Download What changes in the brain to cause schizophrenia?

Cognitive Deficits in Neurodevelopmental
Disorders (Schizophrenia)
Carrie E. Bearden, Ph.D.
Psychiatry and Biobehavioral Sciences and Psychology
Semel Institute for Neuroscience and Human Behavior
University of California, Los Angeles
[email protected]
Today’s Lecture
• Phenomenology
• Genetics
• What is inherited?
-cognitive/structural brain changes
- cellular signaling changes
• Genetics Part II- high risk models
Schizophrenia literally means “split-mind”
• “Schizm” or splintering of the “phren” or mind
• Not multiple personality disorder!
•
“I call dementia precox schizophrenia because, as
I hope to show, the splitting of the different psychic
functions is one of its most important features. In
each case there is a more or less clear splitting of
the psychological functions: as the disease
becomes distinct, the personality loses its unity”.
– -Eugen Bleuler (1857-1939)
• Splintering of various mental faculties
(thought, affect, etc.) so that they are no
longer coordinated
• Onset between the late teens and early 30s
• Onset for women usually later (25 - mid-30s)
Components
• Thought Form (loosening of associations,
incoherence, neologisms)
• Thought Content (delusions of persecution,
grandeur, thought control)
• Attention and Perception (“over-attention”,
hallucinations, voices)
• Affect, Motivation, Social Functioning (blunted or
silly affect; anhedonia; social withdrawal)
• Cognitive deficits
DSM-V Criteria
• Either hears voices or has bizarre delusions, or has
two or more of following, for 1-month or more
–
–
–
–
–
Delusions
Hallucinations
Formal thought disorder
Grossly disorganized behavior or catatonia
Flat or inappropriate affect
• Deterioration from a previous level of functioning in
work, social relations, and/or self-care
• Continuous signs of the disturbance for at least 6
months, including prodromal/residual symptoms
Delusions
• False beliefs involving misinterpretation of
surroundings
• Persecutory (most common): person believes
he/she is being tormented, ridiculed, spied on
i.e. someone or thing out to get him/her
• Referential (very common): certain
environmental cues are directed at him/her
(e.g. from newspaper, gesture, TV, song lyrics,
etc.)
Delusions (continued)
• Bizarre delusions: clearly implausible, doesn’t
derive from ordinary life experiences
–
–
–
–
Thought insertion
Thought withdrawal
Thought broadcasting
Delusion of control
• Person must have conviction about delusion,
despite clear contradictory evidence
• Must not be consistent with cultural norms
Hallucinations
• False Perceptions
• Hearing things that other
people don’t hear
• Seeing things that others don’t
see
• Smelling, tasting, or feeling
unusual sensations that other
people don’t experience
• Conviction & in the absence of
other stimuli
• Not while falling asleep or
waking up
Other Symptoms
• Disorganized Thinking:
– Ascertained through speech
– Loose associations, “word salad,” tangential speech
– Must impair communication
• Disorganized Behavior
– Problems in goal-directed behavior
– Can range from child-like silliness to unpredictable
agitation (shouting and swearing)
– Appearance: can appear disheveled, unusual clothing
– Inappropriate sexual behavior e.g. public
masturbation
• Catatonic Motor Behavior
– marked decrease in reactivity to environment
– maintaining rigid posture and resisting effort to be
moved
Negative Symptoms
• Negative Symptoms: diminution or loss of
normal functioning
– Affective flattening: restriction in range and intensity of
emotional expression (affect)
– Alogia (poverty of speech): decrease in production of
thoughts/speech
– Avolition: decrease in goal-directed behavior
Heterogeneity of
Schizophrenia
• Symptoms - not all are present in every case, can differ
across time in a case
• Age at onset - differs markedly between males (late teens)
and females (mid twenties)
• Premorbid functioning - for some, comes from ‘out of blue’,
for others, insidious
• Course of illness - episodic versus chronic
• Differential diagnosis -Psychotic symptoms may also be
present in mania and depression, or in substance abuse
and organic brain syndromes (dementia)
Gerald 0-3:15
Part I: http://www.youtube.com/watch?v=gGnl8dqEoPQ
Part II: http://www.youtube.com/watch?v=i6h8Ic-I7R0
What changes in the brain to
cause schizophrenia?
