illness his-tory are shown in Table 1.

Ideally, the patients should have beenmedication-free for at least 2 weeks beforethe trial. Only 4 patients (1 in the haloperidolgroup and 3 in the olanzapine group) werenot taking the medication when fulfilling theinclusion criteria. For 8 medicated patients(5 were on antipsychotics, 2 were on a com-

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bination of antipsychotics and lithium, and 1was on antidepressants), a washout period ofat least 4 days was utilized prior to the trial.The rationale for the short washout periodwas based on the practical difficulties ofmanaging severely disturbed patients in thehospital setting. None of our study patientswas on depot long-acting antipsychotics be-fore starting the recording. The only psycho-tropic drug allowed for both groups waszolpidem, 10 mg/day, but not on the night ofrecording. To ensure patients were substance-free, all underwent urinalysis drug screeningbefore the PSG study. Urinalysis was carriedout to detect the possible use of phencyclid-ine, benzodiazepines, amphetamines, barbi-turates, cannabis, cocaine, methadone, andopiates. Patients who presented a seriousgeneral medical condition or neurologicaldisease were excluded. Clinical evidence ofprimary sleep disorder or a previous historyof drug or alcohol abuse were also criteriafor excluding patients.

The study was approved by the School ofMedicine of the University of São PauloEthics Committee and was conducted in ac-cordance with the Helsinki Declaration of1975. Written informed consent was ob-tained from participants, or the person le-gally responsible for them, before the study.

Study design

Patients were randomly and consecutivelyassigned to treatment with either olanzapine,15 mg/day (7 subjects: 3 males, 4 females;mean age: 38.6 years, range: 22-62), or halo-peridol, 10 mg/day (5 subjects, all females;mean age: 39.2 years, range: 23-49) in adouble-blind design. The duration of treat-ment ranged from 31 to 51 days (mean ± SD,43.7 ± 4.9 days, or approximately 6 weeks).The olanzapine group (42.3 ± 5.5 days) didnot differ significantly (P > 0.05) from thehaloperidol group (45.6 ± 3.8 days) in termsof treatment days. Both drugs could be flex-ibly adjusted within the therapeutic range asclinically warranted (olanzapine, 5-20 mg/day; haloperidol, 3-15 mg/day). Furthermore,the two drugs to be compared had the sameappearance and were packaged identically,and matched in order to satisfy the require-ments of a double-blind study. Patients per-formed the PSG sleep study immediatelybefore (pre-treatment or time zero) and again6 weeks after (post-treatment or time one)olanzapine or haloperidol treatment. Mostof the patients performed the second PSGrecording on or about the 42nd day. Twopatients performed the second PSG test be-fore the 42nd day according to the criteria of

Table 1. Demographic variables of maniac patients and previous illness of the haloperidol and olanzapinegroups at baseline.

Parameter Haloperidol group Olanzapine group(N = 5) (N = 7)

Age (mean ± SD in years) 39.2 ± 11.2 38.6 ± 14.2Female/Male 5/0 4/3Mean number of previous manic episodes 7.6 (0-19) 4.4 (0-12)*Mean number of manic episodes in the last year 0.2 (0-1) 0.5 (0-1)Mean age (in years) at onset of manic symptoms 31.0 (23-49) 29.9 (18-50)Mean number of previous depressive episodes 4.2 (0-20) 6.3 (0-14)Mean number of depressive episodes in the last year 0.2 (0-1) 1.1 (0-4)*Mean age (in years) at onset of depressive symptoms 35.0 (26-47) 36.0 (20-45)Mean number of previous admissions 2.3 (0-8) 2.9 (0-11)Psychotic features during mood episodes 5 (100.0%) 5 (71.4%)*

Data are reported as mean number or age of patients with range in parentheses or as indicated in table.*P < 0.05 compared to the haloperidol group (ANOVA).

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lowering either Clinical Global Impression -Bipolar version (CGI-BP) or YMRS scores.

