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BIOMED 370: The Treatment of Mood Disorders March 9, 2005

BIOMED 370: The Treatment of Mood Disorders March 9, 2005. Lawrence H. Price, M.D. Professor of Psychiatry and Human Behavior Brown University School of Medicine Clinical Director and Director of Research Butler Hospital 345 Blackstone Blvd Providence, RI 02906.

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BIOMED 370: The Treatment of Mood Disorders March 9, 2005

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  1. BIOMED 370: The Treatment of Mood DisordersMarch 9, 2005 Lawrence H. Price, M.D. Professor of Psychiatry and Human Behavior Brown University School of Medicine Clinical Director and Director of Research Butler Hospital 345 Blackstone Blvd Providence, RI 02906

  2. BASIC PRINCIPLES OF ANTIDEPRESSANT USE Achieve adequate dosing Gradual titration upward. Prepare patient for early side effects. Treat for adequate duration 4-6 weeks for an acute trial. 6 months or longer for maintenance. Assess adequacy of response Ensure adherence Avoid complex dosing schedules. Make sure prescription is affordable. Address side effects.

  3. PHASES OF TREATMENT FOR DEPRESSION Kupfer, J Clin Psychiatry,52(suppl 5):28, 1991..

  4. ANTIDEPRESSANT TREATMENTS I. PRIMARY ANTIDEPRESSANTS II. MOOD STABILIZERS (Thymoleptics) III. STIMULANTS IV. ELECTROCONVULSIVE THERAPY (ECT) V. SURGICAL APPROACHES VI. COMBINATION BIOMEDICAL APPROACHES VII. NOVEL BIOMEDICAL APPROACHES VIII. PSYCHOSOCIAL TREATMENTS IX. OTHER SOMATIC TREATMENTS

  5. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES I. PRIMARY ANTIDEPRESSANTS A. Selective serotonin reuptake inhibitors (SSRIs) B. Mixed monoamine reuptake inhibitors C. Monoamine receptor antagonists D. Tricyclic (TCAs) and related heterocyclics E. Monoamine oxidase inhibitors (MAOIs) F. NMDA antagonists

  6. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES A. Selective serotonin reuptake inhibitors (SSRIs) 1. Fluoxetine (Prozac®, Sarafem®) 2. Sertraline (Zoloft®) 3. Paroxetine (Paxil®) 4. Fluvoxamine (Luvox®) 5. a. Citalopram (Celexa®) b. Escitalopram (Lexapro®)

  7. 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT Stimulationof postsynaptic 5-HT receptors 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT Synaptic 5-HT Selective Serotonin Reuptake Inhibitors (SSRIs): Mechanism of Action 5-HT 5-HT Release 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT Downregulation of presynaptic 5-HT1A autoreceptors Reuptake transporter Inhibition of 5-HTreuptake transporter 5-HT = serotonin. Blier and Abbott. J Psychiatry Neurosci. 2001;26:37.

  8. Effective in 60%-70%of patients Ease of dosing Broad comorbidity coverage(eg, anxiety disorders) Lower side effect burden vs TCAs Safer in overdose vs TCAs Nausea and headaches Orgasmic dysfunction anddecreased libido Interactions with tryptophan,MAOIs, fenfluramine Discontinuation syndrome Weight gain Selective Serotonin Reuptake Inhibitors (SSRIs): Pros/Cons Pros Cons Richelson. Mayo Clin Proc. 2001;76:511.

  9. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES B. Mixed monoamine reuptake inhibitors 1. NE/(DA) reuptake inhibitor a. Bupropion (Wellbutrin®, Zyban®) 2. NE/5-HT reuptake inhibitors a. Venlafaxine (Effexor®) b. Duloxetine (Cymbalta®)

  10. O NH Cl Bupropion (1985) Bupropion Ascher et al. J Clin Psychiatry. 1995;56:395. Croft et al. Clin Ther. 1999;21:643. Coleman et al. Clin Ther. 2001;23:1040.

