BRIGHT LIGHT THERAPY AND MELATONIN IN MOTOR RESTLESS BEHAVIOUR IN DEMENTIA: A PLACEBO-CONTROLLED STUDY

Transcription

1 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int. J. Geriatr. Psychiatry 16, 106±110 (2001) BRIGHT LIGHT THERAPY AND MELATONIN IN MOTOR RESTLESS BEHAVIOUR IN DEMENTIA: A PLACEBO-CONTROLLED STUDY P. M. JUDITH HAFFMANS*, ROB C. SIVAL, STEFAN A. P. LUCIUS, QUIRINE CATS AND LIES VAN GELDER Parnassia, Psycho-Medical Centre, The Hague, The Netherlands ABSTRACT Objective. The purpose of this study was to evaluate the e ects of bright light therapy combined with melatonin on motor restless behaviour in dementia. Design. Double-blind, placebo-controlled, cross-over trial consisting of four periods. One week wash-out was followed by a 2-week period of light therapy in combination with placebo or melatonin. The second wash-out period of 1 week was followed by 2 weeks of treatment (cross-over). Setting. Twenty-four bed medium-stay psychogeriatric ward at a Dutch psychiatric teaching hospital. Patients. Ten patients, who met the criteria for dementia (DSM-IV) and motor restless behaviour (subscale 10 of the GIP), were included. Informed consent was obtained by proxy. Intervention. All subjects were exposed during 25 consecutive days for 30 minutes to 10,000 lux bright light and randomly administered 2.5 mg melatonin or placebo at h. Assessments. Clinical Global Impression (CGI), Dutch version of the geriatric behavioural observation scale (GIP), Social Dysfunction and Aggression Scale (SDAS) were assessed after each wash-out and treatment period. Outcome criteria were CGI, assessing motor restless behaviour, the SDAS, measuring extrovert aggression and the GIP, assessing social, psychomotor and emotional behaviour. Results. Six demented inpatients completed the trial. Positive e ects were found for the treatment combined with placebo. Patients were less restless and more co-operative. The condition with melatonin showed no additional positive e ects, additionally, patients became more aggressive and showed the same or more disturbed behaviour. Conclusions. Bright light therapy has a positive e ect on motor restless behaviour. Light therapy in combination with melatonin has no positive e ects. The results might be explained by a possible overshoot of chronobiological synchronisation or the timing of the melatonin intake. Copyright # 2001 John Wiley & Sons, Ltd. KEY WORDS Ð melatonin; restless behaviour; dementia; bright light therapy INTRODUCTION * Correspondence to: Dr P. M. J. Ha mans, Parnassia Research Centre, Monsterseweg 83, 2553 RJ The Hague, The Netherlands. Tel: Fax: j.ha mans@ parnassia.nl Contract/grant sponsor: Mr Dr J. B. G. Schmitz Fund, The Netherlands. Dementia is characterised by progressive cognitive function de cits including loss of memory, comprehension, concentration and attention, orientation and perception and social behaviour. In addition, disturbances in behaviour may occur. Types of disturbed behaviour include aggressive behaviour, physically nonaggressive behaviours and verbally agitated behaviours (Cohen- Mans eld et al., 1992). The physically nonaggressive behaviours include, among others, pacing and motor restless behaviour. This motor restless behaviour often appears at twilight: a phenomenon called `sundowning' (Bliwise et al., 1993; Burney- Puckett, 1996). Bliwise et al. (1993) suggested three hypotheses for a possible physiological basis of sundowning, i.e. (1) a REM-sleep disturbance, (2) a sleep apnoea and (3) a dysregulation of the suprachiasmatic nucleus (SCN) resulting in a disturbance of the circadian rhythm and the sleep±wake cycle. The sleep±wake cycle is mediated by the hormone melatonin. Being produced in the pineal, melatonin gives a signal as Zeitgeber, i.e. stimulus of the SCN, in proportion to the brightness of the environmental light. The melatonin level is low during the daytime and increases during the night Copyright # 2001 John Wiley & Sons, Ltd. Received 20 July 1999 Accepted 28 April 2000

