Handout for the Neuroscience Education Institute (NEI) online activity: Cognitive Impairment in Schizophrenia: The Great Unmet Need

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1 Handout for the Neuroscience Education Institute (NEI) online activity: Cognitive Impairment in Schizophrenia: The Great Unmet Need

2 Learning Objectives Assess and monitor cognitive impairment in patients with schizophrenia over time Incorporate evidence-based treatment strategies into the management of cognitive impairment in schizophrenia Describe the underlying neurobiology of cognitive impairment in schizophrenia Describe novel mechanisms under investigation for the treatment of cognitive impairment in schizophrenia

3 Question Schizophrenia is primarily a: A. Cognitive disorder B. Psychotic disorder

4 Pretest Question 1 During adolescence, what general brain changes occur? A. Pruning of excitatory synapses and proliferation of inhibitory circuits B. Pruning of both excitatory synapses and inhibitory circuits C. Proliferation of inhibitory circuits and pruning of excitatory synapses D. Proliferation of both excitatory synapses and inhibitory circuits

5 Pretest Question 2 What novel mechanism has the best evidence of efficacy for cognitive symptoms in schizophrenia A. Anti-inflammatory B. Cholinergic C. GABAergic D. Glutamatergic

6 Cognitive Impairment in First-Episode, Drug-Naïve Schizophrenia Drug naïve first-episode schizophrenia (n=37) Previously treated (n=65) Z-Score Abstraction Verbal Attention Verbal Fluency Verbal Learning Memory Visuomotor Spatial Memory Saykin AJ et al. Arch Gen Psychiatry 1994;51(2): Sensorymotor

7 Cognitive Impairment in Schizophrenia at Baseline of Clinical Trial Mean T Score Healthy Normative Sample, N=300 Schizophrenia Patients, N=323 0 Composite Processing Speed Attention Working Memory Verbal Learning Visual Learning Reasoning Social Cognition Keefe RS et al. Schizophr Res 2011;125(2-3):161-8.

8 Cognitive Functioning Correlates With Functional Ability N=117 schizophrenia patients. N=77 healthy controls. August SM et al. Schiz Research 2012;134:76-82.

9 Cognitive Impairment Is Pervasive in Schizophrenia Majority of schizophrenia patients demonstrate cognitive impairment relative to healthy controls 1,2 Small percentage do not, but might still be below expectations Almost all monozygotic twins perform worse than unaffected co-twin 3 98% of schizophrenia patients have cognitive functioning lower than expected based on mother's education 1 1. Keefe et al. Biol Psychiatry 2005;57(6): Reichenberg et al. Schizophr Bull 2009;35(5): Goldberg et al. Arch Gen Psychiatry 1990;47:

10 Low Premorbid IQ Increases Risk of Schizophrenia; Evident by Age 13 * * *Included participants ages Excluding these studies yielded similar results. Dickson H et al. Psychol Med 2012;42(4):

11 Low Premorbid IQ Increases Risk of Schizophrenia; High IQ Is Not Protective Schulz J et al. Schizophr Bull 2014(40):

12 Premorbid IQ Does Not Correlate With Risk of Affective Disorders Schulz J et al. Schizophr Bull 2014(40):

13 Premorbid Scholastic Achievement Is Poor and Declines During Adolescence Iowa State Percentile Rank Grade 4 a Grade 8 a Grade 11 b c d e f 35 Vocabulary Reading Language Sources of information a Iowa Tests of Basic Skills. b Iowa Tests of Educational Development. c Significantly lower than median percentile rank (F=5.89, df=1, 45, p<0.05). d Significantly lower than: median percentile rank (F=7.80, df=1, 45, p<0.01), grade 4 (F=5.04, df=1, 45, p<0.05), grade 8 (F=4.97, df=1, 45, p<0.05). e Significantly lower than: median percentile rank (F=5.63, df=1, 45, p<0.05), grade 8 (F=6.40, df=1, 46, p=0.01). f Significantly lower than median percentile rank (F=4.77, df=1, 45, p<0.05). Fuller R et al. Am J Psychiatry 2002;159: Math Composite

14 Specificity of Poor Premorbid Cognitive Function and Decline in Schizophrenia Full-Scale IQ Age at IQ Assessment Meier MH et al. Am J Psychiatry 2014;171(1):

15 Decline in Verbal Ability During Adolescence Predicts Risk of Psychosis Verbal ability at age 18 did not predict schizophrenia or schizoaffective disorder: 0.78 ( ), P=.06 Decline in verbal ability from age 13 to 18 did predict schizophrenia or schizoaffective disorder: 0.88 ( ), P< population-based cohorts of adolescent boys and young men (total N=10,717) MacCabe JH et al. JAMA Psychiatry 2013;70(3):