Schizophrenia as a Genetic Disorder
• Evidence for a role of
genetics:
– Aggregates in families
– Closer genetic
relationship, risk (e.g. MZ
twin risk = ~50%,
while DZ = ~13-15%)
More complicated than just
genetics…
• not Mendelian:
– Not fully penetrant (MZ twin risk is not 100%)
– Some symptoms can arise from non-genetic causes (I.e.
psychosis from drug abuse = phenocopy)
– Affected/unaffected boundary not clear- spectrum disorder
– Multiple genes: a combination of genes  risk
• Environmental factors :
– prenatal influences - birth complications, maternal
influenza, maternal stress
– environmental factors - cannabis use, urban environments
Schizophrenia & Genes
• Significant genetic component
• The mode of transmission is complex, involving
many genes and gene-environment interactions
• The genes do not produce symptoms, but
changes in brain structure and function that
make one susceptible to symptoms
• Current theory: Schizophrenia is highly
polygenic - can result if one has a certain
critical number of predisposing genes and (at
least in some cases) particular environmental
stressors (diathesis-stress)
Hypothesized Model of Illness Progression
Severe
Early Insults
Disease Genes
Viral Infections
EnvironmentalToxins
Triggers
Moderate
Disability
Biological Vulnerability
Cognitiv
e
Affective
Vulnerability Indicators
Social
Isolation
Avolition,
School
Failure
Early Symptoms
108 Genome-Wide Significant Risk Loci!
Ripke et al. 2014
?
Schizophrenia
Schizophrenia
If schizophrenia is genetic, then what are the
specific risk factors being inherited?
Two possibilities:
• Neural changes (brain
structure/function)
• Cellular signaling changes
Neurocognitive impairment as an indicator of
genetic liability to schizophrenia
 Schizophrenia increasingly viewed as extreme end of a set of quantitative traits;
neurocognitive deficits possible indicators of this liability.
Cognitive impairment is:
 Present in first-episode schizophrenia and even before illness onset
 remains relatively stable throughout the course of illness;
 not accounted for by effects of symptoms or medication;
 Found among clinically unaffected relatives of SZ patients
For cognitive measures, attention found to have moderate to high relative risk
in subgroup of families with high genetic loading for schizophrenia (Chen
1998; Egan 2000)
Wechsler Intelligence Scale for Children (WISC) Subtest Scores for 7-YearOlds Who Later Developed Schizophrenia, Their Unaffected Siblings, and
Nonpsychiatric Comparison Children
Niendam et al. AJP 2003
Deficits in Spatial Working Memory Co-Vary
with Genetic Liability to Schizophrenia
100
Probands
MZ Co-Twins
DZ Co-Twins
Healthy Controls
% Correct
90
80
70
Load 1
Load 3
Memory Set Size
Glahn et al., Biological Psychiatry 2003;53:624-626.
Load 5
Least Square Mean Number of Words per Trial
+/- Standard Error
Deficits in Verbal Learning and Recall Co-Vary with
Genetic Liability to Schizophrenia
16
Proband
MZ-cotwin
DZ-cotwin
Healthy
14
12
10
8
6
4
2
0
Free Recall
van Erp et al. 2007
Cued Recall
Trial Type
Recognition
Hippocampal Volumes across Risk Groups
van Erp, T. G. M. et al. Arch Gen Psychiatry 2004;61:346-353.
Copyright restrictions may apply.