  11. N(CH3)2 OH CH H3CO Venlafaxine (1993) Venlafaxine Wellington and Perry. CNS Drugs. 2001;15:643. Kent. Lancet. 2000;355:911. Thase et al. Br J Psychiatry. 2001;178:234 .

  12. NH S O Duloxetine (2004) Duloxetine Pitsikas. Curr Opin Investig Drugs. 2000;1:116. Goldstein et al. J Clin Psychiatry. 2002;63:225.

  13. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES C. Monoamine receptor antagonists 1. Serotonin receptor antagonists a. Trazodone (Desyrel®) b. Nefazodone (Serzone®-withdrawn 2004) 2. NE/5-HT receptor antagonist a. Mirtazapine (Remeron®)

  14. Cl N N N N N O O Nefazodone (1994) Nefazodone Schatzberg et al. J Clin Psychiatry. 2002;63:18. Kent. Lancet. 2000;355:911.

  15. N N N CH3 Mirtazapine (1996) Mirtazapine Anttila and Leinonen. CNS Drug Rev. 2001;7:249. Kent. Lancet. 2000;355:911.

  16. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES D. Tricyclics (TCAs) and related heterocyclics 1. Tertiary amines a. Amitriptyline (AMI; Elavil®) b. Imipramine (IMI; Tofranil®) c. Clomipramine (CMI; Anafranil®) d. Doxepin (DOX; Sinequan®) e. Trimipramine (Surmontil®) 2. Secondary amines a. Nortriptyline (NOR; Pamelor®, Aventyl®) b. Desipramine (DMI; Norpramin®) c. Protriptyline (PRO; Vivactyl®) d. Amoxapine (Asendin®) 3. Tetracyclics a. Maprotiline (Ludiomil®)

  17. TCA-inhibition of NA + 5-HT reuptake transporters 5-HT Tricyclic Antidepressants (TCAs): Proposed Mechanism of Action NA Synaptic NA NA NA NA NA NA NA NA NA NA NA Reuptake transporters NA NA Stimulation of postsynaptic intracellular processes Synaptic 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT NA = noradrenaline; 5-HT = serotonin. Kandel et al. Principles of Neural Science. 1991.

  18. Effective in 60%-70%of patients Potent NA reuptake inhibitors Some are also potent 5-HT reuptake inhibitors Analgesic effects Interact with cholinergic, histaminic, and adrenergic receptors, causing Dry mouth Urinary hesitance Blurred vision Constipation Sedation Weight gain Orthostatic hypotension Cardiac conduction effects Discontinuation syndrome Potentially lethal in overdose Tricyclic Antidepressants (TCAs): Pros/Cons Pros Cons Feighner. J Clin Psychiatry. 1999;60(suppl 4):4.

  19. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES E. Monoamine oxidase inhibitors (MAOIs) 1. Hydrazines a. Phenelzine (Nardil®) b. Isocarboxazid (Marplan®) 2. Non-hydrazine a. Tranylcypromine (Parnate®) [b. Selegiline {deprenyl} (Eldepryl®)]

  20. MAO-inhibition prevents breakdownof NA + 5-HT 5-HT Monoamine Oxidase Inhibitors (MAOIs): Proposed Mechanism of Action NA Synaptic NA NA NA NA NA NA NA NA MAO NA NA NA NA NA NA NA NA Reuptake transporters NA Stimulation of postsynaptic intracellular processes Synaptic 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT MAO 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT 5-HT NA = noradrenaline; 5-HT = serotonin. Kandel et al. Principles of Neural Science. 1991.

  21. Older Monoamine Oxidase Inhibitors (MAOIs): Pros/Cons • Older MAOIs • Irreversibly inhibit MAO-A and MAO-B • Enhance synaptic levels of all 3 monoamines Pros • Effective in 60%-70% of patients • Some patients (eg, those with atypical depression) may respond betterto MAOIs Cons • Food restrictions • Orthostatic hypotension • Weight gain • Sexual dysfunction • Potentially lethal drug interactions with opiates, SSRIs, sympathomimetics Feighner. J Clin Psychiatry. 1999;60(suppl 4):4. Lotufo-Neto et al. Neuropsychopharmacology. 1999;20:226.