16 Cognitive Impairment Remains Stable After Psychosis Onset Patient baseline Patient retest Control retest Inhibition* WCST Perseverative Responses* Category Switching Category Fluency Letter Fluency** Letter Number Sequencing Digit Span Backward patients and 107 age/gender-matched controls assessed at baseline and at 1-year follow-up *Significant time x group interaction **Significant time effects for patients and controls Haatveit B et al. Psychiatry Res 2015;228(3):

17 Cognitive Impairment Begins Premorbidly and Persists Throughout the Course IMPAIRMENT Premorbid risk Prodrome Acute Chronic Genetic vulnerability Mild cognitive impairment Disability Childhood (~0 13) Change in thoughts Social isolation Reduced school performance Adolescence (~13 18) Hallucinations Delusions Disorganized thoughts Cognitive deficits Social deficits Loss of insight Loss of function Early adulthood (~20s) Loss of function Medical complications Unemployment Homelessness Adulthood Insel TR. Nature 2010;468:187-93; McGorry PD et al. Arch Gen Psychiatry 2008;65:25-7; Correll CU. J Clin Psychiatry 2013;74:e04; Mosolov SN et al. Ann Gen Psychiatry 2012;11:1.

18 ASSESSING AND TREATING COGNITIVE IMPAIRMENT: CURRENT STANDARD OF CARE

19 NIMH MATRICS Initiative Goals were to create a standardized cognitive battery: As an outcome measure in clinical trials of medications As an outcome measure for studies of cognitive remediation As a measure of cognitive change in repeated testing applications As a cognitive reference point for non-intervention studies of schizophrenia and related disorders Led to the MATRICS Consensus Cognitive Battery (MCBB)

20 Cognitive Domains Assessed in the MCCB Cognitive Domain Speed of processing Attention/Vigilance Working Memory Verbal Learning and Memory Visual Learning and Memory Reasoning and Problem Solving Social Cognition Tests Category Fluency BACS Symbol Coding Trial Making A Continuous Performance Test Letter-Number Span WMS-III Spatial Span Hopkins Verbal Learning Test-R Brief Visuospatial Memory Test-R NAB Mazes MSCEIT Managing Emotions

21 Comprehensive Cognitive Performance Assessments MATRICS Consensus Cognition Battery (MCCB) CogState Cambridge Neuropsychological Test Automated Battery (CANTAB) ADVANTAGES Address all 7 MATRICS cognitive domains Sufficient items to generate test-retest reliability Associated with change index to calculate amount of change that will define improvement/worsening DISADVANTAGES Significant time to administer and score Require tester training and credentials Acquisition costs Missing data create scoring challenges Keefe RSE et al. Schizophr Bull 2015;Epub ahead of print.

22 Brief Cognitive Performance Assessments Brief Assessment of Cognition in Schizophrenia (BACS) Brief Cognitive Assessment (BCA) ADVANTAGES Address most domains yet take less time Evidence that shorter tests are equally sensitive Lower cost DISADVANTAGES Shorter tests often have less reliability Reduced number of domains tests Testers require training and supervision Keefe RSE et al. Schizophr Bull 2015;Epub ahead of print.

23 Interview-Based Measures of Cognition Schizophrenia Cognition Rating Scale (SCoRS) Cognitive Assessment Interview (CAI) Measure of Insight into Cognition ADVANTAGES Brief (~15 min per interview) Good relationship to realword function Good test-retest reliability High correlation with some performance-based measures of cognition DISADVANTAGES Weak relationship to objective cognitive and functional measures Validity and correlations with performance-based measures depend on availability of informant Some training required Keefe RSE et al. Schizophr Bull 2015;Epub ahead of print.

24 Performance-Based Measures of Functional Capacity UCSD Performance-Based Skills Assessment (UPSA) Test of Adaptive Behavior in Schizophrenia (TABS) Independent Living Scale (ILS) ADVANTAGES Able to predict failures to achieve milestones May correlate more strongly with real-world functioning than cognitive measures Easily tolerated High test-retest reliability and minimal practice effects in large-scale clinical trials DISADVANTAGES Relationship to cognitive change may be indirect Comprised of functional tasks that are not consistently required across cultures Lack alternate forms; practice effect in real world? Ceiling effect for highfunctioning patients Keefe RSE et al. Schizophr Bull 2015;Epub ahead of print.