Polysomnographic procedures

PSG recording was performed with a 21-channel polygraph (Nihon-Kohden, neuro-fax, EEG 4400 series, Washington, DC,USA) within a sleep laboratory. Full-mon-tage clinical PSG parameters were used, in-cluding electroencephalogram (C3/A2; C4/A1; sensitivity, 70 µV/cm; high-pass filter,0.5 Hz; low-pass filter, 70 Hz), electro-oculogram (sensitivity, 70 µV/cm; high-passfilter, 0.5 Hz; low-pass filter, 70 Hz), sub-mental electromyogram (sensitivity, 2 µV/cm; low-pass filter, 5 Hz; high-pass filter, 70Hz), electromyogram of the anterior tibialismuscle to assess periodic leg movements(sensitivity, 10 µV/cm; high-pass filter, 5Hz; low-pass filter, 70 Hz), and respiratorymonitoring and electrocardiogram, as rec-ommended by Rechtschaffen and Kale’sstandardized guidelines (25). Paper speedwas 10 mm/s. The first sleep recording timestarted at 10 to 12 pm except for 1 patientwhose first sleep recording time began at1:37 am, and the second sleep recordingtime started at 10 to 12 pm for all patientsexcept 3 (0:24 to 1:00 am). We performedall-night PSG evaluation for one night dur-ing the patient’s usual sleeping time beforeadmission to the study and about 42 daysafter treatment. On sleep-study days, pa-tients were not allowed to take daytime naps.

Measurements and sleep polysomnographicvariables

Baseline psychopathology and clinicalseverity were rated by the YMRS and theCGI-BP, respectively. Both scales were ratedweekly from baseline until the end of thetrial. The following scales were used to ratethe intensity of side effects: Abnormal In-voluntary Movement Scale (AIMS), BarnesAkathisia Rating Scale (BARS), and UKU

Side Effect Rating Scale. The PSG measure-ments of sleep parameters for pre- and post-treatment records are detailed below.

The YMRS comprises 11 questions onheightened mood, manic behavior and cog-nition rated with a Likert severity scale rang-ing from 0 to 4 (14). The YMRS is the mostwidely used rating scale for manic patients,with evidence of well-established reliabilityand validity.

The CGI-BP for the severity of illness isa modified version of the original ClinicalGlobal Impression for rating the severity ofmanic and depressive episodes and the de-gree of change (26). The score ranges from 0to 7 on the Likert scale. The revised scaleprovides a focused set of instructions tofacilitate interrater reliability.

Sleep parameters were scored visuallyby one of the authors (SMT) according toRechtschaffen and Kale’s criteria (25). Therater was blind to the medication status andpsychiatric condition of the patient. The fol-lowing 3 groups of sleep outcome were meas-ured as continuous variables:

Sleep continuity indexes. These indexesinclude total recording time, total sleep time,sleep efficiency (total recording period inrelation to total sleep time), sleep latency(time from the beginning of the recordingperiod to the onset of stage 2 sleep for at least10 uninterrupted min), slow wave sleep(SWS) latency (the time between sleep onsetand the first SWS period), total wake time(intermittent wakefulness that is bound bysleep), wake after sleep onset, and numberof awakenings. All intervals were measuredin minutes.

Sleep architecture indexes. These indexescorrespond to percent time spent asleep indifferent stages of sleep. The time of eachstage is reported in minutes, percentage ofsleep period time, and their distribution byfractions of night. Non-REM sleep was de-fined as the sum of stages 1, 2, 3, and 4 ofsleep, taken as a percentage of sleep periodtime. In contrast, SWS or delta sleep was

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defined as the sum of stages 3 and 4 of sleep,taken as a percentage of sleep period time.

REM sleep indexes. These indexes in-clude REM latency (the time between sleeponset and the first REM period, minus anywakefulness occurring during the interval),total REM time, total REM activity (sum ofvisually scored eye movement density fromeach 60-s REM epoch, on a 0 to 8 Likertscale), and total REM density (rate of REMactivity divided by REM time).

Statistical analysis

Sociodemographic and PSG variables arereported as means, standard deviation (SD)or range. Fisher’s exact test was used tocompute binary outcome. For continuousoutcome, the Student t-test and analysis ofvariance (ANOVA) were chosen to identifybetween-group differences and associations.All tests were two-tailed, with the level ofsignificance set at 0.05.