Proportions of medication-naive patients
negatively (P=0.0004) associated with
hippocampus group contrast effect
Slide courtesy of Carol Tamminga
-Intelligence, working memory and perceptual organization shared
highest genetic variance with schizophrenia (not processing speed)
-rg = −0.75 between SZ and IQ; suggests same genes contribute to
individual differences in intelligence and to liability to schizophrenia
Arch Gen Psychiatry. 2007;64(12):1348-1355. doi:10.1001/archpsyc.64.12.1348
Cognitive Decline as a Predictor of Psychosis in the General
Population; Dunedin Birth Cohort
IQ was stable across childhood for all groups but declined for the
schizophrenia group between ages 13 and 38 (0.39 SD)
Meier et al. AJP 2014
Cognition: IQ in Premorbid , Clinical High Risk & Psychosis
Phases (in Liu, Keshavan, Tonick, Seidman, SZ Bull 2015)*
PRE
-0.54
PRO-C
-0.81
FE
-1.01
CSZ
-1.1
FE-CSZ
Memory
-1.2 to
1.5
*Cross-sectional studies from 4 meta-analyses – L. Seidman
PRE: Woodberry, Giuliano & Seidman, 2008; PRO-C: Giuliano et al. 2012; FE: MesholamGately, Giuliano, et al. 2009; CSZ: Heinrichs & Zakzanis, 1998
NAPLS 1 Profile by Group
(Seidman et al 2010, Arch Gen Psychiatry)
NAPLS2, Submitted – Seidman et al., 2016
Neuropsychological Profile by Diagnostic Group Accounting for Age
0.2
0.0
Z Score
-0.2
-0.4
-0.6
-0.8
CHR Non-Converters (n=600)
Control
CHR Converters (n=89)
-1.0
Executive
Verbal Abilities Attention/Working
Declarative
Fx/Visual Abilities
Memory Abilities Memory Abilities
Task
Babble
Upsit
NAPLS 2 Tests of Retrieval from Semantic
Knowledge (subjects with 2+ assessments)
WASI Vocabulary
Verbal Fluency
Smell Identification
Trajectories by age centered. Linear mixed effects models adding ‘group’ x ‘time’ as a fixed
effect fit the data better than those with only mean age, sex, and maternal education but
group by time interaction effects were not significant.
NAPLS 2: Tests of Memory
(subject with 2+ assessments)
Verbal Memory
Visual Memory
Spatial Working Memory
Trajectories centered on age. Linear mixed effects models adding ‘group’ x ‘time’ as a fixed
effect fit the data better than those with only mean age, sex, and maternal education but
group by time interaction effects were not significant.
We are able to observe thinner grey matter in
living subjects using MRI
Cannon, 2001
Basis of Structural Changes
• If people with schizophrenia (for the most part)
don’t have full blown symptoms until late
adolescence or early adulthood, when or how do
these underlying brain changes occur?
• Your brain is a dynamic structure, changing
substantially across your lifespan.
• The genetic and environmental factors that
contribute to risk for schizophrenia may do so by
directly influencing neural development, or by
interacting with ongoing developmental processes.
Synaptogenesis and Pruning
Neuronal Cell Death/Synaptic Pruning

Synaptogenesis
Synaptic
Density

Birth
4yrs-10yrs
Adolescence
Age 
• Grey matter changes
– Typical Development
• synapses are overproduced early in development
• across development and during adolescence, normal
pruning process occurs eliminating 40% of cortical
synapses (Huttenlocher, 1979)
Structural Changes Emerge Across Development

Overaggresive or accelerated pruning
Synaptic
Density

Psychosis
threshold
Selemon & Goldman-Rakic
Glantz & Lewis
Changing Grey Matter Across Adolescence
Sun, 2009
Is Neuroanatomic Change Predictive of Psychosis Onset?
Cortical thickness change over time among converting CHR subjects (n=35), non-converting
CHR (n=239), and healthy controls (n=135)
Converters vs.
Controls
Converters vs.
Nonconverters
FDR Corrected P-Maps
2
Wald χ =14.82, P=0.0001, AUC=0.71
Cannon et al, Biol Psych 2014
•
•
• At Sensitivity = 0.60
- Specificity = 0.77
- PPV = 0.40
- NPV = 0.88
• At Sensitivity = 0.78
- Specificity = 0.65
- PPV = 0.37
- NPV = 0.92
Differential GM loss among cases who had not received antipsychotic medications
during the inter-scan interval
Prefrontal GM loss was significantly correlated with pro-inflammatory index in plasma
Summary
• Disruption of neural systems part of
inherited diathesis to schizophrenia
• Both structural and functional brain
changes emerge across adolescence
• This time period may represent a window
in which it is possible to intervene and
prevent development of abnormal circuitry
If schizophrenia is genetic, then what are the
specific risk factors being inherited?
