the neurobiology of mood and psychotic...
TRANSCRIPT
![Page 1: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/1.jpg)
www.mghcme.org
The Neurobiology of Mood and Psychotic Disorders
Daphne J. Holt, MD, PhD
Co-Director, Schizophrenia Clinical and Research Program Department of Psychiatry, Massachusetts General Hospital
Associate Professor, Harvard Medical School
![Page 2: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/2.jpg)
www.mghcme.org
Disclosures
Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest
to disclose.
![Page 3: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/3.jpg)
www.mghcme.org
Overlap/comorbidity?
• 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 also show evidence of biological overlap –
dimensional/symptom-focused approaches are now gaining favor in biological research
![Page 4: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/4.jpg)
The Psychiatric Genetics Consortium, Lancet 2013
Genetic pleiotropy is high across disorders –
many shared genetic risk variants
![Page 5: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/5.jpg)
www.mghcme.org
Overview of talk
• The big picture: Gene x Environment interactions in mood and psychotic disorders
• Schizophrenia:
– Abnormalities in brain structure and function – Abnormalities in neurochemistry – Genetics and epigenetics
• Mood disorders:
– Abnormalities in brain structure and function – Abnormalities in neurochemistry – Genetics and epigenetics
• Summary
![Page 6: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/6.jpg)
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
![Page 7: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/7.jpg)
Heritability of Common Illnesses
Huntington’s Disease 100%
Autism 90%
Bipolar Disorder 80%
Schizophrenia 80%
Asthma 80%
ADHD 70%
Coronary Artery Disease 65%
Hypertension 62%
Major Depression 40%
Alcoholism (in males) 35%
![Page 8: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/8.jpg)
genetic vulnerability,
present from birth changes in brain
structure/function
symptoms
and impaired functioning
prenatal or later-in-life events,
effects depend on developmental stages/critical periods
genes x E brain function x E symptoms X E
E
![Page 9: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/9.jpg)
Veling et al, Int J Epidem, 2007
One environmental influence on schizophrenia risk:
Minority status increases the risk of developing schizophrenia 2-4 fold,
unrelated to ethnicity or socioeconomic status
The increase in risk correlates with
discrimination rates Relative rate
(compared to
average rate) of
developing
schizophrenia:
4 x
2 x
1.5 x
Discrimination, urban living, bullying, childhood abuse = social stress
![Page 10: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/10.jpg)
Akdeniz et al JAMA Psych 2014
Greater social stress-induced activation of the brain
in minority participants compared to controls,
which correlated with discrimination levels
![Page 11: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/11.jpg)
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
![Page 12: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/12.jpg)
Colizzi et al Schiz Bull 2015
G x E interactions underlying schizophrenia
Example: DRD2 gene x cannabis use
Risk for schizophrenia Relative risk
for a psychotic disorder
Relative risk
for a psychotic disorder
![Page 13: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/13.jpg)
www.mghcme.org
Abnormalities in brain structure and function in schizophrenia
• Enlarged ventricles and loss of brain volume
– Localized or diffuse?
– Static or progressive? Reversible?
– Role of antipsychotics?
– How early do these start? (During the prodrome or earlier?)
• Inefficient function and abnormal connectivity (“dysconnectivity”) of the prefrontal cortex and other regions
• Related to impairments in cognition? Social cognition?
• A fundamental expression of the pathophysiology, or secondary to having the illness or its treatments?
• A large-scale network coordination problem – frontoparietal attention network vs. default network
• Abnormalities in subcortical structures may drive other changes: e.g., hippocampus
• Sensory/perceptual abnormalities may play an important role: bottom up vs. top down?
![Page 14: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/14.jpg)
Neuroimaging: Across Space and Time Anatomy, Physiology, Metabolism, Electrophysiology, Neurochemistry
High-Field fMRI
PET
Optical Imaging
Anatomic MR
EEG/MEG
TMS
Cortical Stim
Courtesy of Bruce Rosen
![Page 15: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/15.jpg)
Johnstone et al, Lancet 1976
Ventricular enlargement and brain volume loss in schizophrenia
![Page 16: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/16.jpg)
0.001 0.1 0.05 0.001
Kuperberg et al, Arch Gen Psych 2003
Ventricular enlargement
widespread cortical thinning in schizophrenia
![Page 17: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/17.jpg)
Area 9 Area 17
Selemon et al, Arch Gen Psych 1995
![Page 18: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/18.jpg)
Nakamura et al, Biol Psych 2007
Kasai et al, Am J Psych 2003
Brain volume reductions may be progressive
during the early years of psychosis
An active pathological process, which may be reversible?
