Brain Chemistry And The Medical Treatment Of Major Depression

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  • 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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