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Mood disorders: depression

Mood disorders: depression. March 26, 2019. Mood Disorders. Thought Disorders. Major Depressive Disorder (MDD). MDD w/ Psychotic Features. Schizophrenia. Schizotypal Personality Disorder. BPD w/ Psychotic Features. Bipolar Disorders (BPD). Schizoaffective Disorder.

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Mood disorders: depression

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  1. Mood disorders: depression March 26, 2019

  2. Mood Disorders Thought Disorders Major Depressive Disorder (MDD) MDD w/ Psychotic Features Schizophrenia Schizotypal Personality Disorder BPD w/ Psychotic Features Bipolar Disorders (BPD) Schizoaffective Disorder Schizoid Personality Disorder Dysthymic Disorder Borderline Personality Disorder Obsessive Compulsive Disorder Generalized Anxiety Disorder Panic Disorder Agoraphobia Simple Phobias Post-Traumatic Stress Disorder Anxiety Disorders

  3. Hypo-motivated, low pleasure: Gloomy, incapable of fun, Humorless Pessimistic, skeptical Guilt-prone, low self-esteem Introverted, restricted social life Sluggish, inactive, passive Few interests Long sleeper (> 10 hrs/night) Thoughtful, deeply emotional Reliable, dependable, devoted Hyper-motivated, high pleasure Cheerful, exuberant Articulate, jocular Optimistic, carefree self-assured Extroverted, people-seeker High energy level, several plans, lots of ideas Versatile with broad interests Short sleeper (< 5 hrs/night) Flighty, impulsive, over-confident Over-involved, meddlesome Fine Line Between Normal Mood & Disorders

  4. What is abnormal?Major Depression Yes No N ‘Often Tearful’ ‘Often Sad’ ‘+ Sad < 2 wks’ ‘+ Can’t Cheer Up’ ‘+ Interferes w/ Functioning’ Sadness

  5. Stahl S M, Essential Psychopharmacology (2000) MANIA MIXED EPISODE HYPOMANIA NORMAL MOOD DEPRESSION

  6. DSM Etiologic View of Mood Disorders Situational disorders Bereavement* Adjustment disorder with depressed mood ‘Symptomatic’ disorders Mood disorder due to a general medical condition Substance-induced Mood disorder Idiopathic Disorders Depressive Disorders Major Depressive Disorder Dysthymic Disorder Seasonal Affective Disorder Bipolar Disorders Bipolar I – manic +/-depressive episodes Bipolar II – depressive + hypomanic (not full manic) episodes * eliminated in DSM-V

  7. Major Depressive Disorder (MDD) • One or more Major Depressive Episodes • No manic episodes • Not attributable to other psychotic disorder

  8. Major Depressive Episode *one of these is required • 5 or more of the following nearly every day for  2 weeks • Depressed mood* • Loss of interest or pleasure* • Sleep disturbance (hyper- or insomnia) • Feeling worthless, guilt, self-depreciation • Diminished energy • Trouble concentrating or indecisiveness • Appetite disturbance (weight gain or loss) • Psychomotor agitation or retardation • Recurrent suicidal thoughts, plans or attempts • Clinically significant distress or impairment • Not attributable to direct physiologic effects of drug or medical condition

  9. ‘Sub-syndromal’ depression

  10. The facts of major depressive disorder: • More than 50% of depressed patients remain untreated • Of those that are treated, only 1 in 2 is responsive to treatment • 1 in 10 workers have taken time off for depression • Cost of MDD to employers: in Europe, 54 billion euros; in the US, 37 billion dollars from WHO, lundbeck.com

  11. European Depression Association • launched a Depression Manifesto on Depression Day 2015 • Depression Manifesto: calls for action in four priority areas • 1) eliminating stigma & discrimination • 2) ensuring fair funding and parity of care • 3) enabling better & earlier access to care and treatment • 4) improving lives of people living w/ depression “A broken mind must be treated as efficiently as a broken leg”– Amelia Mustapha, director of the EDA

  12. Stressful Life Events and MDD Odds Ratio of an MDD Occurrence in the Month following the SLE

  13. Manic Symptoms • Increased self-esteem or grandiosity • Decreased need for sleep • Increased talking or pressure of speech • Racing thoughts or flight of idea • Distractibility • Agitation or increased goal-directed activity • Excessive involvement in pleasurable activities with high potential for adverse consequences

