2010-V14 aanvraag Van der Werf

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  • 1.SLAAP- EN STEMMINGSSTOORNISSEN BIJ DE ZIEKTE VAN PARKINSON; EENBEHANDELSTUDIE MET LICHTTHERAPIE.(Sleep and mood disorders in Parkinsons disease: a treatment study using brightlight therapy)Dr. Ysbrand D. van der Werf1,2,5, Dr. Odile A. van den Heuvel1,3,5, Dr. Henk W.Berendse4,5, Dr. Elisabeth M. Foncke4,5Afdelingen 1Anatomie & Neurowetenschappen, 2Slaap en Cognitie, NederlandsInstituut voor Neurowetenschappen, 3Psychiatrie, 4Neurologie, VU University MedicalCenter (VUmc), 5Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. OVERZICHTSlaapstoornissen en depressie vormen een belangrijke bedreiging voor de kwaliteitvan leven van mensen met de ziekte van Parkinson. Vaak treden deze stoornissenvroeg op in het beloop van de ziekte, nog voorafgaand aan de kenmerkendebewegingsstoornissen. Naast een directe invloed op het welzijn, verergeren dezesymptomen de motorische verschijnselen. Helaas zijn er op dit moment beperkte,veelal medicamenteuze mogelijkheden om slaap en stemming bij Parkinsonpatinten te verbeteren, waarbij regelmatig bijwerkingen optreden. Het verbeterenvan slaap- en stemmingsstoornissen langs niet-farmacologische weg zou niet alleendirect bijdragen aan het verbeteren van de kwaliteit van leven, maar bovendien viaeen gunstig effect op de motorische verschijnselen een additioneel effect hebben opde kwaliteit van leven.Zeer recent hebben wij evidentie gekregen voor het gunstig effect van lichttherapieop stemming en slaap bij ouderen met en zonder dementie, vanuit onderzoek vanonze afdelingen Psychiatrie (Vumc-GGZ inGeest) en Slaap en Cognitie (NIN). Lichtis een goedkope en gemakkelijk te implementeren behandeling zonder bijwerkingendie potentieel een grote bijdrage kan leveren aan de kwaliteit van leven.De hier voorgestelde studie beoogt de effecten van lichttherapie bij Parkinsonpatinten te onderzoeken in een gerandomiseerde placebo-gecontroleerdebehandelstudie. Tachtig patinten met de ziekte van Parkinson worden gencludeerden verdeeld over de placebo- en de echte behandeling. Na 3 maanden behandelingvindt een evaluatie plaats, waarna de placebo-groep alsnog de echte behandelingkrijgt. Na nog eens drie maanden vindt dan een eindevaluatie plaats, waarmee delange-termijn effecten van de behandeling worden gemeten. Als primaireuitkomstmaten worden stemmingsmaten genomen. Daarnaast willen wij slaap-parameters meten en (afhankelijk van additionele financiering) de motorischesymptomen, een aantal fysiologische parameters (cortisol en melatonine uitspeeksel) en biologische ritmes vaststellen (actigrafie). De behandeling en allemetingen zijn non-invasief. DOELHet directe doel van dit onderzoek is een therapie te ontwikkelen die ingezet kanworden in de klinische praktijk. Wij verwachten dat lichttherapie een gunstig effect zalhebben op stemming en de verstoorde slaap in de ziekte van Parkinson. Ditonderzoek past binnen de lijn van onderzoek van de afdelingen Neurologie,Anatomie en Neurowetenschappen en Psychiatrie van het VU Medisch Centrum, dieeen traditie hebben in onderzoek en behandeling van niet-motorische symptomen bijde ziekte van Parkinson. Het hier voorgestelde project is ingebed in een grotere lijnvan onderzoek, waarvoor van verschillende bronnen financiering wordt gezocht. Hethier aangevraagde deel betreft de centrale financiering voor de behandeling enmeting van slaap en stemming. De secundaire maten worden afhankelijk vanadditionele financiering meegenomen.

