Neuropsychology of Schizophrenia: Implications for Treatment

1. Neuropsychology of Schizophrenia: Implications for Treatment Bernice A. Marcopulos, Ph.D., ABPP-Cn Neuropsychology Lab Western State Hospital

2. Talk Overview Provide an overview of the main neuropsychological findings in persons with schizophrenia (PWS) and functional implications

3. Talk overview Provide evidence that schizophrenia is a neurodevelopmental disorder that affects brain functions Review neuropsychological test findings Review neuropsychological interventions

4. History Over the past 15 years, there has been a steady increase in interest in the cognitive deficits associated with schizophrenia (Goldstein, 1987; Heinrichs, 1993; Keefe, 1995) Cognitive deficits were observed early in the study of the disease

5. Schizophrenia is a Brain Disease Kraeplin (1907) dementia praecox - gradual cognitive deterioration "the fact is decisive that the morbid anatomy has disclosed not simple inadequacy of the nervous constitution but destructive processes in the background of the clinical picture."

6. History However, during the middle of this century, the neurological basis of schizophrenia was not appreciated Psychosocial etiologies were favored �schizophreno-genic mother�

7. History Efficacy of neuroleptic drugs which block dopamine in the brain prompted researchers to look for �biochemical imbalance�

8. Schizophrenia is a neurodevelopmental disorder Weinberger (1987) high probability that schizophrenia will manifest itself in late adolescence or early adulthood the role of �stress� in onset and relapse the therapeutic efficacy of neuroleptics

9. Schizophrenia is a neurodevelopmental disorder ��if a lesion affects a brain structure or region that has yet to mature functionally, the effects of the lesion may remain silent until that structure or system matures.� (Weinberger, 1987, p. 662)

10. Pre- and perinatal environmental risk factors of schizophrenia Place or time of birth Winter Urban Prenatal infection Maternal malnutrition Prenatal stress Obstetric complications

11. Evidence for neurodevelopmental encephalopathy Increased association with prenatal viral exposure Mednick et al.(1988) large epidemiological study in Finland. Influenza epidemic in 1957. Those at risk during the 2nd trimester had significantly more hospitalizations for schizophrenia

12. Evidence for CNS Abnormality Physical Abnormalities more abnormalities than controls not associated with cognitive deficits (Green et al., 1989) evident in early development (Walker - home movies)

13. Evidence for neurodevelopmental encephalopathy Increased frequency of minor physical anomalies enlarged ventricles head circumference hair whorls very fine hair covered epicanthus low seated ears furrowed tongue curved 5th finger single palmar crease webbed toes 3rd toe longer than 2nd

14. Evidence for CNS Abnormality Neurological Soft Signs Abnormalities comprising deficits in sensory integration, motor coordination, and sequencing of complex motor acts More prevalent in schizophrenia (Dazzan & Murray, 2002) Can decrease with stabilization of symptoms Associated with outcome

15. Evidence for neurodevelopmental encephalopathy Increased frequency of obstetric complications Abnormal fetal development associated with abnormal delivery (Gunther-Genta, Bovet, & Hohlfield (1994)

16. Evidence for CNS Abnormality Detectable at or near onset of illness Meta-analysis of 58 MRI studies (Wright et al., 2000) Enlarged lateral and 3rd ventricles Mild reduction (2%) in global cerebral volume Prefrontal, hippocampus, amygdala, parahippocampal gyrus, superior temporal gyrus, cingulated gyrus, thalamus & insula Increased volume of basal ganglia Due to antipsychotics Also seen in unaffected relatives to a lesser degree No further volume reduction (Whitworth et al., 2005)

17. Evidence for CNS Abnormality Abnormalities have been found in frontal (i.e., frontal-striatal-thalamic-cerebellar axis), temporolimbic, dopaminergic, and glutaminergic systems (Keshavan et al., 2004)

18. Evidence for CNS Abnormality fMRI of �high risk� children Offspring of parent with schizophrenia 10-16% risk of developing schizophrenia-related illness compared with 1% of general population (Gottesman et al., 1982) Reduced activation in frontal and parietal areas Abnormalities in frontal and parietal heteromodal association cortex may precede illness (Keshavan et al., 2002)

19. Premorbid cognitive functioning Children from 1946 birth cohort who later developed schizophrenia had lower mean scores on educational tests at ages 8, 11, & 15 (Jones et al., 1994) Children seen at child guidance clinic � those who developed schizophrenia had lower IQs and impaired speech, language and reading (Ambleas, 1992) Premorbid language dysfunction - 12 fold increase (Bearden et al., 2000)

20. Premorbid cognitive functioning Children who later developed schizophrenia fell below state norms on the Iowa Tests of Basic Skills for every category for grades 4, 8 & 11 (Fuller et al., 2002) Linear decline in language across time Statistically significant difference at grade 11

21. Premorbid behavioral abnormalities Elaine Walker and colleagues (1993, 1994) study of home movies Children who later developed schizophrenia show less joy and more negative facial expressions of emotion when compared with healthy siblings

22. Early detection of high risk children Unusual movements and coordination problems in mid-childhood significantly associated with adult schizophrenia (Rosso, et al., 2000) More likely to have delayed milestones (Jones et al, 1994)

23. Neurocognitive Deficits Heinrichs (2005) has cogently argued for the primacy of cognition in characterizing schizophrenia, stating, �Cognitive differences between schizophrenia patients and healthy people have emerged systematically as the most powerful findings across hundreds of studies and two decades of neuroscience-based research� (p. 238).

