Actigraphy in human psychopharmacology: a review

human psychopharmacology

Hum Psychopharmacol Clin Exp 2003; 18: 39–49.

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.471

REVIEW

Actigraphy in human psychopharmacology: A review

Neil Stanley*

HPRU Medical Research Centre, University of Surrey, Egerton Road, Guildford, Surrey GU2 7XP, UK

Over the last 25 years wrist actigraphy has predominantly been used in sleep research and chronobiology where the tech-nique has proved useful in the measurement of sleep and the characterisation of the sleep/wake cycle. Whilst there are a largenumber of studies published that have used actigraphy, there have only been relatively few studies that have shown that thetechnique is capable of measuring drug-induced changes in nocturnal and/or diurnal behaviour. Thus the use of actigraphy tomeasure drug effects in clinical trials has up till now remained on the periphery of psychopharmacology. However this maybe because of the disparate nature of the studies published rather than lack of usefulness. This paper reviews the relevantliterature and in doing so concludes that there is a convincing body of evidence for the utility of actigraphy as a technique inhuman psychopharmacology. Copyright # 2003 John Wiley & Sons, Ltd.

key words— actigraphy; psychopharmacology; sleep; daytime sedation; activity

INTRODUCTION

The mechanical measurement of human activitybegan in the late 1950s, when Schulman and Reisman(1959) used modified self-winding wristwatches tomeasure hyperactivity in children. Colburn et al.(1976) described the first solid state wrist worn acti-graph and since then advances in technology haveresulted in a greater sophistication and flexibility inrecording, a reduction in size, increased memoryand extended operation of the monitoring devices(Kripke et al., 1978; Redmond and Hegge, 1985) tothe point where a number of actigraphs are commer-cially available. Whilst there are differences in theway the different actigraphs work, essentially themotion sensor of the actigraph generates a signal vol-tage each time it moves, this count is then stored in asolid state memory and can be downloaded onto a per-sonal computer using a proprietary interface unit.Data can be analysed using the relevant proprietarysoftware, although many individual research groups

have developed their own algorithms. Actigraphs havebeen used in a number of different areas of sleepresearch, medicine, chronobiology and psychiatry(Tryon, 1985, 1991; Teicher, 1995; Klosch et al.,2001), however, this review concentrates on the pub-lished work using actigraphy in the field of humanpsychopharmacology and reviews studies that haveused actigraphy in well-designed clinical trials tomeasure drug-induced changes in both nocturnal anddiurnal behaviour.

It has been proposed that actigraphy may be a usefultool in human psychopharmacology (Stanley, 1997).This review examines the available evidence to supportits utility in the measurement of CNS drug effects.

Due to the lack of established methodologies andthe number of different variables reported by the var-ious authors this review eschews the extensive use ofreview tables as their resultant complexity would notresult in the desired clarity.

ACTIGRAPHS AND THE MEASUREMENTOF SLEEP

Over the years, one of the main uses of actigraphs hasbeen in the assessment of sleep/wake (Kripke et al.,

Received 25 October 2002

Copyright # 2003 John Wiley & Sons, Ltd. Accepted 22 November 2002

* Correspondence to: Mr N. Stanley, HPRU Medical ResearchCentre, University of Surrey, Egerton Road, Guildford, Surrey GU27XP, UK. Tel: 01483 689799. Fax: 01483 689790.E-mail: [email protected]

1978; Sadeh et al., 1995). A number of automatic sleep/wake detection algorithms have been developed andrefined that now correlate well with traditional sleepEEG in their measurement of sleep time (Mullaneyet al., 1980; Cole and Kripke, 1988; Sadeh et al.,1989; Cole et al., 1992; Sadeh et al., 1994). Actigraphshave many advantages over traditional EEG; they arecheaper; there is no need for specialist technical staff;they are quicker and easier to analyse; and are moreacceptable to the subjects and allow long term continu-ous monitoring. However, they are limited in the factthat they only allow the identification of sleep and/orwake and cannot give information concerning sleeparchitecture.

The American Sleep Disorders Association haspublished a comprehensive review of the use of acti-graphy for the evaluation of sleep disorders (Sadehet al., 1995). Although written from a clinical per-spective it provides an excellent overview of sleeprelated actigraph studies, the empirical data on thevalidity of actigraphy in assessing sleep–wake pat-terns and the use of actigraphy in assessing clinicaland control groups from infancy to elderly. One ofthe conclusions reached by the authors was that,despite certain limitations, actigraphy ‘may be a use-ful cost-effective method for assessing specific sleepdisorder, such as insomnia and schedule disorders,and for monitoring their treatment process’. Such aconclusion is also relevant if applied to the realm ofclinical trials of hypnotic agents.

