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Adult Psychopathology
Mood Disorders
• Depression
– Major depression
– Dysthymia
– Postpartum depression
• Bipolar disorder
– Bipolar I
– Bipolar II
– Cyclothymia
Major Depression
• Marked change in mood
• Diagnosis entirely behavioural
– Persistent sad mood, loss of appetite, insomnia,
restlessness, feelings of: worthlessness, guilt,
helplessness, pessimism, cognitive difficulties,
social withdrawal, decreased energy, etc.
• Behaviours must persist at least 2 weeks
• Isolated or recurrent, mild, major, or severe
Epidemiology
• Affects 8-17% of population at least once
• Over 1 million Canadians; over 120 million
world wide
• Projected to be second-leading cause of
disability worldwide by 2020
Comorbid Conditions
• Anxiety disorders
• Attention-deficit hyperactivity disorder
• Suggest roles of serotonin, norepinephrine,
and dopamine in depression
• (More on this later)
Numbers
• Heritable
• Family risk about 9% vs. 3% in controls
• Concordance of 0.43 for MZ and 0.28 for
DZ twins
• Adoption studies mixed, but sample sizes
quite small
• No shared environmental effect to speak of
Dysthymia
• Less severe condition than major depression
• Chronic
– Altered eating patterns, insomnia or
hypersomnia, low energy, low self-esteem, poor
concentration, feelings of hopelessness
• Heritable, 2-3 times more common in
females
Postpartum Depression
•
•
•
•
•
Form of clinical depression
Can affect men too post-childbirth
5-25% prevalence rate in women
Typically lasts hours to days
Wide range of symptoms
– Sadness, hopelessness, low self-esteem, guilt, sleep
disturbance, exhaustion, social withdrawal, etc.
• Some interesting correlations
Meta-analyses
• Predominately environmental factors have been examined
• SES is significant, but even when controlled, higher
prevalence in African-American
– Heritability and ethnicity
Predictor
Prenatal depression
Low self-esteem
Childcare stress
Life stress
Low social support
Marital difficulty
Single parent
Low socioeconomics
History of depression
<Beck (2001)>
Correlation
0.44-0.46
0.45-0.47
0.45-0.46
0.38-0.40
0.36-0.41
0.38-0.39
0.21-0.31
0.19-0.22
0.38-0.39
Ethnicity
Prevalence of PPD
Overall
15.7%
African-American
25.2%
Native American
22.9%
Caucasian
15.5%
Hispanic
15.3%
Asian/Pacific
11.5%
<Segre et al. (2006)>
Hormones and PPD
• Has been suggested that post-childbirth hormonal
changes are causative factor
– Not supported (e.g., O’Hara, 1995)
– Also, fathers can experience PPD…
• Diathesis-stress models, gene-environment
interaction
– Some women are susceptible to stress of childbirth
and/or hormonal shifts
– Hormones simulating pregnancy and parturition induce
PPD-like symptoms, but only in some women
Bipolar Disorder
• Not a single disorder; category of mood disorders
characterized by abnormally elevated mood (mania),
sometimes followed by depressive episodes, generally
interspaced with normal periods
• Affects about 1% of world’s population; 17% lifetime risk
for suicide
• Bipolar I
– At least one or more manic episodes; may be episodes of major
depression as well
• Bipolar II
– At least one manic and one major depressive episode
Affect
• Mania
– Euphoria, grandiosity, increased energy,
increased irritability, decreased need for sleep,
rapid speech, risk taking
• Depression
– Low mood, low energy and motivation,
insomnia, feelings of hopelessness
Cyclothymia
• Milder form of bipolar II
• Recurrent mood disturbances between hypomania
and dysthymic mood
– Ranging from mild elation to mild depression
• Generally goes through cyclic periods
• Typically unrelated to life events (from selfreports), although may be triggered by general
stress levels
• Lifetime prevalence of 0.4-1%
– Equal in sexes, but women seek treatment more
Numbers
• Heritable
• Family risk of 9% vs. 1% in controls
• Concordance of 0.4-0.65 for MZ and 0.050.07 for DZ twins
• Adoption study (Mendlewicz & Rainer,
1977) found 7% of biological parents vs.
0% of adoptive parents show bipolar
disorder
Bipolar Linkage
• Early linkage studies inconsistent
• Suggestions of autosomal dominant loci
largely rejected
• Polygenic effect
• Possible loci: 4p, 5q, 10q, 12q, 13q, 18p,
21q, 22q, Xq (and more!)