Two possibilities:
• Neural changes (brain
structure/function)
• Cellular signaling changes
Many of the first
psychiatric drugs were
discovered
serendipitously & led to
the production of new
hypotheses about the
causes of mental
disorders
The pathophysiology is studied
to reveal possible causes
Etiology
Pathophysiology
The mechanisms of action
of those treatments are revealed
and used to infer pathophysiology
Phenomenology
Treatment
It is noted that certain phenotypes
respond to particular interventions
The Dopamine Story, Part I
• For many years was no effective treatment
• Chlorpromazine (Thorazine)
– ~ 1950 Synthesized as an anti-histamine to produce
sedation
– Discovered, by chance, also to have antipsychotic
efficacy
• Some patients show symptom reduction after
prolonged treatment
• This is not a general effect of tranquilizers
– Categorized as a “neuroleptic” based upon its ability to
produce extreme slowness or absence of movement
(neurolepsis)
The Dopamine Story, Part II
• More related drugs were discovered, with common antipsychotic
effects and common side effects (Fluphenazine, thioridazine,
Haloperidol)
• Carlsson and Lindqvist (1963)
– Delivered available antipsychotic drugs to rabbits - found that
they all elevated the levels of 3-methoxytyramine (3-MT) in brain
– 3-MT is the catabolite (breakdown product) of the monoamine
dopamine which is produced after COMT breaks it down.
Therefore, it seems that these drugs are having an impact on
dopaminergic function
Affinity for Dopamine Receptors
Predicts Antipsychotic Efficacy
• All clinically efficacious
antipsychotic drugs are
DA receptor antagoniststhey block DA receptors.
• The specific dopamine
receptor they block is the
D2 type
• D2 receptors most
prevalent in striatum
Blocking striatal dopamine
has antipsychotic effects
Creese et al. (1976) Science 192:481-3
The Dopamine Story, Part III
• L-dopa treatment of Parkinson’s disease,
which helps enhance DA production, can
cause psychosis
• Long-term or high dose intake of stimulant
drugs can elicit psychosis
– Increasing problem with treatment of adults for AD/HD
• L-dopa augments DA synthesis and release,
and stimulant drugs increase DA release.
Increasing dopamine can cause psychotic
symptoms
Summary of evidence:
• Certain drugs have been shown to reduce
psychotic symptoms
• Those drugs were found to be dopamine
antagonists
• The better the drug was at blocking dopamine, the
better an antipsychotic it is.
• Drugs that increase dopamine levels can lead to
psychosis
• What would be the logical conclusion to draw
about dopamine from this evidence?
BUT…. Initial Dopamine Hypothesis has
Limitations
• Only about 1/3 of all patients will respond well to
one or the other of these pharmacological
interventions
• All patients treated with these drugs will develop
severe side effects that limit compliance
• Once again, there is an issue of a therapeutic lag
• Even amongst those 1/3 of patients that will
respond well to treatment, not all symptoms will be
equally affected
Drug Effects on Symptoms
• Positive symptoms of the disorder are more
affected than the other symptoms
• Negative and cognitive symptoms are
generally not improved with these drug
treatments, even when positive symptoms
are constrained
• “old” D2 antagonist drugs may increase
negative and cognitive symptoms (or produce
so-called ‘secondary’ negative/cognitive
symptoms)
Dopamine and the
Frontal Lobe
• Decrease in dopamine levels in the PFC may
be related to cognitive deficits in
schizophrenia.
• Cognitive deficits and metabolic dysfunction
of frontal cortex in schizophrenia reversed by
dopamine receptor agonists or drugs that
stimulate dopamine release.
• Striatal and frontal dopamine levels and
effects may differ
Dopamine Distribution
• Released primarily
into:
– basal ganglia (striatum)
– frontal lobe
• Nigrostriatal System
– (role in movement)
• Mesolimbic System
– (role in reinforcement/reward)
• Mesocortical System
– (role in short-term memory,
planning, and problem solving)
Dopamine might be PART of the story, but
cannot explain everything
A New Suspect:
Glutamate
•
NMDA receptor hypofunction hypothesis
(Stone et al., 2007,2011)
•
NMDA receptor antagonists increase
glutamate and result in neurotoxic
changes in animals
Review: Howes et al . Glutamate and dopamine in
schizophrenia: An update for the 21st century. J of
Psychopharmacology 2015.
PCP is an NMDA Antagonist
• PCP produces a
“non-competitive”
blockade of the
NMDA receptor.
• Ketamine shares
this effect.
• Schizophrenia
may also involve
low levels of
glutamate
PCP (Humans and Animals)
PCP and ketamine are NMDA (glutamate receptor) antagonists.
They cause a set of symptoms much closer to the full spectrum
of schizophrenia symptoms than dopamine agonists do.