A number of papers have reported a significant cor-relation between actigraphy and EEG in the measure-ment of total sleep time (TST), the percentage ofsleep, sleep efficiency (SE%) and sleep onset latency(SOL), of between 85 and 95% for most normal andclinical samples (Stampi and Broughton, 1988;Newman et al., 1988; Cole et al., 1992; Dunhamet al., 1991; Stanley et al., 1996a; Jean-Louis et al.,1996a). TST, or the number of sleep minutes, is thetime scored as sleep during the period in bed. SE%is a very good overall descriptor of a night’s sleep,being the TST divided by the time in bed (TIB). How-ever, one problem in trying to assess the utility of acti-graphy in measuring changes in sleep is that themajority of the above authors have used their own sta-ging algorithms rather that those in the relevant pro-prietary software package. If the actigraph is to beconsidered to be a useful tool in psychopharmacologythe staging algorithms that are supplied with theinstruments have to be shown to be accurate. Theaverage user would wish to be able to use actigraphsconfidently without a desire to develop their own algo-rithm. Thus a recent study (Stanley et al., 2000) was

performed comparing the ‘gold standard’ of sleepEEG with both the Ambulatory Monitoring Inc 32-CMini-Motionlogger (ACTION3 v.3.15 software)and the Cambridge Neurotechnology Actiwatch(Sleepwatch 98 v.4.08 software). Data from 382recordings were used to measure TST, SE% andSOL. Correlations were performed using Spearman’srho. Median disagreement between the actigraph andEEG and the range of the disagreement were calcu-lated. There were quite strong, positive and significant(all p> 0.0001) correlations between the Mini-Motionlogger (AMI), Actiwatch (CNT) and EEG inthe identification of the three variables. The TST(min) was for EEG mean 440.8� 25.7, median448.8; AMI mean 440.0� 45.0, median 457.0,rho¼ 0.548; CNT mean 430.9� 25.5, median 434.5,rho¼ 0.513.

The SE% was EEG mean 93.96� 4.74, median 95.3;AMI mean 91.63� 9.36, median 95.2, rho¼ 0.413;CNT mean 89.74� 5.31, median 90.5, rho¼ 0.398.

The SOL (min) was EEG mean 11.56� 13.04,median 7.0; AMI mean 9.57� 10.42, median 8.0,rho¼ 0.528; CNT mean 7.03� 10.51, median 3.0,rho¼ 0.617.

The authors concluded that the correlations betweenthe Mini-Motionlogger, Actiwatch and EEG were sig-nificant, but in the case of the Mini-Motionloggerweaker than those obtained by other researchers (e.g.Stampi and Broughton, 1988; Newman et al., 1988;Cole et al., 1992; Dunham et al., 1991; Stanley et al.,1996a; Jean-Louis et al., 1996a). However, the resultssuggest that both devices, when used in a routine man-ner with data analysed by the proprietary software, areable to measure sleep/wake parameters relativelyaccurately. Such accuracy may be considered suffi-cient if one is using actigraphs in a placebo controlledcrossover designed trial where sensitivity to drug-induced change would be more important than the pre-cise measurement of sleep.

DETECTION OF NOCTURNAL DRUG EFFECTS

Actigraphy has been used in a number of studies tomeasure drug-induced changes in sleep parameterscaused by drugs.

Hypnotics

Mattman et al. (1982) investigated the night-time anddaytime carryover effects of three benzodiazepinehypnotics (triazolam (0.25, 0.5 and 1 mg), nitrazepam(10 mg) and flunitrazepam (2 mg) (all doses for a 70 kgperson were adjusted for body weight). Eighteen

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Copyright # 2003 John Wiley & Sons, Ltd. Hum Psychopharmacol Clin Exp 2003; 18: 39–49.

young healthy adults participated in the study and allrecordings were performed in the subject’s home.Actigraphy was recorded throughout the night andthe mean night-time activity and the percentage ofactivity epochs (periods of 7.5 min) were calculated.All the active compounds significantly reduced noc-turnal activity compared with placebo. The daytimeresults indicated that triazolam (0.5 mg) and flunitra-zepam both significantly reduced activity from 0900to 1500 the day after drug administration and thiswas confirmed by a significant increase in subjectivedaytime sleepiness (temazepam 1 mg, flunitrazepam2 mg), experimenter rated tiredness (temazepam0.5 mg, flunitrazepam 2 mg) and performance on apsychometric test (flunitrazepam 2 mg).

