Modafinil and unconstrained motor activity in schizophrenia: Double-blind crossover placebo-controlled trial

Avolition affects quality of life in chronic schizophrenia.We investigated the effect of modafinil upon unconstrainedmotor activity in 18 male patients. In a randomised crossoverdesign study, wrist-worn actigraphic monitors were used toobjectively record motor activity over a 20 h period. Patients’ total activity was significantly greater when given the drug.These data suggest that modafinil increases quantifiable motorbehaviour in schizophrenia and may have an impact on avolition.

INTRODUCTION

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INTRODUCTION

Schizophrenia is associated with diverse cognitive and behavioural impairments which may have an impact on independent living.One classification of schizophrenia into three sub-syndromesincludes the category ‘psychomotor poverty’, encompassingsymptoms of alogia, flatness of affect and avolition (Liddle et al, 1992).This last symptom involves an inability to initiate and persistin goal-directed behaviour, which can seriously constrain patients’abilities to maintain social interaction. Methods of measuring and influencing the magnitude of spontaneous motor activityin people with schizophrenia are needed to lessen the negativeimpact of this debilitating symptom (Farrow et al, 2005).

In this study we recorded the spontaneous, unconstrained motorbehaviour of people with schizophrenia in order to determinewhether such behaviour might be influenced by modafinil, anovel wakefulness-promoting agent currently licensed in theUSA and the UK for the treatment of narcolepsy (Cephalon, 1999).Congruent with its wakefulness-promoting properties, in animalmodels modafinil increases activity in the anterior hypothalamusand anterior cingulate – structures implicated in arousal(Lin et al, 1996). Of particular relevance to modafinil’sapplication in schizophrenia is its activity with respect to the human dopaminergic system. Animal models have differentiated modafinil’s pharmacological properties from those ofamphetamines (Lin et al, 1996), and there is evidence thatits wakefulness-promoting effects are not antagonised by haloperidol(Mignot et al, 1994). In humans, peak modafinil plasma levelsoccur 2–4 h following oral dosing (Cephalon, 1999).As well as its use in the treatment of narcolepsy, modafinilhas been investigated in a range of psychiatric disorders thathave fatigue or anergia as a central feature, such as depression (DeBattista et al, 2004). There have been preliminary reportsof its general use in schizophrenia to ameliorate negativesymptoms (e.g. Rosenthal & Bryant, 2003; given at a dosageof 100–200 mg per day).

In order to investigate whether the lower dosage of modafinilmight be of use in the remediation of avolition in schizophreniawe conducted a trial of its acute effects, including an objectivemeasure of volume of movement.

METHOD

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METHOD

In a randomised double-blind study with a placebo-controlledcrossover design, 18 right-handed patients with schizophrenia(DSM–IV; American Psychiatric Association, 1994) receiveda single dose of either 100 mg modafinil or placebo. A nineteenthparticipant who relapsed midway through the study was unableto provide two actigraphic data-sets and was excluded from allanalyses (a CONSORT diagram is presented in a data supplementto the online version of this report). All participants werecommunity-based out-patients but for monitoring purposes wereadmitted on two separate occasions (during ‘drug’and ‘placebo’ conditions, a week apart) to a psychiatricward for 24 h. Modafinil or placebo was administered at 08.00h and movement recording began at 12.00 h. Participants hada mean age of 38 years (s.d.=9), an illness duration of 15years (s.d.=10), a Scale for the Assessment of Negative Symptoms(SANS; Andreasen, 1985) score of 11.0 (s.d.=2.3), a Scalefor the Assessment of Positive Symptoms (Andreasen, 1985) scoreof 3.7 (s.d.=2.1), and a Mini-Mental State Examination (Folstein et al, 1975) score of 29.4 (s.d.=0.6). Twelve patients were taking oralatypical antipsychotic medication, two were taking oral typicalmedication and four were receiving typical depot medication.All patients were stable at the time of the study, having receivedno change in oral medication for a minimum of 4 weeks or indepot medication for 12 weeks prior to enrolment.

Patients wore an Actiwatch (Cambridge Neurotechnology Ltd, Cambridge,UK) to measure their cumulative activity over a 20 h period.The Actiwatch is a wrist-worn device containing a miniatureuniaxial accelerometer, which produces a digital integrationof the amount and duration of all movement over 0.05 g (equivalentto an acceleration of approximately 0.5 m/s²). As an indicatorof normal daytime activity, a study of 107 young people aged16–19 years recorded mean Actiwatch readings of 162 565(s.d.=68 620), a dimensionless measure, over a 24 h period (NancyButte, personal communication, 2005). All participants gavewritten informed consent, and the study was approved by theNorth Sheffield Research Ethics Committee.

RESULTS

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RESULTS

Over a 20 h period, during the modafinil condition participantsexhibited significantly greater motor activity (mean 135 090,s.d.=59 341) than when receiving placebo (mean 120 778, s.d.=56783):mean increase 12%; paired t=2.46, P=0.012 (Fig. 1). Therewas a significant negative correlation between SANS avolitionscore and Actiwatch-measured motor activity (r=–0.41; P=0.044, one-tailed t-test) during the placebo condition, butno such correlation during the modafinil condition (r=–0.31;P=0.104). There was no correlation between age, duration ofillness or chlorpromazine equivalent drug dosage and motor activity.

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Fig. 1 Average cumulative activity over 20 h (2400 epochs of 30 s) for 18 patients with schizophrenia during drug (modafinil) and placebo conditions. Patients were significantly more active during the drug condition (P=0.012). Cumulative activity measure (y axis) isdimensionless (see text for details).

DISCUSSION

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DISCUSSION

In a group of community-based patients with chronic but stable schizophrenia, administration of a single dose of 100 mg ofmodafinil was associated with significantly increased motoractivity over a 20 h period. This increase in activity wasdetected on average approximately 9 h after drug administration.Modafinil’s positive effect on activity may reflect a generalised increase in motor behaviour, or an effect thatis more specific to those most ‘avolitional’ atthe outset. In support of the latter proposal, post hoc examinationof our data revealed that there was a significant negativecorrelation between motor activity on placebo and percentageincreased activity on modafinil (r=–0.43; P=0.037).

Using the Actiwatch to augment ratings obtained using the SANSfacilitates a more objective, scalar measure of bodily movementand severity of avolition. This additional quantification issimple to acquire, unobtrusive to patients and may be particularlyuseful where change is anticipated (as with putative behaviouralor pharmacological interventions).

Our study findings are potentially limited, however, in tworespects. First, we studied patients within the confines ofa psychiatric ward and therefore must remain circumspect indrawing inferences about ambulatory, community-based activity.Second, although we have a sum of the total activity undertakenby our participants, we are limited in the extent to which wemay infer purpose (i.e. goal direction) in such activity. Nevertheless,our data suggest that administration of modafinil is associatedwith an increase in unconstrained motor activity in chronicschizophrenia and this may have implications for future strategiesaimed at increasing volitional behaviour in those affectedby negative symptoms. In the light of recent reports of modafinil’scognitive-enhancing effects in chronic schizophrenia (Turner et al, 2004), and with further understanding of the brain systems throughwhich it acts (Spence et al, 2005; Hunter et al, 2006), theclinical potential for its use remains promising, although furtherwork is required.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

M.D.H. is supported by the Wellcome Trust. We thank ProfessorNancy Butte, Baylor College of Medicine, Texas, USA, for normativeActiwatch data. We also thank Dr Russell Green and nursingstaff from Rowan Ward, The Longley Centre, Northern GeneralHospital, Sheffield, UK.

REFERENCES

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