Creating Healthy Lifestyles for People Living with Mental Illness

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Creating Healthy Lifestyles for People Living
with Mental Illness

• Silvio Conte Center for Neuroscience Research
• Washington University
• Thank You! to
• Juanita Bishop, Myrtle Carter, Lisa Dickman,
  Meghan Flatley, Justin Grothe, Joan Hirst, Lori
  Ingram, Justin Carol McKenna, Melissa Sapa, Art
  Schaffer, Jenn Staplins, Emily Thomason

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Speakers

• John W. Newcomer, MD, Washington University
  School of Medicine
• Screening and Monitoring Cardiometabolic Risk in
  Patients with Major Mental Disorders During
  Treatment
• Collins E. Lewis, MD, Washington University
  School of Medicine
• Substance Abuse Issues in People with Mental
  Illness
• Jan E. Markham, RN, BSN, Midwest Psychiatry,
  Independence Center
• Helping Clients Promote Lifestyle Change
• Deanna M. Barch, Ph.D., Conte Center Director
• Improving Cognitive Function in Mental Illness

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Improving Cognitive Function in Schizophrenia

• Deanna M. Barch
• Cognitive Control and Psychopathology Laboratory,
  
• Silvio Conte Center for Neuroscience Research
• Washington University
• Sources of Funding NIMH, Dana Foundation,
  NARSAD, McDonnell Foundation

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Disclosure of Interests

• Source of Research Support
• NIMH, Dana Foundation, NARSAD, NIA
• Consulting Relationships
• None
• Stock Equity 10,00
• None
• Participation in Speakers Bureaus
• None
• Pharmaceutical Research Support
• Novartis

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Outline of Talk

• Cognition in Schizophrenia
• Cognitive Remediation
• Pharmacological Remediation

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Why focus on cognition in schizophrenia?

• Cognitive Profile in schizophrenia
• Bilder et al., 2000

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What about cognition as a predictor?

• It is an aspect of schizophrenia that is very
  predictive of functional outcome (Green, 1997)

Bowie et al., 2008
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What about cognition as a predictor?
Bowie et al., 2008
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It is present in first degree relatives
Dellawalla, et al. (2006) Schizophrenia Bull
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Does it predict onset of psychosis?

• Offspring of individuals with schizophrenia
• Children who went on to develop schizophrenia
  spectrum disorders had more problems with
  sustained attention than their siblings who do
  not develop such disorders (Cornblatt et al.,
  1999)
• National Collaborative Perinatal Project
• Children who later developed schizophrenia had
  more severe problems with a test of processing
  speed and working memory than their siblings who
  did not develop schizophrenia (Niendam et al.,
  2003)
• Ultra High Risk Studies
• High scores on clinician rated attention problems
  predict development of psychosis (Yung et al.,
  2004)
• In some, but not all studies, UHR individuals
  show memory and thinking problems compared to
  controls on cognitive testing. It is not clear
  whether the severity of these problems predicts
  conversion to psychosis.

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Do Cognitive Deficits Progress During the Course
of Schizophrenia?
First episode (dotted line) - never treated
duration of illness - 2 yrs Chronic (solid line)
- previously treated but drug-free at time of
testing duration of illness - 9 yrs
From Saykin, et al (1994) Arch Gen Psychiatry
51124-131.
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How Should We Improve Cognition?

• Cognitive Remediation
• Adjunctive Medications

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Wykes et al - CRT

• Theoretical Approach
• Teach new information processing strategies
• Individualize the therapy
• Aid transfer of new cognitive skills to real life
• What do they actually do?
• 40 face to face sessions
• Cognitive testing (on different tasks) at
  baseline, end of treatment and six month
  follow-up
• Also assessed symptoms and social behavior all
  three time points
• 95 subjects (43 in active group, 42 in standard
  care control group)

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Cognitive Remediation


Cognitive Flexibility
Working Memory
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Cognitive Remediation

• The amount of improvement in working memory
  associated with the amount of improvement in
  social behavior!

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Hogarty et al., 2004

• Cognitive Rehabilitation

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Adjunctive Treatment

• Medications specifically targeted at improving
  cognition
• Keep individuals on their same stable primary
  antipsychotic
• Add a medication that may specifically improve
  memory and thinking
• Determine whether this improves life function
• Combine with cognitive rehabilitation?

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Potential Avenues

• Many possible neurobiological targets
• Three particularly promising avenues
• Cholinergic targets
• Dopaminergic targets
• Glutamatergic targets
• Gabaergic targets

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Why the cholingergic system?