Using the same analysis protocol used by Mattmanet al. (1982), Borbely et al. (1983a) studied the effectsof midazolam (7.5 and 15 mg) and triazolam (0.25 and0.5 mg) on nocturnal and diurnal activity in 15 healthyyoung adults. In addition to the whole night analysisin this study the night was further divided into halvesand the differences in activity levels from placebowere calculated. Compared with placebo both dosesof triazolam significantly reduced night-time activitywith even greater reductions seen in the first half ofthe night. Midazolam also significantly reduced entirenight-time activity but only at the 15 mg dose,although both doses significantly reduced activity inthe first half of the night. Daytime activity duringthe first 4 h after awakening was examined for carryover effects and none were found. Some hangovereffect was observed with triazolam (0.5 mg) using apsychometric test. Using the same design Borbelyet al. (1983b) investigated the effects of flunitrazepam(2 mg) and flurazepam (30 mg) on activity levels dur-ing sleep. Both drugs caused a significant reduction,

compared with placebo, in overall nocturnal activityand activity during both halves of the night.

The same design was used once again by Borbelyet al. (1984) who reported that single bedtime dosesof 20 and 30 mg temazepam significantly reducedoverall night-time activity compared with placebo,however, this effect was entirely explained by a signif-icant reduction in activity in the first half of the night.Again no carry-over effect was observed in the morn-ing following dosing.

Borbely (1984) in a review of his group’s workreported data from his previous studies (Borbely et al.,1983a, 1983b, 1984) to demonstrate the use of actigra-phy to measure the time course of hypnotic action.

Once again using the same methodology Borbelyet al. (1988) studied the hypnotic action and residualeffects of zolpidem (10 and 20 mg) on the treatmentnight and the following night. Zolpidem (20 mg)was found to reduce significantly the percentage ofactivity epochs during the night. This was reflectedin a significant reduction in the subjective assessmentof the number of awakenings during the night and thedepth of sleep in the 20 mg zolpidem condition. Noeffects on activity levels were detected on the nightfollowing medication.

Walsh et al. (1991) used actigraphy to measure day-time sleep at home following triazolam (0.25 and0.5 mg) or placebo in a study of physiological sleeptendency during a simulated night shift schedule.Fifteen subjects were required to work a 4 day simu-lated night shift in the laboratory and then return hometo sleep during the day. Actigraph records were scoredwith sleep defined as the first of three successiveepochs with activity less than or equal to 20 units(accumulated movements). A screening night, whereEEG and actigraphy were recorded, allowed this

Table 1. Studies that have reported nocturnal drug effects using traditional sleep variables

Authors Drugs SOL WASO SE% TST

Lavie (1990) Midazolam (7.5 mg) YWalsh et al. (1991) Triazolam (0.25 mg, 0.5 mg) YDrennen et al. (1991) Potassium (96 meq/day) N Y Y NBoudreau et al. (1993) Mefloquine (250 mg/week) YHauri et al. (1995a) Transdermal nicotine NGarfinkel et al. (1995) Melatonin (2 mg) Y YShamsi et al. (1996) 3-IPA (100 mg, 200 mg, 300 mg) YJean-Louis et al. (1996a) Melatonin (?) N Y Y NGarfinkel et al. (1997) Melatonin (2 mg) N Y Y NHindmarch et al. (2000) Tea, coffee YSmits et al. (2001) Melatonin (5 mg) YJockovich et al. (2000) Melatonin (1 mg) N N N NShamir et al. (2000) Melatonin (2 mg) YShilo et al. (2002) Caffeinated and decaffeinated coffee Y Y

SOL sleep onset latency; WASO, wake after sleep onset; SE%, sleep efficiency; TST, total sleep time.

actigraphy in human psychopharmacology 41


scoring method to be validated. The mean TST fromEEG recordings was 409.9 min whilst the actigraphestimated TST at 414.4 min. Actigraph recordingrevealed a significant increase in TST for subjectson triazolam versus placebo. This finding of longerTST was also reflected in a significant increase in sub-ject reports of increased length and depth of sleep ontriazolam.

In a parallel-group design patient study of the pre-operative hypnotic effects of brotizolam (0.25 mg)and zopiclone (7.5 mg), Kawahara et al. (2002) foundthat TST was significantly longer with brotizolam thanwith zopiclone. They also reported that when the 8 hnight (2200–0600) was divided into four 2 h blocks inthe group taking zopiclone there was a reduction in thesleep time in period 4 (0400–0600), compared withthe other periods. In the brotizolam group there wasno difference between the periods.

Melatonin

In a placebo controlled crossover study of 12 elderlysubjects complaining of long-term insomnia, Garfinkelet al. (1995) investigated the effects on sleep qualityof 2 mg controlled release melatonin given 2 h beforethe desired bedtime for 3 weeks. They found that aftertreatment with melatonin there was a significantincrease in SE% and a significant decrease in wakeafter sleep onset (WASO), although no effect was seenfor sleep latency or TST.

In a repeat of their 1995 study Garfinkel et al.(1997) used 21 independently living elderly subjectscomplaining of long-term insomnia and being treatedwith benzodiazepines. They found that 3 weeks treat-ment with 2 mg controlled release melatonin signifi-cantly increased SE% and TST. It also reduced SOLand WASO. The fragmentation index (percentage ofnumber of quiet episodes which are shorter than1 min from the total of quiet episodes) was signifi-cantly lower with melatonin compared with placeboas was the number of awakenings.

