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Warren.Cognition.December.2008
Warren.Cognition.December.2008
Warren.Cognition.December.2008
Warren.Cognition.December.2008
Warren.Cognition.December.2008
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Warren.Cognition.December.2008

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The slides that accompanied a lecture on cognition in schizophrenia.

The slides that accompanied a lecture on cognition in schizophrenia.

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  • 1. Psychotic Illness, Cognition, and Functional Outcomes Richard G Petty MD, MSc, MRCP(UK), MRCPsych, Promedica Research Center, Georgia State University College of Health Sciences, Loganville, Georgia, USA rpettyus@aol.com Sunday, July 26, 2009
  • 2. Disclosure Richard G. Petty, MD, MSc, MRCP(UK), MRCPsych  Consultant  AstraZeneca; Bristol Myers Squibb; Eli Lilly and Company; Janssen Pharmaceuticals  Speaker’s Bureau  Abbott Laboratories; AstraZeneca; Avanir Pharmaceuticals; Janssen Pharmaceuticals  Grant Support  British Diabetic Association; Bristol Myers Squibb; British Heart Foundation; Du Pont Merck, Inc.; Eli Lilly and Company; Janssen; Medical Research Council (UK); National Institute of Mental Health; Pfizer  Dr. Petty’s presentation will include the discussion of off- label, experimental, and/or investigational use of drugs or devices Sunday, July 26, 2009
  • 3. Learning Objectives  Define the domains of cognitive impairment observed in patients with psychotic illness  Identify differences among response, relapse prevention, remission, and functional recovery criteria in measuring and treating cognitive impairment  Evaluate treatment options that may positively or negatively impact cognition in schizophrenia and other psychotic illness  Review the roles of psychosocial interventions and cognitive remediation for improving functional outcomes Sunday, July 26, 2009
  • 4. Sunday, July 26, 2009
  • 5. Schizophrenia and Bipolar Disorder: Causes and Courses Sunday, July 26, 2009
  • 6. The Causes of Schizophrenia and Bipolar Disorder Sunday, July 26, 2009
  • 7. The Causes of Schizophrenia and Bipolar Disorder It is often said that schizophrenia and bipolar disorder are diseases of unknown aetiology This is inaccurate Sunday, July 26, 2009
  • 8. The Causes of Schizophrenia and Bipolar Disorder It is often said that schizophrenia and bipolar disorder are diseases of unknown aetiology This is inaccurate We know a lot about the causes of these illnesses, but we do not know why they cause schizophrenia and bipolar disorder: i.e. we don’t understand all of the pathogenic mechanisms Sunday, July 26, 2009
  • 9. Heteromodal Association Cortex: •Dorsolateral Prefrontal Cortex (Brodmann areas 9 and 46) •Inferior Parietal Lobule (Brodmann area 39 and 40) •Superior Temporal Gyrus (Brodmann area 22) Pearlson, G.D., Petty, R.G., et al. Neuropsychopharmacology 14:1-17, 1995 Sunday, July 26, 2009
  • 10. Heteromodal Association Cortex: •Dorsolateral Prefrontal Cortex (Brodmann areas 9 and 46) •Inferior Parietal Lobule (Brodmann area 39 and 40) •Superior Temporal Gyrus (Brodmann area 22) Pearlson, G.D., Petty, R.G., et al. Neuropsychopharmacology 14:1-17, 1995 Sunday, July 26, 2009
  • 11. The Time Course of Schizophrenia Sunday, July 26, 2009
  • 12. The Time Course of Schizophrenia  Earliest signs often identifiable in infancy and childhood:  Motor incoordination1  Failure to acquire speech by age two increases risk of subsequent schizophrenia five fold2  At ages 7-11 pre-schizophrenic children show impaired language and mathematical skills2,3  Increased shyness and inconsequential behaviours3  Strong evidence for other abnormalities of neurodevelopment:  Birth difficulties4  Minor physical anomalies of developmental origin5  Evidence of aberrant migration of frontal and temporal neurons6 1. Walker , E., and Lewine, Am J Psychiatry 1990; 89: 704-716 2. Jones, P., et al., Lancet 1994; 344: 1398-1402 3. Done, DJ., et al., Brit Med Journal 1994; 309: 699-703. 4. McNeil, TF. Epidemiological Reviews 1995; 17: 107-112 5. Mellor ,CS. Brit J Psychiatry 1992; 160: 467-472 6. Akbarian et al. Arch Gen Psychiatry 1993; 50: 178-187 Sunday, July 26, 2009
  • 13. The Time Course of Schizophrenia (Cont.) Sunday, July 26, 2009
  • 14. The Time Course of Schizophrenia (Cont.)  Prodromal symptoms of depression and social withdrawal  Gender differences in age of onset  Variable course:  10-15% recover completely1  ~50% function quite well 30 years after severe illness2  Duration of untreated psychosis (DUP) is a strong predictor of outcome3, despite having little impact on cognitive performance4, suggesting that psychosis itself may either damage only some regions of the brain, or that DUP undermines other aspects of development  Spreading waves of gray matter loss occur in early-onset schizophrenia5 1. Watt, DC., et al., Psychol Med 1983; 13: 663-670 2. Harding, CM., et al., Br J Psychiatry 1992; 161 (Suppl 18): 27-37 3. Crow, TJ., et al., Br J Psychiatry 1986; 148: 120-127 4. Norman, RMG., et al., Br J Psychiatry 2001; 179: 340-345 5. Thompson, PM., et al., Proc Natl Acad Sci USA 2001: 98: 11650-11670 Sunday, July 26, 2009
  • 15. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655 Sunday, July 26, 2009
  • 16. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655 Sunday, July 26, 2009
  • 17. Thompson, P. et al., Proc Natl Acad Sci USA 2001; 98: 11650-11655 Sunday, July 26, 2009
  • 18. Brain Volume Changes in First-Episode Schizophrenia: A 1-Year Follow-Up Study  First-episode schizophrenia (n=34) 10 and matched healthy subjects (n=36) 8 % Change in Volume  MRI obtained at inclusion and after 1 6 year 4  Outcome measured at 2 years 2  Total brain volume and cerebral gray volume significantly decreased and 0 lateral ventricle volume significantly increased in patients compared with -2 controls -4  The decrease in global gray matter Total Cerebral Lateral volume significantly correlated with Brain Gray Ventricle outcome and with cumulative dosage Volume Volume of antipsychotic medication Cahn, W., et al. Arch Gen Psychiatry. 2002;59(11):1002-1010. Sunday, July 26, 2009