2 LIGHT THERAPY AND RESTLESS BEHAVIOUR 107 (Arendt and Deacon, 1997). The daily uctuations in melatonin concentrations change in ageing. The older people grow, the more these uctuations will attenuate, which can change the sleep±wake cycle and the need for sleep (Haimov and Lavie, 1995). Patients su ering from senile dementia complicated by disturbed behaviour show an increase in the amplitude of the sleep±wake rhythm and the level of melatonin production after treatment with bright light (Okawa et al., 1994). In another study, Alzheimer patients with sundowning and sleep maintenance problems were treated with bright light, resulting in improved sleep quality, less sundowning and an increase in the circadian rest± activity amplitude (Satlin et al., 1992; Mishima et al., 1994; van Someren et al., 1997). Moreover progression in cognitive functioning was found during the exposure to bright light (Murphy and Campbell, 1996). In adults, oral administered melatonin has an acute sleep promoting and sleep entraining e ect (Arendt and Deacon, 1997). Maurizi stated the hypothesis that the attenuation of the melatonin rhythm could explain the neuropathology of Alzheimer's disease and suggested administration of melatonin (Maurizi, 1997). The aim of this study was to evaluate a possible additional e ect of melatonin on motor restless behaviour and sundowning in demented patients treated with bright light. METHODS The study was approved by an independent medical±ethical committee. Before entering the trial the patient and his representative were informed both verbally and in writing. A written by proxy informed consent was obtained. Patients Ten patients were recruited from a 24-bed psychogeriatric medium-stay ward of a psychiatric teaching hospital. Included were patients su ering from senile dementia (DSM-IV criteria; APA, 1994) with manifest disturbed behaviour de ned as a Clinical Global Impression on disturbed behaviour 53 (CGI; Guy, 1976) and a minimal score of 3 on one of the items of subscale 10 of the GIP (Verstraten and van Eekelen, 1988) measuring restless behaviour. Excluded were patients who su ered from any other Axis-I diagnosis or severe somatic illnesses, and patients who used b-blockers or lithium. Design The study was a 6-week, double-blind, placebocontrolled, cross-over trial on the e ects of melatonin in combination with bright light. Subjects were randomly assigned to receive 2.5 mg melatonin or placebo. Bright light was given in the morning under personal guidance. After a wash-out period of 1 week, baseline measurements were assessed. Hypnotics and/or psychopharmacological treatment for disturbed behaviour was stopped. The 2-week treatment period with bright light, 10,000 lux (25 days) was followed by a 1-week wash-out period and another 2 weeks of treatment. All co-medication was kept at a constant dose. During the trial, buspiron up to a maximum of 30 mg/day was allowed in case of severe motor restless behaviour. Two patients were prescribed 10 mg buspiron a day, three patients 30 mg/day. In case of severe sleep disturbances oxazepam 10 mg was allowed at least one hour after intake of the trial medication. One patient was prescribed oxazepam. In those cases, the use of buspiron or oxazepam was part of the treatment, regardless of the trial. Intervention Bright light therapy was given between 8 a.m. and 11 a.m. The patients were requested to look into the 10,000 lux device at a distance of 30±50 cm for 30 minutes. Presence of a nurse assured a proper treatment. In the periods of treatment patients received melatonin (2.5 mg) or placebo at h in addition to bright light therapy in the morning. The medication was given as powder dissolved in water. In the wash-out period all patients received placebo medication in order to maintain the habit of medication intake. Instruments and assessments Senile dementia was assessed according to DSM- IV criteria (APA, 1994). The severity of dementia was assessed at baseline by the Clinical Dementia Rating Scale (CDR; Hughes et al., 1982). The CDR can be scored from 0 (healthy) to 3 (severe dementia). The CDR was assessed by the geriatrician at baseline.