25 Interview-Based Assessments of Real-World Functioning Specific Levels of Functioning (SLOF) ADVANTAGES Assesses social functioning, vocational and nonvocational productive functioning, and residential independence and self-care Functional scales are acceptably correlated with performance-based measures DISADVANTAGES Requires input of informants Changes are likely to take longer to detect Keefe RSE et al. Schizophr Bull 2015;Epub ahead of print.

26 Cognitive Remediation Therapy Designed to improve neurocognitive abilities, including attention and memory Pencil/paper tasks; computer exercises; can be tailored to address individual areas of weakness Improvement in executive functioning predicts improved daily functioning FOCUS (Function and Overall Cognition in Ultrahigh risk States) trial Wykes T et al. Am J Psychiatry 2011;168(5):472-85; Penades et al. Schizophr Res 2006;87:323-31; Penades et al. Psychiatry Res 2010;177:41-5; Medalia, Choi. Neuropsychol Rev 2009;19:353-64; Eack et al. Arch Gen Psychiatry 2010;67(7):674-82; Cella et al. Schizophr Res 2014;156-60; Eack et al. Psychiatry Res 2013;209:21-6; Farenny et al. Schizophr Res 2013;150:58-63; Glenthøj LB et al. Trials 2015;16:25.

27 Cognitive Remediation Therapy: Meta-analysis 2,104 participants Durable effects on global cognition and functioning Effect size 0.45 (95% CI ) No treatment element (remediation approach, duration, computer use, etc.) was associated with cognitive outcome More effective when patients were stable More effective when combined with psychiatric rehabilitation Wykes T et al. Am J Psychiatry 2011;168(5):

28 Auditory Cortical Plasticity Drives Training- Induced Cognitive Changes in Schizophrenia Dale CL. Schizophr Bull 2015;Epub ahead of print.

29 PREMORBID SCHIZOPHRENIA: IS THE EARLIEST MANIFESTATION A DISRUPTION IN BRAIN DEVELOPMENT/CONNECTIVITY?

30 Brain Development/Connectivity: What Are the Implications for Cognitive Impairment? Cognition Requires Proper Signaling Throughout the Brain attention sensory processing reasoning problem solving planning visual processing organizing working memory decision making response inhibition learning semantic memory episodic memory Millan MJ et al. Nat Rev Drug Discovery 2012;11:

31 Brain Changes During Normal Development birth age 5 age 20 Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

32 Brain Changes During Normal Development Competitive elimination of synapses (loss of dendritic arborization) Prefrontal excitatory synapses Prefrontal DA innervation Prefrontal inhibitory synapses age 5 ages 6 19 age 20 Adapted from Stahl SM. Stahl's Essential Psychopharmacology. 4th ed and Insel TR. Nature 2010;468(7321):

33 The "At-Risk" Brain Increased glx Increased striatal DA (glutamate and synthesis and release glutamine) capacity; predictive of conversion Competitive elimination of synapses (loss of dendritic arborization) de la Fuente-Sandoval 2013 & 2011 Decreased volume in frontal and temporal areas (similar to but less than in schizophrenia) Wood 2013 Prefrontal excitatory synapses Howes 2009 & 2011, Bonoldi 2013 Prefrontal DA innervation Prefrontal inhibitory synapses age 5 ages 6 19 age 20 Adapted from Stahl SM. Stahl's Essential Psychopharmacology. 4th ed and Insel TR. Nature 2010;468(7321):

34 Intracranial volume Progressive Brain Changes Decreased in Schizophrenia Premorbid Prodrome First episode Chronic Decreased* Gray matter Decreased** White matter Glx Increased*** *Most pronounced in frontal and temporal areas **Twin studies suggest it reflects genetic risk rather than the effects of the illness ***In medicated first-episode patients, glx is normal Haijma et al. Schizophr Bull 2013;39(5):

35 The "At-Risk" Brain Competitive elimination of synapses (loss of dendritic arborization) Prefrontal excitatory synapses Prefrontal DA innervation Prefrontal inhibitory synapses age 5 ages 6 19 age 20 Adapted from Stahl SM. Stahl's Essential Psychopharmacology. 4th ed and Insel TR. Nature 2010;468(7321):

36 Competitive Elimination: Normal Development normal synaptic normal synaptic glu low activity NMDA-R AMPA-R LTP strong synapse survives competitive elimination weak synapse is competitively eliminated