In another study on melatonin Jean-Louis et al.(1996b) found that melatonin significantly improvedsleep compared with baseline in 13 subjects. Melato-nin had no effect on SOL or TST but was found to sig-nificantly increase SE% and to reduce WASO, totalwake time and arousal (defined by the authors as‘measured activity above the threshold for sleep’).

Studying 25 children (aged 6–12) with chronic sleeponset insomnia Smits et al. (2001) reported that 5 mgmelatonin given at 6 pm improved actigraphic measuredSOL as well as parent diary estimations of sleep onsetafter 4 weeks of treatment compared with placebo.

Jockovich et al. (2000) in a crossover design studyof 19 emergency medics working night shift wereunable to demonstrate an effect of 1 mg melatoningiven 30 to 60 min prior to their anticipated bedtimeon any of the actigraphically measured sleep para-meters. The authors point to the small sample size, lackof standardisation of night shifts as well as limitationswith actigraphy (i.e. it being only an indirect measureof sleep: its reduced accuracy in sleep/wake determina-tion in insomnia and the lack of reliability and validityfor its use in an unsupervised natural environment) asexplanations for the lack of positive results.

Caffeine

Hindmarch et al. (2000) conducted a naturalisticinvestigation of the effects of day-long consumptionof tea, coffee and water on alertness, sleep onset andsleep quality in 30 healthy volunteers. They receivedequal volume drinks equivalent to either one or twocups of tea (containing 37.5 or 75 mg of caffeine),or coffee (75 or 150 mg of caffeine), or water, in a ran-domised 5-way crossover design. Drinks were admi-nistered on four occasions during the day (900,1300, 1700 and 2300). There was also an overall dif-ference between caffeinated and non-caffeinated bev-erages for TST, as measured by the actigraphs, withcaffeinated beverages reducing time asleep. Theeffects of caffeine were dose dependent withincreased levels of caffeine resulting in shorter sleeptimes. However, the highest caffeine dose, coffee150 mg, had the most pronounced effect on sleep time,while the beverages containing 37.5 and 75 mg of caf-feine had comparable mean scores. Interestingly, therewas considerable variation in total sleep time betweenindividuals which was partly, but not completely,explained by variation in daily levels of habitual caf-feine intake: individuals with a lower caffeine intaketended to display a greater disruption in sleep time.

In a randomised, double-blind crossover study of 1day consumption of caffeinated versus decaffeinatedcoffee in six healthy young volunteers, Shilo et al.(2002) found that caffeinated coffee significantlynegatively affected actual sleep time, SOL, SE%,number of sleep bouts and movement and fragmenta-tion index. Subjective assessment of sleep qualityfailed to reveal significant differences.

Hypnotics and transmeridian flights

In a naturalistic study of eastward and westward flights,Lavie (1990) found that compared with placebo 7.5 mgmidazolam significantly increased TST on nights 1 and

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3 after an eastward flight crossing seven time zonescompared with placebo in 18 healthy subjects.

Zopiclone (7.5 mg) has also been found to havebeneficial effects on sleep (Daurat et al., 2000), whentaken after a westward flight across five time zonesimproved sleep duration on nights 2 and 3 after theflight compared with placebo in 24 subjects. Theamount of nocturnal activity, taken by the authors tobe a measure of sleep fragmentation, was significantlylower with zopiclone than placebo on the first nightafter the flight.

Other substances

In a study of the effects of dietary potassium supple-mentation (96 meq/day) for 1 week on actigraphicmeasures of sleep, Drennen et al. (1991) reported asignificant increase in SE% and decrease in WASOwith potassium supplementation compared with pla-cebo. TST and sleep onset and offset timings werenot significantly changed.

Boudreau et al. (1993) recorded 24 h activity data inan unspecified sub-group of 359 US marines takingpart in a randomised double-blind clinical trial toassess tolerance to two prophylactic mefloquine regi-mens (250 mg weekly or 250 mg daily for 3 days fol-lowed by 250 mg per week) compared with 300 mgweekly chloroquine over a 12 week period. Although24 h activity data were obtained, only the nocturnalepisodes of sleep were reported. Four variables ofeach night’s sleep were measured: TST; percentageof sleep; average activity score and the sleep qualityindex. The sleep quality index (Aubert-Tulkens et al.,1987) estimates the time spent in restless movementand the frequency of brief non-movement episodes,indicating disruption or fragmentation of sleep. Sleepdata from individual subjects were averaged for each2 week monitoring interval (weeks 1–2, 5–6 and 11–12). There were no significant group differences inany of the four sleep variables, except the percentageof sleep in weeks 5–6 when members of the groupwere involved in field exercises that disrupted theirsleep. Although more subjects on meloquine com-plained of insomnia, these complaints could not becorrelated with individual actigraph records. It is tobe regretted that although actigraphy was recorded24 h a day an assessment of the drug effects on day-time levels of activity was not reported.

