Contemporary Treatments for Sleep Disorder Thomas C. Neylan, M.D. San Francisco Veterans Affairs Medical Center NCIRE- The Veterans Health Research Institute University of California, San Francisco Thomas.Neylan@ucsf.edu

Sedative-Hypnotic Pharmacodynamics GABA Most abundant CNS inhibitory neurotransmitter Primary inhibitory VLPO neurotransmitter Effects of medications enhancing GABA Sedative Anxiolytic Muscle relaxation Anticonvulsant Multiple GABA receptors (GABAA, GABAB) All of the sedative-hypnotics promote their sedative effect by enhancing the normal inhibitory activity of GABA, which is the most abundant CNS inhibitory neurotransmitter. There is a global CNS effect, as well as inhibition in the ventrolateral preoptic nucleus (VLPO), which is a key region of sleep regulation. Substances that enhance GABA activity may function as hypnotics, sedatives, anxiolytics, muscle relaxants, and anticonvulsants. There are several types of GABA receptors. Sedative-hypnotics interact with the GABAA receptor. Benca RM. Diagnosis and treatment of chronic insomnia: A review. Psychiatric Services 2005;56:332-343. Rowlett JK, Cook JM, Duke AN, Platt DM. Selective antagonism of GABAA Receptor Subtypes: An in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs. CNS Spectrums 2005;10:40-48. Mitler MM. Nonselective and selective benzodiazepine receptor agonists – where are we today? Sleep. 2000;23(Suppl 1):S39-47. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. The Journal of Pharmacology and Experimental Therapeutics 2002;300:2-8. VLPO = ventrolateral preoptic nucleus

Sedative-Hypnotic Pharmacodynamics (Cont.) Compounds interacting with GABAA receptor complex Benzodiazepine receptor agonists Barbiturates Neurosteroids Alcohol Benzodiazepine receptor agonists are positive allosteric modulators of GABA at the GABAA receptor complex A wide variety of substances, including some toxins, interact with the GABAA receptor complex at various attachment sites. Among these are benzodiazepine receptor agonists (including the sedative-hypnotics), barbiturates, neurosteroids, alcohol, and picrotoxin. The benzodiazepine receptor agonists are positive allosteric modulators of GABA at the GABAA receptor complex. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. The Journal of Pharmacology and Experimental Therapeutics 2002;300:2-8. Rowlett JK, Cook JM, Duke AN, Platt DM. Selective antagonism of GABAA Receptor Subtypes: An in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs. CNS Spectrums 2005;10:40-48.

GABAA Receptor Complex Cl- Cl- Cl-   Extracellular  γ BZ receptor site  Cell membrane The GABAA receptor complex controls the influx of negative chloride ion into the neuron. When GABA attaches to the receptor complex, chloride ions are able to enter the cell. If a benzodiazepine receptor agonist also is present at the BZ receptor site, the process is enhanced allowing more chloride ions to enter the cell. This has the effect of enhancing the hyperpolarization and the inhibitory action of GABA. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. The Journal of Pharmacology and Experimental Therapeutics 2002;300:2-8. Rowlett JK, Cook JM, Duke AN, Platt DM. Selective antagonism of GABAA Receptor Subtypes: An in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs. CNS Spectrums 2005;10:40-48. Intracellular Cl-

GABAA Receptor Complex  Subunit Subtypes Partial myorelaxation, ataxia <5 α5 Myorelaxation (only at high doses), ataxia 10-15 α3 Anxiolytic, myorelaxation 15-20 α2 Sedation, amnesia, partial anticonvulsant, ataxia 60 α1 Known Action Mediated % of CNS GABAA Receptors  Subunit There are 6 known GABAA α subunits (α1-α6) in the CNS.1 Recent animal studies using a variety of approaches have increased our understanding of the physiologic and pharmacologic properties of the various α subunits. The α1 subunit is associated with sedation, amnesia, ataxia, and anticonvulsant effects and is the most widespread in the CNS1-3; the α2 subunit is associated with anxiolytic and myorelaxation effects and the α3 and α5 subunits with myorelaxation and ataxia.1,3 Subunits α4 and α6 are insensitive to BzRAs.1 Nonselective BzRAs, such as the classic benzodiazepines, demonstrate more or less indiscriminate binding to a variety of GABAA complexes, including those with α1, α2, α3, or α5 subunits.3 Some newer nonbenzodiazepine agents bind selectively to α1 receptor types, with low affinity for α2 and α3.3 1. Möhler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2-8. 2. Crestani F, Assandri R, Täuber M, Martin JR, Rudolph U. Contribution of the α1-GABAA receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology. 2002;43:679-684 3. Mendelson WB, Roth T, Casella J, et al. The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev. 2004;8:7-17.

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance Department of Defense (DOD) Deployment Related Medical Research Program (DRMRP) Advanced Technology/Therapeutic Development Award NCIRE/UCSF/SFVAMC: (Neylan- Initiating PI) SRI: (Kilduff)

Orexin/Hypocretin Pathways Wake & REM sleep Sleep/wake balance NonRem Sleep Wake Saper et al., 2005

Primary Hypothesis regarding Mechanism Hypocretin (Hcrt) antagonists produce fewer functional impairments than BzRAs because the latter produce a global inhibition of neural activity whereas Hcrt specifically disfacilitates wake-promoting systems.

Hypocretin/Orexin Antagonist Almorexant Promotes Sleep Without Impairment of Performance in Rats S.R. Morairty, A. Wilk, W. T.C. Neylan, T.S. Kilduff. Front Neurosci. 2014 Jan 31;8:3.

Design- Human Trial Parallel group randomized controlled trial; Almorexant 100mg Almorexant 200mg Zolpidem 10mg Placebo Medication free healthy men and women Ages 19-39 Study medications administered mid-point during habitual wake period (3PM) Neurocognitive performance assessed pre-dose, during peak concentration (60 to 120 minutes post-dose), and during the residual phase up to 6 hours post dose

Subjects (N=203) ` ALM 100mg ALM 200mg ZOL 10mg Placebo N 48 53 49 52 Age 26 (20–38) 26 (19–38) 27 (20–38) % Female 63 66 61 62 Educ (yrs.) 16.2 (1.6) 16.0 (2.1) 16.0 (1.7) 16.0 (1.5)

Results- Continuous Performance Test

Results- Psychomotor Vigilance # of Lapses

Results- Psychomotor Vigilance Median Reaction Time

Results

Summary For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. Performance decrements for ALM was less than ZOL but greater than PBO. Some cognitive measures demonstrated a dose effect of ALM

Conclusion A hypocretin/orexin receptor antagonist produces less functional impairment than a benzodiazepine receptor agonist

Collaborators Steve Batki MD Linda Chao PhD Beth Cohen MD Richard Hauger, MD Sabra Inslicht PhD Daniela Kaufer, PhD Thomas Kilduff PhD Shira Maguen PhD Dieter Meyerhoff PhD Stephen Morairty PhD Aoife O’Donovan PhD Madhu Rao MD Anne Richards MD Kristin Samuelson PhD Norbert Schuff PhD Karen Seal MD Mike Weiner MD Rachel Yehuda, PhD