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Home , Bitopertin, Cycloserine, Glutamatergic

Glutamatergic Agents for the Treatment of

Robert W. Buchanan, M.D.

Maryland Psychiatric Research Center Department of Psychiatry University of Maryland School of Medicine 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 • The Glutamatergic System

• Glutamate is the major CNS excitatory - 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 (learning/memory) Glutamate in Schizophrenia

• PCP blocks the gated by the NMDA-type glutamate : - Induces both positive and negative symptoms and cognitive impairments - Chronic PCP administration produces prefrontal 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 site of the NMDA receptor NMDA/AMPA 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 () • D- (agonist) • D-cycloserine () • AMPA receptor • (positive allosteric modulators) • • (Gly T1 inhibitor) • RG1678 (Gly T1 ) • D- 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 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 Domain Average Neurocognition z-Score -0,15 -0,05 CONSIST Study: Average of Nine Cognitive 0,05 0,15 -0,1 -0,2 0,2 0,1 0 D - D cycloserine removed) cycloserine (outliers versusplacebo, t=0.38, p=0.70 df= 122, - - cycloserine Specific 16 Adjusted for Baseline Score D - cycloserine cycloserine versusplacebo: t=2.50, p=0.018 df=122, Glycine Glycine versusplacebo: t=1.02, df=122, p=0.31

(outliers removed) D - cycloserine - Week Z

- scores by Treatment, Glycine Buchanan et al, et Buchanan Psychiatry,J Am 2007

Placebo

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 (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 • 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: • ; 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 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 – DSM-IV Schizophrenia or Schizoaffective disorder – 18-65 years – ≥ 6 months of clozapine treatment (200+ mg/day) – Minimum clozapine blood level: 350 ng/ml – BPRS total score ≥ 45 or CGI ≥ 4 and BPRS positive symptom score ≥ 8 with at least one item ≥ 4 • Minocycline: 200 mg/day

BPRS Positive symptom items

15

14,5

14 Minocycline 13,5 Placebo 13

12,5 BPRS Factor Psychosis BPRS

12

Minocycline - Placebo Difference= -0.87 ± SE 0.53, Effect Size= 0.34, p=0.104 Minocycline - Placebo Difference=-0.90 ± SE 0.54, Effect Size= 0.39, p=0.098 with one outlier removed

Kelly et al, submitted for publication SANS total and subscale scores

• SANS total score; p=NS

• SANS anhedonia subscale; p=NS

• SANS avolition subscale; – Minocycline/Placebo difference= -0.22 ± 0.09 (SE); p=0.012 – Effect size= 0.34 for avolition

Kelly et al, submitted for publication MCCB Composite and Domain Scores

• Composite score; p=0.56 • Domain x treatment interaction; F(6,41.6)= -2.78, p=0.03 MCCB Working Memory Domain Effect Size 36 Baseline Composite Score 0.08 35 Endpoint Attention/Vigilance 0.08 34 Processing Speed 0.09 33 32 Problem Solving 0.004 31 Social Cognition 0.1 30 Verbal Learning -0.35 29 Visual Learning 0.11 28 27 Working Memory 0.41 Minocycline Placebo

Kelly et al, submitted for publication Glutamatergic Agents for the Treatment of Schizophrenia

Conclusions: • Glutamatergic agents that modulate the NMDA receptor glycine site how shown inconsistent benefit for negative symptoms and cognitive impairments - Ability to adequately dose the drug - Optimal schedule of administration - Complexity of conducting large-scale studies • Adjunctive glutamatergic agents may be of potential benefit for those people who fail to adequately respond to clozapine