1. Neurochemical Models of Schizophrenia: Transcending the Dopamine Dogma Leslie Citrome, MD, MPH Professor of Psychiatry New York University School of Medicine Orangeburg, New York

2. Disclosure Leslie Citrome, MD, MPH Leslie Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals,* Avanir Pharmaceuticals, Azur Pharma Inc, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company,* Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals,* Jazz Pharmaceuticals, Merck,* Novartis,* Pfizer Inc,* Sunovion,* Valeant Pharmaceuticals,* and Vanda Pharmaceuticals. *Denotes a relationship in effect any time during the past 12 months

3. Dopamine Pathways and Key Brain Regions Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

4. Positive symptoms Hyperactive! High Schizophrenia: Too Much Dopamine? Mesolimbic pathway Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

5. Negative symptoms Cognitive s ymptoms Hypoactive Affective symptoms DLPFC VMPFC Low Schizophrenia: Too Little Dopamine? Mesocortical pathway Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

6. Sodhi M, et al. Expert Rev Neurother. 2008;8(9):1389-1406. Copyright © 2011 Expert Reviews. NONE OF THE CURRENTLY AVAILABLE ANTIPSYCHOTICS

7. SGAs: D 2 /5-HT 2A Antagonism Conventional first generation Atypical second generation Dopamine D 2 antagonist (blocker) Serotonin 5-HT 2A antagonist (blocker) Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. NEXT

8. Dopamine neuron Serotonin neuron D2D2 Atypical antipsychotic (serotonin- dopamine antagonist) 5-HT 2A Antagonism Stimulates Dopamine Because 5-HT 2A Function Is to Act as a Brake on Dopamine “5-HT 2A Antagonism Releases the Brake” Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. NEXT

9. “Tuning” Dopamine Output 5-HT 2A antagonism D 2 antagonism DA released DA blocked Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

10. Which Action Predominates? 5-HT 2A antagonism D 2 antagonism The answer depends on the region of the brain Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

11. Mesocortical Nigrostriatal Tuberoinfundibular 5-HT 2A Treat cognition, mood, negative Sx Minimize EPSMinimize prolactin elevation Takahashi H, et al. Biol Psychiatry. 2006;59(10):919-928. Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. Thus SGAs, Although They Can Block D 2 Receptors, Do Not Lead to Decreases in DA in Regions of the Brain Where DA Is Needed!

12. Mesolimbic D2D2 But SGAs Do Lead to Decreases in DA in Regions of the Brain Where There May Be Too Much! Treat positive Sx Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

13. Limitations of the Dopamine Model No consistent dopamine abnormalities have been discovered to date (except perhaps with COMT, an enzyme that breaks up dopamine) There are agents that have no D 2 binding affinity, yet reduce positive symptoms Ketamine induces increases in positive and negative symptoms not blocked by D 2 receptor antagonists Krystal JH, et al. Arch Gen Psychiatry. 1994;51(3):199-214. Patil ST, et al. Nat Med. 2007;13(9):1102-1107.

14. Schizophrenia: What About Glutamate? Glutamate is distributed widely and is the primary excitatory neurotransmitter in the human CNS Involved in both fast synaptic transmission and also in plasticity and higher cognitive functions Glutamate also can induce neurotoxicity Antagonists to glutamate receptors (ketamine and PCP) exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia AND can induce positive and cognitive symptoms in healthy volunteers Susceptibility genes for schizophrenia can influence the function of glutamate receptors Moghaddam B. Neuron. 2003;40(5):881-884. Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

15. d ‑ Ser = d-serine DTNBP1 = dysbindin mGluR = metabotropic glutamate receptor NRG1 = neuregulin 1 PSD = post-synaptic density proteins Sodhi M, et al. Expert Rev Neurother. 2008;8(9):1389-1406. Copyright © 2011 Expert Reviews. The Glutaminergic Synapse

16. Glutamate Pathways and Key Brain Regions thalamus striatum brainstem neurotransmitter centers NA NA = nucleus accumbens Additional deficits in schizophrenia come from dysfunction outside DLPFC areas, such as auditory and visual cortex. Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

17. Glutamate Receptors: Many Types Ionotropic (ie, involve ion channels) –AMPA: GluR1, GluR2, GluR3, GluR4 –Kainate: GluR5, GluR6, GluR7, GluR KA-1, GluR KA-2 –NMDA: NMDA R1 (isoforms A-G) and NMDA R2 (isoforms A-D) Metabotropic (G-protein coupled, ie, involve chemical second messengers) –Type I (mGluR1 and 5) –Type II (mGluR2 and 3) –Type III (mGluR4, 6, 7, and 8) Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