To further explore the differential effectof medication on sleep measures, the mixedbetween-within subject ANOVA design waschosen to select those PSG variables (de-pendent or criterion variables) which pre-sented a time-drug interaction effect, timeeffect and drug effect for the type of treat-ment drug (haloperidol or olanzapine) andthe time frame of trial (before and afterintervention). These two latter variables areconsidered to be independent or predictorvariables. Mixed ANOVA is an extension ofthe repeated measure design, and allowssimultaneous comparison of the between-group design (olanzapine or haloperidol),and within-group or repeated measure de-sign (pre-intervention and after intervention).The F statistic was used to calculate the ratioof variance due to the effects to the variancedue to error. Its level of significance was setat α = 0.05. For the variables selected byANOVA the post hoc paired-sample t-testwas used to compare the mean score for eachgroup on two different occasions (before

and after intervention), separately for theolanzapine and haloperidol group. All statis-tical analyses were performed using the SPSSpackage (Chicago, IL, USA).

Results

The mean final dosage for the haloperi-dol group was (mean ± SD) 5.8 ± 3.8 mg(range 3-10 mg) or 290 mg chlorpromazineequivalent, and the mean dosage for theolanzapine group was 13.6 ± 6.9 mg (range5-20 mg) or 272 mg chlorpromazine equiva-lent. There was no statistically significantdifference between the final dosage of twotypes of antipsychotics (Student t-test = 1.52;P > 0.05). At the end of the trial, the twogroups did not differ significantly concern-ing the overall side effects as measured byAIMS, BARS and UKU. The study samplewas severely ill, as demonstrated by the highYMRS and CGI-BP scores at baseline. Ad-ditionally, pre-treatment YMRS and CGI-BP scores were similar (P > 0.05) for bothgroups (Table 2). After treatment with halo-peridol, the study group showed a signifi-cant (P = 0.003) decrease in YMRS andCGI-BP scores. The group treated witholanzapine also showed a significant (P <0.05) decrease from the beginning to the endof the experiment in both YMRS total scoresand CGI-BP scores. However, the differ-ences between drugs were not statisticallysignificant (P > 0.05). Thus, the two drugswere similar in efficacy in reducing total

Table 2. Comparison of Young Mania Rating Scale (YMRS) and Clinical GlobalImpression - Bipolar version (CGI-BP) scores for the haloperidol (N = 5) and olanzapine(N = 7) groups before and after treatment.

Scale Haloperidol group Olanzapine group

Before treatment After treatment Before treatment After treatment

YMRS 30.6 ± 8.6 4.8 ± 10.7* 30.6 ± 5.0 10.4 ± 13.8*CGI-BP 13.0 ± 2.0 4.6 ± 3.6* 11.3 ± 1.8 6.4 ± 3.0*

Data are reported as mean ± SD.*P < 0.05 compared to pre-treatment (Student t-test).

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Table 3. Time-drug interaction effect, main effect of time and drug on polysomnographic measures for the haloperidol (N = 5) and olanzapine (N =7) groups, unmedicated and 6 weeks after medication.

Measure Haloperidol Olanzapine ANOVA (P value)*

Unmedicated Medicated Unmedicated Medicated Time-drug Time Drug

Sleep continuity variablesTotal sleep time (min) 356.1 ± 85.2 343.8 ± 136.0 280.0 ± 91.5 325.2 ± 54.3 NS NS NSNumber of awakenings (>30") 14.4 ± 6.2 31.4 ± 24.3 21.3 ± 11.1 20.0 ± 6.5 NS NS NSTotal wake time (min) 32.5 ± 25.2 94.0 ± 104.3 142.0 ± 92.5 55.2 ± 44.2 0.02 NS NSTime awake after sleep onset (min) 39.1 ± 25.8 75.1 ± 79.3 109.7 ± 70.8 32.2 ± 20.7 0.02 NS NSSleep efficiency (%) 89.8 ± 7.6 76.8 ± 27.9 66.7 ± 20.3 85.7 ± 10.9 0.02 NS NSSleep latency (min) 11.6 ± 19.9 32.3 ± 31.7 62.9 ± 102.9 15.5 ± 15.3 NS NS NSSWS latency (min) 40.5 ± 35.9 76.7 ± 115.0 25.5 ± 25.3 19.8 ± 11.7 NS NS NS