Also a contribution of antipsychotic medications
![Page 19: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/19.jpg)
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
![Page 20: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/20.jpg)
The stages of psychotic illness
Fusar-Poli, JAMA Psych 2013
Note: ~ 25-30% of people who are “clinically high risk” develop schizophrenia
![Page 21: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/21.jpg)
Timeline of Human Brain Development
Thompson & Nelson, American Psychologist 2001
![Page 22: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/22.jpg)
Cannon TICS 2015
Excessive pruning and loss of cortical connections over time
increased vulnerability to psychosis
![Page 23: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/23.jpg)
Satterthwaite et al JAMA Psych 2016
Similar pattern of “excessive pruning”
in adolescents with low level psychotic symptoms
![Page 24: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/24.jpg)
Buckner et al, NYAS 2008; Adapted from Fox et al, 2005
![Page 25: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/25.jpg)
One example: reduced functional connectivity between mid/posterior
and dorsal anterior cingulate cortex in schizophrenia
0.15
1.0
Co
rre
lation
(r)
Control subjects
*
Schizophrenia patients
*
Holt et al, Biol Psych 2011,
Much evidence (from diffusion tensor imaging, EEG & resting-state connectivity studies)
for “dysconnectivity” in schizophrenia
![Page 26: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/26.jpg)
An abnormally small hippocampus is one of the most replicated findings in schizophrenia
localized to a subregion of the hippocampus?
Can segment the human hippocampus into its subfields using MRI
![Page 27: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/27.jpg)
Schoebel et al, Arch Gen Psych 2009
Hyperactivity of the hippocampus, particularly CA1, in psychosis
![Page 28: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/28.jpg)
Schoebel et al, Neuron 2013
Hypermetabolism of the CA1 subfield of the hippocampus
predicts CA1 atrophy in at-risk prodromal patients
20 prodromal patients;
10 developed psychosis
during the follow-up period
(mean 2.4 years)
Also modeled this pattern of changes in ketamine-treated mice -
showed that excessive extracellular glutamate plays a role
![Page 29: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/29.jpg)
Atrophy of the hippocampus in schizophrenia begins in the CA1 subfield
and then spreads to involve the other subfields over the course of the illness
Ho et al, Mol Psych 2016
![Page 30: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/30.jpg)
www.mghcme.org
Abnormalities in neurochemistry in schizophrenia
• Dopamine
– Increase in presynaptic synthesis and release
• Glutamate • Hypofunction of glutamate NMDA receptors
• GABA • Deficits in the fast-spiking parvalbumin-containing
interneurons
• Neurotrophic factors • Inflamation
![Page 31: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/31.jpg)
Seeman, Synapse 1987
Dopamine neurotransmission is
dysregulated in schizophrenia
![Page 32: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/32.jpg)
Laruelle et al, Biol Psych 1999
In vivo evidence for the dopamine hypothesis of schizophrenia:
excessive dopamine release in acutely psychotic patients
![Page 33: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/33.jpg)
Cannon TICS 2015
Cellular model (unified hypothesis?) of schizophrenia
NMDA receptor hypofunction
(due to a reduction in dendritic spines, increased pruning, neuroinflamation)
deficit in functioning of GABAergic interneurons (fast spiking, parvalbumin-containing)
“disinhibition” of hippocampal pyramidal cells, thalamic nuclei, dopamine neurons
Increases in extracellular glutamate further atrophy, loss of connections
![Page 34: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/34.jpg)
www.mghcme.org
Abnormalities in genetics/epigenetics in schizophrenia
• Schizophrenia is highly polygenic GWAS with > 36K patients and > 100K
controls: 108 SNP “hits” meeting significance threshold – Still these loci only account for 3.4% of the liability for schizophrenia – Loci in genes encoding synaptic proteins, calcium channels, glutamate
receptors, the D2 dopamine receptor, the major histocompatibility complex (MHC)
– many common alleles with very small effects
• 11 rare copy number variants (CNVs) identified: large deletions or duplications that confer a relatively high amount of risk for schizophrenia, can be de novo, incidence of clinically relevant ones ~5% (use of chromosomal microarray analysis as a diagnostic test?)
• High degree of pleiotrophy in common SNPS and CNVs– one gene or allele affecting multiple phenotypic traits– i.e., common risk variants for schizophrenia, bipolar disorder and major depressive disorder
Owen et al, Lancet 2016
![Page 35: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/35.jpg)
Nature 2014
![Page 36: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/36.jpg)
Sekar et al, Nature 2016
Schizophrenia risk proportional to the C4 allele’s tendency to
increase C4A expression, which mediates pruning
![Page 37: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/37.jpg)
Houston et al, Neuropsychopharm Rev 2013
Epigenetic mechanisms– accounting for “missing heritability?”: 1) those that alter DNA directly, i.e., via methylation 2) histone modification 3) non-coding RNAs, e.g., microRNA, that modify gene expression
![Page 38: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/38.jpg)
www.mghcme.org
Abnormalities in brain structure and function in mood disorders
• Hypofunction of the prefrontal cortex, particularly the dorsolateral prefrontal cortex (DLPFC), and striatum
• Overactivity of the amygdala
– also present in first-degree relatives
– correlations with levels of childhood adversity
• Overactivity of the subgenual cingulate cortex and anterior insula
• Reduced volume of the hippocampus - correlations with the number of episodes/chronicity and treatment resistance
• Clinical heterogeneity and state vs. trait effects may account for inconsistent findings ongoing work identifying mood disorder subtypes related to specific symptoms and treatment response
![Page 39: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/39.jpg)
Drevets, Curr Opin Neurobio 2001
The finding of amygdala hyperactivity
in unipolar and bipolar depression is highly replicated
![Page 40: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/40.jpg)
y = -7
A. FH-
B. FH+
C. FH+ > FH-
Amygdala
0.001 0.001 0.05
Face A > Face W Face W > Face A 0.05
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
![Page 41: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/41.jpg)
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
50 70 90 110
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
50 70 90 110
Left
Am
ygd
ala
Sign
al C
han
ge (
%):