3 108 P. M. J. HAFFMANS ET AL. Table 1. Mean scores on outcome variables BLT placebo BLT melatonin Scale Before treatment After treatment Before treatment After treatment CGI motor r. 5.0 (1.3) 3.7 (1.3) 4.4 (0.9) 4.1 (0.7) GIP 10 item (0.8) 1.9 (0.5) 2.1 (0.4) 2.0 (0.0) GIP 10 item (0.7) 1.5 (0.8) 1.8 (0.9) 1.3 (0.5) Mean scores and their standard deviations. p p The Clinical Global Impression/Improvement (CGI; Guy, 1976) is a seven-point clinical observation scale which is weekly rated by the geriatrician for every subject participating in the study. The Gedragsobservatieschaal voor Intramurale Psychogeriatrie (GIP; Verstraten and van Eekelen, 1988) was performed every 2 weeks to assess di erent types of behaviour. The GIP consists of 14 subscales directed at di erent types of behaviour, including social, cognitive, psychomotor and emotional or a ective behaviour. The GIP was assessed by the nursing sta at baseline and after each treatment period. The Social Dysfunction and Aggression Scale (SDAS-9; European Rating Aggression Group, 1992) is a 9-item observation scale covering outward aggressive behaviour in a clinical setting. Each item comprises ve ordered categories (scores ranging from 0ˆnot present, to 4ˆsevere to extreme) with the total score ranging from 0 to 36. The SDAS was assessed by the nursing sta after each period. The SDAS and GIP are part of the current ward procedures. Sociodemographic and psychiatric variables and data on (co-)medication were collected at baseline and during the study period. Analysis Because of expected variability of data of demented patients, a prospective, double-blind, multiple Nˆ1 design was chosen in which every patient served as his/her own control. To examine the relevance for treating other patients, it was desirable to combine the results of the various patients. The medication conditions were randomly assigned. Analysis for repeated measurements of variance (ANOVA) involving three conditions (baseline, placebo, melatonin in combination with bright light) was performed to evaluate the e ects of melatonin. The signi cance level was xed at Descriptive statistics were performed on sociodemographic data, the CGI, SDAS and GIP subscales, speci cally items 2, 3, 5, 9, 10 and 14, focused on restless behaviour, sundowning and aggression, to evaluate possible signi cant e ects of the two treatment modalities. Results are presented as di erences between baseline scores and scores at the end of the rst period of treatment ( placebo condition) and di erences between washout scores and the scores at the end of the second treatment period (melatonin condition). For all statistical tests, p-values below 0.05 (two-tailed) were considered signi cant. RESULTS Ten patients (seven female, three male; mean age 72.1 years) participated in the study. During the rst and second week of treatment, one patient dropped out due to an increase of aggressive behaviour and one because of severe anxiety. Due to transfer to a nursing home at the end of the third week, two patients dropped out of the study. Six patients completed the whole trial period and were taken into analysis. DSM-IV diagnostic classi cation was Dementia Alzheimer type (Nˆ4); Dementia NOS (Nˆ1); Mixed Type Alzheimer/ Vascular Dementia (Nˆ1). The use of buspiron or oxazepam did not di er between the two treatment periods. Bright light therapy and placebo showed a signi cant decrease on the CCI concerning motor restless behaviour ( pˆ0.049). Patients were capable of sitting down quietly more often or to do their pursuits longer as measured by GIP subscale 10 item 3 ( pˆ0.007) and GIP subscale 10 item 5 ( pˆ0.01). Analysis of the double-blind conditions showed no signi cant di erences between baseline

4 LIGHT THERAPY AND RESTLESS BEHAVIOUR 109 and wash-out scores. For both therapeutic conditions, no signi cant changes were found in social dysfunction and aggression (SDAS), or on any of the other subscales (Table 1). DISCUSSION The results of this study show positive e ects of a treatment with 10,000 lux bright light and placebo on motor restless behaviour in patients with dementia. In accordance with the results of Lovell et al. (1995), the treated patients were less restless, and were more able to perform their activities and sit down quietly. It should be noted that the number of patients participating this study was small. In a report by Okawa, treatment by enforcement of social interaction with nurses was e ective in reducing behavioural problems and sleep±wake rhythm disorder in 30% of the demented patients tested (Okawa et al., 1991). A contribution of social interaction to our results should be taken into account. Incidental administration of buspirone, in case of severe restlessness, might have in uenced the results; however, for the both treatment modalities no di erence was found. It was striking that two patients became drowsy in the second period of the treatment, which might be explained by the timing of melatonin intake. In accordance with Abegg et al. (1993), the practical handling of the patients was laborious. The e ect of the treatment with both bright light and melatonin shows no statistical signi cance on any of the (observation) scales, so melatonin does not yield