Chapter 8: Major Depressive Disorder

1. Chapter 8: Major Depressive Disorder Lorie A. Ritschel Charles F. Gillespie EiríkurÖ. 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/energywith ≥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 • Subgenualcingulate: Plays a role in the regulation of negative states by coordinating projections to brain areas including the hypothalamus, amygdala, and frontal cortex • Treatment targets: Subgenualcingulate 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 (notfor 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.