  • 19. Brain Volume Changes in First-Episode Schizophrenia: A 1-Year Follow-Up Study  First-episode schizophrenia (n=34) 10 and matched healthy subjects (n=36) 8 % Change in Volume  MRI obtained at inclusion and after 1 6 year 4  Outcome measured at 2 years 2  Total brain volume and cerebral gray volume significantly decreased and 0 lateral ventricle volume significantly increased in patients compared with -2 controls -4  The decrease in global gray matter Total Cerebral Lateral volume significantly correlated with Brain Gray Ventricle outcome and with cumulative dosage Volume Volume of antipsychotic medication Cahn, W., et al. Arch Gen Psychiatry. 2002;59(11):1002-1010. Sunday, July 26, 2009
  • 20. Longitudinal MRI Assessment of First-Episode Schizophrenia 29-year-old 4 episodes 26-year-old 3 episodes 23-year-old male First episode Courtesy of Dr Jeffrey Lieberman Sunday, July 26, 2009
  • 21. So in Response to the Question: Do Schizophrenic Individuals Have a Difference in Brain Structure? Healthy twin Twin with SZP Gray matter may be 2-10% smaller in SZ. Olfactory bulbs (General loss revealed best by ventricle size) may be ~ 20% smaller in SZ Sunday, July 26, 2009
  • 22. Ruling out Medication Effects Patients with Schizophrenia Medication- matched patients without schizophrenia Difference Vidal, CN., et al., 8th Annual Meeting of the Organization for Human Brain Mapping, Sendai, Japan, June 2002 Sunday, July 26, 2009
  • 23. Sensory gating anomaly measured electrophysiologically: (a) Observed in schizophrenic patients (~90%) but in only 8% of the general population (b) Autosomal dominant transmission, even in healthy relatives of schizophrenia patients (c) This trait has been mapped to the vicinity of a gene on chromosome 15: the gene is a nicotine receptor A, abnormal ratio Schizophrenia patient N, normal ratio α Sunday, July 26, 2009
  • 24. Early Insults Triggers? Disease Genes Environment Viral Infections e.g. Stress Environmental Toxins Biological Factors Cognitive Early Negative/ Attenuated Emerging Brain Deficits Disorganized Positive Sx Psychotic Sx Abnormalities Sx Structural Biochemical Targets for Intervention Functional AGE 0 9 12 15 18 21 Sunday, July 26, 2009
  • 25. Early Insults Triggers? Disease Genes Viral Infections Environment SCHIZ e.g. Stress Environmental OPHR Toxins Biological Factors ENIA Biological Vulnerability Cognitive Early Negative/ Attenuated Emerging Brain Deficits Disorganized Positive Sx Psychotic Sx Abnormalities Sx Structural Biochemical Targets for Intervention Functional AGE 0 9 12 15 18 21 Sunday, July 26, 2009
  • 26. Natural History of Schizophrenia Good Function Psycho- pathology Poor 15 20 30 40 50 60 70 Age (Years) Pathological Process Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549 Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334 Sunday, July 26, 2009
  • 27. Natural History of Schizophrenia Good Mild motor, Function Social, cognitive Non-specific Impairments Psycho- Behavioural pathology disturbances Minor physical anomalies Stable Premorbid Prodromal Progression Improving? Relapsing Poor 15 20 30 40 50 60 70 Age (Years) Pathological Process Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549 Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334 Sunday, July 26, 2009
  • 28. Natural History of Schizophrenia Good Mild motor, Function Social, cognitive Non-specific Impairments Psycho- Behavioural pathology disturbances Minor physical anomalies Stable Premorbid Prodromal Progression Improving? Relapsing Poor 15 20 30 40 50 60 70 Age (Years) Defects of cell Increased dopamine sensitivity Neurodegeneration Pathological Process migration Dysconnections Decreased NMDA (?Increased Glutamate) Apoptosis (?Oxidative stress; EAA?) Robinson, D., et al., Am J Psychiatry. 1999;156(4)544-549 Lewis, DA., and Lieberman, JA. Neuron 2000; 28: 325-334 Sunday, July 26, 2009
  • 29. Sunday, July 26, 2009
  • 30. Cognition: The Central Problem in Schizophrenia Sunday, July 26, 2009
  • 31. Cognition: The Central Problem in Schizophrenia Is There Any Way In Which We Can Improve It? Sunday, July 26, 2009
  • 32. Historical Perspective Sunday, July 26, 2009
  • 33. Historical Perspective  The cognitive and functional impairments in schizophrenia have been the hallmark since the illness first emerged, and led Kraepelin to coin the term “Dementia Praecox” in 1896  Eugen Bleuler, while disagreeing with Kraepelin on some issues, viewed cognitive impairment as a core component of the “schizophrenias” Sunday, July 26, 2009
  • 34. Historical Perspective  The cognitive and functional impairments in schizophrenia have been the hallmark since the illness first emerged, and led Kraepelin to coin the term “Dementia Praecox” in 1896  Eugen Bleuler, while disagreeing with Kraepelin on some issues, viewed cognitive impairment as a core component of the “schizophrenias” Sunday, July 26, 2009
  • 35. Historical Perspective  The cognitive and functional impairments in schizophrenia have been the hallmark since the illness first emerged, and led Kraepelin to coin the term “Dementia Praecox” in 1896  Eugen Bleuler, while disagreeing with Kraepelin on some issues, viewed cognitive impairment as a core component of the “schizophrenias”  Experimental approaches to the study of cognition in schizophrenia are more than 100 years old Sunday, July 26, 2009
  • 36. Historical Perspective Sunday, July 26, 2009
  • 37. Historical Perspective  Some of the earliest studies addressed topics that are still major issues of research today:  Verbal skills  Procedural learning  However, in the interim, the focus of treatment and research was heavily slanted toward other aspects of the illness  Positive symptoms  Negative symptoms Sunday, July 26, 2009