Shamsi et al. (1996) investigated the effects of 3-indole pyruvic acid (IPA) on sleep and morning afterperformance in ten volunteers who had previouslycomplained of mild insomnia. Three doses of IPA(100, 200 and 300 mg) were compared with placebo

to assess their effect on sleep, as measured by EEGand wrist actigraph, cognitive function and psycho-motor performance. Treatments were taken for fourconsecutive nights. The results show that IPA had noeffects on any aspect of sleep architecture. However,SE% as measured by both EEG and actigraphy wassignificantly higher on night 1 when subjects hadtaken 200 or 300 mg IPA compared with subjectswho had received either placebo or 100 mg IPA. Nofurther effects were found on nights 2, 3 or 4 withany of the treatments. There were no adverse effectsof IPA on cognitive function or psychomotor perfor-mance in the morning following night-time dosing.

Given the long development of actigraphy as a surro-gate measure of sleep it is unsurprising that the majorityof papers using actigraphy in psychopharmacology usethem to measure aspects of sleep. In light of this factperhaps it should also be expected that the papersreviewed here demonstrate that actigraphy is a usefultool in the measurement of nocturnal drug effects.

ACTIGRAPHY AND ANAESTHESIA

Whilst actigraphy is unable to measure sleep architec-ture, Weinbroum et al. (2001) found that actigraphicrecordings accurately indicated the presence and timeof occurrence of all relevant perioperative eventsincluding those related to anaesthesia. They reporteda study of 18 patients who underwent minor to med-ium lower-body surgical procedures with spinal orepidural anaesthesia with sedation by propofol, mida-zolam, or isoflurane-based general anaesthesia. Thereduced muscle activity associated with administra-tion of midazolam or propofol was considered as areduction in the patient’s stress response and wasrecorded by the actigraph 3 to 5.5 min before bloodpressure decreased significantly, 0.5 to 2.5 min beforea significant decrease in heart rate was detected, and0.5 to 1.5 min before respiration rate slowed. Thesefindings held true for drug administration duringregional, and for patients undergoing isoflurane-basedgeneral, anaesthesia. The recognition of the variousanaesthetic events made by the attending anaesthe-siologist compared with the recorded actigraph dataof changes in any given parameter (e.g. the initiallevel of sedation and the level of awakening), revealedthat the physician’s assessment was significantlydelayed by 2 to 5 min, mainly for the effect of mida-zolam and propofol. The authors concluded that realtime actigraphic monitoring can provide clear-cutand objective indications of changes in the depth ofanaesthesia or sedation and its associated events dur-ing surgery and recovery.



MEASUREMENT OF DIURNAL DRUG EFFECTS

From a movement point of view we are all very muchalike during sleep and under anaesthesia, thus detect-ing drug induced changes in activity should be com-paratively easy to measure. However, individualactivity patterns/levels during the day are by their nat-ure much more variable, thus to pick up diurnal drugeffects in populations requires well-designed studiesthat to a certain degree have a measure of control overthe subjects’ activities. By having similar activity pro-files the sensitivity of the technique in detecting drugeffects is increased by removing much of theconfounding ‘noise’ caused by the different levels ofactivity seen in free living patients with their variablelifestyles. A group in which activity is to a degreecontrolled is psychiatric in-patients and some workhas been performed in this population.

Actigraphs in psychiatry

Although actigraphy has primarily been developed tomeasure sleep/wake its calculation of this variable isbased on the measurement of movement and thus itcan be used in to measure change in locomotor beha-viour. Altered locomotor activity is a cardinal sign of anumber of psychiatric disorders (Teicher, 1995),indeed, DSM-IV lists 30 disorders having diagnosticcriteria that require an assessment of activity levels.Psychomotor retardation is a predominant feature ofdepressive illness and relates not only to a reductionin motor activity but also to alterations of concentra-tion, memory recall and other aspects of informationprocessing (Widlocher and Ghozlan, 1989). Only a fewstudies have been performed using activity to quantifythe effects of drugs on patients with affective disorders.Lithium has been found to increase daytime activitylevels in patients with bipolar depression, Kupfer et al.(1974) reported this finding in a small group of respon-ders. Lithium was also found to attenuate daytime(Weiss et al., 1974; Heninger and Kirstein, 1977) andnight-time (Heninger and Kirstein, 1977) activity in pre-dominantly manic patients. Joffe et al. (1987) demon-strated an increase in activity levels in bipolar patientstreated with carbamazepine. In contrast, amitriptylinedecreased the activity levels of responsive unipolarpatients (Kupfer et al., 1974).