• Induce positive symptoms
– Delusions and hallucinations
– Thought disorder
• Induce negative symptoms
– Social withdrawal
– Flattened affect
• Induce cognitive symptoms
– Working memory, attention, executive function deficits
Dopamine and
Glutamate
• There is an interactive dopamine-glutamate
circuitry between the striatum and the
cortex.
• Low levels of glutamate may be the
primary source of other disruptions,
including lower prefrontal dopamine (which
causes cognitive deficits) and higher
striatal dopamine (which causes
psychosis).
Schizophrenia Genetics, Part II
Majority of cases of unknown etiology; But- rare genomic copy number
variants (CNVs) may account for a larger proportion of schizophrenia
cases than was previously believed.
Also provide strong evidence for genetic pleiotropy, challenging widely
held views of diagnostic ‘categories’
22q11.2 microdeletion syndrome (22q11.2DS) is a CNV which conveys
the greatest increase in risk for SZ/also highly penetrant for multiple
childhood disorders
22q11.2 Microdeletion Syndrome





Velocardiofacial/DiGeorge Syndrome
Estimated incidence -~ 1/2000 live births (Grati et al 2015)
Results from hemizygous deletion of chromosome 22q11 (~3 Mb)
Cardiac defects, immune deficiency, craniofacial anomalies
Morbid risk of schizophrenia ˜ 25x the general population risk (Bassett et
al.2010; Murphy et al.1999); accounts for ~1% of sporadic SZ cases (Stefansson
et al., 2008; Karayiorgou et al. 2010)
 Elevated rates of Autistic Spectrum Disorder (12-50%), ADHD (33-40%)
and anxiety disorder (40-50%) in childhood (Schneider et al. 2014; Richards et al.
2014)
Jonas et al., Biol
Psych 2013
Prevalence of Schizophrenia Spectrum Disorders by Age in
22q11DS (n=1402); 41% of adults age 25+
Total N=1402
Schneider et al AJP 2014
Does Cognitive Decline Predict Psychosis in 22q11DS?
(N=430)
Vorstman et al JAMA Psychiatry 2015
Verbal IQ decline significantly increased risk for psychosis (OR 3.5; 95%
CI=1.77-9.04, p=0.001)
Longitudinal Findings: 3-way (brain region x time x group) interactions associated
with psychotic symptom change over time
Brain Regions associated with Social Processes
Green et al Nat Rev Neurosci 2015
Mouse Models of Sz: 22q11.2 Deletion Syndrome
Kellendonk et al 2009
Bryan Charnley, Portrait Series
http://www.bryancharnley.info/
Apart from my pictures, I regard my
illness as completely negative,
involving the sufferer in a vicious
downward spiral. Current medical
practice attempts to suppress both
the patient and his symptoms,
convenient but evasive. My
paintings stand as an attempt to
penetrate this wall of silence and I
hope they can throw some light on
a condition which has largely
eluded medical science”.
Conventional portrait painted
in two sittings. Is it a good
likeness? Drug dosage was
two 3 mg. tablets of Depixol
daily plus two 25 mg.
Tryptisol. I was sleeping a
lot. 11th to 16th April 1991.
Series of slides courtesy of Dr. Robin Murray
20 April
‘Very paranoid’, Bryan writes in the diary. The person upstairs is
reading my mind and speaking back to me in a sort of ego
crucifixion… The large rabbit ear is because I am confused and
extremely sensitive to human voices, like a wild animal’
6 May
‘I feel like a target for people’s cruel remarks.
18 May
‘My mind seems to be thought-broadcasting very severely and it is
beyond my will to do anything about it. I have summed this up by
painting my brain as an enormous mouth’
23 May
‘The blue is there because I feel depressed ….The wavy lines are
because just as I feel I am safe, a voice from the street guts me
emotionally by its ESP of my conditions…
13 June
Bryan has cut out his antidepressant drug completely since 24 May. His selfportrait shows two decapitated egg shells, their contents devoured.
‘The eggs have been emptied like a head stripped of its contents, It has
nothing left in it, no more secrets’
Final Portrait
Take Home Messages
• Schizophrenia is a complex illness with genetic and
environmental causes
• Disruptions in both glutamatergic and dopaminergic
systems implicated in disease pathophysiology
• Structural brain changes and concomitant cognitive
changes proximal to (prior to?) illness onset
• Utility of high-penetrance models: 22q11DS may account
for only small proportion of risk for psychotic illness
overall, but dysregulated genes/pathways may contribute
to broader psychosis susceptibility