  • 38. Cognitive Dysfunction  The Surgeon General’s Report (1999) notes that “dysfunction of fundamental cognitive processes is at the center of schizophrenia…” and goes on to say “Problems in such fundamental areas as paying selective attention, problem-solving, and remembering can cause serious difficulties in learning new skills and performing daily tasks.” Page 272 Sunday, July 26, 2009
  • 39. Prevalence 15 With deficits Without deficits 85 Sunday, July 26, 2009
  • 40. Prevalence 15  As few as 15% of “stable” outpatients would be With considered deficits “neuropsychologically Without normal” deficits  This implies an 85% rate of impairment 85  In contrast, specific delusions and hallucinations are present in only 25% - 40% of patients Palmer, BW et al. Neuropsychology, 1997; 11: 437-477 Paulsen, JS et al. J Int Neuropsych Soc, 1995; 1: 88-99 Sunday, July 26, 2009
  • 41. Course of Cognitive Impairment in Individuals with Schizophrenia Using “Typical Neuroleptics” Standard deviations 0 Normal –1 –2 –3 Initial 2 Years 20 Years Premorbid Onset Therapy After Start After Onset of Therapy Sunday, July 26, 2009
  • 42. Course of Cognitive Impairment in Individuals with Schizophrenia Using “Typical Neuroleptics” Standard deviations 0 Normal ? –1 Psychosis-Free Patients –2 –3 Initial 2 Years 20 Years Premorbid Onset Therapy After Start After Onset of Therapy Sunday, July 26, 2009
  • 43. Cognitive Dysfunction and Negative Symptoms Cognitive Negative Dysfunction Symptoms Keefe RSE. The assessment of neurocognitive treatment response and its relation to negative symptoms in schizophrenia. In: Keefe RSE, McEvoy JP, eds. The Assessment of Negative Symptoms and Cognitive Deficit Treatment Response. Washington: American Psychiatric Press 2001 Sunday, July 26, 2009
  • 44. Cognitive Dysfunction and Negative Symptoms Cognitive Negative Dysfunction Symptoms Mutual Exacerbation Keefe RSE. The assessment of neurocognitive treatment response and its relation to negative symptoms in schizophrenia. In: Keefe RSE, McEvoy JP, eds. The Assessment of Negative Symptoms and Cognitive Deficit Treatment Response. Washington: American Psychiatric Press 2001 Sunday, July 26, 2009
  • 45. Cognitive Dysfunction and Adaptive Dysfunction Sunday, July 26, 2009
  • 46. Cognitive Dysfunction and Adaptive Dysfunction  Cognitive deficits are more strongly correlated with adaptive dysfunction and outcome than any other symptom domain  Cognitive impairment predicts overall outcome better than negative symptoms  Positive symptoms, despite being distressing and distracting, do not predict adaptive dysfunction or outcome Green, MF. Am J Psychiatry. 1996;153:321-330 Sunday, July 26, 2009
  • 47. Cognitive Dysfunction in Schizophrenia  The major determinant of outcome  Can be subdivided into three principle domains:  Global cognitive function:  Wechsler Digit Symbol Substitution Test  Specific deficits:  Learning  Executive function  Working memory  Social cognition Dickinson, D. British Journ al of Psychiatry 2008; 193: 354-356 Sunday, July 26, 2009
  • 48. Cognitive Dysfunction in Schizophrenia  The major determinant of outcome  Can be subdivided into three principle domains:  Global cognitive function:  Wechsler Digit Symbol Substitution Test  Specific deficits:  Learning  Executive function  Working memory  Social cognition Dickinson, D. British Journ al of Psychiatry 2008; 193: 354-356 Sunday, July 26, 2009
  • 49. Cognitive Impairments in Schizophrenia Severe Impairments (2-3 SD below the mean)  Serial learning:  Process of learning through exposure and practice  Vigilance:  Ability to sustain attention and effort  Motor speed:  Rate at which simple and skilled motor acts are performed  Verbal fluency:  Producing words on demand based on conceptual categories or phonological information Note: The “mean” refers to the average level of performance of normal individuals who are similar in age and education attainment Sunday, July 26, 2009
  • 50. Cognitive Impairments in Schizophrenia Severe Impairments (2-3 SD below the mean)  Serial learning:  Process of learning through exposure and practice  Vigilance:  Ability to sustain attention and effort  Motor speed:  Rate at which simple and skilled motor acts are performed  Verbal fluency:  Producing words on demand based on conceptual categories or phonological information Note: The “mean” refers to the average level of performance of normal individuals who are similar in age and education attainment Sunday, July 26, 2009
  • 51. Cognitive Impairments in Schizophrenia (Continued) Severe Impairments (2-3 SD below the mean)  Executive function:  Ability to concentrate  Ability to distinguish important information from unimportant  Ability to prioritize  Ability to perform mental or physical acts in proper sequence  Ability to modulate behavior based on social cues Sunday, July 26, 2009
  • 52. Cognitive Impairments in Schizophrenia (Continued) Moderate Impairments (1-2 SD below the mean)  Delayed recall:  Ability to recall information without cues or prompts  Distractibility:  Inability to ignore irrelevant information and focus on relevant information  Immediate memory span  Ability to remember, briefly, a short list of information Sunday, July 26, 2009
  • 53. Cognitive Impairments in Schizophrenia (Continued) Moderate Impairments (1-2 SD below the mean)  Visuomotor skills:  Ability to integrate visual information and motor skills  Working memory:  Ability to remember information for a very brief period while using it for other operations (e.g. remembering a list of numbers while adding them together) Sunday, July 26, 2009