Sleep architectureStage 1 (% SPT) 6.2 ± 8.6 5.7 ± 6.6 4.4 ± 5.8 4.5 ± 2.9 NS NS NSStage 2 (% SPT) 59.3 ± 16.3 43.9 ± 18.8 43.4 ± 14.8 39.8 ± 10.3 NS NS NSStage 3 (% SPT) 3.3 ± 2.4 2.0 ± 2.1 3.4 ± 3.1 4.9 ± 4.0 NS NS NSStage 4 (% SPT) 5.2 ± 5.5 11.4 ± 12.7 12.3 ± 11.8 18.5 ± 16.7 NS NS NSSWS (% SPT) 8.5 ± 6.0 13.4 ± 14.7 15.7 ± 12.8 23.4 ± 17.4 NS NS NSStage REM (min) 73.8 ± 24.6 70.9 ± 43.4 61.6 ± 38.0 81.6 ± 28.2 NS NS NSStage REM (% SPT) 20.0 ± 5.7 16.9 ± 10.3 16.3 ± 8.6 22.5 ± 6.2 NS NS NS1st night fraction SWS distribution 23.3 ± 30.7 31.7 ± 30.9 29.2 ± 35.5 57.8 ± 30.2 NS 0.01 NS2nd night fraction SWS distribution 9.8 ± 10.6 21.5 ± 25.7 15.2 ± 12.7 29.2 ± 31.2 NS NS NS3rd night fraction SWS distribution 3.0 ± 6.8 4.3 ± 5.7 3.9 ± 9.6 11.2 ± 11.8 NS NS NS

REM measuresREM latency (min) 84.4 ± 86.0 55.6 ± 29.4 33.6 ± 35.7 79.7 ± 43.9 NS NS NSTotal REM activity 39.1 ± 23.7 66.7 ± 36.0 56.0 ± 28.1 96.0 ± 63.4 NS 0.04 NSTotal REM density 0.6 ± 0.2 0.8 ± 0.4 0.8 ± 0.2 1.3 ± 0.7 NS NS NS

Data are reported as mean ± SD. SWS = slow wave sleep; % SPT = percentage of sleep period time; REM = rapid eye movement.*Effect of time-drug interaction, main effects of time and drug, respectively, for F statistics. ANOVA was used to compare olanzapine andhaloperidol. NS = non-significant.

YMRS and CGI scores for manic patients.To determine whether the changed score

of a particular variable was followed by anincrease/decrease in manic episodes, eachPSG variable (difference between pre- andpost-treatment values) was tested for asso-ciation with YMRS and CGI variations. Therewas no significant correlation between PSGvariables and clinical rating scales (data notshown). The baseline PSG measures for thepresence of psychotic features was similar(P > 0.05) for psychotic manic patients andfor those without psychotic symptoms.

Table 3 presents the mean ± SD values ofPSG variables for both groups. At baseline,the olanzapine group showed significantlygreater total wake time (P < 0.05) and timeawake after sleep onset (P < 0.05) compared

to the haloperidol group. Additionally, theolanzapine group presented significantly lessefficient sleep (P < 0.05). The remainingPSG variables were largely similar betweenthe two treatment groups. It should be pointedout that there was no correlation between thestarting time of first and second sleep record-ings and REM sleep latency.

Moreover, mixed ANOVA statistics wereused to compute the following effects: effectof time-drug interaction, time effect and drugeffect for both groups. Three sleep continu-ity variables emerged as significant (P =0.02) for time-drug interaction effect: totalwake time, wake time after sleep onset, andsleep efficiency. A time effect for both groupscould be observed for total REM activity (P= 0.04) and SWS distribution by fraction of

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night during the first third of the night (P =0.01). No significant drug effect was ob-served for any PSG measure.

