Brain Chemistry And The Medical Treatment Of Major Depression

Slide 1: Brain Chemistry and the Medical Treatment of Major Depression William J. Giakas, M.D.

Slide 2: What is Major Depression?  Mood disorder  Common condition  Affects both the brain and body  Multiple causes  Chronic, recurring  Debilitating for individual and family  Treatment resistance is a challenge

Slide 3: What Are The Challenges?  Correct diagnosis  Proper medication selection  Managing adverse effects  Proper dosing and duration  Compliance with treatment  Achieving full remission

Slide 4: General Approach • Assess medical and psychiatric history • Address stress and coping skills • Normalize sleep • Encourage exercise • Healthy diet • Pharmacotherapy

Slide 5: Chemical Messengers  Acetylcholine (ACh)  Norepinephrine (NE)  Dopamine (DA)  Serotonin (5-HT)  Gamma-Aminobutyric Acid (GABA)  Neuropeptides

Slide 7: Choosing an Antidepressant  Clinical diagnosis and particular features  Side effect profile  History of prior antidepressant treatment  Efficacy and rate of response  Ease of dosing  Drug interactions  Withdrawal potential  Expense

Slide 8: Identifying Target Symptoms General Medical Psychiatric  Fever  Depressed mood  Cough  Irritability  Sputum  Impaired Concentration production  Mental slowing  Chest discomfort  Poor appetite  Weakness  Insomnia  Headache  Nausea

Slide 9: Biological Options • Single action antidepressant • Antidepressant with multiple action • Combination antidepressants • Add-on therapies • Augmentation strategies • Antidepressants + VNS or ECT

Slide 10: Single-Action Antidepressants  Lexapro  Celexa  Zoloft  Prozac  Paxil  Luvox

Slide 11: Serotonin and Behavior 5-HIAA Impulsivity HI LO

Slide 12: Serotonin Pathways

Slide 13: Pitfalls in SSRI Treatment  Somnolence  Sexual SEs  Diarrhea  Nausea  Anxiety  Insomnia  EPS  Headaches  Tremors  Increased fatigue  Diaphoresis  Withdrawal  Confusion  Hyponatremia

Slide 14: Multi-Action Antidepressants  Effexor-XR  Cymbalta  Wellbutrin-XL  TCAs  MAOIs

Slide 15: Tricyclic Antidepressants SRI M1 TCA Α1,2 NRI H1,2

Slide 16: Monoamine Oxidase Inhibitors (MAOIs)  More difficult to use  Dietary compliance issues  Risk of hypotension or hypertension  Possible advantage, MAOI activity increases with age  Proven more effective than TCAs in atypical depression

Slide 17: Remeron (5-HT and NE)  Increases serotonin and norepinephrine  Less nausea and sexual side effects  Mild 1 antagonist  Weight gain and somnolence  Anticholinergic effects  Agranulocytosis  Can  cholesterol and triglycerides

Slide 18: Effexor-XR (5-HT, NE, +-DA)  Approved for MDD and GAD  Effective for severely depressed patients  Use in retarded, hypersomnia, atypical, and weight gaining depressives  Baseline hypertension is not exclusionary  Nausea can be treated with Zofran  Diaphoresis can be treated with clonidine or benztropine  May be less effective for PMS-related anxiety

Slide 19: Effexor-XR  Effects 5HT, NE, DA  Potential for a more rapid onset of action  Minimal inhibition of CYP 2D6  Once daily dosing  Ascending dose-response curve  No effect on histamine, muscarinic, or alpha- adrenergic receptors

Slide 20: Wellbutrin (DA and NE)  Dopamine and norepinephrine enhanced  Higher incidence of seizures (0.4%)  No known serious drug interactions  No sexual side effects  Appetite-suppressing  Stimulant effects ( ADHD and smoking)  No benefit in PMS-related depressive exacerbations

Slide 21: Benefits of “Adverse” Effects  Appetite suppression  Inhibited ejaculation  Weight gain  Antihistamine (H1)  Sedation  Urinary retention  Stimulation  H2-blockade  Constipation  Diarrhea

