Treatment of InsomniaPresentation Objectives:Function of SleepSlide 4The Sleep CycleDuring the Sleep CycleDuring the Sleep Cycle (cont.)Sleep needs vary over the life cycle.Sleep patterns and characteristics change over the life cycle.Sleep Promoting CNS NeurotransmittersPowerPoint PresentationConditions of Insomnia:Insomnia PrevalenceCauses and Types of InsomniaReduced Total Sleep Time Impacts Health & Next-day FunctioningSlide 16Slide 17Slide 18Slide 19Slide 20Slide 21AntidepressantsTCAs (Not FDA approved for hypnotic use)SSRIs/SNRIs (Not FDA approved for hypnotic use)Effects of Newer Antidepressants on Sleep and Waking BehaviorTrazodone (Not FDA approved for hypnotic use)Select Benzodiazepines*BenzodiazepinesMOA of BZDs and Non-BZDs: The Role of GABAA ReceptorsMOA and GABAA Receptor ComplexNon-Benzodiazepines (GABA-A Receptor Allosteric Modulators)Non-benzodiazepines, cont.Non-benzodiazepines (cont)Slide 34Slide 35Slide 36Ramelteon (Rozerem)Slide 38Slide 39Slide 40ConclusionsSlide 42Information on sleep and sleep disordersMiodrag Radulovacki M.D., Ph.D.Department of PharmacologyUICTreatment of InsomniaPresentation Objectives: Briefly review function of sleep and neurotransmitters associated with promotion of sleepReview current and newly approved therapies for the treatment of insomnia – including mechanisms of action and pharmacologyDiscuss agents in clinical development for the potential treatment of insomnia and their mechanisms of actionFunction of Sleep“If sleep does not serve an absolutely vital function, then It is the biggest mistake the evolutionary process ever made.” A. RechtschaffenFunction of Sleep1. Restoration and recovery Sleep serves to reverse and/or restore biochemical and / or physiological processes degraded during prior wakefulness2. Energy conservation10% reduction of metabolic rate below basal level3. Memory consolidation4. Thermoregulation5. HomeostasisThe Sleep CycleAlternating states and stages of sleep that occur over an 8-hour time period:NREM: Non-Rapid Eye Movement; Stages 1-4; 75% of the nightREM: Rapid Eye Movement; Dreams occur; 25% of the nightDuring the Sleep CycleBrain waves represent different stages of sleep.NREM Stages of Sleep REM SleepDuring the Sleep Cycle (cont.)Body temperature lowersHormone levels rise and fallSleep needs vary over the life cycle.Newborns/Infants0 - 2 months:2 - 12 months:10.5-18 hours14-15 hoursToddlers/Children12 mo - 18 mo:18 mo - 3 years:3 - 5 years:5 - 12 years:13-15 hours12-14 hours11-13 hours10-11 hoursAdolescentsOn Average: 9.25 hoursAdults/Older PersonsOn Average: 7-9 hoursSleep patterns and characteristics change over the life cycle.Newborns/InfantsMore active in sleep; 50% REM; several periods of sleep; need napsToddlersSleep begins to resemble adult patternsChildrenExperience more deep sleepAdolescentsShift to later sleep-wake cycle; experience daytime sleepinessAdultsNeed regular sleep schedule to obtain sufficient, quality sleep Older AdultsMore likely to have medical problems; sleep disrupters & disorders; sleep less efficientlySleep Promoting CNS Neurotransmitters GABA (inhibitory amino acid) Ventral Lateral Pre-Optic Nucleus (VLPO) within anterior hypothalamus -- “command & control center” for sleepInhibitory connections to thalamus, descending projections inhibit cell bodies and dendrites of serotonin, norepinephrine, histamine, acetylcholine-producing inter-neurons Role: Initiation and maintenance of sleep spindles and SWSMelatonin (hormone of darkness)Secreted from pineal gland during darkness/ indirectly feedbacks to SCNHigh levels secreted prior to sleepLevels low during wakefulnessConditions of Insomnia:InsomniaPrimary InsomniaSecondaryInsomniaInsomnia that is not a result of another condition-hyper-arousal disorder Insomnia resulting from:•Psychiatric: depression, anxiety•Medical conditions: pain, CV, neurological or GI illnesses•Substance abuse•Behavior•Another primary sleep disorder• RLS/PLMS•Apnea•Narcolepsy•Circadian rhythm disordersOver 30% of American adults experience occasional insomnia; 10% on a chronic basisThose most at risk:WomenOlder adults Pts w/ psychiatric disordersPts w/ medical disorders (pain syndromes, asthma, CV 2nd / 3rd shift workersInsomnia PrevalenceCauses and Types of Insomnia CauseType DurationChange: acute illness; jet lag, emotional stressStress: loss of loved one or jobAcuteTransient: few nights a weekShort Term: 1 – 2 weeksVariety of physical, medical, psychiatric or environmental conditionsChronic> 1 month (at least 3 nights a week)Not associated with underlying or known cause.Primary> 1 monthChronic stress, hyperarousal, or behavioral conditioning may contribute.ChronicReduced Total Sleep Time Impacts Health & Next-day FunctioningIncreased number (4.5-fold) of serious accidents or injuries2 200,000 MVA each year caused by drowsiness (US DOT)Impaired alertness & memoryImpaired psychomotor performanceIncreased healthcare utilization3 and absenteeism1Mahowald et al. Sleep Medicine. 2000; 1: 179. 2Balter et al. J Clin Psychiatry. 1992; 53 Suppl: 34 3Simon et al, Am J Psychiatry. 1997; 154: 1417Treatment of Insomnia Behavioral Interventions – CBT (Cognitive Behaviral Therapy) PharmacologicalOTCs (Over-The-Counter)DiphenhydramineDoxylamineL-TryptophanMelatoninAlcoholPlant based herbals – Valerian, Chamomile, Hops, Lemon Balm, Lavender, Ylang Ylang, Melissa, Passion Flower, Kava KavaBarbituratesChloral HydrateAntidepressantsGABA-A Receptor Allosteric ModulatorsBenzodiazepinesNon-Benzodiazepines Melatonin Receptor AgonistsAntidepressantsTricyclic Antidepressants (TCAs)SSRIs/SNRIsTrazodoneTCAs (Not FDA approved for hypnotic use)Tertiary amines (amitriptyline, doxepin,imipramine..) greater sedation than secondary amines (desipramine, nortriptyline, protriptyline) TCAs decrease REM sleep & prolong REM latencyMay increase TST but may worsen periodic limb movements (PLMs)/ specific agents may prolong SWSMOA: Block 5-HT and NE reuptake/ anticholinergic and antihistaminic activity Weak alpha-1 blockade results in orthostatic hypotensionTCAs have poor sleep onset activityAcute withdrawal can cause REM reboundSSRIs/SNRIs (Not FDA approved for hypnotic use)Antidepressant drugs can both improve and disturb