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The Neurobiology of Mood and Psychotic Disorders
Daphne J. Holt, MD, PhD
Co-Director, Schizophrenia Clinical and Research ProgramDepartment of Psychiatry, Massachusetts General Hospital
Associate Professor, Harvard Medical School
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Overview of talk
• Genetics: Consistent evidence for overlap across disorders
• Gene x Environment interactions, epigenetics
• Abnormalities in brain structure and function, neurochemistry and inflamation
• Summary
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Disease Incidence and Overlap
• Major Depressive Disorder (MDD)– Overall lifetime incidence: 17% in the U.S. (lower in other countries, e.g., in Japan 3%)– Among those with MDD, lifetime incidence of psychosis: ~18%
• Bipolar Disorder (BD)– Overall lifetime incidence: ~4% (including Bipolar I & II and subthreshold); 1% for Bipolar I– Among those with BD, lifetime incidence of psychosis: 25%
• Schizophrenia (SZ)– Overall lifetime incidence: 0.7%, ~3% defined broadly (with 5+ fold variation in incidence across
the world, highlighting the importance of environmental factors)– Among those with SZ, lifetime incidence of MDD: 25%
• Genetics and neuroimaging studies show evidence of biological overlap –dimensional/symptom-focused approaches are now gaining favor in biological research
The Psychiatric Genetics Consortium, Lancet 2013
Many shared genetic risk variants across disorders
The Brainstorm Consortium, Science 2018
Genetic overlap observed with an ever increasing number of disorders
such as OCD, PTSD, TS…
The Genetics of Personality Consortium JAMA Psych 2015
Overlap with personality traits too:
polygenic scores for neuroticism explain 15% of the variance
in neuroticism and predict MDD
Genes Environment
Heritability of
Schizophrenia: 80%
Bipolar Disorder: 90%
Major Depression: 40%
Mood Disorders: childhood trauma
Schizophrenia:
-in utero events, such as infections, nutritional
deficiencies
-childhood trauma/bullying
-urban living
-minority status/discrimination
-cannabis use
G x E
Houston et al, Neuropsychopharm Rev 2013
Epigenetic mechanisms1) those that alter DNA directly, i.e., via methylation 2) histone modification 3) non-coding RNAs, e.g., microRNA, that modify gene expression
Keller et al, Arch Gen Psych 2010
Increased BDNF promoter methylation in the Wernicke area of suicide victims
G x E interactions underlying depression
Example: 5HTTLPR gene x stressful life events
S carriers: reduced structural and functional
connectivity and hyperactivity of the amygdala
Pezawas et al, Nat Neurosci 2005
Greater sensitivity to adverse life events
Caspi et al, Science 2003
Genetic variation in the FKBP5 gene x early adversity
Matosin et al Biol Psych 2018
Colizzi et al Schiz Bull 2015
G x E interactions underlying schizophrenia
Example: DRD2 gene x cannabis use
Risk for schizophreniaRelative risk
for a psychotic disorder
Relative risk
for a psychotic disorder
Interaction between increased genetic risk for schizophrenia
and obstetric (intra-uterine) complications
Ursini et al, Nat Med 2018
GWAS signal for depression (3 significant loci) only in women
with no reported adversity →
contribution of genetics to depression may be more heterogeneous
for those with histories of adversity
Peterson et al, Am J Psych 2018
genetic vulnerability,
present from birthchanges in brain
structure/function
symptoms
and impaired functioning
prenatal or later-in-life events,
effects depend on developmental stages/critical periods
E
The Overall Model
Johnstone et al, Lancet 1976
Ventricular enlargement and brain volume loss in schizophrenia
0.0010.1 0.050.001
Kuperberg et al, Arch Gen Psych 2003
Ventricular enlargement →
widespread cortical thinning in schizophrenia
Area 9 Area 17
Selemon et al, Arch Gen Psych 1995
Cannon TICS 2015
Excessive pruning and loss of cortical connections over time →
increased vulnerability to psychosis
Sekar et al, Nature 2016
Schizophrenia risk proportional to the C4 allele’s tendency to
increase C4A expression, which mediates pruning
Satterthwaite et al JAMA Psych 2016
Similar pattern of “excessive pruning”
in adolescents with low level psychotic symptoms
Specific types of therapy (e.g., cognitive enhancement treatment) may reverse or
prevent progressive changes in the brain during the early stages of schizophrenia
Eack et al, Arch Gen Psych 2010
Fetal fortification exposure alters cortical development during adolescence
8 9 10 11 12 13 14 15 16 17 18
Age at MRI scan
Co
rtic
al th
ick
ne
ss
Healthy, born pre-rollout
Healthy, born post-rollout
Schizophrenia, born pre-
rollout
Unexposed group
starts to thin
Exposed group
starts to thin
Eryilmaz et al, JAMA Psych 2018
vmPFC
AH
A key circuit affected in neuropsychiatric disorders
Ressler & Mayberg, Nat Neurosci 2007
Abnormalities of the subgenual cingulate gyrus in major depression
Greater frontal-amygdala connectivity in resilient
(vs. non-resilient) female adolescents
Fischer et al, JAMA Psych 2018
Drevets Curr Opin Neurobio 2001
The finding of amygdala hyperactivity
in unipolar and bipolar depression has been highly replicated
y = -7
A. FH-
B. FH+
C. FH+ > FH-
Amygdala
0.0010.001 0.05
Face A > Face WFace W > Face A0.05
Overactivity of the amygdala in children of
patients with depression has been observed in 3 studies (Monk et al, 2008; Swartz et al, 2014, Chai et al, 2015)
Barbour et al, under review
Also found in young adults
with a first-degree
relative with depression
Wolf et al, JAMA Psych 2015
Overactivity of the amygdala in youth with subclinical, psychotic-like symptoms
Control (n=16)
-0.1
-0.05
0
0.05
0.1
0.15
0.2
0 10 20 30 40 50 60 70 80 90 100 110 120
Seconds
% S
ign
al C
han
ge
Schizophrenia(n=18)
Abnormally sustained hippocampal response
to emotional stimuli in schizophrenia
Holt et al, Biol Psych 2005
X 160
+ +
Average perfusion of the hippocampus
(ml/100g/min)
Se
ve
rity
of su
bclin
ica
l d
elu
sio
ns
0
2
4
6
8
10
12
14
20 30 40 50 60 70
x = -27
Hipp
Hipp
Wolthusen et al, Biol Psych CNNI, 2018
Levels of subclinical delusions predicted the resting activity (perfusion)
of the hippocampus bilaterally
These data, which resemble similar findings in patients with psychotic disorders,
suggest that the phenomenology and biology of subclinical
and clinical psychosis are on a continuum
r = .27
p = .02
n = 77
Dopamine synthesis is elevated in schizophrenia and bipolar disorder patients
compared to healthy subjects, and correlates with positive symptom severity
Jauhar et al, JAMA Psych, 2017
What are the molecular and cellular mechanisms
underlying these changes in the brain?
Cannon TICS 2015
Cellular model of schizophrenia
Neuroinflamatory pathways in the pathogenesis of depression
Jeon & Kim J Inflam Res 2018
Goldsmith et al, Mol Psych 2016
Changes in cytokines in schizophrenia, bipolar
disorder and depression
Miller et al Biol Psych 2009
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Conclusions/Discussion
genetic vulnerability,
present from birthchanges in brain
structure/function
symptoms
and impaired functioning
prenatal or later-in-life events,
effects depend on developmental stages/critical periods
E