Simple Solution for Challenging Questions of CNS Disorders; One Size Fit It All? G. Emil Tsai, MD, PhD UCLA School of Medicine

Transcription

1 Simple Solution for Challenging Questions of CNS Disorders; One Size Fit It All? G. Emil Tsai, MD, PhD UCLA School of Medicine

2 Disclosure Consultant: Amgen, Genentech,, Chugai SyneuRx International ( 心悅生醫 )

3 CNS Disorder 1990 WHO report indicated that 5 of the 10 leading causes of disability were CNS conditions Major CNS Disorders are: Depression/major depressive disorder Schizophrenia Epilepsy Insomnia Alzheimer's disease Parkinson s s Disease Migraine Attention deficit hyperactivity disorder

4 Outline

5 Is there a common vulnerability?

6 Neuropsychopharmacology (2010) 35, ;

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8 Main CNS Neurotransmitters Excitation Inhibition Glutamic acid -aminobutyric acid

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10 A common mechanism for CNS illnesses: NMDA (N methyl( methyl D aspartate) Account for 85% synapses in CNS. The mechanism for cognition, experience dependent learning, plasticity and CNS development. When NMDA fails, it fails in different ways. 10

11 Long Term Potentiation Experience-dependent Learning

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13 Neurodevelopmental model of schizophrenia TR Insel Nature 468, (2010)

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15 Experiment Behavior Hippocampal neurogenesis Stress Alone Depressed Decreased Stress + Prozac Normal Normal Stress + x-ray + Prozac Depressed (decreased by the x- rays)

16 Outline

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18 The $42.6 million CATIE study The effectiveness of most marketed antipsychotic medications in almost 1,500 patients for 18 months. They found three-quarters of the patients wanted to switch to a different medication after 18 months, which was attributed to: the medication s lack of efficacy side effects

19 Post-synaptic PCP Mg ++ GCS glycine L-Serine serine recemase D-serine DAAO Gly-T1 OH-pyruvate sarcosine glycine D-serine glycine glutamate aspartate ASC-1 glycine D-serine D-alanine G72 ± DAAO OH-pyruvate Astrocyte Pre-synaptic

20 Cluster Profile of Schizophrenia Cluster 1 Cluster II F(1.51) p CSF glutamate <.0005 VBR <.0005 BPRS thought 3.88 disorder <.0005 Tsai et al 1998 Biol Psychiat

21 Gene of Adam, G72 Only in great apes Only human codes G72 protein Strongly linked to schizophrenia and bipolar disorder

22 Post-synaptic PCP Mg ++ GCS glycine L-Serine serine recemase D-serine DAAO Gly-T1 OH-pyruvate sarcosine glycine D-serine glycine glutamate aspartate ASC-1 glycine D-serine D-alanine G72 ± DAAO OH-pyruvate Astrocyte Pre-synaptic

23 H D-cycloserine NH2 C C O CH2 NH O A partial agonist of the NMDA-glycine site

24 Dose Finding Study of D-cycloserine SANS SANS Placebo D-cycloserine (mg/day) Reaction time Placebo Sternberg s s Item recognition Paradigm

25 D-cycloserinea A Partial Agonist of NMDA Receptor

26 Preclinical Studies of D-serineD D-serine is selectively enriched in forebrain (Kumashiro,, 1995 ) with regional distribution and the postnatal changes closely parallelling the NMDA receptors (Hashimoto, 1993) D-serine is located close to the NMDA receptor on dendritic spines (Schell, 1997) D-serine is present in animal dialysate and human CSF

27 Serine racemase synthesises D-serine from L-serine Forebrain astrocytes Neuronal expression Serine racemase D-serine Wolosker et al., (1999) Kartvelishvily et al., (2006)

28 Disruption of Serine Racemase

29 Disruption of Serine Racemase

30 D-serine H O NH2 C C CH2 OH OH

31 Improvement of Negative Symptoms by D-serine D Treatment 1 SANS -3-7 D-serine Placebo

32 D-alanine H O NH2 C C CH3 OH A full agonist of the NMDA-glycine site D-alanine passes the blood-brain brain barrier freely Very low D-alanineD level in the brain except pituitary EC M (D-serine 0.93 M)

33 Improvement of Negative Symptoms by D-alanineD Treatment D-alanine Placebo Week 2 Week 4 Week6

34 Post-synaptic PCP Mg ++ GCS glycine L-Serine serine recemase D-serine DAAO Gly-T1 OH-pyruvate sarcosine glycine D-serine glycine glutamate aspartate ASC-1 glycine D-serine D-alanine G72 ± DAAO OH-pyruvate Astrocyte Pre-synaptic

35 Borowsky Neuron 1993

36 Borowsky Neuron 1993

37 [11C]GSK931145

38 n PNAS 1998 Validation of Glycine Transporter-I

39 Administration of 10 μm glycine and 10 μm d-serine increase the amplitude of the evoked NMDAR currents of pyramidal cells in WT mice but not in GlyT1(+/-) mice. Tsai G et al. PNAS 2004;101: by National Academy of Sciences