18. Ionotropic Glutamate Receptors: The Fine Print –AMPA (amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) Na + and K + – rapid kinetics Widely distributed, predominantly post-synaptic receptors Greatest density of the 3 ionotropic receptors –Kainate Na + and K + – rapid kinetics Predominantly pre-synaptic Located in hippocampus and cortex –NMDA (N-methyl-D-aspartate) Na +, K +, and Ca + – slower kinetics Structurally complex; activation occurs only if simultaneous glutamate and glycine binding and partial depolarization of the membrane potential Predominantly post-synaptic; concentrated primarily in the limbic system, co-localized with AMPA receptors Ca + as a second messenger; wide range intracellular responses → complex neurophysiologic phenomenon Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

19. Metabotropic Glutamate Receptors: The Fine Print –Seven transmembrane domains G-protein coupled Similar to most dopamine, serotonin, noradrenaline receptors Activate phospholipase C or inhibit adenylate cyclase –Type I—post-synaptic Occur in hippocampal, amygdala, and thalamic neurons Less in the cortex and ventral striatum –Types II and III—presynaptic modulators of glutamate release Type II mGluR2 restricted to the cortex and dentate gyrus mGluR3 only metabotropic subtype expressed on glia Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

20. NMDA, AMPA, and Metabotropic Receptors Gibb RL. Masters thesis. Lethbridge, Alberta: University of Lethbridge; 2001. Adapted from Hsueh YP, Sheng M. Prog Brain Res. 1998;116:123-131. Relationships between glutamate receptors and synaptic proteins: NMDA, AMPA, and metabotropic (mGluR) receptors bind to specific domain of synaptic proteins, such as PSD-95, GRIP, and HOMER, respectively All 3 can be found on a GABA interneuron mGluRs are located at the periphery of the synapse, whereas NMDA and AMPA receptors are located more centrally mGluRs also can be presynaptic and on glial cells

21. Metabotropic Glutamate Receptors mGluR2 and mGluR3—primarily on presynaptic neurons; coupled to G- proteins mGluR3 also is found on glia (astrocytes); regulates the expression of the glial glutamate transporter (ie, reuptake of glutamate) Agonists for mGlu2/3 receptors and allosteric potentiators of mGlu2 receptors block the effects of psychomimetics (such as PCP, amphetamine, 5-HT 2A agonists) in animals and/or humans –These agents prevent glutamatergic hyperexcitations in limbic circuits that have been associated with the actions of psychotogens and possibly in the symptoms of schizophrenia Weinberger DR. Nat Med. 2007;13(9):1018-1019. Copyright © 2007, Nature Publishing Group. Schoepp DD. Neuropsychopharmacology. 2006; 31(Suppl 1):S25-S26.

22. LY2140023, an mGlu2/3 Agonist: Efficacy and Tolerability Acute Schizophrenia 28-Day Phase II RCT Both LY2140023 and olanzapine resulted in improvements in PANSS, PANSS-P, PANSS-N, CGI-S vs placebo (MMRM, P < 0.0001) LY2140023 was not associated with EPS or prolactin elevation; it was associated with nausea LY2140023 resulted in weight loss vs placebo compared with weight gain seen with olanzapine Patil ST, et al. Nat Med. 2007;13(9):1102-1107. Copyright © 2007 Nature Publishing Group. **P ≤ 0.01; ***P ≤ 0.001 LY2140023 Olanzapine (15 mg/d) Placebo 15 10 5 0 -5 -10 -15 -20 -25 01234 Week Change in PANSS Total ** *** **

23. LY2140023: Current Status Second study failed to replicate the first – This was a failed study where the active control (olanzapine) also did not separate from placebo Other studies in progress as noted in www.clinicaltrials.gov (7 listed as of January 30, 2011) Kinon BJ. Presented at: American Neuropsychiatric Association (ANPA) 21st Annual Meeting; March 17-20, 2010; Tampa, Florida.

24. Ionotropic Glutamate Receptors as Targets AMPA Ampakine CX516 was tested in a RCT as an adjunct to antipsychotics—no advantage Kainate Topiramate as an adjunct to antipsychotics—1 positive RCT, 1 equivocal RCT, but topiramate has been associated with cognitive dulling NMDA Multiple RCTs of adjunctive glycine, D-serine, D-cycloserine, sarcosine, and investigational agents—NMDA receptors may be the best option as a therapeutic target Goff DC, et al. Neuropsychopharmacology. 2008; 33(3):465-472. Citrome L. Expert Rev Neurother. 2009;9(1):55-71. Kantrowitz JT, Javitt DC. Clin Schizophr Relat Psychoses. 2010;4(3):189-200.