37 NMDA, Brain Development, and Proper Signaling NMDA receptors During brain are comprised development, of 4 subunits the subunit composition of NMDA receptors switches Ideally, this makes the receptor more suitable for optimal timing of firing and thus swifter integration of environmental stimuli Timing of switch differs by brain region and may coincide with risk windows Abnormalities in a mature NMDA receptor subunit profile may affect LTD and LTP such that pruning in adolescence becomes random Insel TR. Nature 2010;468(7321):187-93; Feinberg I. J Psychiatr Res ;17:

38 Premorbid NMDA and GABA Receptors glu GAD67 (glutamic acid decarboxylase) alpha 2 GABA-R hypofunctional receptor NMDA NMDA receptor and synapse glu GABA

39 Mesocortical Pathway to DLPFC hypofunctional NMDA glutamate synapse normal low DA neuron negative symptoms cognitive symptoms

40 Mesolimbic Pathway hypofunctional NMDA glutamate synapse normal high DA neuron overactivation positive symptoms

41 Neuroinflammation and NMDA Receptor Dysfunction Epidemiological studies consistently show increased risk of schizophrenia following pre- and perinatal infections Microglial activation: reduced neurotrophic function, production of proinflammatory cytokines, production of free radicals, and increased glutamate NMDA-R activation: antioxidant production NMDA-R hypofunction: leaves brain vulnerable to neurotoxicity Activation of IL-6/NOX2 pathway can induce loss of parvalbumincontaining interneurons, which would increase activation/desynchrony of the second glutamate cortical neuron Could inflammation be a cause of increased glutamate in at-risk/ first-episode patients rather than (or in addition to) NMDA-R hypofunction? Kahn RS, Sommer IE. Mol Psychiatry 2015;20:84-97; Canetta S et al. Am J Psychiatry 2015;171(9):960-8.

42 Cholinergic System Modulates DA, Glutamate, and GABA PFC glu neuron PPT/LDT ACh neuron 7 4ß2 VTA stimulation activates stimulation Glu release activates DA release glu GABA ACh DA VTA DA neuron GABA interneuron PPT: pedunculopontine tegmental nucleus LDT: laterodorsal tegmental nucleus

43 Multiple Susceptibility Genes Converge on NMDA Synapses in Schizophrenia dysbindin neuregulin DISC1 neuregulin GAD67 GABA 2 GABA-R CHRNA7 ACh RGS4 DAOA ErbB4 RGS4 D2RD3R MAO-A MTHFR RGS4 D-serine AKT glu COMT NUR77 DA TOH calcyon spinophilin 5HTT 5HT MAO-A NMDA receptor RGS4 Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

44 FROM NEUROBIOLOGY TO CLINICAL PRACTICE: NOVEL TREATMENT MECHANISMS

45 Clinical Translation: Treatment Mechanisms Beyond Dopamine Neurobiological data: rationale for why current antipsychotics don't seem to improve cognition Prospect of novel mechanisms Glutamatergic GABA-ergic Cholinergic Anti-inflammatory

46 Novel Treatment Mechanisms: Glutamate glutamate neuron glial cell AMPA modulators CX-516 piracetam cyclothiazide LY direct acting glycine site agonists d-cycloserine glutamate d-serine glycine glycine transporter inhibitors sarcosine bitopertin (RG1678) glycine transporter mglu receptor modulators AMPA receptor NMDA receptors postsynaptic metabotropic receptor LY LY

47 Glutamate Positive Modulators: Results Not Promising for Cognition Meta-analysis of 17 studies (N=1,391) Measure: standardized mean differences (SMDs) between active drug and placebo (added to antipsychotic) No significant effect on overall cognitive function (total or each individual agent) 11 studies, n=858; SMD=0.08, 95% CI No significant effect on each of 8 cognitive domains n= ; SMD= Iwata Y et al. Mol Psychiatry 2015;Epub ahead of print.

48 Novel Treatment Mechanisms: GABA GABA binding site BZ binding site alpha 2/3 selective MK-0777 negative results Buchanan RW et al. Biol Psychiatry 2011;69:442-9; Stahl SM. Stahl's Essential Psychopharmacology. 4th ed

49 Novel Treatment Mechanisms: Cholinergic PFC PFC glu neuron nicotinic receptor glutamate agonists: alpha 7 nicotine VTA DMXB-A encenicline TC-5619 RG-3847 muscarinic 1/4 receptors agonist xanomeline nicotinic receptor agonists: alpha 4 beta 2 PPT/LDT ACh neuron cholinesterase inhibitors donepezil rivastigmine galantamine varenicline VTA DA neuron GABA interneuron Opler LA et al. CNS Spectrums 2014;19(2):

