Chapter 8: Major Depressive Disorder

Chapter 8: Major Depressive

Disorder

Lorie A. Ritschel

Charles F. Gillespie

Eirikur O. Arnarson

W. Edward Craighead

Terminology

Depression is a term used to describe symptoms and behaviors, not a diagnostic label

Biology, emotions, behaviors, and cognitions contribute to the etiology and maintenance of depression

Major depressive disorder (MDD) is a mood disorder characterized by one or more major depressive episodes (MDE) without a history of manic, mixed, or hypomanic episodes, and not due to a medical condition, medication, or substance

Diagnostic Criteria for MDE

DSM-5 includes nine symptomsFive (or more) must be present during the same 2-

week period AND cause clinically significant distress or impairment AND may not be attributable to physiological effects of a substance or medical condition

Symptoms must include either:Depressed mood most of the day, nearly every day

(dysphoria)Loss of interest or pleasure in all, or almost all, activities

most of the day, nearly every day (anhedonia)

Diagnostic Criteria (cont.)

In addition to dysphoria or anhedonia, must also experience at least four additional symptoms nearly every day:Significant weight loss or gain, or decrease or increase in

appetiteInsomnia or hypersomniaPsychomotor agitation or retardationFatigue or loss of energyFeelings or worthlessness or excessive inappropriate guiltDiminished ability to think or concentrate, or indecisivenessRecurrent thoughts of death or suicidal ideation (with or

without a specific plan)

DSM-5 Criteria for Major Depressive Disorder (MDD)

DSM-5 includes nine symptomsFive (or more) must be present during the same 2-

week period AND cause clinically significant distress or impairment

Symptoms must include either:Depressed mood most of the day, nearly every day

(dysphoria)Loss of interest or pleasure in all, or almost all, activities

most of the day day, nearly every day (anhedonia)

Diagnostic Criteria for MDD (cont.)

In addition to dysphoria or anhedonia, must also meet at least four additional symptoms nearly every day (i.e. a total of 5 of 7 symptoms):Significant weight loss or gain, or decrease or increase in

appetiteInsomnia or hypersomniaPsychomotor agitation or retardationFatigue or loss of energyFeelings or worthlessness or excessive inappropriate guiltDiminished ability to think or concentrate, or indecisivenessRecurrent thoughts of death or suicidal ideation (with or

without a specific plan)

Specifiers for MDD

Single or recurrent episode Mild (2), Moderate (3), Moderate-Severe (4 or 5)

or Severe (4 or more with motor agitation)

With psychotic features (mood-congruent or incongruent)

In partial or in full remission With catatonia Following used as descriptors:

with anxious distress

with mixed features

with melancholic features

with atypical features

with peripartum onset

with seasonal pattern

NOTE: Premenstrual Dysphoric Disorder promoted from DSM-IV Appendix

Dysruptive Mood Dysregulation Disorder (initial age btw 6 and 18)

DSM-5 Diagnostic Criteria for Bipolar Disorders

Bipolar I (BD-I)Criteria met for at least 1 manic episodeNot better explained by a schizophrenia spectrum

disorder (e.g., schizophrenia)

Bipolar II (BD-II)Criteria met for at least 1 hypomanic episode AND 1

depressive episodeCriteria never met for manic episodeNot better explained by schizophrenia spectrum disorder

DSM-5 Criteria: Manic and Hypomanic Episodes

Manic episode- notably different elated, expansive, or irritable mood and increased activity/energy with ≥3 (≥4 if only irritable) of the following lasting for at least 1 week and causing significant distress or impairment:

Inflated self-esteem (grandiosity) Decreased need for sleep Racing thoughts or flight of ideas More talkative/pressured speech Activities with potential for painful consequences Increased goal-directed activity Distractibility

Hypomanic episode- Same symptom criteria, but… Shorter (4 days instead of one week)

Not severe enough to cause marked impairment in functioning (no psychotic features and no hospitalization)

DSM-5 Criteria: Depressive Episodes in Bipolar Disorder

Depressive Episode: total of ≥ 5 of the following 9 symptoms for 2 weeks or longer with significant distress and/or decline in functioningIntense sadness and/or loss of interest must be present

and other options are:• Insomnia or hypersomnia• Psychomotor agitation or retardation, • Changes in weight or appetite• Loss of energy • Difficulty concentrating or making decisions• Feelings of worthlessness or guilt• Suicidal ideation or behavior

Specifiers for Bipolar Disorders

Type of current (or most recent) episodeSeverity: mild, moderate, moderate-severe, severeWith psychotic features: mood congruent or incongruent

In partial or in full remissionWith catatoniaAs descriptors:

