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ANTIDEPRESSANTS

ANTIDEPRESSANTS. Samaiya Mushtaq CHEM 5398. DEPRESSION. Types Symptoms Diagnosis Causes Treatment. TYPES OF DEPRESSION. Major depression Chronic depression (Dysthymia) Atypical depression Bipolar disorder/Manic depression Seasonal depression (SAD). SYMPTOMS.

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ANTIDEPRESSANTS

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  1. ANTIDEPRESSANTS Samaiya Mushtaq CHEM 5398

  2. DEPRESSION • Types • Symptoms • Diagnosis • Causes • Treatment

  3. TYPES OF DEPRESSION • Major depression • Chronic depression (Dysthymia) • Atypical depression • Bipolar disorder/Manic depression • Seasonal depression (SAD)

  4. SYMPTOMS • persistently sad, anxious, or empty moods • loss of pleasure in usual activities (anhedonia) • feelings of helplessness, guilt, or worthlessness • crying, hopelessness, or persistent pessimism • fatigue or decreased energy • loss of memory, concentration, or decision-making capability • restlessness, irritability • sleep disturbances • change in appetite or weight • physical symptoms that defy diagnosis and do not respond to treatment (especially pain and gastrointestinal complaints) • thoughts of suicide or death, or suicide attempts • poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)

  5. DIAGNOSIS • Extensive patient and family history • Blood test for hypothyroidism • Current medication • DSM-IV • One of the first two symptoms • Five other symptoms

  6. CAUSES OF DEPRESSION • Genetics • Death/Abuse • Medications

  7. TREATMENT FOR DEPRESSION • Psychotherapy • Electroconvulsive therapy • Natural alternatives • Medication • SSRIs • MAOIs • TCAs • SNRIs • NDRIs • TeCAs

  8. NEUROTRANSMITTERS AND THE CATECHOLAMINE HYPOTHESIS • Neurotransmitters pass along signal • Smaller amount of neurotransmitters causes depression

  9. MONOAMINE OXIDASE (MAO) AND DEPRESSION • MAO catalyze deamination of intracellular monoamines • MAO-A oxidizes epinephrine, norepinephrine, serotonin • MAO-B oxidizes phenylethylamine • Both oxidize dopamine nonpreferentially • MAO transporters reuptake extracellular monoamine

  10. MONOAMINE OXIDASE INHIBITORS (MAOIS) • History • Isoniazid • Iproniazid • Current Drugs • Mechanism of Action • Side Effects Isoniazid Iproniazid

  11. MAOIS ON THE MARKET • MAO Inhibitors (nonselective) • Phenelzine (Nardil) • Tranylcypromine (Parnate) • Isocarboxazid (Marplan) • MAO-B Inhibitors (selective for MAO-B) • Selegiline (Emsam)

  12. MAOIS MECHANISM OF ACTION • MAO contains a cysteinyl-linked flavin • MAOIs covalently bind to N-5 of the flavin residue of the enzyme

  13. MAOIS SIDE EFFECTS • Drowsiness/Fatigue • Constipation • Nausea • Diarrhea • Dizziness • Low blood pressure • Lightheadedness, • Decreased urine output • Decreased sexual function • Sleep disturbances • Muscle twitching • Weight gain • Blurred vision • Headache • Increased appetite • Restlessness • Shakiness • Weakness • Increased sweating

  14. MAOIS SIDE EFFECTS • Side effects have put MAOIs in the second or third line of defense despite superior efficacy • MAO-A inhibitors interfere with breakdown of tyramine • High tyramine levels cause hypertensive crisis (the “cheese effect”) • Can be controlled with restricted diet • MAOIs interact with certain drugs • Serotonin syndrome (muscle rigidity, fever, seizures) • Pain medications and SSRIs must be avoided

  15. THE RECEPTOR SENSITIVITY HYPOTHESIS • Supersensitivity and up-regulation of post-synaptic receptors leads to depression • Suicidal and depressed patients have increased 5HT-α2 receptors

  16. TRICYCLIC ANTIDEPRESSANTS (TCAS) • History • Imipramine • Current Drugs • Mechanism of Action • Side Effects Imipramine

  17. TCAS ON THE MARKET • Amitriptyline • Desipramine (Norpramin) • Doxepin (Sinequan) • Imipramine (Tofranil, Tofranil-PM) • Nortriptyline (Pamelor) • Protriptyline (Vivactil) • Trimipramine (Surmontil)

  18. TCAS MECHANISM OF ACTION • TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake • TCAs also allow for the downregulation of post-synaptic receptors • All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

  19. TCAS SIDE EFFECTS • Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence • Histamine H1 receptor antagonism - sedation and weight gain • Adrenergic α receptor antagonism - postural hypotension • Direct membrane effects - reduced seizure threshold, arrhythmia • Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

  20. TCAS SIDE EFFECTS • Nonselectivity results in greater side effects • TCAs can also lead to cardiotoxicity • Increased LDH leakage • Slow cardiac conduction • High potency can lead to mania • Contraindicated with persons with bipolar disorder or manic depression