50 Adjunct Cholinesterase Inhibitors: Meta-analysis Cognitive domains Attention (1 RCT, n=73, MD % CI ) Visual memory (2 RCTs, n=48, MD % CI ) Verbal memory and language (3 RCTs, n=42, MD % CI ) Executive functioning (1 RCT, n=24, MD % CI ) Singh J et al. Cochrane Database Syst Rev 2012;1:CD

51 Galantamine: Also a Nicotinic PAM Duration Dosage Participants Measures Outcome 8 weeks 24 mg/d 14 schizophrenia or schizoaffective patients (8 galantamine, 6 placebo) 12 weeks 12 weeks 12 months 16 mg/d 24 schizophrenia patients (12 galantamine, 12 placebo) 24 mg/d 86 schizophrenia patients (42 galantamine, 44 placebo) 24 mg/d 32 schizophrenia or schizoaffective patients (15 galantamine, 17 placebo) RBANS Several Several Several Significant effect on composite score (attention and delayed memory) Significant effect on RCFT (recognition) Significant effect on digit symbol and verbal memory WAIS-III No significant effects PAM: positive allosteric modulator. Vreeker A et al. Eur Neuropsychopharmacol 2015;Epub ahead of print.

52 Nicotinic Modulators Nicotine (nasal spray, gum, or patch) Significant enhancing effect on working memory, attention, and novelty detection (placebo-controlled trials) Seen in tobacco users and non-tobacco users DMXB-A (alpha 4 and 7 partial agonist) 1 positive study, 1 negative study Alpha 7 agonists TC-5619: 1 positive study, 1 negative study RG-3487: negative study Encenicline: 2 positive studies Vreeker A et al. Eur Neuropsychopharmacol 2015;Epub ahead of print.

53 Encenicline: Positive Effects on EEG Biomarkers Cognitive processing markers: Mis-Match Negativity (p=0.02) and p300 (p=0.008) Early sensory processing marker: p50 (p=0.07) 0.3 mg: n=8 1.0 mg: n=9 Placebo: n=4 Preskorn SH et al. J Psychiatr Pract 2014;20(1):12-24.

54 Alpha 7 Nicotinic Receptor Agonist: Encenicline Keefe RS et al. Neuropsychopharmacol 2015;Epub ahead of print.

55 Is Social Cognition a Separate Entity? Encenicline Post Hoc Re-analysis Original Analysis (Keefe et al., 2015) MATRICS Consensus Cognitive Battery (MCCB), 7 domains Post Hoc Re-analysis (Ho et al., 2015) MATRICS Consensus Cognitive Battery (MCCB), 6 domains Placebo Encenicline 0.27 mg: p=0.038, ES=0.55 Encenicline 0.9 mg: p=0.024, ES= Keefe RS et al. Neuropsychopharmacol 2015;Epub ahead of print; Ho A et al. Presented at USPMHC

56 Novel Treatment Mechanisms: Targeting Inflammation Adjunct Minocycline in Early-Phase Schizophrenia 54 early-phase schizophrenia patients were randomly allocated in a 2:1 ratio to minocycline 200 mg/day. Adjunct antipsychotics were initiated no more than 14 days prior to study entry. Antipsychotics included risperidone, olanzapine, quetiapine, and clozapine ( mg/day chlorpromazine-equivalent doses). Levkovitz Y et al. J Clin Psychiatry 2010;71(2):

57 Personalized Medicine? FEP responders: increased DA synthesis FEP nonresponders: no increase in DA synthesis FEP responders: normal glx FEP nonresponders: elevated glx Neuroimaging for DA striatal synthesis? Frontal glx? Microglial activation? Demjaha A et al. Biol Psychiatry 2014;75(5):e11-3; Demjaha A et al. Am J Psychiatry 2012;169(11):

58 From Neurobiology to Clinical Practice: Summary Currently, best evidence may be for cholinergic strategies (nicotinic) Interpreting negative study results NMDA/GABA changes occur premorbidly Importance of biomarkers to identify and ideally treat before psychosis onset; staging treatment? Most completed trials included predominantly older, chronic, male patients Ongoing trials have more diverse patient populations

59 Summary Cognitive impairment Is a risk factor for schizophrenia Precedes psychosis onset by several years May continue to progress after psychosis onset Determines functional outcomes Is generally unaffected by current antipsychotics Best current treatments Cognitive intervention combined with rehabilitation programs

60 Hope for the Future Near term Best data exist for cholinergic strategies Promising novel cognitive training interventions Longer term Biomarkers, new cognitive tools, and other factors for earlier detection and treatment implementation Glutamatergic, GABA-ergic, cholinergic, and/or antiinflammatory mechanisms