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Brain Chemistry And The Medical Treatment Of Major Depression

Brain Chemistry And The Medical Treatment Of Major Depression

  1. 1. Brain Chemistry and the Medical Treatment of Major Depression William J. Giakas, M.D.
  2. 2. What is Major Depression? <ul><li>Mood disorder </li></ul><ul><li>Common condition </li></ul><ul><li>Affects both the brain and body </li></ul><ul><li>Multiple causes </li></ul><ul><li>Chronic, recurring </li></ul><ul><li>Debilitating for individual and family </li></ul><ul><li>Treatment resistance is a challenge </li></ul>
  3. 3. What Are The Challenges? <ul><li>Correct diagnosis </li></ul><ul><li>Proper medication selection </li></ul><ul><li>Managing adverse effects </li></ul><ul><li>Proper dosing and duration </li></ul><ul><li>Compliance with treatment </li></ul><ul><li>Achieving full remission </li></ul>
  4. 4. General Approach <ul><li>Assess medical and psychiatric history </li></ul><ul><li>Address stress and coping skills </li></ul><ul><li>Normalize sleep </li></ul><ul><li>Encourage exercise </li></ul><ul><li>Healthy diet </li></ul><ul><li>Pharmacotherapy </li></ul>
  5. 5. Chemical Messengers <ul><li>Acetylcholine (ACh) </li></ul><ul><li>Norepinephrine (NE) </li></ul><ul><li>Dopamine (DA) </li></ul><ul><li>Serotonin (5-HT) </li></ul><ul><li>Gamma-Aminobutyric Acid (GABA) </li></ul><ul><li>Neuropeptides </li></ul>
  6. 7. Choosing an Antidepressant <ul><li>Clinical diagnosis and particular features </li></ul><ul><li>Side effect profile </li></ul><ul><li>History of prior antidepressant treatment </li></ul><ul><li>Efficacy and rate of response </li></ul><ul><li>Ease of dosing </li></ul><ul><li>Drug interactions </li></ul><ul><li>Withdrawal potential </li></ul><ul><li>Expense </li></ul>
  7. 8. Identifying Target Symptoms <ul><li>General Medical </li></ul><ul><li>Fever </li></ul><ul><li>Cough </li></ul><ul><li>Sputum production </li></ul><ul><li>Chest discomfort </li></ul><ul><li>Weakness </li></ul><ul><li>Headache </li></ul><ul><li>Psychiatric </li></ul><ul><li>Depressed mood </li></ul><ul><li>Irritability </li></ul><ul><li>Impaired Concentration </li></ul><ul><li>Mental slowing </li></ul><ul><li>Poor appetite </li></ul><ul><li>Insomnia </li></ul><ul><li>Nausea </li></ul>
  8. 9. Biological Options <ul><li>Single action antidepressant </li></ul><ul><li>Antidepressant with multiple action </li></ul><ul><li>Combination antidepressants </li></ul><ul><li>Add-on therapies </li></ul><ul><li>Augmentation strategies </li></ul><ul><li>Antidepressants + VNS or ECT </li></ul>
  9. 10. Single-Action Antidepressants <ul><li>Lexapro </li></ul><ul><li>Celexa </li></ul><ul><li>Zoloft </li></ul><ul><li>Prozac </li></ul><ul><li>Paxil </li></ul><ul><li>Luvox </li></ul>
  10. 11. Serotonin and Behavior 5-HIAA LO Impulsivity HI
  11. 12. Serotonin Pathways
  12. 13. Pitfalls in SSRI Treatment <ul><li>Somnolence </li></ul><ul><li>Diarrhea </li></ul><ul><li>Anxiety </li></ul><ul><li>EPS </li></ul><ul><li>Tremors </li></ul><ul><li>Diaphoresis </li></ul><ul><li>Confusion </li></ul><ul><li>Sexual SEs </li></ul><ul><li>Nausea </li></ul><ul><li>Insomnia </li></ul><ul><li>Headaches </li></ul><ul><li>Increased fatigue </li></ul><ul><li>Withdrawal </li></ul><ul><li>Hyponatremia </li></ul>
  13. 14. Multi-Action Antidepressants <ul><li>Effexor-XR </li></ul><ul><li>Cymbalta </li></ul><ul><li>Wellbutrin-XL </li></ul><ul><li>TCAs </li></ul><ul><li>MAOIs </li></ul>
  14. 15. Tricyclic Antidepressants TCA Α 1,2 M1 NRI H 1,2 SRI