  22. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES F. NMDA Antagonists 1. Excitatory amino acid (EAA) release inhibitor a. Lamotrigine (Lamictal®)

  23. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES II. MOOD STABILIZERS (THYMOLEPTICS) A. Lithium (Li; Li2CO3, LiCl) B. Anticonvulsants 1. Valproate (VPA; Depakote®) 2. Carbamazepine (CBZ; Tegretol®)

  24. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES III. STIMULANTS Older A. Dextroamphetamine (Dexedrine®) B. Methylphenidate (Ritalin®) C. Pemoline (Cylert®) Novel D. Modafinil (Provigil®)E. Atomoxetine (Strattera®)

  25. BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIES IV. ELECTROCONVULSIVE THERAPY (ECT) A. Unilateral B. Bilateral V. SURGICAL APPROACHES A. Orbitofrontal leucotomy B. Stereotactic subcaudate tractotomy C. Stereotactic limbic leucotomy

  26. VI. COMBINATION BIOMEDICAL APPROACHES Definition: Simultaneous use of two or more different drugs acting on the core symptoms of affective illness

  27. COMBINATION MONOTHERAPY AGENTS FOR DEPRESSION • Multiple primary antidepressants(agents with different mechanisms of action) Examples: • SSRI+NRI • MRTZ+reuptake inhibitor EXCEPTIONS: MAOI+reuptake inhibitor • Thymoleptics (esp. Li) • Stimulants • ECT

  28. OTHER COMBINATION AGENTS FOR DEPRESSION 1. Benzodiazepines 2. Neuroleptics (antipsychotics) 3. Gabapentin 4. Triiodothyronine (T3) 5. Estrogen, testosterone 6. 5-HT1A antagonists (pindolol) 7. a2-adrenoceptor antagonists (e.g., yohimbine, idazoxan) 8. DA receptor agonists (e.g., pergolide, bromocriptine, pramipexole, ropinirole)

  29. VII. NOVEL BIOMEDICAL APPROACHES TO DEPRESSION Pharmacologic Neurophysiologic stimulation

  30. NOVEL PHARMACOLOGIC APPROACHES TO DEPRESSION 1. Novel anticonvulsants a. Topiramate (Topamax®) b. Levetiracetam (Keppra®) c. Oxcarbazepine (Trileptal®) d. Tiagabine (Gabatril®) 2. Antiglucocorticoids a. Ketoconazole b. Metyrapone c. Aminoglutethimide 3. Thyroxine (high-dose T4) 4. Inositol 5. DHEA 6. Fatty acids (Omega-3, EPA) 7. Tramadol 8. Hypericum perforatum (St. John’s wort) 9. S-adenosyl methionine (SAM-e) 10. Mifepristone (RU-486) 11. Riluzole 12. Substance P antagonists 13. CRF antagonists 14. Reboxetine (Vestra) 15. Gepirone (5-HT1A agonist) 16. Selegiline Transdermal

  31. NOVEL NEUROPHYSIOLOGIC STIMULATION APPROACHES TO DEPRESSION 1. Continuation ECT 2. Repetitive transcranial magnetic stimulation (rTMS) 3. Magnetic seizure therapy (MST) Vagus nerve stimulation (VNS) Deep brain stimulation (DBS)

  32. VNS Pulse Generator & Lead • Pacemaker-like pulse generator • Bipolar lead with two stimulating electrodes • Intermittent stimulation • 30 sec on/5 min off • 24 hours/day • On-demand therapy mode • 10.3 mm thick • Weighs 38 grams • Battery life of 8-12 years (Model 101)

  33. Vagus Nerve Stimulation • Pulse generator programming controlled through a telemetric wand attached to a PC • ON/OFF cycle is programmable • Typical cycle: • 30 sec ON • 5 min OFF

  34. VIII. PSYCHOSOCIAL ANTIDEPRESSANT TREATMENTS •Cognitive therapy •Behavior therapy •Interpersonal psychotherapy •Brief psychodynamic therapy • Social skills training