It has been reported (Raoux et al., 1994) that thebasic activity level of hospitalised major depressedpatients, on the first day of treatment, is related tothe severity of psychomotor retardation, as measuredby the Salpetriere retardation rating scale (Widlocher,1983). Improvement, i.e. an increase, in activity level

after 4 weeks of treatment with tricyclic antidepres-sants and benzodiazepines was linked to an impr-ovement in depressive mood as measured bythe Montgomery–Asberg depression rating scale(Montgomery and Asberg, 1979). This study con-firmed the results from a previous study by this groupinto long term motor activity in depressed patientsundergoing treatment (Royant-Parola et al., 1986).

Stanley et al. (1999a) reported a randomised, parallelgroup, double-blind study conducted in 14 general prac-tice patients with a diagnosis of depression to assesspossible differences between fluoxetine and dothiepinin their effects on 24 h behavioural activity monitoredfor the first 10 days of treatment. Patients taking dothie-pin (75 mg rising to 150 mg in the second week, nocte)were found to be significantly less active over the courseof the day, with respect to those treated with fluoxetine(20 mg mane). A lower level of behavioural activity wasparticularly noticeable in the early morning (0600–0800) following dothiepin but this early morning ‘iner-tia’ was not observed in those patients treated withfluoxetine. This change in activity over the first weeksof treatment led the authors to hypothesise that actigra-phy may be useful in measuring the early onset of anti-depressant activity (Stanley et al., 1999b).

In a randomised, double-blind, crossover, clinicallybased trial, Shamir et al. (2000) studied 19 patientswith DSM-IV schizophrenia treated with the normaltreatment regimen were given melatonin (2 mg, con-trolled release) or placebo for two treatment periodsof 3 weeks. Melatonin replacement significantlyimproved SE% compared with placebo in this popula-tion. The improvement in SE% was significantlygreater in patients who had a low baseline SE% com-pared with those who had a high SE%. The authorsconclude that melatonin improves sleep efficiency inpatients with schizophrenia whose sleep quality is low.

Volkers et al. (2002) used actigraphs to investigate24 h motor activity after treatment with imipramine orfluvoxamine in 54 hospitalised patients with majordepressive disorder. Motor activity was measured dur-ing a medication-free period of at least 7 days and thenduring 4 weeks double-blind treatment with imipra-mine or fluvoxamine at the dose required to maintaina therapeutic efficacy of the drugs. Both the Hamiltondepression rating scale (Hamilton, 1980) and theSalpetriere retardation rating scale (Widlocher, 1983)significantly improved in both groups. There were nosignificant differences between patients in either groupin: motor activity during wake, motor activity duringsleep, fragmentation index during wake, fragmentationindex during sleep and immobility index during sleep.However, after treatment with imipramine there was a

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significant difference in mean motor activity duringwake and a higher fragmentation index during sleepin comparison to the medication-free period.

As can be seen from the above studies all, bar one,used in-patients, only Stanley et al. (1999a) have beenable to measure drug effects in a small sample ofpatients living in the community with their more vari-able activity patterns. However, this study was positedas a pilot study and as yet no other study has yet beenpublished to replicate their finding.

THE MEASUREMENT OF DAYTIME SEDATION

Whilst there has been some work using actigraphs tomeasure nocturnal drug effects, there has been only asmall amount of work utilising actigraphs to measurethe changes in behaviour caused by psychoactivedrugs during the day in non-patient populations. Oneof the basic assumptions of human psychopharmacol-ogy is that the effects of psychoactive drugs can ulti-mately be judged by changes in human behaviour. Theassessment of the extent to which a central nervoussystem (CNS) active drug affects the activities of dailyliving has traditionally been measured during the dayby the use of psychometric tests and/or subjectivequestionnaires or rating scales. However, the use ofpsychometric testing raises interesting methodologi-cal issues. Psychomotor tests provide a snapshot ofCNS function at the time of testing, therefore todescribe accurately the pharmacodynamic profile ofa drug would require almost continuous testing. Toovercome the problems of discrete time points, psy-chometric testing requires an objective assessment,likely to be affected by psychoactive drugs, of beha-viour on a continuous basis. Actigraphy is such a mea-sure. A change in overt behaviour will be reflected inactigraphy readings and drugs that are behaviourallyactive will cause changes in overt bodily movementwhich will also be recorded on the actigraph. Acti-graphs as a continuous measure of the motor compo-nent (activity) of behaviour are thus capable ofmeasuring changes in activity whenever they occur,not just during the night.

Kecklund et al. (1991) found that actigraphs wereable to measure the differences between the level ofactivity associated with a number of behaviouralactivities: a 30 min walk; typewriting; reading a news-paper; ‘active bed-rest’; ‘quiet bed-rest’ and sleep.They reported that all daytime activities had signifi-cantly different activity levels compared with sleep.Thus it has been hypothesised (Stanley, 1997) that areduction in daytime activity levels, in subjects per-forming similar activities in a placebo-controlled

crossover study, may be a measure of ‘sedation’ andmay correlate with traditional measures of daytimesedation such as psychometrics and questionnaires.