  • 54. Cognitive Impairments in Schizophrenia (Continued) • Mild Impairments (0.5-1 SD below the mean)  Perceptual skills:  Ability to recognize and identify stimuli such as sounds, smell, and sights  Delayed recognition memory:  Ability to remember after a time delay  Confrontation naming:  Presented with an object, ask to identify it  IQ:  Most patients with schizophrenia have an IQ in the 90s Sunday, July 26, 2009
  • 55. Cognitive Impairments in Schizophrenia (Continued) No Impairment  Word recognition reading  Long-term factual memory  Both of which have important implications for psychoeducation:  Written materials are helpful  Large font  Short sentences  Concepts explained in concrete terms Sunday, July 26, 2009
  • 56. Cognitive Functioning: Implications for Psychoeducation  Use conversational tone; personalized, empathetic, motivational tone to materials  Interactive style with self-discovery quizzes, fill-in charts, open-ended questions, as well as interactive exercises with mental health professionals will facilitate learning  Graphic style should include: - Larger type, bold type Sunday, July 26, 2009
  • 57. Cognitive Dysfunction and Adaptive Dysfunction Sunday, July 26, 2009
  • 58. Cognitive Dysfunction and Adaptive Dysfunction  Cognitive deficits are more strongly correlated with adaptive dysfunction and outcome than any other symptom domain  Cognitive impairment predicts overall outcome better than negative symptoms  Positive symptoms, despite being distressing and distracting, do not predict adaptive dysfunction or outcome Green, MF. Am J Psychiatry. 1996;153:321-330 Sunday, July 26, 2009
  • 59. Assessing Cognitive Dysfunction  A number of tests exist to evaluate the type and extent of cognitive dysfunction  Some can be easily performed by clinicians! Sunday, July 26, 2009
  • 60. What Impact Do Cognitive Symptoms Have On Functioning? Sunday, July 26, 2009
  • 61. What Impact Do Cognitive Symptoms Have On Functioning?  Functional limitations vary from individual to individual  Generally, we see: Decreased concentration and attention Memory impairment Difficulty with following multi-step problems Difficulty remembering and following verbal commands Difficulty filtering irrelevant information Sunday, July 26, 2009
  • 62. What Impact Do Cognitive Symptoms Have On Functioning? Sunday, July 26, 2009
  • 63. What Impact Do Cognitive Symptoms Have On Functioning?  Decreased ability to prioritize  Decreased ability to problem solve  Impaired interpersonal skills  Deceased ability to learn new information Sunday, July 26, 2009
  • 64. Neurocognitive Deficits and Functional Ability Community Functioning Neurocognitive Instrumental and Social Deficits Problem-Solving Skills Psychosocial Skill Acquisition 0.8 0.7 P<.0001 0.6 Large 0.5 0.4 Medium 0.3 0.2 Small 0.1 0.0 Secondary Immediate Executive Vigilance Summary Verbal Verbal Function Scores Memory Memory (Card Sorting) Green MF et al. Schizophrenia Bull. 2000;26:119-136. Sunday, July 26, 2009
  • 65. Neurocognitive Deficits and Functional Ability Community Functioning Neurocognitive Instrumental and Social Deficits Problem-Solving Skills Psychosocial Skill Acquisition 0.8 0.7 P<.0001 0.6 Large 0.5 0.4 Medium 0.3 0.2 Small 0.1 0.0 Secondary Immediate Executive Vigilance Summary Verbal Verbal Function Scores Memory Memory (Card Sorting) Green MF et al. Schizophrenia Bull. 2000;26:119-136. Sunday, July 26, 2009
  • 66. Typical Profile of Cognitive Deficits in Schizophrenia, Major Depressive Disorder, and Euthymic Bipolar Disorder Schizophrenia 1 Major Depressive Disorder Euthymic Bipolar Disorder 0.5 Z Score (SD Units) 0 -0.5 -1 -1.5 -2 Verb Mem Verb Mem Vis Mem Fluency Trails B WCST Block Vocab (delayed) (immed) Design WCST = Wisconsin Card Scoring Test. Buchanan RW et al. Schizophrenia Bull. 2005;31:5-19. Sunday, July 26, 2009
  • 67. The Role of Antipsychotics in Cognitive Functioning  What role do medications play in enhancement of cognitive functioning?  Do “atypicals” show differences over the older medications?  Do the “atypicals” show differences among one another? Sunday, July 26, 2009
  • 68. Conventional Antipsychotics and Cognitive Impairment Sunday, July 26, 2009
  • 69. Conventional Antipsychotics and Cognitive Impairment  Conventional antipsychotics are not effective for cognitive impairment1-3  Attention worsens initially but may improve slightly after several weeks of treatment1-3  Motor functions worsen1-3  Other functions remain about the same or worsen1-3  Absence of “practice effects”3 1Cassens, G, et al. Schizophr Bull. 1990;16:477-499; 2Medalia, A., et al. Clin Neuropsychol. 1988;3:249-271; 3Blyler, R., et al. Cognitive effects of typical antipsychotic treatment: another look. In: Sharma, T., Harvey, PD., eds. Cognitive Deficits in Schizophrenia. Oxford, UK: Oxford University Press 2001 Sunday, July 26, 2009
  • 70. Rationale for Developing Interventions to Improve Cognition in Schizophrenia • Evidence that cognitive deficits are core features of schizophrenia • Evidence for relationships between cognition and functional outcome in schizophrenia • Increasing research focus on the basic studies of neuropharmacology of cognition • NIMH Initiative—Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) NIMH = National Institute of Mental Health. Buchanan RW et al. Schizophrenia Bull. 2005;31:5-19. Sunday, July 26, 2009
  • 71. Effect Sizes* for Average Improvement in Cognition With “Atypical” Antipsychotics Healthy Control Mean (Theoretical) 0.0 ∆ in Baseline (Standard Deviation) -0.5 -1.0 -1.5 Immediate Secondary Vigilance Executive Visual Verbal Spatial Memory Memory Functions Motor Fluency Functions Skills *Values represent average improvement as measured by changes from baseline in standard deviations; figures are weighted for the study group size in each study and collapsed across all newer medications. Harvey PD, Keefe RS. Am J Psychiatry. 2001;158:176-184. Sunday, July 26, 2009