2. KOSTEN EN AANGEVRAAGD BEDRAG2011 20122013 2014Aanvraag:Onderzoeks- 10.000 20.000 20.000 10.000 60.000assistent 0.5 fte, 3jaarMateriaal: testen, 20.000 20.000vervoerskosten,hardware voor lampplaatsen,vragenlijsten, etc.Extra financiering aangevraagd bij ZonMW clinical fellow/Hersenstichting (dr O.A. vanden Heuvel):Assistent in 37.000 38.000 39.000 40.000 164.000opleiding,1.0 fte, 4 jaar Totaal 244.400 Totaal elders 164.400 Aanvraag 80.000Deze aanvraag zal ons, bij toekenning, in staat stellen om de 1) lichttherapie uit tevoeren, 2) de slaapscores en stemmingsmetingen te doen en 3) de gedragsmatigeritmes te meten, met de hulp van een onderzoeksassistent. Mochten wij extrafinanciering verkrijgen bij de Hersenstichting of NWO ZonMW, breiden wij hetpersoneel uit met een promovendus, bepalingen van cortisol en melatonine in hetspeeksel. Dit levert, naast een promotie en kennis over de fysiologische ritmes, meerarmslag op om de gegevens vlot uit te werken en te publiceren. 3. APPENDIX: ACHTERGROND EN UITGEWERKT PROTOCOLBACKGROUNDDisturbances of mood and sleep in Parkinsons diseaseParkinsons disease (PD) is the second most frequent neurodegenerative disorder.PD has long been considered as a pure motor disorder secondary to basal gangliadegeneration with typical motor symptoms, such as bradykinesia, rigidity, tremor, andpostural imbalance. However, it has become well established that Parkinsonsdisease affects patients lives in a much broader sense than merely the motorimpairment (Rodriquez-Oroz et al. 2009; Park & Stacy 2009). The quality of life of PDpatients as well as their caregivers largely depends on the presence of so-callednon-motor features, which are highly prevalent in PD. Frequent non-motor disordersin PD are autonomic dysfunctions, olfactory impairments, sleep disorders,depression, anxiety, psychosis, cognitive dysfunctions/dementia, and impulse-controldisorders. Some non-motor features appear in the course of the disease or inresponse to dopaminergic treatment, but other symptoms (including depression andsleep disturbances) appear before motor symptoms are even recognized.Depression occurs in about 40-50% of patients throughout the course of the disease(Cummings, 1992). Sleep dysfunction is even more common, occuring in about 60-95% of all PD patients (Stacy 2002; Menza et al. 2010). Sleep disorders in PDinclude a reduced total sleep time, reduced sleep efficiency, increased sleepfragmentation and excessive daytime sleepiness. The relationship betweendepression and sleep is complex and not well understood. Depressed mood is one ofthe major risk factors for sleep disorders in PD (Larsen and Tandberg, 2001).Conversely, a major concern of chronic poor sleep is its propensity to facilitate thedevelopment of depression (Pigeon et al, 2008; Roane and Taylor, 2008; Thase etal, 1997), for which Parkinson patients are already at high risk. Despite the highprevalence of mood and sleep disorders in PD and despite the fact that the primarydeterminants of poor quality of life in patients with PD are sleep disturbances,depression and lack of independence, these symptoms are commonlyunderdiagnosed and undertreated. Chronic sleep disorders compromise mental andphysical health, autonomy and well-being of elderly subjects (Van Someren, 2000).Controlled studies in healthy elderly people, moreover, show that even a mild sleepdisturbance is detrimental to cognitive performance and brain function (Van der Werfet al, 2009). Finally, the benefit derived from a good nights sleep on motor function iswell-known among PD patients (Tandberg et al, 1999). Therefore, it is important torecognize disturbances of mood and sleep in patients with PD and to start adequatetreatment as soon as such disorders have been diagnosed.Unmet needs for treatment of depression and sleep disorders in PDAdequate treatment of these chronic sleep and mood disorders in PD constitutes oneof the greatest unmet needs in the care of PD patients. The treatment alternativesfor depression in PD patients have been poorly studied and no evidence-basedparkinson-specific depression treatment guideline exists. The general guideline forthe treatment of depression consists of the following 6 steps: 1) selectiveserotonergic re-uptake inhibitor (SSRI)/serotonergic-noradrenergic re-uptake inhibitor(SNRI), 2) SSRI/SNRI 3) tricyclic antidepressant (TCA), 4) lithium addition to TCA, 5)MAO-inhibitor, 6) electro-convulsive treatment (ECT). Due to both the side-effectsand non-response or incomplete response to SSRI/SNRI/TCAs, the treatment ofdepressive PD patients is often difficult. Lithium addition and, to a lesser degree,MAO-inhbitors are not optimal due to the unfavourable influence on the motorsymptoms (mainly tremor) and the autonomic functions. Moreover, PD patients, whoalready use multiple types of dopaminergic medication, often hesitate or refuse to 4. take antidepressant medication. Hypnotic drugs indicated for sleep disturbances arenot suitable for chronic use due to the development of tolerance and the risk ofdecreased daytime functioning (e.g. excessive daytime sleepiness) and falling,where PD patients already have daytime sleepiness and postural imbalance. Basedon these limitations in available treatment strategies, there is a high need for aneasily available, patient-friendly and effective therapy for mood and sleep disordersin PD. There are indications that improved sleep, for instance after bright lighttherapy, contributes to both motor and cognitive functioning in PD, to the extent thateven dopaminergic medication may be lowered (Willis and Turner, 2007). PDpatients often report being less disabled for 40 to 60 minutes after waking ascompared to later in the day, a phenomenon called sleep benefit (Parkes, 1983).Also, PD patients report better