  21. TETRACYCLIC ANTIDEPRESSANTS (TECAS) • Current Drugs • Mirtazapine (Remeron) • Mechanism of Action • Same as TCAs • Side Effects

  22. SELECTIVE SEROTONIN REUPTAKE INHIBITORS • Most commonly prescribed class • Current drugs • Mechanism of action • Side effects Serotonin

  23. SSRIS ON THE MARKET • citalopram (Celexa) • dapoxetine (Priligy) • escitalopram (Lexapro) • fluoxetine (Prozac) • fluvoxamine (Luvox) • paroxetine (Paxil) • sertraline (Zoloft) • zimelidine (Zelmid) (discontinued) • indalpine (Upstene) (discontinued) Fluoxetine 1:1 Sertraline

  24. SSRIS MECHANISM OF ACTION • Exact mechanism remains uncertain • Ser-438 residue in the human serotonin transporter (hSERT) appears to be a determining factor in SSRI potency • Antidepressants interact directly with hSERT • http://www.mayoclinic.com/health/antidepressants/MM00660

  25. SSRIS SIDE EFFECTS • Anhedonia • Apathy • Nausea/vomiting • Drowsiness or somnolence • Headache • Bruxism (involuntarily grinding of the teeth) • Extremely vivid and strange dreams • Dizziness • Fatigue • Changes in sexual behavior • Suicidal thoughts

  26. SSRIS SIDE EFFECTS • Many disappear within 4 weeks (adaption phase) • Side effects more manageable compared to MAOIs and TCAs • Sexual side effects are common • SSRI cessation syndrome • Brain zaps • Sexual dysfunction

  27. SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS) • Slightly greater efficacy than SSRIs • Slightly fewer adverse effects than SSRIs • Current drugs • Venlafaxine (Effexor) • Duloxetine (Cymbalta) • Mechanism of Action • Very similar to SSRIs • Works on both neurotransmitters • Side effects • Similar to SSRIs • Suicide Venlafaxine 1:1 Duloxetine

  28. NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS) • Current drugs • Bupropion (Wellbutrin) • Mechanims of Action • Similar to SSRIs and SNRIs • More potent in inhibiting dopamine • Also anα3-β4 nicotinic antagonist • Adverse effects • Lowers seizure threshold • Suicide • Does not cause weight gain or sexual dysfunction (even used to treat the two) Bupropion 1:1

  29. ASSIGNED READING • An Introduction to Medicinal Chemistry, by Graham L. Patrick, Chapter 20, pp. 593-8. • Kelly, John. Novel therapeutic targets for the treatment of depression. Current Medicinal Chemistry: Central Nervous System Agents (2003), 3(4), 311-322. Optional Reading: Wong, David T.; Perry, Kenneth W.; Bymaster, Frank P. Case History: The Discovery of Fluoxetine Hydrochloride (Prozac). Nature Reviews Drug Discovery (2005), 4(9), 764-774. Krishnan, K. Ranga. Revisiting monoamine oxidase inhibitors. Journal of Clinical Psychiatry (Memphis, TN, United States) (2007), 68(Suppl. 8), 35-41.

  30. HOMEWORK QUESTIONS • Many of the medications to treat depression are thought to involve systems utilizing the monoamine neurotransmitters, noradrenaline, dopamine, and serotonin (5-HT). Draw the structures of these neurotransmitters. Why are they called monoamines? Illustrate their structural resemblance to one another. • Monoamine oxidase inhibitors (MAOIs) increase CNS synaptic concentrations of these monoamines by inhibiting an enzyme responsible for their degradation. Draw the reaction scheme for the biological degradation of noradrenaline by monoamine oxidase. • Illustrate how the TCAs and SSRIs might resemble the monoamine neurotransmitters, providing one example of each class of antidepressant.

  31. REFERENCES • http://ajp.psychiatryonline.org/cgi/reprint/157/11/1901 • http://www.webmd.com/depression/ • http://pn.psychiatryonline.org/content/41/24/21.full • http://www.mayoclinic.com/health/maois/MH00072 • http://www.springerlink.com/content/b9b8668ff59f89d7/fulltext.pdf • http://www.emsam.com/pi_emsam.pdf • http://www.nevdgp.org.au/info/topics/depression_theory.htm • http://www.uspharmacist.com/content/t/psychotropic_disorders/c/11467/ • http://www.jbc.org/content/284/15/10276.full.pdf+html • http://www.aafp.org/afp/981200ap/cadieux.html • http://www.mayoclinic.com/health/antidepressants/MH00071 • http://books.google.com/books?id=R0W1ErpsQpkC&pg=PA565&lpg=PA565&dq=tcas+mechanism+of+action&source=bl&ots=oASle2Z-pr&sig=36CB_3JY4uD3LIYvqXWmAb3nliY&hl=en&ei=HzfFS9OrB4Tu9gTD6_ixDg&sa=X&oi=book_result&ct=result&resnum=8&ved=0CCoQ6AEwBw#v=onepage&q=tcas%20mechanism%20of%20action&f=false • http://www.informaworld.com/smpp/content~content=a916036122&db=all

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