  35. IX. OTHER SOMATIC ANTIDEPRESSANT TREATMENTS • Sleep deprivation • Light therapy • Exercise • Complementary and alternative therapies

  36. TCAs SSRIs MAOIs Mixed reuptake inhibitors/ Receptor antagonists Peptide antagonists, glutamate modulators and other novel therapies Evolution of Antidepressants 2000 and beyond 1950s 1950s 1980s 1990s

  37. Unmet Needs With Current Antidepressant Therapies • 20%-40% of patients do not respond to any single antidepressant • ~50% of patients who respond have significant residual symptoms • Relapses are common, particularly after discontinuation of therapy • Suboptimal tolerability and side-effect profiles • Low long-term adherence Crown et al. J Clin Psychiatry. 2002;63:963. Pampallona et al. Br J Psychiatry. 2002;180:104.

  38. Conceptual Problems in Classifying Treatments for Bipolar Disorder Antimanics Antidepressants Thymoleptics (Mood Stabilizers)

  39. ANTIMANIC TREATMENTS I. Lithium II. Divalproex (Valproate; Depakote®) III. Atypical neuroleptics‡ III. Carbamazepine (Tegretol®)* IV. Other neuroleptics*‡ V. Electroconvulsive therapy (ECT)* * Not FDA-approved for mania ‡ Mood-stabilizing properties of all such drugs not fully established

  40. Lithium Mechanism: 5-HT and Ach function,  DA function;  PI turnover;  adenylate cyclase activity; regulation of G protein and PKC activity Dose: 600 - 2400 mg/day (0.5-1.5 mmol/L) Pros: Efficacy in mania established, with largest supporting database Response predictors known Cons : Poor tolerance,  patient acceptance, narrow therapeutic index Tremor / neurocognitive effects, weight gain, renal toxicity, nausea, acne, hair loss, hypothyroidism

  41. Signs and Symptoms of Lithium Toxicity Mild: Impaired concentration, lethargy, irritability, muscle weakness, tremor, slurred speech, nausea [plasma lithium = 1.0 - 1.5 meq/L] Moderate: Disorientation, confusion, drowsiness, restlessness, unsteady gait, coarse tremor, dysarthria, muscle fasciculations, vomiting [plasma lithium = 1.5 - 2.5 meq/L] Severe: Impaired consciousness (with progression to coma), delirium, ataxia, generalized fasciculations, extrapyramidal symptoms, convulsions, impaired renal function [plasma lithium > 2.5 meq/L

  42. Divalproex (Valproate) Mechanism: GABA synthesis and release, GABA catabolism, effects of GABA at receptor; regulation of PKC activity Dose: 750 - 2500 mg/day (50-125 g /mL) Pros: Efficacy in mania established Better than Li in mixed states and rapid cyclers Well-tolerated Cons : ? Efficacy in prophylaxis Weight gain, nausea, hair loss, tremor, platelets, liver & pancreas toxicity, ?polycystic ovary disease

  43. Atypical Neuroleptics Clozapine (Clozaril®)* Olanzapine (Zyprexa®) Risperidone (Risperdal®) Quetiapine (Seroquel®) Ziprasidone (Geodon®) Aripiprazole (Abilify®) *Not FDA-approved for mania

  44. Atypical Neuroleptics in Bipolar Disorder: Considerations Effective in acute mania (as are conventional neuroleptics). Superior to conventional neuroleptics with respect to adverse effects. Possibly heterogeneous mechanisms of action and clinical effects with respect to each other. Possible thymoleptic properties. Limitations Limited long-term data Adverse effects Aggressive marketing push

  45. Carbamazepine Mechanism: NE, DA, GABA function; adenylate cyclase activity; blocks adenosine receptors Dose: 400 - 1800 mg/day (4-15 g/mL) Pros: Efficacy in mania established Usually well-tolerated Cons: ? Efficacy in prophylaxis Ataxia and neurocognitive effects, weight gain, nausea, hair loss, leukopenia, hepatotoxicity,  Na, hepatic enzyme induction Oxcarbazepine as alternative?

  46. BIPOLAR ANTIDEPRESSANT TREATMENTS I. Lamotrigine

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