Major Depressive Disorder
Rosanna Scott
What is MDD?
DSM-5 sets 3 criteria:
A
5+ symptoms present in same 2-week period,
where at least one symptom is
(1) depressed mood or
(2) loss of interest or pleasure.
The rest of the symptoms may include:
• Depressed mood most of the day nearly every day.
• In children/adolescents, can be irritable mood.
• Diminished interest/pleasure in all or almost all activities most of
the day nearly every day.
• Weight loss, weight gain, decrease/increase in appetite.
• In children, failure to make expected weight gain.
• Insomnia/hypersomnia.
• Psychomotor agitation/retardation.
• Fatigue or loss of energy.
• Feelings of worthlessness or excessive or inappropriate guilt.
• Diminished ability to think or concentrate, or indecisiveness.
• Recurrent thoughts of death, recurrent suicidal ideation, suicide
attempts, or suicide plans.
B
• The symptoms cause clinically
significant distress/impairment
in social, occupational, or other
important areas of functioning.
C
• The episode is not attributable
to the physiological effects of a
substance or to another medical
condition.
Genetics
40% heritability
Secondary
Features:
Stressful
Life Events
MDD
Neurobiological
Substrates
-HPA Axis Hyperactivity
-Functional abnormalities in
emotion processing, reward
seeking, & emotion
regulation.
Temperament
Neuroticism
-Depressed mood
-Loss of interest/
pleasure
Comorbid
Nonmood &
Medical
Conditions
Associated
Outcomes:
Higher Mortality
-weight/appetite
change
insomnia/hypers
omnia
-psychomotor
change
-fatigue
-feelings of
worthlessness or
guilt
-diminished
ability to
think/concentrate
-indecisiveness
-thoughts of
death/suicide
-irritable mood
Adult to Child Translation
Kovacs and Beck (1977) highlight the symptoms most often
agreed on between adults and children:
• (1) dysphoric mood (sadness, unhappiness), irritability, and
weepiness.
• (2) low self-esteem, self-depreciation, hopelessness
(suicidal ideation), morbid ideas, recent poor school
performance, and disturbed concentration.
• (3) diminished psychomotor behavior, social withdrawal,
and increased aggressiveness.
• (4) fatigue, sleep problems, enuresis/encopresis, weight
loss or anorexia, and somatic complaints.
Adult to Child Translation
• Carlson & Cantwell (1980) found you could
use adult research diagnostic criteria for
children over 7.
• Much higher incidence rate found when
children are interviewed systematically about
their symptoms compared to traditional
evaluation.
• Masked depression: often happens when
depression is comorbid w/ a different
disorder--one they are initially seeking
treatment for.
– Attention is diverted away from the depression.
• Diagnosis is missed.
Masking Behaviors
• Could be:
– Conduct disorders (hyperactivity,
delinquency, aggressiveness, irritability)
– Psychological reactions
– Somatic complaints (headaches,
stomachaches, enuresis)
– School problems (school phobia, poor
performance)
Prevalence
• Point prevalence:
.4% to 2.5% for children
.4% to 8.3% for adolescents
• Lifetime prevalence for adolescents:
15% to 20%
No gender differences in children, 2:1 ratio of girls to
boys in adolescence.
(Birmaher et al. (1996).
Recovery
• Average length of an episode of MDD in
children and adolescents was 7 to 9
months.
• Approximately 90% of MDD episodes
remit within two years post onset.
–
Birmaher et al. (1996).
Suicidality
• Kovacs, Goldston, & Gatsonic (1993)
studied the relationship between
psychiatric disorder and suicide
ideation/attempt.
• Depressed sample (n=142) and
comparison sample (n=49).
• Longitudinal study: Interviews at intake,
2, 6, and 12 months. Beyond 1 year,
follow up interviews were variable.
Suicidality
• Results: Ss w/ affective disorder were
11x more likely to have a suicide
attempt compared to rest of youths.
Cost of Illness
• Annual cost of depressive disorders in
US is about $43 billion.