Kelsoe et al. (2000)
• 443 microsatellite markers
• 20 families (San Diego and Vancouver)
– Have proband and at least two additional
affected members (either bipolar I or II)
Loci
• 12 yielded LODs greater than 2.0 across genome
• Highest scores for 22q13 (GRK3 gene)
• Also high LODs at 5p15 (dopamine transporter
gene), 10q, and 13q
• Some overlap with loci reported for schizophrenia
on these chromosomes
• Suggests many susceptibility genes are common
for the two disorders
– Could be nonspecific susceptibility or different
mutations in the same gene may predispose to different
disorders
GRK3 Gene
• GRK3 widely expressed in brain
• Regulation of G protein-coupled receptor
signaling
• Brain neurotransmission effects, including
dopamine and corticotropin-releasing factor
receptors (and others)
• GRK3 expression induced by amphetamine in rats
(animal model of mania)
• Unclear if GRK3 is a candidate gene in nonNorthern European descended Caucasians
• Selling bipolar genetic tests to public over the internet for
$399 as of March 2008
– Receive cup, spit in cup, mail cup to Psynomics
– Psynomics mails results to client’s doctor indicating likelihood of
developing bipolar disorder
• Two mutations on GRK3 gene
• Kelsoe argues that this moves away from behavioural
diagnosis
• However, only usable for whites of Northern European
ancestry who show some behavioural symptoms and have
at least one other bipolar family member
• As of yet, APA has no policy on genetic testing
• Currently not taking new patients
Bipolar Disorder and
Schizophrenia
• Similar clinical features
– Mood disturbance, cognitive impairment, psychosis
• Both about 1% prevalence rate
• Both have about 10% risk in first-degree relatives
• Some evidence that schizophrenia occurs at
increased frequency in relatives of probands with
bipolar disorder and vise versa
• Loci on chromosomes overlap for disorders
• Problem has been identifying specific genes
and/or biochemical pathways
Chotai, Serretti & Lorenzi (2005)
• 114 schizophrenics and 416 bipolar disorder
• Interaction between tryptophan hydroxulase
(TPH; involved in serotonin synthesis),
serotonin transporter (5-HTTLPR), and
dopamine receptor (DRD4) genes
• Interaction between alleles of TPH and 5HTTLPR genes constitute susceptibility to
schizophrenia but not to bipolar disorder
Silberschmidt & Sponheim
(2008)
• COMT gene, 22q11
– Enzyme degrading dopamine, epinephrine, norepinephrine
– Valine for methionine SNP affects cognitive tasks by reducing
dopamine at four times the regular rate
• Differentiated relatives of schizophrenic and bipolar
disorder patients on various personality dimensions
• Valine allele linked to low narcissism, rejectionability, and
stimulus seeking; seen in relatives of schizophrenics, but
not relatives of bipolar disorder patients
• COMT associated with schizophrenia, but not bipolar
disorder
Anxiety Disorders
• Wide range of types
– Panic disorder, generalized anxiety disorder,
phobias, obsessive-compulsive disorder
– Either involve anxiety or attempt to reduce
anxiety
• Most common form of mental illness;
lifetime prevalence of 29%
• May lead to other disorders, like depression
Panic Disorder
• Fear of specific situation that can cause
more panic attacks
• Lifetime risk of 5%
• Morbidity risk in first-degree relatives of
13%; concordance of 31% for MZ and 10%
for DZ twins
Generalized Anxiety Disorder
• Chronic state of diffuse anxiety; excessive
and uncontrollable worrying
• Runs in families; 10% for first-degree
relatives
• Contrasting twin studies
– Two show no heritability
– Three show about 20%
– Little shared environment
Phobias
• Fear related to specific stimulus
• Predisposition to fear something; specific
stimulus from learning
• 30% familial risk for general phobias (vs.
10% controls), 20% for social phobias (vs.
5% controls)
• Somewhere around 30% heritability
OCD
• Different diagnostic criteria; gives different
results in studies
• On average, 7% risk for family members
(vs. 3% controls)
• Early onset OCD more familial
• Two of three twin studies failed to find
heritability
Co-Occurrence of Disorders
• Diagnostic criteria behaviourally based
• Overlap
• Should we separate mood disorders?
– Relatives of (unipolar) depressives are not at increased
risk for bipolar depression, but relatives of bipolar
depressives are at a 14% risk (vs. 1% controls)
• Individuals with one disorder have close to 50%
chance of having 1+ other disorders in the same
year
Bipolar & Schizophrenia
• Badner & Gershon (2002) find overlapping
linkage for bipolar depression and
schizophrenia in 13q and 22q
• Under DSM-IV, bipolar can only be
diagnosed if patient is not schizophrenic
– So clinically, can’t be comorbid
– But…
Anxiety Disorder Co-occurrence
• Hettema et al. (2005)
• Significant overlap between generalized anxiety
disorder, panic disorder, agoraphobia, and social
phobia
• Non-shared environmental effects primarily
responsible for differences
• Should we have some sort of overarching anxiety
measure (e.g., a?), like g for cognitive ability?
Anxiety and Depression
• Genetically speaking, anxiety and depression are
largely the same thing
• Kendler et al. (1992)
– Major depression and generalized anxiety disorder
– No significant shared environment effects
ra = 1.0
ru = 0.51
Additive
42%
Unique
58%
Major Depression
Unique
31%
Additive
69%
Generalized Anxiety
A New Model
• Internalizing disorders
– Depression and anxiety disorders
• Externalizing disorders
– Alcohol and drug abuse, and antisocial adult
behaviour
• Based on behavioural genetics, not
traditional clinical behavioural diagnostics
Internalizing
Fear
Anxious/misery
Major
depression
Generalized
Anxiety
disorder
Externalizing
Panic
disorder
Animal
phobia
Alcohol
dependence
Other drug
Adult
abuse or
antisocial
dependence behaviour
Situational
phobias
DisorderSpecific
factors
DisorderSpecific
factors
• Genes associated with an internalized disorder will be
associated with other internalized disorders; genes
associated with externalized disorders will be associated
with other externalized disorders
• Genetic effects may be broad in their effects on
psychopathology
• “Generalist genes”
Conduct
disorder