A
pp
roac
hin
g vs
Wit
hd
raw
ing
Face
s
A. B.
Rig
ht
Am
ygd
ala
Sign
al C
han
ge (
%):
A
pp
roac
hin
g vs
Wit
hd
raw
ing
Face
s Resilience Level (CD-RISC Score)
Resilience Level (CD-RISC Score)
Barbour et al, under review
Overactivity of the amygdala in first-degree relatives of
patients with depression may be linked to low resilience
![Page 42: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/42.jpg)
X
Model of mood disorders: reduced prefrontal function leads
to disinhibition of the amygdala and other limbic structures
![Page 43: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/43.jpg)
A meta-analysis showed an average of increased connectivity between
the subgenual prefrontal cortex and default network in depression: a model of rumination
Hamilton et al, Biol Psych 2015
![Page 44: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/44.jpg)
Ressler & Mayberg, Nat Neurosci 2007
Abnormalities of the subgenual cingulate gyrus in major depression
![Page 45: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/45.jpg)
www.mghcme.org
Abnormalities in neurochemistry in mood disorders
• Monoamines: post-mortem, PET, CSF and neuroendocrine studies
demonstrate reduce activity of serotonin neurons in depressed patients (with reductions in serotonin transporter binding sites and receptor densities); alterations in norepinephrine and dopamine as well
• Cortisol: Many depressed patients hypersecrete cortisol; the dexamethasone suppression test (DST), plus the cortisol releasing factor (CRF) stimulation test, indicate hyperactivity of the HPA axis in these patients– may be due to a tendency (genetically mediated) towards CRF hypersecretion, which may lead to overactivity of the immune system. However, both hypercortisolemia and hypocortisolemia can be observed in depressed patients.
• Chronic inflamation: levels of cytokine activation correlate with depression severity; anti-inflamatory agents have therapeutic effects
Saveneau & Nemeroff, Psych Clin N Am 2012
![Page 46: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/46.jpg)
www.mghcme.org
Abnormalities in neurochemistry in mood disorders
• The “neurotrophic hypothesis” of depression is based on:
• Reduced hippocampal BDNF in postmortem samples of
depressed patients
• Impairment of BDNF signaling depression-related behaviors
in rodents; facilitation of BDNF antidepressant effects
• Gender effects (explaining 2-fold higher incidence of depression in
females compared to males): Estrogen has antidepressant effects
but testosterone administered during puberty to rats reverses
depression-associated behaviors
• Abnormalities in energy homeostasis and metabolism
Krishnan & Nestler, Am J Psych 2010
![Page 47: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/47.jpg)
Abdallah et al Annu Rev Med 2015
![Page 48: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/48.jpg)
www.mghcme.org
Abnormalities in genetics/epigenetics in mood disorders
• GWAS of patients with depression have not produced significant findings
thus far; likely underpowered
• Genetically, depression has great overlap with anxiety (GAD), and some
(but less) with bipolar disorder
• Role of clinical heterogeneity in depression genetics: more heritable in
women; possibly 3 genetic factors underlying psychomotor/cognitive, mood
and neurovegetative features of depression, respectively
• GWAS of bipolar patients have identified significant loci in genes encoding
for subunits of calcium channels (L-type alpha), cell surface proteins,
extracellular matrix glycoproteins; some bipolar disorder risk alleles also
increase risk for schizophrenia and some are disease specific
• Different from schizophrenia: few copy number variants (CNVs) associated
with bipolar disorder so far
• G x E interactions observed for mood disorders may be accounted for by
epigenetic mechanisms Craddock & Sklar, Lancet 2013; Flint & Kendler, Neuron 2014
![Page 49: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/49.jpg)
Keller et al, Arch Gen Psych 2010
Increased BDNF promoter methylation in the Wernicke area of suicide victims
![Page 50: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/50.jpg)
Covington et al, J Neurosci 2009
Histone deacetylation condenses chromatin limits transcription;
HDAC inhibitors prevent this
Increased deacetylation of H3 in socially defeated mice and depressed humans
All of these changes were reversed
by treatment with an HDAC inhibitor,
similar to the effects of fluoxetine
![Page 51: The Neurobiology of Mood and Psychotic Disordersmedia-ns.mghcpd.org.s3.amazonaws.com/psychopharm2016/2016... · in mood disorders • GWAS of patients with depression have not produced](https://reader033.vdocuments.us/reader033/viewer/2022050100/5f3fbe775fd81f407e5a403a/html5/thumbnails/51.jpg)
www.mghcme.org
Summary/Conclusion
genetic vulnerability,
present from birth changes in brain
structure/function
symptoms
and impaired functioning
prenatal or later-in-life events,
effects depend on developmental stages/critical periods
E