In their study of the hypnotic action and residualeffects of zolpidem (10 and 20 mg) Borbely et al.(1988) used actigraphy to record the mean activityfor 4 h after awakening the morning following treat-ment. Although zolpidem (20 mg) caused a significantreduction in the percentage of 7.5 min activity periodsduring the night as well as a reduction in subjectivelyassessed awakenings and depth of sleep, there was nochange in daytime activity levels, demonstrating alack of residual effects.

In another study of zolpidem (10 mg) Aguirre et al.(1991) reported a 24 h evaluation of the effects ofzolpidem in ten elderly in-patients. Patients receivedplacebo for 3 nights preceding and following 3 weeksof zolpidem treatment. Actigraphy was recorded forboth the first 5 and the last 5 days of the study. No dif-ference in activity levels was found between placeboand zolpidem for the 24 h period or when day andnight were analysed separately.

Hauri et al. (1995a) (later reported in Wolter et al.,1996) reported on the amount of daytime wrist activityduring a long term study investigating the use of trans-dermal nicotine patches in smoking withdrawal. Theyfound that compared with baseline (when subjectswere smoking ad lib), a reduction in nicotine levels,resulting from the use of patches, caused a reductionin daytime activity throughout the 5 day in-patientand 7 week out-patient phase. Additionally they alsocalculated a ‘drowsiness score’ which was defined asepochs of activity during the day, which could havebeen regarded as indicative of sleep. The daytimedrowsiness score on the last 2 days of hospitalisationwas significantly lower than baseline. As nicotinewithdrawal is known to increase lethargy, the authorsconcluded that even though levels of activity decreasedit was the group interaction in the hospital that pre-vented subjects from falling asleep and indeed drowsi-ness values increased after the inpatient phase andcontinued to increase after the patches were with-drawn. Hauri et al. (1995b) discussing the nocturnaldata from this study reported that actigraphy failedto detect any change in night time sleep efficiency.

Stanley and Hindmarch have conducted a numberof studies (Stanley, 1997), in which the accuracyand utility of actigraphy in measuring drug-induceddaytime sedation has been compared with a standard,validated psychometric test battery that is sensitive tothe behaviourally toxic effects of psychoactive drugs(Hindmarch et al., 1991). In their first double-blindhealthy volunteer study Stanley and Hindmarch



(1996) compared promethazine (25 mg), cetirizine(2.5, 5 and 10 mg), loratadine (10, 20 and 40 mg)and placebo. A psychometric test battery was per-formed prior to treatment and then 90, 180 and360 min post drug. Activity was recorded for 6 h postdose. Promethazine was significantly more sedative,as measured by a reduction in activity per hour, atapproximately 5 h post dose compared with all drugsand placebo ( p< 0.05). Using a shorter epoch lengthof 20 min, in order to improve resolution, a significantreduction in activity was seen at 280 min after drugingestion with promethazine compared with placebo.Although this was the only time point that wassignificant, the shape of the curve indicates thatpromethazine causes a deepening of the post-lunchdip. Again the actigraph results matched those fromthe psychometric testing which showed promethazinesignificantly impaired both objective and subjectiveperformance compared with placebo.

In a later study of two antidepressants Stanley andHindmarch (1997) investigated the psychomotor andcognitive effects of fluvoxamine (50 and 100 mg)and dothiepin (75 mg) in 12 young healthy male volun-teers. Subjects completed a psychometric test batteryprior to dosing and then at 1, 2, 3, 4 and 6 h post doseand wore an actigraph for the duration of the study per-iod. Dothiepin was found to cause a significant reduc-tion in overall daytime activity compared with placeboand both doses of fluvoxamine. The actigraphy resultswere found to be in agreement with that from the psy-chometric test performed on the study and reportedelsewhere (Fairweather et al., 1996) which showeddothiepin caused significant impairment on bothobjective and subjective measures.