40 Spatial Retention Is Better in GlyT1 knockout mice.

41 PPI (Left) and locomotor activity (Right) in GlyT1 WT (+/+) and HZ (+/-) mice. Tsai G et al. PNAS 2004;101: by National Academy of Sciences

42 Glycine transporter-1 agonist antagonist glycine N-methylglycine sarcosine

43 N-methyl Glycine (sarcosine) Natural amino acid Methyl donor GlyT-1 1 antagonist Weak NMDA agonist

44 ** P<0.01, *** P<0.001, Mixed Model Repeated Measures analysis Improvement in Positive and Negative Syndrome Scale (PANSS) Total score over 6 weeks 0 Mean percentage change from baseline in PANSS total score Placebo Sarcosine Study Week ** ***

45 ** P<0.01, *** P<0.001, Mixed Model Repeated Measures analysis Improvement in Global Assessment of Functioning (GAF)) score over 6 weeks Mean percentage change from baseline in GAF score Placebo Sarcosine ** *** Study Week

46 Effect Size (r) Total psychopathology Negative symptom Positive Symptom Cognitive symptom

47 * * * * * * 47 * * * Percentage of immobility time D-serine (mg/kg) i.p. * * * * * * * * * Sarcosine (mg/kg) i.p.

48 30 25 HAMD17 total scores * * ** Citalopram Sarcosine Study Week

49 *** Citalopram Sarcosine *** ** Study Week Global Assessment of Function (Axis V in DSM IV)

50 For Depression Better and Beyond SSRI GlyT 1 1 inhibitor, sarcosine 65% remission rate CGI 4.5 >3.6 50

51 51

52 Bipoterpin, RG1678 Emmanuel Pinard J. Med. Chem. 2010

53 Effect of RG1678 on LTP in rat hippocampal slices

54 Prevention of amphetamine-induced hyperlocomotion by RG1678

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56 New Schizophrenia Treatment New class, first of the class Goal of efficacy: from 20% to 50% improvement Pathophysiology based (NMDA antagonists are psychotogenic) Improve negative and cognitive components Improve Functional outcome 56

57 Nothing New Glycine site agonists GlyT1 inhibitors D-Amino acid oxidase inhibitor tryptophan SSRI, Prozac MAOI

58 D-amino acid Regulation D-amino acid oxidase (DAO) degrades D-amino acids Active in hindbrain and cerebellum

59 Verrall et al., (2007) Eur J Neurosci D-amino acid oxidase expression Frontal cortex Cerebellum

60 Benzoic acid was discovered in the 16th century. The dry distillation of gum benzoin was first described by Nostradamus (1556)

61 Benzoate DAAOI(d amino acid oxidase inhibitors) or NMDA enhancer Application: Food preservatives (E211) Safety: Daily intake: mg/kg, not toxic Ref: INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ( ] CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT NO. 26, )

62 PANSS-Total Placebo BE Quality of life Quality of life Increase 74% Placebo BE P ANSS-P osit ive SANS Placebo BE Placebo BE Confidential for Anchen Pharmaceuticals, Inc Only Negative Sympto

63 63 ES ES PANSS total 1.76 GSA 1.35 PANSS positive 1.83 QLS 1.66 PANSS negative 1.44 SANS 1.25 PANSS general 1.29 CGI 1.20 PANSS cognitive 1.05 HAMD 0.84

64 NIMH (National Institute of Mental Health, USA) Recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS( MATRICS) 7 Cognitive Domains Speed of Processing Attention/ Vigilance Reasoning/ Problem solving erbal & Non-verbal orking memnory Social cognition: Measured by MSCEIT MATRICS Verbal learning/ memory Visual learning/ memory

65 Benzoate improves neurocognition T score change (endpoint - baseline) Placebo Benzoate * * * 0 Speed of Processing Attention / Vigilance Working Memory Verbal Learning Visual Learning Reasoning and Problem Solving Composite neurocognition

66 Comparing benzoate to the other NMDA treatments Effect size of PANSS DAOI: 1.76 Other NMDA agents:

67 Invent the Other Wheel antipsychotic+daao inhibitor Functional improvement Cognitive improvement Improvement in negative symptoms 67

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69 Emil Kraepelin Paul Eugen Bleuler dementia praecox Flattened Affect, Autism, Impaired Association, Ambivalence

70 Slicing or Lumping, Dimensional or categorical prevalence psychosis thought disorder mood autism repetitive cognition reward anxiety Schizophrenia 1% Premenstrual 3-30% Depression 10% OCD 2.5% ADHD 5-10% MCI 22% Dementia 14% Substance 10% Parkinson 0.5-3%

71 1. Reward Circuit 2. Cortico-basal ganglia Reward 3. Corticostriatal, goaldirected 4. Executive function 5. Episodic memory 6,9 Fear & anxiety 7. Emotion regulation 10. Mood 11. Addiction 12,13. Schizophrenia 14. ADHD

72 Brain fails in different way The remedy can be from one mighty source