25. AMPA and Kainate Receptors Na + K+K+ K+K+ K+K+ K+K+ AMPA Kainate Resting State Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

26. Na + K+K+ K+K+ K+K+ K+K+ AMPA Kainate Glutamate Open and Depolarized Na + K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ AMPA and Kainate Receptors Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

27. Na + Ca ++ Glutamate Resting Na + Ca ++ Mg ++ Glycine NMDA NMDA Receptors Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

28. Na + Ca ++ NMDA Glutamate Depolarized and Open Na + Ca ++ Glycine Mg ++ AMPA or kainate NMDA Receptors Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

29. Cortical glutamate regulates brainstem monoaminergic neurons by: Glutamatergic fibers projecting to brainstem neurons (accelerator) Cortical Glutamate Regulates Dopamine Neurons in 2 Possible Ways: Direct Accelerator or Indirect Brake Direct action as an accelerator Cortex + GLU DA Adapted from Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197. Carlsson A, et al. Br J Psychiatry Suppl. 1999(37):2-6.

30. Cortical glutamate regulates brainstem monoaminergic neurons by: Indirectly by fibers projecting to the glutamatergic/gaba-ergic pathway from cortex to brainstem (brake) Cortical Glutamate Regulates Dopamine Neurons in 2 Possible Ways: Direct Accelerator or Indirect Brake Indirect action as brake Cortex + - GLU GABA DA Adapted from Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197. Carlsson A, et al. Br J Psychiatry Suppl. 1999(37):2-6.

31. Cortical glutamate regulates brainstem monoaminergic neurons in 2 possible ways: 1. Directly, by means of glutamatergic fibers projecting to brainstem neurons (accelerator) 2. Indirectly by fibers projecting to the glutamatergic/gaba-ergic pathway from cortex to brainstem (brake) Feedback loops probably exist, possibly via the thalamus and the striatum Cortical Glutamate Regulates Dopamine Neurons in 2 Possible Ways: Direct Accelerator or Indirect Brake Direct action as an accelerator Indirect action as brake Cortex + + - GLU GABA DA Adapted from Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197. Carlsson A, et al. Br J Psychiatry Suppl. 1999(37):2-6.

32. GABA neuron DA neuron glu neuron Overactivation Normal Baseline Hypoactivation NMDA Receptor Regulation of Mesolimbic Dopamine Pathway: Tonic Inhibition Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

33. GABA neuron DA neuron glu neuron High Positive Symptoms Normal state Glutamate acts as a brake on DA Hypoactive state Glutamate brake is off NMDA Receptor Hypofunction in Cortico-Brainstem Projections: Hyperactivity of Mesolimbic Dopamine Pathway Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. Overactivation Normal Baseline Hypoactivation

34. Normal state Cortical glutamate provides tonic excitation of mesocortical DA glu neuron NMDA Receptor Regulation of Mesocortical Dopamine Pathways: Tonic Excitation Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. Overactivation Normal Baseline Hypoactivation

35. Low Affective symptoms Negative symptoms Cognitive symptoms Hypoactive state Excitation is lost NMDA Receptor Hypofunction in Cortico-Brainstem Projections: Hypoactivity of Mesocortical Dopamine Pathways Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. Coyle JT. Cell Mol Neurobiol. 2006;26(4-6):365-384. Overactivation Normal Baseline Hypoactivation

36. More About NMDA Receptors In order for the receptor to be activated, both glutamate AND glycine are required, as well as partial depolarization of the membrane potential D-serine also has high affinity for the glycine site on NMDA receptors An analogue of D-serine, D-cycloserine, also is active at the glycine co-agonist site of NMDA receptors Therapeutic options: administer glycine, D-serine, or D-cycloserine or increase the availability of glycine some other way Stahl SM. CNS Spectr. 2007;12(6):423-427.

37. Glycine Reuptake Pump Inhibition The GLY-T1 reuptake pump is the major route of inactivation of synaptic glycine Several GLY-T1 inhibitors exist, including sarcosine and drugs in clinical development GLY-T1 inhibitors are analogous to drugs that inhibit reuptake of other neurotransmitters (eg, SSRIs and their actions at the serotonin transporter) When GLY-T1 pumps are blocked by a GLY-T1 inhibitor, this increases the synaptic availability of glycine-enhancing NMDA neurotransmission Stahl SM. CNS Spectr. 2007;12(6):423-427.

38. Summary Although all currently available antipsychotic agents have at least some degree of antagonism at the dopamine D 2 receptor, some experimental agents reduce psychotic symptoms in the absence of dopamine D 2 receptor antagonism Glutamate receptor dysfunction upstream of dopamine can be an explanation for the symptoms of schizophrenia Several novel therapeutic targets involving glutamate receptors are under active investigation, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists

39.  Questions? nntman@gmail.com