1. 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

3. 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:
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

4. 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.

5. 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-

6. 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:
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.

7. 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)

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

9. 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.

10. 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 Jan 31;8:3.

11. 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

13. 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)

14. Results- Continuous Performance Test

15. Results- Psychomotor Vigilance # of Lapses

16. Results- Psychomotor Vigilance Median Reaction Time

17. Results

18. 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

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

20. 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