  • 72. Effect Sizes* for Average Improvement in Cognition With “Atypical” Antipsychotics Healthy Control Mean (Theoretical) 0.0 ∆ in Baseline (Standard Deviation) -0.5 -1.0 .39 .39 .43 .27 .18 .20 .13 -1.5 Immediate Secondary Vigilance Executive Visual Verbal Spatial Memory Memory Functions Motor Fluency Functions Skills *Values represent average improvement as measured by changes from baseline in standard deviations; figures are weighted for the study group size in each study and collapsed across all newer medications. Harvey PD, Keefe RS. Am J Psychiatry. 2001;158:176-184. Sunday, July 26, 2009
  • 73. CATIE: Δ in Neurocognitive Composite Score After 2 Months Treatment Perphenazine Risperidone Quetiapine Olanzapine Ziprasidone 0.3 Baseline to 2 Months Z-Score Δ From 0.2 0.1 n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= 149 151 146 163 183 181 211 81 75 84 82 74 90 99 100 93 0.0 TD Patients TD Patients TD Patients TD Patients Excluded Included Excluded Included Ziprasidone Cohort No significant differences between treatments (P=.20) CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness Study; TD = tardive dyskinesia. Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada. Sunday, July 26, 2009
  • 74. CATIE: Δ in Neurocognitive Domains After 2 Months of Treatment Perphenazine 0.7 No significant differences Risperidone 2 Months, Excluding TD Patients between groups (all P>.08). Quetiapine 0.6 Z-Score Δ From Baseline to Olanzapine 0.5 Ziprasidone 0.4 0.3 0.2 0.1 0.0 -0.1 Processing Reasoning Working Verbal Vigilance Speed Memory Memory Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada. Sunday, July 26, 2009
  • 75. CATIE: Δ in Neurocognitive Composite Score After 18 Months of Treatment 0.7 Overall differences Perphenazine between treatments (P<.05) Risperidone 0.6 Quetiapine Baseline to 18 Months Olanzapine 0.5 Z-Score Δ From Ziprasidone 0.4 0.3 0.2 0.1 n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= n= 52 55 46 74 67 54 90 27 27 21 34 23 31 25 41 31 0.0 TD Patients TD Patients TD Patients TD Patients Excluded Included Excluded Included Ziprasidone Cohort Keefe RSE et al. Presented at: 61st SOBP Annual Meeting; May 18-20, 2006; Toronto, Canada. Sunday, July 26, 2009
  • 76. Neurocognitive Effect of Aripiprazole vs. Olanzapine P=.02 0.5 ║ P=.04 ║ Aripiprazole (n=76) Δ From Baseline 0.4 Olanzapine 0.3 (n=93) P=NS P=NS 0.2 P=NS P=NS † * ‡ § 0.1 0 Wk 8 Wk 26 Wk 8 Wk 26 Wk 8 Wk 26 General Cognitive Executive Verbal Learning Functioning Functioning LOCF analyses. *P=.023; †P=.015; ‡P=.055; §P=.087; ║P<.0001 vs baseline. Adapted from Kern RS et al. Psychopharmacology. 2006;187:312-320. Sunday, July 26, 2009
  • 77. Obstacles for Drug Development in Cognition  Lack of consensus on cognitive measures  Uncertainty about relevant neuropharmacologic targets  Lack of consensus on appropriate animal and human models  Concerns regarding likelihood of FDA acceptance of an indication in this area Marder SR, Fenton W. Schizophrenia Res. 2004;72:5-9; Buchanan RW et al. Schizophrenia Res. 2005;31:5-19; Breier A. Schizophrenia Bull. 2005;31:816-822. Sunday, July 26, 2009
  • 78. NIMH/MATRICS Approach to a Clinical Target Use a consensus-building process to  Define the basic elements (separable domains) of the target  Develop methods for measuring each element as a potential endpoint in clinical trials  Develop a clinical trials methodology  Develop animal models  Prioritize molecular targets Marder SR, Fenton W. Schizophrenia Res. 2004;72:5-9; Buchanan RW et al. Schizophrenia Res. 2005;31:5-19. Sunday, July 26, 2009
  • 79. Separable Cognitive Domains in Schizophrenia  Speed of processing  Visual learning  Attention/vigilance and memory  Working memory  Reasoning and  Verbal learning problem solving and memory  Social cognition Nuechterlein KH et al. Schizophrenia Res. 2004;72:29-39. Sunday, July 26, 2009
  • 80. Path Analysis: Neurocognition, Social Cognition, and Functional Outcome (Global Outcome) .01 Functional Social outcome competence .27 .16* † Social domains: .56† cognition: .30† • Social Neurocognition Perception of emotion • Work .20† .10 Social • Independent support living *P<.05; †P<.01, one-tailed. Brekke J et al. Schizophrenia Res. 2005;80:213-225. Sunday, July 26, 2009
  • 81. MATRICS Consensus Cognitive Battery (Estimated Administration Time: 63.5 min) Cognitive Domain Tests Included • Category Fluency Speed of Processing • BACS Symbol Coding • Trial Making A Attention/Vigilance • CPT—Identical Pairs version • Maryland Letter Number Span Working Memory • WMS-III Spatial Span Verbal Learning • Hopkins Verbal Learning Test Visual Learning • Brief Visuospatial Memory Test Reasoning and Problem Solving • NAB Mazes Social Cognition • MSCEIT™ Managing Emotions BACS = Brief Assessment of Cognition in Schizophrenia; CPT = Current Procedural Terminology; WMS = Working Memory in Schizophrenia; NAB = Neuropsychological Assessment Battery; MSCEIT™ = Mayer-Salovey-Caruso Emotional Intelligence Test. MATRICS NCC. Provisional Consensus Cognitive Battery. Available at: http://www.matrics.ucla.edu/provisional-MATRICS-battery-core-11-30-04.pdf. Accessed February 9, 2007. Sunday, July 26, 2009
  • 82. Selected Recommendations From NIMH/FDA Conference, April 23, 2004  Include subjects who are clinically stable  Exclude subjects only if impairment compromises test validity or if they perform at ceiling  For co-medication: compare addition of drug or placebo to current antipsychotic  For broad spectrum antipsychotic: compare experimental drug to an antipsychotic that does not impair cognition  Monitor outcome with MATRICS Cognitive Battery and a co-primary measure of functional capacity or interview- based cognitive assessment Buchanan RW et al. Schizophrenia Res. 2005;31:5-19. Sunday, July 26, 2009
