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Glutamatergic Agents for the Treatment of Schizophrenia Robert W. Buchanan, M.D. Maryland Psychiatric Research Center Department of Psychiatry University of Maryland School of Medicine Glutamatergic Agents for the Treatment of Schizophrenia • The glutamatergic system • Glutamatergic agents for the treatment of negative symptoms and cognition • Adjunctive glutamatergic agents for clozapine non- responders • Lamotrigine • Minocycline The Glutamatergic System • Glutamate is the major CNS excitatory neurotransmitter - Primarily localized in cortical pyramidal neurons - Corticostriatal and thalamocortical projections • Two major classes of glutamatergic receptors: - Ionotropic receptors • N-methyl-D-aspartate (NMDA) • Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) • Kainate - Metabotropic receptors • Group I: mGluRs 1 and 5 • Group II: mGluRs 2 and 3 • Group III: mGluRs 4, 6, 7, and 8 • Glutamatergic mechanisms are important for neuroplasticity, including long-term potentiation and depression (learning/memory) Glutamate in Schizophrenia • PCP blocks the ion channel gated by the NMDA-type glutamate receptor: - Induces both positive and negative symptoms and cognitive impairments - Chronic PCP administration produces prefrontal dopamine depletion • Increased glutamatergic activity is hypothesized to produce positive symptoms - Rationale for mGlu 2/3 antagonist development • Decreased glutamatergic activity is hypothesized to produce negative symptoms and cognitive impairments - Rationale for development of agents that modify the glycine site of the NMDA receptor NMDA/AMPA Glutamate Receptor Complex Yang & Svensson, Pharmacolgy & Therapeutics, 2008 Glutamatergic Agents for the Treatment of Schizophrenia • The glutamatergic system • Glutamatergic agents for the treatment of negative symptoms and cognition • Adjunctive glutamatergic agents for clozapine non- responders • Lamotrigine • Minocycline Glutamatergic Agents for the Treatment of Schizophrenia • NMDA receptor glycine site • D-glycine (agonist) • D-serine (agonist) • D-cycloserine (partial agonist) • AMPA receptor • ampakines (positive allosteric modulators) • Glycine transporter • sarcosine (Gly T1 reuptake inhibitor) • RG1678 (Gly T1 reuptake inhibitor) • D-amino acid oxidase D-Glycine: PANSS Negative Symptom Scores by Treatment and Week Effect Size = 0.8 F = 21.8, P<.001 35 30 25 20 15 10 Glycine 5 Placebo Negative SymptomsNegative 0 Week 0 Week 2 Week 4 Week 6 Heresco-Levy et al, Arch Gen Psych, 1999 D-Cycloserine: Changes in SANS Total Score Goff et al, Arch Gen Psych, 1999 The CONSIST Study (Buchanan et al, Am J Psychiatry, 2007) Study Design: • 16-week, Double-blind, Double-dummy, Placebo-controlled, 4-site multicenter study • Diagnoses: Schizophrenia or schizoaffective disorder • Subjects: • Inpatients and Outpatients • Any antipsychotic other than clozapine • Moderate to severe persistent negative symptoms • Modified SANS total score ≥ 20 • SANS affective flattening or alogia global item score ≥ 3 • No unstable or severe positive, depressive or EPS • BPRS positive symptom score ≤ 18 • BPRS anxiety/depression factor score ≤ 14 • SAS total score ≤ 8 • Glycine: 60 gm/day and D-cycloserine: 50 mg/day CONSIST Study: SANS Total Score 60 50 40 30 D-cycloserine (n=52) 20 Glycine (n=52) Placebo (n=53) 10 Mean SANS Total Score Total SANS Mean 0 0 4 8 12 16 Week D-cycloserine vs. placebo, t= -0.11, df=550, p=0.92 Glycine vs. placebo, t=0.47, df=550, p=0.64 Buchanan et al, Am J Psychiatry, 2007 CONSIST Study: Average of Nine Cognitive Domain-Specific 16-Week Z-scores by Treatment, Adjusted for Baseline Score 0,2 0,15 Score - 0,1 0,05 0 -0,05 -0,1 D-cycloserine D-cycloserine Glycine Placebo -0,15 (outliers removed) Average Neurocognition z Neurocognition Average -0,2 D-cycloserine versus placebo: t=2.50, df=122, p=0.018 D-cycloserine (outliers removed) versus placebo, t=0.38, df= 122, p=0.70 Glycine versus placebo: t=1.02, df=122, p=0.31 Buchanan et al, Am J Psychiatry, 2007 Glutamatergic Agents for the Treatment of Schizophrenia D-Serine: NMDA receptor glycine site agonist Multiple clinical trials have examined efficacy: • Tsai et al (Biol Psych, 1998): D-serine (30 mg/kg/day) effective for PANSS negative and positive symptoms • Heresco-Levy et al (Biol Psych, 2005): D-serine (30 mg/kg/day) effective for PANSS negative and positive symptoms • Weiser et al (J Clin Psych, 2012): D-serine (30 mg/kg/day) was no more effective than placebo for negative symptoms or cognition - largest trial to date High-dose D-Serine Kantrowitz et al, SZ Res, 2010 Glutamatergic Agents for the Treatment of Schizophrenia D-Cycloserine • Study Design (Goff et al, Sz Res, 2008): - 8-week, double-blind, placebo-controlled - Outpatients with schizophrenia (N=50) - Any antipsychotic