Major Depressive Disorder

Rosanna Scott

What is MDD?DSM-5 sets 3 criteria:

A5+ 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.

Genetics40% heritability

Associated Outcomes:Higher Mortality

Secondary Features:-weight/appetite change-insomnia/hypersomnia-psychomotor change-fatigue-feelings of worthlessness or guilt-diminished ability to think/concentrate-indecisiveness-thoughts of death/suicide-irritable mood

Comorbid Nonmood &

Medical Conditions

Stressful Life Events

Neurobiological Substrates

-HPA Axis Hyperactivity-Functional abnormalities in emotion processing, reward

seeking, & emotion regulation.

TemperamentNeuroticism

MDD-Depressed mood-Loss of interest/

pleasure

Adult to Child TranslationKovacs 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).

• 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).

Recovery

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-Pituitary-Cortisol Hypothesis

• Abnormalities in the cortisol response to stress may underlie depression.

(Belmaker & Agam, 2008)

HPA Dysregulation: Lopez-Duran 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 non-MDD 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

Associated Outcomes:-Higher Mortality-decreased performance in school-worse MDD prognosis

Secondary Features:-weight/appetite change-insomnia/hypersomnia-psychomotor change-fatigue-feelings of worthlessness or guilt-diminished ability to think/concentrate-indecisiveness-thoughts of death/suicide-irritable mood

Maladaptive explanatory

style/Learned Helplessness

Stressful Life

Events/comorbid

disorders

Neurobiological Substrates

-HPA Axis Hyperactivity-monoamine deficiency

-Functional abnormalities in emotion processing, reward

seeking, & emotion regulation (amygdala

hyperactivity).

MDD-Depressed mood-Loss of interest/pleasure

SSRIs

CBT

American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Washington, D.C.: Author.

Belmaker, R. H., & Agam, G. (2008). Major depressive disorder. The New England journal of medicine, 358(1), 55-68. doi: 10.1056/nejmra073096

Birhamer, B., Ryan, N. D., Williamson, D. E., Brent, D. A., Kaufman, J., Dahl, R. E., . . . Nelson, B. (1996). Childhood and adolescent depression: a review of the past 10 years. Part 1. J Am Acad Child Adolesc Psychiatry, 35, 427-439.

Carlson, G. A., & Cantwell, D. P. (1980). Unmasking masked depression in children and adolescents. The American journal of psychiatry.

Cicchetti, D., & Toth, S. L. (1998). The development of depression in children and adolescents. American Psychologist, 53(2), 221-241. doi: 10.1037/0003-066X.53.2.221

Cole, D.A., Peeke, L.G., Martin, J.M., Truglio,R., & Seroczynski, A.D. (1998). A longitudinal look at the relation between depression and anxiety in children and adolescents. Journal of Consulting and Clinical Psychology, 66, 451-460.

References

Dahlström, M., Ahonen, A., Ebeling, H., Torniainen, P., Heikkilä, J., & Moilanen, I. (2000). Elevated hypothalamic/midbrain serotonin (monoamine) transporter availability in depressive drug-naive children and adolescents. Molecular psychiatry, 5(5), 514-522. doi: 10.1038/sj.mp.4000766

Kendler, K. S., Kuhn, J., & Prescott, C. A. (2004). The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. American Journal of Psychiatry, 161(4), 631-636.

Kovacs, M. (1996). Presentation and Course of Major Depressive Disorder during Childhood and Later Years of the Life Span. Journal of the American Academy of Child & Adolescent Psychiatry, 35(6), 705-715. doi: http://dx.doi.org/10.1097/00004583-199606000-00010

Kovacs, M., & Beck, A. T. (1977). An empirical-clinical approach toward a definition of childhood depression. Depression in childhood: Diagnosis, treatment, and conceptual models, 1-25.

Kovacs, M., Goldston, D., & Gatsonis, C. (1993). Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. Journal of the American Academy of Child & Adolescent Psychiatry, 32(1), 8-20.

Lopez-Duran, N. L., Kovacs, M., & George, C. J. (2009). Hypothalamic-pituitary-adrenal axis dysregulation in depressed children and adolescents: a meta-analysis. Psychoneuroendocrinology, 34(9), 1272-1283. doi: 10.1016/j.psyneuen.2009.03.016

March, J., Silva, S., Petrycki, S., Curry, J., Wells, K., Fairbank, J., . . . Treatment for Adolescents With Depression Study, T. (2004). Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA : the journal of the American Medical Association, 292(7), 807-820. doi: 10.1001/jama.292.7.807

Nolen-Hoeksema, S., Girgus, J. S., & Seligman, M. E. (1986). Learned helplessness in children: A longitudinal study of depression, achievement, and explanatory style. Journal of Personality and Social Psychology, 51(2), 435-442. doi: 10.1037/0022-3514.51.2.435

Roberson-Nay, R., McClure, E. B., Monk, C. S., Nelson, E. E., Guyer, A. E., Fromm, S. J., . . . Pine, D. S. (2006). Increased Amygdala Activity During Successful Memory Encoding in Adolescent Major Depressive Disorder: An fMRI Study. Biological Psychiatry, 60(9), 966-973. doi: http://dx.doi.org/10.1016/j.biopsych.2006.02.018

Seligman, M. E. (1972). Learned helplessness. Annual review of medicine, 23, 407-412. doi: 10.1146/annurev.me.23.020172.002203

Wagner, K. D., Robb, A. S., Findling, R. L., Jin, J., Gutierrez, M. M., & Heydorn, W. E. (2004). A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry, 161(6), 1079-1083.