additional positive e ects to light therapy in disturbed behaviour. Apparently the addition of melatonin during bright light therapy has contrary e ects in the treatment of motor restless behaviour. These results might be in accordance with Deacon and Arendt (1996), who found similar e ects in normal controls with a phase shift. The e ects could be due to the application of two zeitgebers, which might be too much. Synchronisation might then result in a subsequent desychronisation, i.e. equal or increased disturbed behaviour. A second explanation might be found in the timing of the melatonin intake at h. Unfortunately, melatonin production curves were not assessed in these patients. However, it is possible that melatonin has no or little e ect on the regulation of disturbed behaviour in dementia. In demented patients, daytime melatonin secretion was lower than in controls and una ected by light therapy, while sleep and restlessness improved (van Someren et al., 1996). Accordingly, treatment with bright light modi es the circadian melatonin pro le of depressed patients and healthy controls only marginally (Rao et al., 1990). Although the e ects of melatonin alone on disturbed behaviour are not well known and given the methodological limitations of this study, an alternative consideration which could explain the results is that the (side) e ects of melatonin might have counteracted the e ects of bright light therapy regardless of any e ects on the circadian phase. KEY POINTS. Bright light therapy has a positive e ect on motor restless behaviour in dementia.. Melatonin in combination with bright light does not result in any improvement of motor restless behaviour in dementia. ACKNOWLEDGEMENTS This study was supported by the Mr Dr J.P.G. Schmitz Fund, The Netherlands. REFERENCES Abegg A, Wettstein A Lichttherapie von Verhaltensstorungen als Folge gestorter zirkadianer Rhythmen bei dementiellen Alterspatienten. Schwierigkeiten der praktisch-klinischen Anwendbarkeit. Schweiz. Arch. Neurol. Psychiatr. 144: 63±80. APA Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC. Arendt J, Deacon S Treatment of circadian rhythm disorders Ð melatonin. Chronobiol. Int. 14(2): 185±204. Bliwise DL, Carroll JS, Lee AK, Nekich JC, Dement JC Sleep and `sundowning' in nursing home patients with dementia. Psychiatry Res. 48: 277±292. Burney-Puckett M Sundownsyndrome: etiology and management. J. Psychosoc. Nurs. 34(5): 40±43. Cohen-Mans eld J, Marx M, Werner P Agitation in elderly persons: an integrative report of ndings in a nursing home. Int. Psychogeriatr. 4(suppl. 2): 221±240. Deacon S, Arendt J Adapting to phase shifts, II. E ects of melatonin and con icting light treatment. Physiol. Behav. 59(5): 675±682.

5 110 P. M. J. HAFFMANS ET AL. European Rating Aggression Group Social dysfunction and aggression scale (SDAS-21) in generalized aggressive attacks: a validity and reliability study. Int. J. Meth. Psychiatr. Res. 2: 15±29. Guy W ECDEU, Assessment Manual for Psychopharmacology Revised. US Department of Health, Education and Welfare: Rockville, 217±222. Haimov I, Lavie P Potential of melatonin replacement therapy in older patients with sleep disorders. Drugs Aging 7(2): 75±78. Hughes CP, Berg L, Danzinger WL, Coben LA, Martin RL A new clinical scale for the staging of dementia. Br. J. Psychiatry 8: 741±746. Lovell BB, Ancoli-IsraeÈ l S, Gevirtz R E ect of bright light treatment on agitated behavior in institutionalized elderly subjects. Psychiatry Res. 57: 7±12. Maurizi CP Loss of intraventricular uid melatonin can explain the neuropathology of Alzheimer's disease. Med. Hypotheses 49: 153±158. Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori H, Takahashi K Morning bright light therapy for sleep and behavior disorders in elderly patients with dementia. Acta Psychiatr. Scand. 89: 1±7. Murphy PJ, Campbell SS Enhanced performance in elderly subjects following bright light treatment of sleep maintenance insomnia. J Sleep Res 5: 165±172. Okawa M, Mishima K, Hishikawa Y, Hozumi S, Hori H, Takahashi K Circadian rhythm disorders in sleep±waking and body temperature in elderly patients with dementia and their treatment. Sleep 14: 478±485. Okawa M, Hishikawa Y, Hozumi S, Hori H Sleep±wake disorder and phototherapy in elderly patients with dementia. In Biological Psychiatry, Vol. 1, Racagni C (ed.). Elsevier: Amsterdam; 837±840. Rao ML, Muller-Oerlinghausen B, Machert A, Stieglitz RD The in uence of phototherapy on serotonin and melatonin in non-seasonal depression. Pharmacopsychiatry 23: 155±158. Satlin A, Volicer L, Ross V, Herz L, Campell S Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease. Am. J. Psychol. 149: 1028±1032. van Someren EJW, Hagebeuk EEO, Lijzenga C, Scheltens P, de Rooij SEJA Circadian rest± activity rhythm disturbances in Alzheimer's disease. Biol. Psychiatry 40: 259±270. van Someren EJW, Kessler A, Mirmiran M, Swaab DF Indirect bright light improves circadian rest± activity rhythm disturbances in demented patients. Biol. Psychiatry 41: 955±963. Verstraten PJF, van Eekelen C Handleiding voor de GIP, gedragsobservatie-schaal voor de intramurale psychogeriatrie. (Behavioral Rating Scale for Psychogeriatric Inpatients). Van Loghum Slaterus: Deventer, The Netherlands.