With anxious distress

With mixed features

With rapid cycling

With melancholic features

With atypical features

With peripartum onset

With seasonal pattern

Bipolar Diagnosis: Related Conditions

Other Specified Bipolar and Related Disorder:Patients with brief and recurrent manic or

hypomanic phases that fall short of the duration criteria or too few symptoms (subthreshold variants)

Cyclothymia2 or more years of switching between hypomanic and depressive symptoms that do not meet the full DSM-5 criteria for a hypomanic or a major depressive episode

Prevalence of MDD

Lifetime prevalence rates of approximately 17% (Kessler, Chiu, Demler, & Walters, 2005)Twice as prevalent for women (20%-25% lifetime)

compared to men (9%-12% lifetime)Peak age of onset for first episode of MDD is

between 15 and 19 years of age (Fergusson et al., 2005)

Probability of a second episode is 50%.Probability of recurrence of MDD is greater among those

who have their first episode earlier in life (Lewinsohn, Rohde, Seeley, Klein, & Gotlib, 2003)

Behavioral Models of MDD

Behavioral principlesPositive reinforcement: increasing behavior by providing a

pleasant stimulusNegative reinforcement: increasing behavior by the removal of

an unpleasant stimulusFerster (1965, 1966, 1973), Lewinsohn (1974), Skinner

(1953): depression is related to a reduction in behaviors that elicit positive reinforcement from the environmentThis is due to a low rate of positive reinforcement for behavior

and…Withdrawal in the presence of anxiety (negative reinforcement)

Behavioral Deficits in MDD

Anhedonia and amotivation (Beck, Rush, Shaw, & Emery, 1979) Anhedonia: loss of interest in activities that previously brought pleasureAmotivation: loss of desire to continue to attempt these activitiesDepressed individuals hold a belief that they cannot complete a task and will

not derive satisfaction from having completed one Avoidance (Dimidjian et al., 2007)

Avoidance: passive, short-term strategy of isolation in order to minimize distress

Functions as a negative reinforcer, by minimizing distress (e.g., takes away the annoyance of having to go to work), but also reduces the opportunity to encounter positive reinforcement in the environment (e.g., friendly interactions)

Treatment targets: Increase activity to increase likelihood of experiencing positive reinforcement and block avoidance strategies to decrease negative reinforcement

Cognitive Models of MDD

Beck (1976): Thoughts of depressed individuals are distorted in a negative way due to negative self-statements (negative automatic thoughts), information-processing deficits (cognitive errors), and enduring negative cognitive patterns (schemas/core beliefs)Automatic thoughts: Negative responses to prompting events,

including negative views of self (“I’m unlikable”), world (“I don’t fit in”), and future (“I’ll never have friends”)

Cognitive errors: Perceptual processing errors that screen out positive information and bias negative or neutral information in a negative way

Core beliefs: Stable negative beliefs about self, world, and future shaped by developmental influences and life experiences that organize how one interprets information from the environment

Cognitive Models of MDD (cont.)

Seligman (1975) and Abramson et al. (1989) learned helplessness theory: individuals become depressed because they view their situations as futile and themselves as unable to bring about changes in these situationsPeople give up trying when they have determined that a

situation is terrible and not likely to change no matter what they do

This happens because attributional styles for negative events are internal (“I am so stupid”), global (“I am always terrible at everything”), and stable (“I will be alone for the rest of my life”)

Hopelessness: Combination of negative events and a negative cognitive style

Cognitive Deficits in MDD

Individuals with depression:Have a negative cognitive style, which affects the way they

think, perceive, and remember information.Interpret and recall information and events with a negative

biasEngage in repetitive focus on bad feelings and experiences

from the past and to disengage attention from thought content (rumination)

Show referential attention negative stimuli.Treatment targets: Increase attention to positive

stimuli, decrease rumination, and increase active problem-solving strategies

Biology of MDD

Depression is a heritable, complex genetic disorder passed down through families, additive and multiplicative models of genetic risk studied

Candidate gene association studies have evaluated candidate genes hypothesized to predict differences in risk for MDD• Serotonin transporter gene (5-HTTLPR)• Brain-derived neurotrophic factor gene (BDNF)• Glucocorticoid receptor chaperone protein gene (FKBP5)• Type 1 corticotrophin-releasing hormone receptor gene (CRHR1)• Methodological issues: failed replications, design issues limit conclusions

Genome-wide association studies (GWASs) are better methodologically (e.g., strict significance level, atheoretical, entire genome may be investigated) and have identified candidate genes that may influence MDD

Studies using intermediate phenotypes to investigate specific depression symptom components (e.g., anhedonia)

Biology of MDD (cont.)