  • 83. MATRICS Ranking of Targets Target # Nominations Alpha-7 nicotinic–receptor agonists 31 D1-receptor agonists 30 AMPA glutamatergic–receptor agonists 14 Alpha-2 adrenergic–receptor agonists 14 NMDA glutamatergic–receptor agonists 12 Metabotropic glutamate receptor agonists 12 Glycine-reuptake inhibitors 8 M1 muscarinic–receptor agonists 7 GABA alpha-2 subtype–selective agonists 5 AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; NMDA = N-methyl-D-aspartate; GABA = γ-aminobutyric acid. Tamminga CA. J Clin Psychiatry. 2006;67(suppl 9):9-13; Marder SR. J Clin Psychiatry. 2006;67(suppl 9):31-35. Sunday, July 26, 2009
  • 84. Trial of DMXB-A, an α-7 Nicotinic Agonist  12 patients administered double-blind DMXB-A at 2 doses and placebo  Treatment was for a single day with 2 doses administered  DMXB-A was associated with greater improvement on a cognitive battery Olincy A et al. Arch Gen Psychiatry. 2006;63:630-638. Sunday, July 26, 2009
  • 85. Dopamine D1 Receptor in Schizophrenia Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16. Sunday, July 26, 2009
  • 86. Dopamine D1 Receptor in Schizophrenia  Patients with schizophrenia have substantial impairments in working memory Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16. Sunday, July 26, 2009
  • 87. Dopamine D1 Receptor in Schizophrenia  Patients with schizophrenia have substantial impairments in working memory  D1 receptors in the prefrontal cortex regulate working memory with D1 agonists improving working memory Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16. Sunday, July 26, 2009
  • 88. Dopamine D1 Receptor in Schizophrenia  Patients with schizophrenia have substantial impairments in working memory  D1 receptors in the prefrontal cortex regulate working memory with D1 agonists improving working memory  The effectiveness of D1 agonists for improving working memory has been demonstrated in rodents and nonhuman primates. Studies in schizophrenia patients are being initiated Goldman-Rakic PS et al. Psychopharmacology (Berl). 2004;174:3-16. Sunday, July 26, 2009
  • 89. Serotonin Receptors Roth BL et al. Psychopharmacology. 2004;174:17-24. Sunday, July 26, 2009
  • 90. Serotonin Receptors  5-HT1A receptors are concentrated in the hippocampus; partial agonists and antagonists both improve cognition in animal models Roth BL et al. Psychopharmacology. 2004;174:17-24. Sunday, July 26, 2009
  • 91. Serotonin Receptors  5-HT1A receptors are concentrated in the hippocampus; partial agonists and antagonists both improve cognition in animal models  5-HT2A receptors affect both glutamate and dopamine release; studies in animals suggest that 5-HT2A antagonists improve cognition Roth BL et al. Psychopharmacology. 2004;174:17-24. Sunday, July 26, 2009
  • 92. Serotonin Receptors  5-HT1A receptors are concentrated in the hippocampus; partial agonists and antagonists both improve cognition in animal models  5-HT2A receptors affect both glutamate and dopamine release; studies in animals suggest that 5-HT2A antagonists improve cognition  5-HT6 antagonists are in late-stage testing for cognition Roth BL et al. Psychopharmacology. 2004;174:17-24. Sunday, July 26, 2009
  • 93. Serotonin Receptors  5-HT1A receptors are concentrated in the hippocampus; partial agonists and antagonists both improve cognition in animal models  5-HT2A receptors affect both glutamate and dopamine release; studies in animals suggest that 5-HT2A antagonists improve cognition  5-HT6 antagonists are in late-stage testing for cognition  Drugs affecting these 3 receptors are currently being tested in patient populations Roth BL et al. Psychopharmacology. 2004;174:17-24. Sunday, July 26, 2009
  • 94. Glutamate as a Target Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 95. Glutamate as a Target  Glutamate can affect neurotransmission by acting at multiple receptors, including NMDA and AMPA receptors, as well as metabotropic glutamate (mGlu) receptors Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 96. Glutamate as a Target  Glutamate can affect neurotransmission by acting at multiple receptors, including NMDA and AMPA receptors, as well as metabotropic glutamate (mGlu) receptors  NMDA antagonists such as phencyclidine can cause symptoms of schizophrenia and impair cognition Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 97. Glutamate as a Target  Glutamate can affect neurotransmission by acting at multiple receptors, including NMDA and AMPA receptors, as well as metabotropic glutamate (mGlu) receptors  NMDA antagonists such as phencyclidine can cause symptoms of schizophrenia and impair cognition  Some, but not all, studies of drugs affecting the glycine modulatory site of NMDA receptors—glycine, d- cycloserine, sarcosine, and D-serine—have shown improvement in negative symptoms and cognition in schizophrenia Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 98. Glutamate as a Target  Glutamate can affect neurotransmission by acting at multiple receptors, including NMDA and AMPA receptors, as well as metabotropic glutamate (mGlu) receptors  NMDA antagonists such as phencyclidine can cause symptoms of schizophrenia and impair cognition  Some, but not all, studies of drugs affecting the glycine modulatory site of NMDA receptors—glycine, d- cycloserine, sarcosine, and D-serine—have shown improvement in negative symptoms and cognition in schizophrenia  Drugs affecting AMPA receptors in schizophrenia are currently in clinical trials; agents targeting mGlu 2,3,5 receptors are at different stages of development Coyle JT, Tsai G. Psychopharmacology (Berl). 2004;174:32-38; Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 99. GABA and Schizophrenia mRNA = messenger RNA. Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 100. GABA and Schizophrenia  Coordinated firing of GABA neurons in prefrontal cortex is necessary for pyramidal cell functioning mRNA = messenger RNA. Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 101. GABA and Schizophrenia  Coordinated firing of GABA neurons in prefrontal cortex is necessary for pyramidal cell functioning  Reduced expression of the mRNA for an enzyme that synthesizes GABA has been found in schizophrenia; a subtype, GABAA α2, appears increased in schizophrenia mRNA = messenger RNA. Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 102. GABA and Schizophrenia  Coordinated firing of GABA neurons in prefrontal cortex is necessary for pyramidal cell functioning  Reduced expression of the mRNA for an enzyme that synthesizes GABA has been found in schizophrenia; a subtype, GABAA α2, appears increased in schizophrenia  Clinical trials of a GABAA α2 partial agonist are underway mRNA = messenger RNA. Lewis DA, Moghaddam B. Arch Neurol. 2006;63:1372-1376. Sunday, July 26, 2009