  14. Manic Episode • Distinct period of 1 week of elevated, expansive, or irritable mood, most of the day, every day • At least 3 manic symptoms (4 if mood only irritable), represent a noticeable change from usual behavior • Causes significant impairment in functioning • Not due to a general medical condition or caused by drug use

  15. Bipolar Subtypes • Bipolar I • One or more Manic Episodes, with or without a Major Depressive Episode • Bipolar II • One or more Major Depressive Episodes, with a Hypomanic episode, but no full Manic episodes • Hypomanic episode • > 4 days elevated, expansive, irritable mood • 3 or more manic symptoms, noticeable to others • No functional impairment • ‘Rapid cycling’ if >3 episodes/year

  16. Epidemiologic DifferencesLifetime Rates 18-64 y.o. Weissmann, 1996

  17. Genetics of Affective Disorders • No autosomal syndromes identified – variable inheritance patterns suggest complex disease • Linkage found, but failures to replicate • Family members more likely to have dx • OR 2-4x for MDD, 10x for Bipolar Sullivan, 2000

  18. Twin Studies Kendler, 1993;Sullivan, 2000

  19. Environmental Risk Factors • Early parental loss • Adverse life events • often trigger incidence/relapse • ‘Neurotic’ personality style • Chronic stress (MDD > BPD)

  20. Depression as a progressive and recurrent disorder Dienes, 2006

  21. Gene by environment interactions: the 5-Ht transporter

  22. Increased risk of depression in women with ss genotype and stress Kendler, JAMA 2005

  23. Genotype effects on stress response in Young women Gotlib, 2008

  24. SERT and fear regulation

  25. Other sert facts • s/s people are more likely to have atypical depression (with more unusual features like sleep and eating disturbance) • s/s people are less likely to respond well to anti-depressants and may have manic episodes following treatment • l/l people have more typical melancholic depression and respond better to anti-depressants and placebo (!) • But these results aren’t black and white enough that genotype testing should be used to dictate treatment (yet) • l/l depressed patients are more likely to commit suicide than s/s patients

  26. BDNF & 5-HT regulate each other in brain

  27. BDNF enhances synaptic transmission, plasticity, & spine growth Lu et al,Nat Rev Neurosci14, 401–416 (2013)

  28. Glucocorticoids inhibit CREB-induced BDNF production HPC Glu neuron Neuron, Vol. 34, 13–25, March 28, 2002

  29. BDNF, like SERT, has two alleles: Met/VAl • Valine at position 66 is common • Methionine at position 66 is new, evolutionarily (human-specific function?) • Valine confers better memory, but also higher scores on ”neuroticism index” • Methionine (Met/Met) BDNF helps us turn a deaf ear to 5-HTTs allele fear signals, helps to dampen fear responses evoked by amygdala-cingulate pathway • So, having Met BDNF could help people with s/s genotypes cope better

  30. Molecular phenotype of the BDNF Val66Met polymorphism BDNF *BDNF Met/Met was associated with increased MDD in a human study (w/ reduced BDNF) and relationships between stress and early life adversity with Met were significant (Zhao et al 2018)

  31. Two MDD loci found in CONVERGE study: SIRT1 and LHPP NATURE | VOL 523 |p. 588 30 JULY 2015 5300 controls/5300 MDD; all Chinese women of Han descent

  32. SIRT1, an HDAC, promotes dendritic branching in HPC neurons Codocedoet al, PLoS ONE 2012; 7(10): e47073

  33. Biomarkers • No valid markers at individual level • Indices of NT function (esp. 5-HT) in groups • Depletion of tryptophan (5-HT precursor) induces depression • Antidepressants increase DA, NE and 5-HT availability • Low 5-HT metabolites in CSF associated with suicidality • 5-HT up-regulates BDNF in hippocampus via cAMP pathway • 5-HT modulates DA regulation of VTA-nACC reward system • DA agonists (amphetamine) and 5-HT re-uptake inhibitors induce mania

  34. Biomarkers • Autopsy studies • Volume loss found in • dorsolateral prefrontal cortex • orbitofrontal cortex • heteromodal association cortex • cingulate gyrus • hippocampus • Decreased 5-HT receptor density in frontal cortex and hippocampus

  35. MDD Duration and Hippocampal Anatomy Cobb, 2013

  36. Neuroimaging in MDD Savitz, 2009

  37. Uncorrected PET scan: MDD patients have reduced PFC BF Drevetset al, Nature 1997;386: 824-827

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