other than clozapine - D-Cycloserine: 50 mg, once per week - Primary Outcome measure: SANS total score • Results: - Significant benefit for SANS total score • Most pronounced effects in the affective flattening and anhedonia subscales Glutamatergic Agents for the Treatment of Schizophrenia Glycine Reuptake Inhibitors Sarcosine: • Tsai et al (Biol Psych, 2004): Significant benefit for SANS total score, global psychopathology and positive symptoms • Lane et al (Biol Psych, 2006): Sarcosine failed to separate from placebo in participants treated with clozapine • Lane et al (Int J Neuropsychopharm, 2010): Sarcosine, but not D-serine, was significantly more effective than placebo for PANSS, SANS, and QLS total scores and GAF Effect of Bitopertin (RG1687) on Negative Symptoms Umbricht et al, JAMA Psychiatry, 2014 Glutamatergic Agents for the Treatment of Schizophrenia • The glutamatergic system • Glutamatergic agents for the treatment of negative symptoms and cognition • Adjunctive glutamatergic agents for clozapine non-responders • Lamotrigine • Minocycline Glutamatergic Agents for the Treatment of Schizophrenia Clozapine and Glutamate: • Clozapine interacts with the glutamatergic system, though the exact nature of these interactions are unknown • May act at the glycine site of the NMDA receptor • In pre-clinical studies, acute clozapine administration: • Increased medial prefrontal cortical glutamate and aspartate concentrations (Daly and Moghaddam, Neurosci Letters, 1993; Yamamoto and Cooperman, 1994) • Enhanced NMDA-mediated neurotransmission (Arvanov et al, J Pharmacol Exp Ther, 1997) • Blocked NMDA antagonist induced neurotoxicity (Olney and Farber, J Clin Psych, 1994) • People treated with clozapine have higher serum glutamate levels (Goff et al AM J Psych, 1996; Evins et al, J Neural Trans, 1997) Glutamatergic Agents for the Treatment of Schizophrenia: Lamotrigine Mechanism of Action: • Anticonvulsant drug • Sodium (Na+)-channel antagonism, which regulates glutamate release in the brain • Mediated through the AMPA glutamatergic receptor • Synergistic effect with clozapine on PCP-induced hyperlocomotion • Increases GABA release Glutamatergic Agents for the Treatment of Schizophrenia: Lamotrigine Global Outcome: BPRS or PANSS Total Score Tiihonen et al, SZ Research, 2009 Glutamatergic Agents for the Treatment of Schizophrenia: Lamotrigine Conclusions: • Lamotrigine was superior to placebo: • Global Outcome (effect size: 0.57) • Positive Symptoms (effect size: 0.34) • Negative Symptoms (effect size: 0.43) • Lamotrigine was associated with a significantly higher responder rate • Lamotrigine: 40.7% versus Placebo: 10.0% • NNT = 4 • The study with the most pronounced therapeutic effect had the longest trial duration (Zoccali et al, 2007) Glutamatergic Agents for the Treatment of Schizophrenia: Minocycline Mechanism of Action: • Antibiotic; derivative of tetracycline - Penetrates the blood brain barrier • Glutamatergic actions: - Increases phosphorylation of the GluR1 subunit, which leads to increased AMPA receptor density • Anti-inflammatory actions: - Inhibits 5-lipoxygenase - Inhibits microglia proliferation and activation • Anti-oxidative stress actions: - Inhibits nitric oxide synthase Glutamatergic Agents for the Treatment of Schizophrenia: Minocycline Previous Studies in Schizophrenia: • Levkovitz et al (J Clin Psychiatry, 2010): - Study Design: 22-week; adjunctive; double-blind; placebo- controlled; N=54 - Sample: early onset people with schizophrenia or related disorders - No significant effects for PANSS positive, negative, or general subscales • Chaudhry et al (J Psychopharmacol, 2012): - Study Design: two-country; 8-week; adjunctive; double-blind; placebo-controlled; N=140 - Sample: early onset people with schizophrenia or related disorders - Significant benefit for PANSS negative subscale; the effects for PANSS positive and general subscales varied with country Glutamatergic Agents for the Treatment of Schizophrenia: Minocycline Previous Studies in Schizophrenia: • Liu et al (Sz Research, 2014): - Study Design: 16-week; adjunctive; double-blind; placebo- controlled; N=92 - Sample: early onset people with schizophrenia or related disorders - Significant benefit for SANS total score PANSS negative subscale; no effect on cognition • Khodaie-Ardakani et al (Int J Psychopharm, 2014): - Study Design: 8-week; adjunctive; double-blind; placebo- controlled; N=40 - Sample: multi-episode schizophrenia or related disorders - Significant benefit for PANSS total and positive and negative subscale scores Glutamatergic Agents for the Treatment of Schizophrenia: Minocycline Study Design (Kelly et al, submitted for publication): • 10-week, double-blind, placebo-controlled, 2-site study • Participant Inclusion Criteria
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