motor function after a night of good sleep (Tandberget al, 1999). Such findings indicate that improving sleep of PD patients optimizes thecompensatory potential of PD patients, within the limits of their disease. An obviousimmediate benefit of improved sleep and mood would be the reduction indopaminergic, antidepressant and sleep medication.Circadian rhythms and PDPD is characterized by extensive sleep problems, affecting both night and daytimefunctioning: night-time sleep is less efficient and more fragmented, whereas daytimesleepiness is markedly enhanced. Such a pattern of too much wake during the nightand too much sleep during the day is indicative of impaired circadian rhythmicity.Indeed, several reports show that PD patients are phase-advanced (Bordet et al., 2003;Fertl et al., 1991, 1993): the peak plasma concentrations of melatonin secretion occurearlier in PD patients compared to age-matched controls. This, in combination with theinsecurity patients feel about their postural balance or the need for help to move,leads to a downward spiral where patients expose themselves less frequently tobright environmental light, further aggravating the circadian problems. In addition,photoreception declines with aging, which may result in partial light deprivation of thephoto-sensitive regions of the brain regulating rhythmicity, i.e. the suprachiasmaticnucleus (SCN) and pineal gland. Together, these factors contribute to the attenuatedcircadian rhythm in older age and specifically in PD (Willis, 2008).Circadian rhythmicity can be assessed using actigraphy, i.e. a wrist-worn measurementdevice providing information about movement density and duration. When the actigraphicrecording is coupled to bedtimes, obtained from the patient either in the form of a diary orby measurements using a pressure-pad and ambient light recordings, sleep parameterssuch as fragmentation and efficiency can be measured as well (van Someren, 2006).Actigraphy has proven to be a valid method for measuring sleep and rhythm disturbancesin PD (Stravitsky et al, 2010) and it has been shown by our group to be a sensitivemarker for sleep improvement in PD patients (van Dijk et al, 2009).Stimulation of the light-sensitive regions of the brain, by means of brightenvironmental light (bright light therapy, BLT) may thus help to normalize mood,sleep, circadian rhythms and hypothalamic-pituitary axis (HPA) activity. Phase-advanced rhythms warrant the use of relatively late bright light administration, to interferewith the early onset of melatonin secretion.BLT could be hypothesized to be particularly suitable in the management ofdepression in PD, especially since antidepressants tend to have substantial sideeffects in PD patients. The combined use of bright light therapy with actigraphy willhelp to judge the effects of the treatment on circadian rhythms.Bright light and disturbance of mood and sleepThe beneficial effect of BLT in seasonal affective disorder (SAD) is well accepted,with an early onset of action, and a mild side effect profile. Results of BLT in non-seasonal depression were inconclusive until recently. In Amsterdam a large RCTwas performed in elderly residents of group care facilities, with a variety of 5. neuropsychiatric disorders (Riemersma-van der Lek et al, 2008). The study showedthat BLT strongly attenuated depressive symptoms in these patients. Another doubleblind placebo controlled RCT in Amsterdam focused on the effect of BLT on mood,sleep and circadean rhythm in non-seasonal depression in elderly (Lieverse et al.2010). The results showed that BLT improves mood, sleep and circadian activity andhormonal rhythms (melatonin and cortisol) in these depressed elderly. The effects ofbright light therapy on sleep disturbances has been well-documented, both in primaryand secondary sleep disorders: in primary insomnia, bright light treatmentameliorates sleep quality, cognitive functioning and brain activation indices (Altena etal, 2008a/2008b), and in elderly with dementia BLT for 2 years improved sleepcharacteristics and slowed mental deterioration (Riemersma-van der Lek et al, 2008).Effects of bright light on motor, mood and sleep in PD: earlier studiesIn PD, very few investigations have addressed the use of BLT for sleep and mooddisturbances, and the effects have been inconclusive (Willis and Turner, 2007; Pauset al, 2007). One pilot study used 15 days of BLT in a placebo controlled design; theauthors investigated sleep and depression and found an improvement of depressionscores in the treated group but not the placebo group; as sleep measures the onlyparameter investigated was a one-item daytime sleepiness scale, which did not showa differential effect between groups. An effect on other sleep parameters may thushave gone unnoticed and the authors themselves agree that their study isexploratory and that the data need to be followed up with studies using longertreatments (Paus et al, 2007). Another study was an open-label non-placebo-controlled case series study in 12 patients with PD, who received between 2 and 5weeks of BLT. The results show improvements in psychiatric wellbeing, motorfunction and sleep. Interestingly, the improvement in motor functions even allowed toreduce the daily dose of dopaminergic medication (Willis and Turner, 2007). ARussian study (english abstract available only) reports improvements in 40 PDpatients receiving 10 exposures of BLT, both in motor and in mood scores(Artemenko and Levin, 1996)These first preliminary reports of BLT in PD provide positive findings that warrantfurther study. In addition, the studies indicate that the treatment was well tolerated bythe patients.PROPOSALA randomized, double-blind, placebo-controlled clinical trial desig...

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