A graphic representation of significant PSGmeasures is found in Figure 1. Post hoc paired-sample t-tests performed separately for eachtreatment group showed a difference betweentreatment groups. The olanzapine group sig-nificantly changed from baseline regardingtotal wake time (t = -3.16; 95% CI = -154.1,-19.6; P = 0.020), wake time after sleep onset(t = -3.05; 95% CI = -78.8, -201.6; P = 0.023),and sleep efficiency (t = 3.11; 95% CI = 4.0,33.9; P = 0.021). The effect size of the varia-tions detected was large: eta-squared was 0.62,0.61, and 0.62 for total wake time, wake timeafter sleep onset and sleep efficiency, respec-tively. For the haloperidol group, a time-druginteraction effect could not be demonstrated(P > 0.05).

Discussion

The present randomized double-blindstudy is the first longitudinal investigationof the effects of conventional and atypicalantipsychotic treatment on night sleep inmania. The major findings suggested that

although the efficacy of olanzapine appearsto be comparable to that of haloperidol forthe treatment of acute mania, olanzapineseems to be more effective than haloperidolin improving the continuity measures of thesleep pattern in manic patients.

Olanzapine was as effective as haloperi-dol in the treatment of manic states, as dem-onstrated by the decrease in total YMRSscore and in severity ratings of mania on theCGI-BP. Although a slight difference con-cerning previous illness history, in terms ofnumber of episodes, was identified betweenthe two groups, the psychopathology andseverity of both groups at baseline weremostly similar. The inclusion criterion weadopted was the presence of at least onemanic episode during the past year. At base-line, however, the haloperidol group did havebetter sleep efficiency, longer total sleeptime, lower total wake time, and time awakeafter sleep onset, than the olanzapine groupat baseline. Nevertheless, none of the pre- orpost-treatment clinical variables showed asignificant correlation with the various sleepvariables examined (21,27). These baselinedifferences should be kept in mind wheninterpreting the PSG data.

Figure 1. Comparison of poly-somnographic measures withtime-drug interaction effects af-ter application of the mixedANOVA model to the haloperi-dol (N = 5) and olanzapine (N =7) groups. *P < 0.05 comparedto the pre-treatment period (posthoc paired-sample t-test).

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The results of the present study suggestthat atypical and conventional antipsychoticdrugs appear to differ in their effects onsome PSG measures in mania. Overall sleepimprovement was due to increased sleepcontinuity parameters, sleep stages 2 and 4,REM sleep, and first fraction of night SWS.

Poor sleep continuity is a nonspecificfeature and may occur in several psychiatricdisorders, such as depression, generalizedanxiety disorders, and obsessive-compulsivedisorder (3). In the present study, a signifi-cant improvement in sleep continuity meas-ures was observed only for the olanzapinegroup of manic patients. The validity andconsistency of this finding were documentedby the evidence of the interaction effect ofolanzapine on sleep continuity indexes, witha significant difference between pre- andpost-treatment values for these measures,along with a large effect size. A trend ofinteraction in terms of number of awaken-ings was also observed. Similarly, previousstudies (16-18) also reported this sleep-pro-moting benefit for olanzapine in healthy vol-unteers. Sleep continuity and sleep architec-ture indexes were not significantly changedafter haloperidol administration.

The time-drug interaction effect for theatypical antipsychotic group on sleep conti-nuity indexes indicated that the sleep-pro-moting effect of olanzapine (type of treat-ment drug) did indeed depend on the effectof time of trial (before or after intervention).A possible explanation for this may be theeffects of many receptors mediated by anti-psychotic agents, a combination of them, orvia blockade of histamine-H1 receptors (28)or 5-HT2A/2C (29). Alternatively, the resultmay reflect the slight baseline differencebetween the treatment groups in sleep conti-nuity measures. The possibility that the im-provement in sleep efficiency after olanza-pine administration could have resulted fromthe resolution of underlying pathophysiologi-cal mechanisms of mania remains specula-tive.

In the present study, the main effect ofthe time of treatment on total REM activityand SWS was found in the first third of thenight. Trends toward increased stages 2 and4 of sleep architecture (P = 0.08) and REMdensity (P = 0.07) were additional indicatorsof a time effect.