  • 103. Muscarinic Cholinergic Targets CNS = central nervous system. Friedman JI. Psychopharmacology (Berl). 2004;174:45-53. Sunday, July 26, 2009
  • 104. Muscarinic Cholinergic Targets  Reduction in CNS Ach function impairs cognition, as in Alzheimer’s disease CNS = central nervous system. Friedman JI. Psychopharmacology (Berl). 2004;174:45-53. Sunday, July 26, 2009
  • 105. Muscarinic Cholinergic Targets  Reduction in CNS Ach function impairs cognition, as in Alzheimer’s disease  In animals, cholinergic agonists enhance, and antagonists impair, cognition CNS = central nervous system. Friedman JI. Psychopharmacology (Berl). 2004;174:45-53. Sunday, July 26, 2009
  • 106. Muscarinic Cholinergic Targets  Reduction in CNS Ach function impairs cognition, as in Alzheimer’s disease  In animals, cholinergic agonists enhance, and antagonists impair, cognition  Patients with schizophrenia have reduced M1 receptor numbers in neocortex CNS = central nervous system. Friedman JI. Psychopharmacology (Berl). 2004;174:45-53. Sunday, July 26, 2009
  • 107. Muscarinic Cholinergic Targets  Reduction in CNS Ach function impairs cognition, as in Alzheimer’s disease  In animals, cholinergic agonists enhance, and antagonists impair, cognition  Patients with schizophrenia have reduced M1 receptor numbers in neocortex  Studies of cholinesterase inhibitors in schizophrenia have shown mixed results; best results are with dual cholinesterase inhibitors CNS = central nervous system. Friedman JI. Psychopharmacology (Berl). 2004;174:45-53. Sunday, July 26, 2009
  • 108. Dementia Treatments in Schizophrenia  Memantine does not help cognitive function in schizophrenia1,2  Donepezil has also failed to show cognitive improvement in schizophrenia3 1. Lieberman, J. A., et al. Neuropsychopharmacology advance online publication, 12 November 2008; doi: 10.1038/npp.2008.200. 2. Krivoy, A., et al Eur Neuropsychopharmacol 2008; 18, 117-21 3. Akhondzadeh, S., Gerami, M., Noroozian, M., Karamghadiri, N., Ghoreishi, A., Abbasi, S. H., et al. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32, 1810-5. Sunday, July 26, 2009
  • 109. Social Cognition Sunday, July 26, 2009
  • 110. What is Social Cognition? Sunday, July 26, 2009
  • 111. What is Social Cognition? “The mental operations underlying social interactions, which include the human ability to perceive the intentions and dispositions of others”1 i.e. How we perceive, recall, think about, and interpret information about our actions and the actions of others Sunday, July 26, 2009
  • 112. What is Social Cognition? “The mental operations underlying social interactions, which include the human ability to perceive the intentions and dispositions of others”1 i.e. How we perceive, recall, think about, and interpret information about our actions and the actions of others  Includes:  Impression formation  Attribution theory  Social schemas  Heuristics 1. Brothers, L. Concepts in Neuroscience 1990; 1: 27-61 Sunday, July 26, 2009
  • 113. Social Cognition • Much of the work in social cognition has been directed at understanding how we overcome limitations in our ability to process information • Despite our substantial intellect, we are not able to process all of the stimuli we encounter at any moment • This information overload requires us to develop shortcuts and strategies that make information processing fast and efficient Sunday, July 26, 2009
  • 114. Social Cognition and Schizophrenia: Background  Effective social functioning incorporates many skills, including interpreting verbal and nonverbal social cues  Previous studies investigating social cognition in schizophrenia have focused on the ability to interpret facial expressions and results generally indicate patient deficits in this skill1-3  Additionally, patients with schizophrenia may have more difficulty in recognizing negative facial expressions4,5 Sunday, July 26, 2009
  • 115. Social Cognition and Schizophrenia: Background  Effective social functioning incorporates many skills, including interpreting verbal and nonverbal social cues  Previous studies investigating social cognition in schizophrenia have focused on the ability to interpret facial expressions and results generally indicate patient deficits in this skill1-3  Additionally, patients with schizophrenia may have more difficulty in recognizing negative facial expressions4,5 1. Walker, E., McGuire, M., & Bettes, B. The British Journal of Clinical Psychology, 1984; 23: 37-44. 2. Feinberg, T.E., Rifkin, A., Schaffer, C., et al. Archives of General Psychiatry, 1986; 43, 276-279. 3. Zuroff, D.C. & Colussy, S.A. Journal of Clinical Psychology, 1986; 42: 411-417. 4. Burch, J.W. (1995). Journal of Clinical Psychology,1995; 51: 140-151. 5. Bell, M., Bryson, G., Lysaker, P. Psychiatry Research, 1997; 73: 73-82. Sunday, July 26, 2009
  • 116. Social Cognition and Schizophrenia: Background (Continued)  Relatives of patients with schizophrenia also performed more poorly than controls in recognizing nonverbal cues1  A social-cognitive model of the etiology and development of schizophrenia is necessary to account for the associated deficits in social cognition and other symptomatology2  Emerging evidence analyzing brain activity in schizophrenia indicates that deficits in facial affect recognition could be a result of hypoactivity in specific brain regions3  “Atypical” antipsychotics seem to positively influence social cognition in schizophrenia patients4 Sunday, July 26, 2009