24. Neurocognitive Deficits Neurocognitive deficits are a core, stable trait of the schizophrenic illness that accounts for much of the functional impairment observed (Green, 1996; Green, Kern, Braff, & Mintz, 2000; Green & Nuechterlein, 1999)

25. Neuropsychological Deficits in Schizophrenia Heterogeneous cognitive deficits in up to 61-78%(Heinrichs & Zakzanis, 1998): Memory deficits, esp. verbal Lower intelligence Poor attention

26. Neuropsychological Deficits in Schizophrenia A large proportion of this patient population is impaired on standard neurocognitive tests Meta-analysis suggests that any selective deficits in functions like verbal memory are relative and exist against a background of general dysfunction (Heinrichs & Zakzanis, 1998, p. 437)

27. Cognitive Functions Intelligence 3 trajectories (Weickert & Goldberg, 2000) Widespread impairment early in development; Low premorbid scores on children who later develop Schizophrenia (Seidman et al., 2006) Low IQ as risk factor (Reichenberg, et al., 2006) Cognitive deficits at onset of psychosis Little or no decline Working Memory factor most susceptible

28. Decline in IQ? IQ decline observed during adolescence for children with schizophrenia Due to inability to acquire new information and abilities rather than cognitive deterioration (Bedwell, et al., 1999)

29. Cognitive Functions Executive Functions WCST fewer categories increased perseverations

30. Cognitive Functions Language �schizophasia� - thought disorder affects speech neologisms paraphasias perseverations

31. Memory Functions Impaired memory is most common in schizophrenia, but also occurs in other psychiatric disorders, esp. depression (Egeland et al., 2003) Both patients with depression and schizophrenia show working memory problems Schizophrenia shows acquisition failure Depression shows primarily retrieval problems

32. Memory Impairment in Schizophrenia Aleman, Hijman, de Haan, & Kahn (1999) meta-analysis in Am J Psych Memory impairment disproportionate to overall level of intellectual impairment Compared with normals, impairments on: Long term recall Short term recall

33. Memory Impairment in Schizophrenia Meta-analysis Moderator variables which did NOT have an effect on memory Medication status Duration of illness Severity of psychopathology Positive symptoms Age

34. Memory Impairment in Schizophrenia Meta-analysis Moderator variables which did have an effect on memory Negative symptoms

35. Summary on Cognitive Dysfunction in Schizophrenia All cognitive deficits most associated with negative symptoms -implies more severe disease, more neurological involvement

36. Cognitive effects from typical antipsychotics (Blyler & Gold, 2000) Possible improvement Wechsler Memory Scale No effect WAIS Verbal fluency Stroop Mazes

37. Cognitive effects from typical antipsychotics (Blyler & Gold, 2000) Possible improvement attention on CPT � sx reduction effect? No effect or possibly worsen WCST Trails Simple reaction time manual motor tests Some side effect medications (anti-Ach) can make cognitive functioning worse

38. New antipsychotics may improve cognition Risperidone associated with greater gains in learning acquisition, recall consistency, and recognition on the CVLT (Kern et al., 1999) Risperidone treated patients improved by 1 SD from baseline Haloperidol by 0.25 SD

39. New antipsychotics may improve cognition Pharmacological mechanism for improvement as yet unknown, but believed to be mediated by cortical dopaminergic transmission

40. New antipsychotics may improve cognition Meta-analysis by Woodward, Purdon, Meltzer & Zald (2005) Atypicals (Clozapine, Olanzapine, Quetiapine, Risperidone) have a mild cognitive remediation effect and are superior to typicals in improving cognition Improvements noted in Learning and Processing Speed

41. Neurocognitive deficits predict adaptive functioning Verbal memory related to community outcome Vigilance predicts social effectiveness Executive function related to work/productivity, independence in ADLs, social competence and global measures of functioning (Velligan et al., 2000)

42. Vocational Outcome Only 16 to 30% of patients with schizophrenia are employed effective med tx has little impact no correlation with BPRS or SANS cognitive variables most predictive processing speed working memory reasoning

43. Clinical Implications of Neuropsychological deficits Cognitive deficits underlie adaptive behavior deficits which medications cannot improve Improvement in cognition may improve social skills, work skills, etc; Cognitive domains of executive functioning, verbal fluency and verbal working memory correlate with recovery from schizophrenia (Kopelowicz et al., 2005)

44. Rationale for Developing Cognitive Rehabilitation Neuropsychological studies of PWS show deficits believed to be part of primary symptom complex Deficits have functional implications re: successful discharge Many patients referred for Neuropsychological testing show deficits

45. Effects of cognitive deficits Cognitive deficits are related to insight; insight related to treatment compliance Cognitive deficits related to social perception Interferes with learning so that patients cannot benefit from traditional rehab approaches

46. Definition of Cognitive Rehabilitation(Sohlberg & Mateer, 1989) �Cognitive Rehabilitation has been defined as the therapeutic process of increasing or improving an individual�s capacity to process and use incoming information so as to allow increased functioning in everyday life. This includes both methods to restore cognitive function and compensatory techniques�

47. Effects of Cognitive Remediation Patients on atypicals benefit more from Cog Rehab Cognitive performance improvement indirectly related to changes in social functioning (Wykes et al., 1999; Spaulding et al., 1998) Cog Rehab improved self-esteem (Wykes et al., 1999)

48. Does Cog Rehab work? Mueser, Bond & Drake (2001) Critical review of community based treatment outcomes Promising results suggesting cog rehab has impact and other areas of functioning but too few studies, rehab methods and outcome variables differ, to draw specific conclusions More research needed

49. Recommendations Understand neurocognitive status when designing interventions All patients on atypicals; few, if any on anticholinergics Error-free learning, reinforcement, feedback Encourage/enhance empowerment and recovery

50. Case Presentation