Neurochemistry of DepressionMonoamine hypothesis: MDD caused by a deficiency in the

CNS concentration or reception function of the neurotransmitters norepinephrine (NE) or serotonin (5-HT)• Deficiencies in 5-HT or NE signaling play a role in depression and suicide• Treatment: medications that increase the extracellular level of 5-HT (e.g.,

selective serotonin reuptake inhibitors) and NE (e.g., tricyclic antidepressants) by inhibiting the reuptake of 5-HT and NE are efficacious in treating MDD

A genetic polymorphism chronic exposure to stress may decrease the expression related to brain-derived neurotrophic factor (BDNF), a neurotransmitter that plays a role in the regulation of neuronal survival, differentiation, and function. which negatively impacts hippocampal function, episodic memory, and HPA-axis function

Biology of MDD (cont.)

Neuroendocrinology of DepressionThe Hypothalamic-Pituitary-Adrenal (HPA) Axis is a feedback loop

responsible for responding to stressors through the release and inhibition of the stress hormone cortisol• Dysregulation of the HPA axis (e.g., high amounts of cortisol in the bloodstream,

excessive cortisol secretion and insufficient cortisol suppression) is a state marker of depression

• Early life exposure to stressors and elevated cortisol may have a persistent effect on later HPA axis dysregulation

Psychoneuroimmunology of DepressionConcurrent secretion of cortisol and pro-inflammatory cytokines act in

a feedback loop to stimulate and terminate the inflammatory response to acute stress• HPA axis dysregulation and systemic inflammation may play a role in the etiology

of depression due to the body's inability to regulate physiological reactions to psychosocial stress

Biology of MDD (cont.)

Brain anatomy and brain functionIn a circuit-based view of brain function, multiple brain regions play

an integrated role in the regulation of physiology and behaviorHippocampus: plays a central role in the regulation of HPA axis

activity and explicit memory• Hippocampal atrophy has been associated with exposure to traumatic stress

and prolonged exposure to stress hormones, and reduced hippocampal volume has been associated with risk for a lifetime duration of depression

Subgenual cingulate: Plays a role in the regulation of negative states by coordinating projections to brain areas including the hypothalamus, amygdala, and frontal cortex• Treatment targets: Subgenual cingulate is a target for deep brain stimulation

for patients with treatment-resistant depression (Mayberg et al., 2005)

Integrative Model of MDD

Diathesis-stress model:Individual predisposition (diathesis) may be biological and/or

psychologicalPredisposition is activated by environmental factors (acute or

prolonged stress)Dynamic and transactional process:

Developmental: External environment influences an individual, individual likewise impacts the environment

Interactive: Emotions may be regulated by the limbic system (neurobiology) or the cortex (cognitions)

Intervention in one domain (e.g., neurobiology, cognitions, emotion, behaviors) will indirectly affect the other domains

Assessment of Depression

Clinical interviews:SCID – Semistructured interview of current and lifetime Axis I disorders

based on DSM criteria LIFE – Semistructured interview to assess the longitudinal course of Axis

I symptoms and disordersSelf-report measures:

BDI-II – Intensity of current cognitive and somatic symptoms of depression

CES-D – Screening measure for the general population (not for diagnosis or symptom severity)

Clinical rating scales:HAM-D – Most common measure of depression change in research,

measures intensity of depression and change of levels of depression over time

QIDS – Symptom severity across the nine DSM symptom domains

Psychological Treatment of MDD

Generally effective for treating MDD and equally efficacious as antidepressant medications

Behavior TherapyFocused on decreasing unpleasant events, decreasing

avoidance-based strategies, and increasing pleasant events in order to increase opportunities for positive reinforcement from the environment

Cognitive Behavior TherapyFocused on recognizing and correcting cognitive errors,

changing underlying core beliefs, and preventing future depressive episodes

Somatic Treatment of MDD

Somatic treatments include electroconvulsive therapy, transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation, and antidepressant medications.

Most antidepressants work by directly altering monoamine (serotonin and norepinephrine) neurotransmitter activity, specifically altering synaptic concentrations of monoamines. Monoamine oxidase inhibitors (MAOIs) Tricyclic antidepressants (TCAs) Selective serotonin reuptake inhibitors (SSRIs) Dual serotonin and norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants (e.g., buproprion) Augmenting medications (antipsychotic medications, thyroid agents, antianxiety

medications) Most medications have significant side-effect profiles, some have treatment-

emergent symptoms (e.g., suicidal ideation). Even among efficacious psychological and psychiatric treatments, more work is

needed to determine which patients will respond best to which treatment.