  15. 16. Monoamine Oxidase Inhibitors (MAOIs) <ul><li>More difficult to use </li></ul><ul><li>Dietary compliance issues </li></ul><ul><li>Risk of hypotension or hypertension </li></ul><ul><li>Possible advantage, MAOI activity increases with age </li></ul><ul><li>Proven more effective than TCAs in atypical depression </li></ul>
  16. 17. Remeron (5-HT and NE) <ul><li>Increases serotonin and norepinephrine </li></ul><ul><li>Less nausea and sexual side effects </li></ul><ul><li>Mild  1 antagonist </li></ul><ul><li>Weight gain and somnolence </li></ul><ul><li>Anticholinergic effects </li></ul><ul><li>Agranulocytosis </li></ul><ul><li>Can  cholesterol and triglycerides </li></ul>
  17. 18. Effexor-XR (5-HT, NE, +-DA) <ul><li>Approved for MDD and GAD </li></ul><ul><li>Effective for severely depressed patients </li></ul><ul><li>Use in retarded, hypersomnia, atypical, and weight gaining depressives </li></ul><ul><li>Baseline hypertension is not exclusionary </li></ul><ul><li>Nausea can be treated with Zofran </li></ul><ul><li>Diaphoresis can be treated with clonidine or benztropine </li></ul><ul><li>May be less effective for PMS-related anxiety </li></ul>
  18. 19. Effexor-XR <ul><li>Effects 5HT, NE, DA </li></ul><ul><li>Potential for a more rapid onset of action </li></ul><ul><li>Minimal inhibition of CYP 2D6 </li></ul><ul><li>Once daily dosing </li></ul><ul><li>Ascending dose-response curve </li></ul><ul><li>No effect on histamine, muscarinic, or alpha-adrenergic receptors </li></ul>
  19. 20. Wellbutrin (DA and NE) <ul><li>Dopamine and norepinephrine enhanced </li></ul><ul><li>Higher incidence of seizures (0.4%) </li></ul><ul><li>No known serious drug interactions </li></ul><ul><li>No sexual side effects </li></ul><ul><li>Appetite-suppressing </li></ul><ul><li>Stimulant effects ( ADHD and smoking) </li></ul><ul><li>No benefit in PMS-related depressive exacerbations </li></ul>
  20. 21. Benefits of “Adverse” Effects <ul><li>Appetite suppression </li></ul><ul><li>Weight gain </li></ul><ul><li>Sedation </li></ul><ul><li>Stimulation </li></ul><ul><li>H2-blockade </li></ul><ul><li>Constipation </li></ul><ul><li>Diarrhea </li></ul><ul><li>Inhibited ejaculation </li></ul><ul><li>Antihistamine (H1) </li></ul><ul><li>Urinary retention </li></ul>
  21. 22. Focus of Research in Depression Neurotransmitters Surface Receptors Intracellular Signaling Cascades
  22. 23. Hippocampus <ul><li>Critical in regulation of motivation and emotion </li></ul><ul><li>Lesions associated with severe amnesia </li></ul><ul><li>Widespread connections to diverse brain regions involved in mood regulation </li></ul>
  23. 24. Temporal Lobe and Hippocampus
  24. 25. Neuroplasticity <ul><li>Alterations of dentritic function </li></ul><ul><li>Synaptic remodeling </li></ul><ul><li>Long-term potentiation </li></ul><ul><li>Axonal sprouting </li></ul><ul><li>Neurite extension </li></ul><ul><li>Synaptogenesis </li></ul><ul><li>Neurogenesis </li></ul>
  25. 26. Evidence Linking Hippocampal Function To Depression <ul><li>Hippocampus is 15-20% smaller </li></ul><ul><li>Stress response causes ↑ glucocorticoids (GC) </li></ul><ul><li>HPA axis abnormalities (DST) </li></ul><ul><li>Primate data using implanted GC pellets </li></ul><ul><li>Stress studies in animal models </li></ul>
  26. 27. Potential Mechanisms of Cell Loss and Atrophy Glucocorticoids Neurotrophic Factors Glutamate