There are limited and contradictory dataabout the effects of pharmacological agentson REM sleep. Unmedicated manic patientsoften exhibit REM disturbances similar tothose seen in depression: shortened REMlatency and increased REM density (6), whichcan be corrected by lithium (9) and antide-pressant medications (29). In healthy con-trols, 10-mg olanzapine increased the REMlatency but decreased REM sleep time (16-18) via an antagonistic effect on muscariniccholinergic receptors. Previous studies havenot found a significant increase in REMlatency in schizophrenic patients receivinghaloperidol (27), but acute administration ofolanzapine to schizophrenics produced a sig-nificant increase in REM density (30). Theanticholinergic effects of olanzapine maypredict the decrease of REM activity andREM density in electroencephalogram sleeprecords. The identification of an inverse trendin the present study could be attributable to atime effect rather than to a direct drug effect.Since our patients improved clinically aftertreatment with olanzapine and haloperidol,it seems unlikely that a specific effect of thedrug variable would be responsible for dif-ferent alterations in REM measures.

An SWS deficit has been described inmania, although this finding has not beenconfirmed in studies with a greater numberof patients (6,10). Lithium carbonate did notaffect delta sleep in manic or normal indi-viduals (9), but was reported to be increasedin depressed patients after lithium treatment(31). Acute administration of olanzapine tohealthy volunteers and to schizophrenic pa-tients increased SWS sleep (16,30). Previ-ous studies (32) with the selective 5-HT2C

antagonists ritanserin and ketanserin pre-

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dicted that administration of 5 mg olanzapinerepresents an alive central occupancy of 5-HT2C receptors of at least 70% and mayproduce a 50% increase in SWS (29). Theantagonistic effects of olanzapine on brain5-HT2C receptors could well influence SWS,but our results showed that changes in SWSwere more related to the time effect than to adirect drug effect. An alternative explana-tion may be that drug effects are more promi-nent acutely, so that after 6 weeks’ treatmentthis effect could no longer be observed.

Unfortunately, most manic patients can-not cooperate sufficiently to participate inmeaningful sleep studies, which could col-lect enough conclusive data. Drug treatmentwith antipsychotics or lithium carbonatetends to have a significant effect on sleeprecords. These difficulties are the main rea-sons that have limited the sample size of thisstudy to 12 patients. Technically speaking,in the PSG procedures, the approach of vi-sual ratings for SWS coupled with the ab-sence of computerized assessments of PSGmeasures has restricted the interpretabilityof our findings. Pretest adaptation or accli-matization nights for the sleep laboratoryprocedure are desirable, but this require-ment is hard to meet for agitated manics.Some PSG studies (9,10) with manic pa-tients have suggested that the first nighteffect is not so important, since no signifi-cant inter-night difference in PSG variables

was detected. Another limitation of the pres-ent study is some baseline between-groupdifference for previous illness history andpre-treatment PSG measures, which mayhave biased the direction of the findings.

Aside from the difficulties in conductingsleep studies on restless and unmedicatedmanic inpatients, PSG records may provideinformation which sheds light on how manicstates are affected by psychopharmacologi-cal agents, and which strengthens the neuro-biological validity of mania. Determiningthe difference in the latency of onset of thetherapeutic effect between a “sleep-promot-ing” antipsychotic (i.e., olanzapine), and“sleep-disrupting” antipsychotic (i.e., halo-peridol) would be very important from aclinical-therapeutical point of view. Indeed,the pharmacological response to atypicalantipsychotics and sleep abnormalities war-rant further investigation to confirm theirpotential as trait/state markers of pathophysi-ological abnormality in manic conditions.The efficacy of olanzapine may be partiallyrelated to its favorable pharmacological pro-file in manic patients through its sleep conti-nuity-promoting effects observed in PSG.Indeed, it is premature to recommend olan-zapine as a fast-acting agent to improvesleep disturbances in psychiatric patients.Future studies should first repeat these pre-liminary findings, employing a larger sam-ple size and a placebo group.

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