– 85% attributed to MDD, including costs of
treatment, absenteeism from work, losses
productivity, and premature death.
– 70-80% of depressed teenagers do not
receive treatment.
Comorbidity
• 40% to 70% of depressed children and
adolescents develop a comorbid
disorder.
• Most frequently:
– Dysthymia
– Anxiety disorders
– Disruptive disorders
– Substance abuse
Anxiety Before Depression?
• Some studies suggest a temporal sequence
hypothesis.
– Mean age for anxiety is younger than mean age
for depression.
– Children w/ comorbid A & D were younger when
they became depressed.
• Bleaker prognosis
– One study shows that in children w/ comorbid A &
D, 2/3 were diagnosed with A before D.
• Similarly, a separate study found that about 2/3 of
adolescents w/ A later developed D.
– Conversely, only 6.5% of adolescents w/ D later develop A.
Cole et al. (1998)
• Their results support the temporal
sequence hypothesis.
• 3 major findings:
– 1: individual differences in D & A
constructs were stable over time.
– 2: high lvls of children’s self-reported & of
parent-reported A predicted increases in
self- and parent-reported D over time.
– 3: high lvls of self- and parent-reported Din
children did not predict increases in A over
time.
Monoamine Deficiency
Hypothesis
• Postulates there is a deficiency in
serotonin or norepinephrine
neurotransmission in the brain.
– Strong support: its predictive power.
• Almost every compound that’s been
synthesized for purpose of inhibiting NE or
serotonin reuptake has been proved to be a
clinically effective antidepressant.
(Belmaker & Agam, 2008)
Dahlstrom et al. (2000)
• Based on monoamine hypothesis of
depression.
– Polymorphism in serotonin transporter
gene is associated w/ both anxious-related
personality traits and major depression
– Hypothesis: alterations in seratonin
transporter availability in certain regions of
the brain will occur with depression.
Participants: 41 drug-naïve patients.
-age range: 7.7 to 17.4 years
-mean age: 13.2 years
First split into two groups:
a.) suffering from depressive disorder
n=31
b.) not suffering from depressive disorder
n=10
The depressed group was split into two more
groups:
1.) major depression present (n=25)
2.) other depressions present (n=6)
Results
-at 1h post injection, depressive Ss showed
higher SERT binding ratios than nondepressed
Ss.
•p=.02
•No significant difference b/w depressed subgroups
Hypothalamic-PituitaryCortisol Hypothesis
• Abnormalities in the cortisol response to
stress may underlie depression.
(Belmaker & Agam, 2008)
HPA Dysregulation: LopezDuran et al., (2009)
• Completed two meta-analyses,
computing effect sizes for different
measures of cortisol in MDD
children/adolescents compared to a
norm group.
Meta-analysis 1:
Dexamethasone suppresion
test
•17 studies comparing MDD and non-MDD
controls on post DST cortisol levels.
–The pooled effect size for group differences
was .57 (z = 4.18, p < .01; 95% CI .28-.86),
indicating less suppression/greater cortisol
levels after DST in MDD children/adolescents.
Meta-analysis 2: Basal
Cortisol Levels
• 17 studies comparing MDD and nonMDD control group on cortisol levels at
baseline (not stress induced).
– The pooled effect size for group
differences was .20 (z = 4.53, p < .01; 95%
CI .11-.29)
Amygdala Activity
• Roberson-Nay et al (2006) hypothesized that
there would be hyperactivity in the amygdala
of MDD adolescents.
– Research has shown this hyperactivity in
MDD adults at resting states and when
viewing evocative faces.
• Results: MDD showed greater left amygdala
activation (p<.001) and poorer memory
performance (p=.03) in comparison to healthy
control group.
Temperament?
• DSM-5 labels neuroticism and negative
affectivity as a “well-established risk
factor” for MDD.
– Individuals higher in neuroticism are more
likely to experience an MDD should a
stressful life event occur.
Interrelationship of
Neuroticism, Sex, and
Stressful Life events
• Each increased in SD in neuroticism
score carried a hazard ratio for onset of
depression of 1.72 (for women alone it’s
2.09).