Slide 22: Focus of Research in Depression Neurotransmitters Intracellular Signaling Surface Receptors Cascades

Slide 23: Hippocampus  Critical in regulation of motivation and emotion  Lesions associated with severe amnesia  Widespread connections to diverse brain regions involved in mood regulation

Slide 24: Temporal Lobe and Hippocampus

Slide 25: Neuroplasticity  Alterations of dentritic function  Synaptic remodeling  Long-term potentiation  Axonal sprouting  Neurite extension  Synaptogenesis  Neurogenesis

Slide 26: Evidence Linking Hippocampal Function To Depression  Hippocampus is 15-20% smaller  Stress response causes ↑ glucocorticoids (GC)  HPA axis abnormalities (DST)  Primate data using implanted GC pellets  Stress studies in animal models

Slide 27: Potential Mechanisms of Cell Loss and Atrophy Glucocorticoids Glutamate Neurotrophic Factors

Slide 28: Glutamate  Excitatory neurotransmitter  Calcium mobilization “memory”  Extrusion of Ca++ is ATP or ionic gradient dependent  Excess cytosolic calcium produces “promiscuous” overactivity of calcium-dependent enzymes  Reduction in glial cells

Slide 29: Glucocorticoids  Decrease glucose transport  Increase intracellular cytosolic calcium  Inhibit transcription of calcium-ATPase pump  Increases glutamate concentrations in the hippocampal synapse

Slide 30: Neurotrophic Factors  Brain-derived neurotrophic factor (BDNF)  B cell lymphoma protein-2 (bcl-2)

Slide 31: Brain-Derived Nerurotrophic Factor (BDNF)  BDNF produces antidepressant effects in behavioral models of depression  Antidepressants increase BDNF in animals and neuronal sprouting  ↑ BDNF in postmortem brains of subjects treated with antidepressants

Slide 32: B Cell Lymphoma Protein- 2 (bcl-2)  Over-expression is neuroprotective against ischemia, MPTP, β-amyloid, free radicals, excess glutamate, and ↓ BDNF  Social stress worsens stroke outcome by suppressing bcl-2 expression in mice

Slide 33: Intracellular Signaling Source: Manji HK, Quiroz JA, Gould TD (2003)

Slide 34: How Antidepressants Effect Neuroplasticity  Upregulates the CREB cascade  Induce regeneration of axon terminals  Increase number of new neurons in the dentate gyrus granule cell layer

Slide 36: Neurotrophic Effects of Li  Markedly reduces neurological deficits and decreased brain infarct in a rat model of stroke  Reduces damage due to quinolinic acid, an excitotoxin, in a rat model of Huntington’s disease  Enhances hippocampal neurogenesis  Increases total grey matter in bipolar patients

Slide 37: What Does This Mean For The Treatment of Depression?  Shift towards continuation treatment  Lower the threshold for treatment?  Possible reduced morbidity due to other complicating medical conditions  Exercise also increases BDNF, so exercise  Psychosocial interventions matter

Slide 38: Electroconvulsive Therapy

Slide 39: ECT in Major Depression  80%-90+% response rates  More rapid response  50%-60% response rates in TCA failures  No pharmacologic trial has ever shown superiority over ECT  20% > TCAs and 45% > MAOIs  Marked superiority in psychotic depression

Slide 42: Treatment Adequacy  Seizure is necessary but not sufficient  Duration alone not adequate  Bilateral vs. Right Unilateral  Electrical dosage relative to seizure threshold  Postictal seizure suppression

Slide 43: High Dose vs. Low Dose Unilateral vs. Bilateral Sackeim, et al, Arch Gen Psych, June 2000

Slide 44: Seizure Suppression EMG EEG

Slide 45: AD vs. ECT + AD Gagne et al., Am J Psych, Dec 2000

Slide 46: Vagus Nerve Stimulation (VNS) • FDA-approved for TRD • Requires 4 antidepressant failures • Implanted pacemaker-like device • Can combine with medication • No cognitive side effects