After re-analysis of their data showing a reductionin day-time activity to be a measure of sedation,Stanley et al. (1999c) introduced the concept of day-time ‘sleep-like’ behaviour which is similar to the‘drowsiness score’ reported by Hauri et al. (1995a)(later renamed as the ‘daytime inactivity index’ inWolter et al., 1996). The sleep/wake detection algo-rithm of the actigraph scores 1 min epochs of data aseither sleep, which is assigned a value of ‘1’, or wakewhich has a value of ‘0’. Running the algorithm ondaytime data identifies periods that the algorithmidentifies as sleep. However, subjects on the studiesare kept vigilant throughout the day and thus althoughdata may be scored as ‘sleep’ it is more accurate todescribe such behaviour as ‘sleep-like’. A mean levelof daytime ‘sleep-like’ activity equalling ‘1’ wouldindicate that, at that time, all the subjects were exhibit-ing behaviour which the algorithm identifies as sleepand ‘0’ that they were all fully awake. Utilising this

concept it was shown that in various studies conductedby the group in each case the verum (promethazine(25 and 30 mg) and mianserin (30 mg)) caused a sig-nificant increase in the amount of daytime ‘sleep-like’activity compared with placebo. This finding was mir-rored in a significant reduction in behavioural activity.This increase in daytime ‘sleep-like’ activity wasreflected in both psychometric and subjective assess-ment of psychomotor performance and sedation. Theresults of these studies confirm that data derived fromthe sleep/wake detection algorithm can accuratelyreflect the rise and fall of daytime sedation (Alfordet al., 2000; Stanley and Hindmarch, 2001).

Roehrs et al. (2000) used waking actigraphy toinvestigate the effects of reduced time in bed and thesedating effects of the first generation antihistaminediphenhydramine (50 mg). Seventeen young adult sub-jects (6 males, 11 females) completed the study whichconsisted of four treatment periods placebo-8 h TIB,placebo-4 h TIB, placebo 0 h TIB and diphenhydra-mine 50 mg 8 h TIB. The subjects were dosed at0900 and throughout the day (0700–1800) and worea wrist actigraph. In a similar fashion to Wolter et al.(1996), activity was recorded in 30 s epochs and scoredfor percent of time marked as ‘inactive’. Also the totalactivity count per epoch data was analysed from 1000–1600 for comparability with data from the multiplesleep latency test (MSLT) (Carskadon et al., 1986) alsorecorded. Mean inactivity time over the two time per-iods was significantly reduced with both diphenhydra-mine (50 mg) and placebo-0 h TIB compared with theother conditions. However, the analysis of the activitycount data failed to discriminate between the condi-tions. The authors speculated that the inactive epochsobserved might reflect Williams’s (1959) construct of‘lapses’, which was developed to explain the increas-ing occurrence of brief gaps in continuous perfor-mance during sleep deprivation. They also pointedout that the software used to analyse the inactive datawas developed for the measurement of nocturnal sleepand not daytime activity and thus the algorithm mayneed to be modified to make it more sensitive to thesmall reductions or brief lapses in waking activitydue to sleepiness. The authors also said that more workwas needed to show that this effect was not limited tothe first generation antihistamines and that the resultscould be replicated. As mentioned above the author’sconcept of ‘inactive’ epochs is essentially the same asthat reported by Wolter et al. (1996) with transdermalnicotine and the same as the ‘sleep-like’ behaviour thatStanley et al. (1999c) reported with a different firstgeneration antihistamine and an antidepressant. Thusthe pre-existing work of Wolter et al. (1996) and

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Stanley et al. (1999c) demonstrate that the effect foundby Roehrs et al. (2000) is not unique to first generationantihistamines. It also provides a body of evidence thatactigraphy can measure a drug-induced reduction indaytime activity.

In a study to investigate the effects of slow releasecaffeine on vigilance and performance during a periodof continuous wakefulness in 16 healthy volunteers,Beaumont et al. (2001) found that compared with pla-cebo caffeine (300 mg b.i.d at 2100 and 0900) pro-duced significantly greater amounts of activity perhour for the vast majority of hours throughout the64-h sleep deprivation period.

CONCLUSION

The above review presents an, albeit small, body ofevidence to show that actigraphy is sensitive to mea-suring the effects of medication on both nocturnal anddiurnal activity in healthy volunteers, occupationalgroups and patients. It also demonstrates that theeffects on activity are often reflected in both subjec-tive and objective (psychometric) measures of sleepand sedation. However, two notes of caution need tobe raised, the first is that the reporting of actigraphyresults may be biased in favour of positive result. Acti-graphy is rarely the primary variable and it is possiblethat many more studies have used it but due to the lackof measurable effect the results have not beenreported, however this must, by its very nature, remaina supposition. However, it may offer an explanation asto why there are only very few studies that report non-significant findings using actigraphy. The other cau-tion concerns the lack of an established standardisedmethodology or accepted variables which means thatthere are few studies that are directly comparable andthus there is limited evidence of reproducibility. Theactigraphy community should be encouraged todevelop such methodologies and define variables.However, the author believes that there is sufficient evi-dence of utility presented in this review to justify theuse of actigraphy in future well-designed studies inves-tigating the effects on the CNS of medications both onsleep and daytime sedation. It can thus be hoped thatwith increased use of commercially available acti-graphs and their proprietary software, actigraphy willfurther demonstrate that it is an important method inthe psychopharmacological armamentarium.

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Actigraphy in human psychopharmacology: a review

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