• Acetylcholine important for learning, memory and
  attention in animals and humans
• Cholingergic dysfunction critical in Alzheimers
  disease (where we also see memory and learning
  problems)
• Acetylcholine acts at two types of receptors
• Nicotinic
• Muscarinic
• Evidence of decreases in both of these types of
  receptors in the cortex and hippocampus of people
  with schizophrenia (Freedman et al., 1995 Dean
  et al., 2002)

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Cholinesterase Inhibitors

• Stop the breakdown of acetylcholine, leaves it
  around longer
• Widely used in Alzheimers Disease
• Aricept (Donepezil)
• Exelon (Rivastigmine)
• Do not seem to help cognition reliably in
  schizophrenia
• However, lots of people with schizophrenia smoke
• May cause desensitization of nicotine receptors
• This may make standard cholinesterase inhibitors
  less effective

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Nicotinic Receptors

• As bad as smoking is for your health, it does
  improve cognition, at least temporarily
• However, nicotinic receptors desensitize rapidly
• Lots of people with schizophrenia smoke
• May be self-medication
• Medications that target the ?7 nicotinic receptor
  subtype may improve cognition
• DMXB-A has improved cognition in a small proof of
  concept trial, but not in a larger trial

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Muscarinic Receptors

• Xanomeline

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Why the dopamine system?

• Much evidence that dopamine influences cognition
  from both human and animal studies
• Both cortical and subcortical dopamine important
• Indirect dopamine agonist (? dopamine release)
  can improve cognition in schizophrenia (Barch and
  Carter, 2005)
• However, indirect agonists can hit receptors that
  can make some symptoms worse (e.g., D2 receptor
  activation can increase delusions and
  hallucinations)
• Want to target the helpful receptors
• Promising Targets
• D1 receptors in cortex
• Tricky because of inverted U-shape curve problem

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Dopamine and brain function
Just Right!
Prefrontal Function
Too Little!
Too Much!
Dopamine Signaling
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Why the glutamate system?

• Primary excitatory neurotransmitter for 60 of
  neurons in the brain and all cortical pyramidal
  neurons (Gray et al., 2007)
• NMDA is an important glutamate receptor
• Evidence to suggest that NMDA hypofunction may
  contribute to the development of schizophrenia
  and cognitive deficits (Olney, Newcomer,
  Farber, 1999(
• Can try to augment NMDA receptor function
• Hard to try to hit NMDA receptor with direct
  agonist due to problems associated with too much
  activation and excitotoxity
• allosteric modulators (glycine site) have shown
  some promise
• Can try to augment AMPA or Kainate receptors,
  other glutamate receptors (mGluR sites)

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Why the GABA system?

• GABA is the primary inhibitory neurotransmitter
  in human brain
• Some evidence that synchronized GABA function in
  the dorsolateral prefrontal cortex important for
  working memory function (Rao et al., 2000)
• Deficits in synchronized pyramidal cell activity
  in DLPFC in schizophrenia may contribute to
  working memory deficits (Cho et al., 2006)
• May be due to problems with GABAA receptors
  containing ?2 subunits
• Preliminary Evidence that allosteric modulator of
  these GABA receptors can improve cognition and
  brain function!
• Currently being studied as part of the TURNS
  network

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Lewis et al In press
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Take Home Messages

• Cognitive dysfunction in a central part of
  schizophrenia
• It predicts outcome and in some cases onset!
• Challenges
• We need to understand the source of these
  cognitive deficits
• Genetics
• One cause or more
• We need more and better treatment options
• Cognitive Rehabilitation
• Cognitive Behavioral Therapy
• Adjunctive Medications to Improve Cognition

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Conte Center Research Projects

• Sibling Study in Schizophrenia Understanding
  cognitive and neurobiological risk and protective
  factors for the development of schizophrenia
• Cognitive Enhancing Adjunctive Medications for
  Schizophrenia Examine whether adding medications
  designed to enhance memory and thinking can
  improve cognitive and life function in
  schizophrenia
• Metabolic Processes in Schizophrenia Examining
  whether some types of anticpsychotic medications
  may be less likely to contribute to the metabolic
  syndrome
• Neurobiology of Bipolar Disorder Identifying
  similarities and differences in the
  neurobiological deficits present in BDP with and
  without psychosis
• Generalized Anxiety Disorder Using fMRI to
  understand neural changes associated with
  cognitive changes in GAD
• To Volunteer or Refer someone, contact Juanita
  Bishop at 747-2162