– As level of long term contextual threat
increases, hazard ratio increases.
Kendler, Kuhn, & Prescott (2004)
Learned Helplessness
• Learned helplessness: when experience with
uncontrollable events can lead to the expectation that
no responses in one’s repertoire will control future
outcomes.
– Have a maladaptive explanatory style (MES)
• Explain bad events as internal, stable, and global.
– Helplessness deficits: motivational, cognitive, and emotional.
• Seligman’s past research found that MES was
significantly correlated w/ high depression scores.
– Missing link: how do life events play into this?
Seligman (1972)
“In summary, experience with uncontrollable trauma
typically has three basic effects: (a) animals become
passive in the face of trauma, i.e., they are slower to
initiate responses to alleviate trauma and may not
respond at all; (b) animals are retarded at learning that
their responses control trauma, i.e., if the animal makes
a response which produces relief, he may have trouble
"catching-on" to the response-relief contingency; and (c)
animals show more stress when faced with trauma they
cannot control than with equivalent controllable trauma.
This maladaptive behavior appears in a variety of
species including man, and over a range of tasks which
require voluntary responding.”
Nolen-Hoeksema, Girgus, &
Seligman (1986)
• Hypothesis: MES will be associated w/
higher levels of depression, lower
school achievement, and higher
incidences of helpless behavior in
classroom.
• Tested kids 3, 6, 10, and 12 months
after initial assessment
Nolen-Hoeksema, Girgus, &
Seligman (1986)
• Results:
– MES reported more depression and also predicted
level of depression at subsequent testing times.
– Correlations:
• Explanatory style w/ teacher ratings of helpless
behaviors in classroom (r=-.51, p<.0002).
• Test scores w/ classroom helpless behaviors (r=.64,
p<.0001).
• Levels of depression w/ helpless behaviors in classroom
(r=.27, p<.05).
• Levels of depression w/ test scores (r=-.2, p <.05).
Uncontrollable Life Event
Feeling Helpess/Learned Helplessness Deficits
Additional Negative Effects
MES
Vulnerability to Depression in Future Negative Events
Treatment: SSRIs
• Wagner et al. (2004) compared
treatment of citalopram to a placebo
group.
• N=178
• Mean age=12.1 years
• Treatment lasted 8 weeks
SSRI Results
• SSRI
improvement
was statistically
and clinically
significant
compared to
placebo.
– Effect
size=2.9
SSRI vs. CBT
• March et al. (2004) compared 4
treatment groups:
– Fluoxetine alone
– CBT alone
– Fluoxetine and CBT combined
– Placebo
• n=429 patients, 12-17 years.
• Treatment was 12 weeks long.
Results
• Fluoxetine + CBT was superior to placebo,
fluoxetine alone, and CBT alone (p=.001, .02,
.01, respectively).
• Fluoxetine alone was superior to CBT alone
(p=.01).
• Rates of response for fluoxetine with CBT
were 71.0% (95% CI, 62%-80%); fluoxetine
alone, 60.6% (95% CI, 51%-70%); CBT
alone, 43.2% (95% CI, 34%-52%); and
placebo, 34.8% (95% CI, 26%-44%).
Genetics
-40% heritability
-Neuroticism
CBT
Stressful
Life
Events/com
orbid
disorders
Secondary
Features:
Neurobiological
Substrates
MDD
-HPA Axis Hyperactivity
-monoamine deficiency
-Functional abnormalities in
emotion processing, reward
seeking, & emotion
regulation (amygdala
hyperactivity).
-Depressed mood
-Loss of interest/
pleasure
SSRIs
Maladaptive
explanatory
style/Learned
Helplessness
Associated
Outcomes:
-Higher Mortality
-decreased
performance in
school
-worse MDD
prognosis
-weight/appetite
change
insomnia/hypers
omnia
-psychomotor
change
-fatigue
-feelings of
worthlessness or
guilt
-diminished
ability to
think/concentrate
-indecisiveness
-thoughts of
death/suicide
-irritable mood
References
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