  27. 28. Glutamate <ul><li>Excitatory neurotransmitter </li></ul><ul><li>Calcium mobilization “memory” </li></ul><ul><li>Extrusion of Ca ++ is ATP or ionic gradient dependent </li></ul><ul><li>Excess cytosolic calcium produces “promiscuous” overactivity of </li></ul><ul><li>calcium-dependent enzymes </li></ul><ul><li>Reduction in glial cells </li></ul>
  28. 29. Glucocorticoids <ul><li>Decrease glucose transport </li></ul><ul><li>Increase intracellular cytosolic calcium </li></ul><ul><li>Inhibit transcription of calcium-ATPase pump </li></ul><ul><li>Increases glutamate concentrations in the hippocampal synapse </li></ul>
  29. 30. Neurotrophic Factors <ul><li>Brain-derived neurotrophic factor (BDNF) </li></ul><ul><li>B cell lymphoma protein-2 (bcl-2) </li></ul>
  30. 31. Brain-Derived Nerurotrophic Factor (BDNF) <ul><li>BDNF produces antidepressant effects in behavioral models of depression </li></ul><ul><li>Antidepressants increase BDNF in animals and neuronal sprouting </li></ul><ul><li>↑ BDNF in postmortem brains of subjects treated with antidepressants </li></ul>
  31. 32. B Cell Lymphoma Protein-2 (bcl-2) <ul><li>Over-expression is neuroprotective against ischemia, MPTP, β -amyloid, free radicals, excess glutamate, and ↓ BDNF </li></ul><ul><li>Social stress worsens stroke outcome by suppressing bcl-2 expression in mice </li></ul>
  32. 33. Intracellular Signaling Source: Manji HK, Quiroz JA, Gould TD (2003)
  33. 34. How Antidepressants Effect Neuroplasticity <ul><li>Upregulates the CREB cascade </li></ul><ul><li>Induce regeneration of axon terminals </li></ul><ul><li>Increase number of new neurons in the dentate gyrus granule cell layer </li></ul>
  34. 36. Neurotrophic Effects of Li <ul><li>Markedly reduces neurological deficits and decreased brain infarct in a rat model of stroke </li></ul><ul><li>Reduces damage due to quinolinic acid, an excitotoxin, in a rat model of Huntington’s disease </li></ul><ul><li>Enhances hippocampal neurogenesis </li></ul><ul><li>Increases total grey matter in bipolar patients </li></ul>
  35. 37. What Does This Mean For The Treatment of Depression? <ul><li>Shift towards continuation treatment </li></ul><ul><li>Lower the threshold for treatment? </li></ul><ul><li>Possible reduced morbidity due to other complicating medical conditions </li></ul><ul><li>Exercise also increases BDNF, so exercise </li></ul><ul><li>Psychosocial interventions matter </li></ul>
  36. 38. Electroconvulsive Therapy
  37. 39. <ul><li>80%-90+% response rates </li></ul><ul><li>More rapid response </li></ul><ul><li>50%-60% response rates in TCA failures </li></ul><ul><li>No pharmacologic trial has ever shown superiority over ECT </li></ul><ul><li>20% > TCAs and 45% > MAOIs </li></ul><ul><li>Marked superiority in psychotic depression </li></ul>ECT in Major Depression
  38. 42. Treatment Adequacy <ul><li>Seizure is necessary but not sufficient </li></ul><ul><li>Duration alone not adequate </li></ul><ul><li>Bilateral vs. Right Unilateral </li></ul><ul><li>Electrical dosage relative to seizure threshold </li></ul><ul><li>Postictal seizure suppression </li></ul>
  39. 43. High Dose vs. Low Dose Unilateral vs. Bilateral Sackeim, et al, Arch Gen Psych, June 2000
  40. 44. Seizure Suppression EMG EEG
  41. 45. AD vs. ECT + AD Gagne et al., Am J Psych, Dec 2000
  42. 46. Vagus Nerve Stimulation (VNS) <ul><li>FDA-approved for TRD </li></ul><ul><li>Requires 4 antidepressant failures </li></ul><ul><li>Implanted pacemaker-like device </li></ul><ul><li>Can combine with medication </li></ul><ul><li>No cognitive side effects </li></ul>

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