1. Chapter 8: Major Depressive Disorder
Lorie A. Ritschel
Charles F. Gillespie
Eiríkur Ö. Arnarson
W. Edward Craighead

2. 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

3. Diagnostic Criteria for MDE
DSM-5 includes nine symptoms
Five (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)

4. 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 appetite
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings or worthlessness or excessive inappropriate guilt
Diminished ability to think or concentrate, or indecisiveness
Recurrent thoughts of death or suicidal ideation (with or without a specific plan)

5. DSM-5 Criteria for Major Depressive Disorder (MDD)
DSM-5 includes nine symptoms
Five (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)

6. 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 appetite
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings or worthlessness or excessive inappropriate guilt
Diminished ability to think or concentrate, or indecisiveness
Recurrent thoughts of death or suicidal ideation (with or without a specific plan)

7. 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)

8. DSM-5 Diagnostic Criteria for Bipolar Disorders
Bipolar I (BD-I)
Criteria met for at least 1 manic episode
Not 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 episode
Criteria never met for manic episode
Not better explained by schizophrenia spectrum disorder

9. 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)

10. 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 functioning
Intense 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

11. Specifiers for Bipolar Disorders
Type of current (or most recent) episode
Severity: mild, moderate, moderate-severe, severe
With psychotic features: mood congruent or incongruent
In partial or in full remission
With catatonia
As descriptors:
With anxious distress
With mixed features
With rapid cycling
With melancholic features
With atypical features
With peripartum onset
With seasonal pattern

12. 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)
Cyclothymia
2 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

13. 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)

14. Behavioral Models of MDD
Behavioral principles
Positive reinforcement: increasing behavior by providing a pleasant stimulus
Negative reinforcement: increasing behavior by the removal of an unpleasant stimulus
Ferster (1965, 1966, 1973), Lewinsohn (1974), Skinner (1953): depression is related to a reduction in behaviors that elicit positive reinforcement from the environment
This is due to a low rate of positive reinforcement for behavior and…
Withdrawal in the presence of anxiety (negative reinforcement)

15. Behavioral Deficits in MDD
Anhedonia and amotivation (Beck, Rush, Shaw, & Emery, 1979)
Anhedonia: loss of interest in activities that previously brought pleasure
Amotivation: loss of desire to continue to attempt these activities
Depressed 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

16. 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

17. 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 situations
People 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

18. 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 bias
Engage 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

19. 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)

20. Biology of MDD (cont.) Neurochemistry of Depression
Monoamine 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

21. Biology of MDD (cont.) Neuroendocrinology of Depression
The 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 Depression
Concurrent 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

22. Biology of MDD (cont.) Brain anatomy and brain function
In a circuit-based view of brain function, multiple brain regions play an integrated role in the regulation of physiology and behavior
Hippocampus: 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)

23. Integrative Model of MDD
Diathesis-stress model:
Individual predisposition (diathesis) may be biological and/or psychological
Predisposition 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

24. 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 disorders
Self-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

25. Psychological Treatment of MDD
Generally effective for treating MDD and equally efficacious as antidepressant medications
Behavior Therapy
Focused 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 Therapy
Focused on recognizing and correcting cognitive errors, changing underlying core beliefs, and preventing future depressive episodes

26. 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.