  • 117. Social Cognition and Schizophrenia: Background (Continued)  Relatives of patients with schizophrenia also performed more poorly than controls in recognizing nonverbal cues1  A social-cognitive model of the etiology and development of schizophrenia is necessary to account for the associated deficits in social cognition and other symptomatology2  Emerging evidence analyzing brain activity in schizophrenia indicates that deficits in facial affect recognition could be a result of hypoactivity in specific brain regions3  “Atypical” antipsychotics seem to positively influence social cognition in schizophrenia patients4 1. Toomey, R., Seidman, L.J., Lyons, M.J., et al. Schizophrenia Research, 1999; 40: 121-130. 2. Penn, D. L., Spaulding, W., Reed, D., & Sullivan, M. Schizophrenia Research, 1996; 20: 327-335. 3. Streit, M., Ioannides, A., Sinnemann, T., et al. American Journal of Psychiatry, 2001; 158: 1429-1436. 4. Kee, K.S., Kern, R.S., Marshall, B.D. Jr., & Green, M.F. Schizophrenia Research, 1998; 31: 159-165. Sunday, July 26, 2009
  • 118. Psychosocial Approaches to Specific Targets 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838; 3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757. Sunday, July 26, 2009
  • 119. Psychosocial Approaches to Specific Targets  Facial affect recognition can be enhanced with special training1 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838; 3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757. Sunday, July 26, 2009
  • 120. Psychosocial Approaches to Specific Targets  Facial affect recognition can be enhanced with special training1  Cognitive training can improve working memory2 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838; 3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757. Sunday, July 26, 2009
  • 121. Psychosocial Approaches to Specific Targets  Facial affect recognition can be enhanced with special training1  Cognitive training can improve working memory2  Attention can be improved with specialized training3 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838; 3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757. Sunday, July 26, 2009
  • 122. Psychosocial Approaches to Specific Targets  Facial affect recognition can be enhanced with special training1  Cognitive training can improve working memory2  Attention can be improved with specialized training3  Cognitive Enhancement Therapy (CET) improved neurocognition and processing speed4 1. Wolwer W et al. Schizophr Res. 2005;80:295-303; 2. Bell MD et al. J Rehabil Res Dev. 2005;42:829-838; 3. Silverstein S et al. Psychiatr Q. 1998;69:95-105; 4. Hogarty GE et al. Psychiatr Serv. 2006;57:1751-1757. Sunday, July 26, 2009
  • 123. A First Study on Using Medication to Enhance Social Cognition Sunday, July 26, 2009
  • 124. Interpersonal Perception Task (IPT)  The IPT was developed to assess nonverbal communication and social perception1  The IPT evaluates 5 domains of social cognition: - Status - Intimacy - Kinship - Competition - Deception (Lying) Sunday, July 26, 2009
  • 125. Interpersonal Perception Task (IPT)  The IPT was developed to assess nonverbal communication and social perception1  The IPT evaluates 5 domains of social cognition: - Status - Intimacy - Kinship - Competition - Deception (Lying) 1. Archer, D. & Costanzo, M. (1988). The interpersonal perception task: A new video about non-verbal communication and social perception. Berkeley, CA: University of California, Extension Media Center. Sunday, July 26, 2009
  • 126. Interpersonal Perception Task (IPT)  IPT contains 30 brief videotape scenes  Each scene is 30-60 seconds in length  Each scene is paired with a question that has 2 or 3 possible answers  The people in each scene are not actors and the situations are real  Viewer must “decode” something important about the people she or he has just seen  Decoding is based on non-verbal information Sunday, July 26, 2009
  • 127. Comparison of Conventional Antipsychotics and Olanzapine (Total IPT Scores) 100 90 80 70 60 CAP 50 OLZ 40 30 20 10 0 Baseline Endpoint Sunday, July 26, 2009
  • 128. Comparison of Conventional Antipsychotics and Olanzapine (Total IPT Scores) 100 90 p <.0001 80 70 p =0.13 60 CAP 50 OLZ 40 30 20 10 0 Baseline Endpoint p Values based on two-tailed t-tests for independent samples Littrell, K. H., Petty, R. G., et al. Schizophrenia Research 66(2), 201-202, 2004 Sunday, July 26, 2009
  • 129. Cognitive Training: Effects on Employment Rate Supported employment with 45 cognitive training 40 Supported employment alone 35 30 Percent Working 25 20 15 10 5 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Month McGurk SR, et al. Am J Psychiatry. 2007; 164:437-441. Sunday, July 26, 2009
  • 130. Cognitive Training: Effects on Employment Rate Supported employment with 45 cognitive training 40 Supported employment alone 35 30 Percent Working 25 20 15 10 5 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 Month McGurk SR, et al. Am J Psychiatry. 2007; 164:437-441. Sunday, July 26, 2009
  • 131. Conclusions  Improvement of functional outcomes in schizophrenia is likely to emerge from medicines that target neurocognitive impairments, as well as persistent positive or negative symptoms  Additional improvement in these domains may occur with targeted psychosocial interventions Sunday, July 26, 2009
  • 132. Lithium and Cortical Grey Matter Bearden, CE., et al. Biological Psychiatry, June 2007 Sunday, July 26, 2009
  • 133. Useful Addresses  Healia.com  www.RichardGPettyMD.com  rpettyus@aol.com Sunday, July 26, 2009

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