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Antidepressants

Antidepressants. Cesar A. Soutullo, M.D. UC-3 Psychopharm Lectures. Classic & New Antidepressants. 5-HT Reuptake Inhibitors (SSRI) Fluoxetine (& R-FLX), Paroxetine, Sertraline, Fluvoxamine, Citalopram NE/5-HT Reuptake Inh. (SNRI) Venlafaxine, Milnacipran, Duloxetine

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Antidepressants

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  1. Antidepressants Cesar A. Soutullo, M.D. UC-3 Psychopharm Lectures

  2. Classic & New Antidepressants • 5-HT Reuptake Inhibitors (SSRI) • Fluoxetine (& R-FLX), Paroxetine, Sertraline, Fluvoxamine, Citalopram • NE/5-HT Reuptake Inh. (SNRI) • Venlafaxine, Milnacipran, Duloxetine • DA/NE Reuptake Inh.: Bupropion • 5-HT Rec. Modulators: Trazodone, Nefazadone • Pre, Post-Synaptic agonist/antag: Mirtazapine • NE Reuptake Inh. Old:TCA, New: Reboxetine • MAO inhibitors: (reversible & not)

  3. Antidepressant Efficacy • Mood Disorders: • Major Depression • Dysthymia & Subthreshold depression • Bipolar Disorder (combined w Mood Stab) • Schizoaffective, depressed type • Anxiety Disorders: • OCD, Panic, GAD, PSTD • Impulse Control Disorders: • Klepto, Comp Shopping, Trichotilo, Binge Eat, Paraphilias, IED • Affective-spectrum disorders: • IBS, migraines, fibromialg, chron pain, enuresis

  4. SSRIs • Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram • Clomipramine (TCA) also SRI • Sertraline: weak DA uptake inh • Paroxetine: weak anticholinergic • 5-HT potency: parox>fluvox>sertr>fluox • Similar efficacy to TCA, better safety

  5. SSRIs • Treatment of acute & maintenance depr. (prevent relapse & recurrence) • Relapse: 1 yr 2 yr • 70% 80% placebo • 50% 70% psychotherapy • 20% 20% SRI

  6. SSRIs • Absolute contraindication in combination w MAOI or L-Triptophan (5-HT syndr) • Fluoxetine longest t1/2: 9-11 days, the others 20-24 hrs • SRI good GI absorb, Liver metabolized • Prozac & Paxil p450 2D6; Luvox, Zoloft 3A4

  7. SSRIs Side Effects • Usually safe & well tolerated • CNS • Nervousness, jitteriness • Insomnia (Proz) / sedation (Pax, Luv), fatigue • Headaches, Tremmors • GI • Naus / Vom 11-16%, Diarr (Zol), Constip (Pax), anorexia (Pro), dry mouth • Caution in Hepatic Disease • Sexual 5-HT2 (25-50%) • delayed orgasm, libido, erection/lubrication • Induction of Mania • Pregnancy: Fluoxetine OK, others no data

  8. SSRIs Interactions • Absolute contraind. MAOI, L-Tryptophan • Wait 2 wks (more with Prozac) if switching • p450 system: • Luvox: 1A2 (TCA, clozapine, theoph, tylenol, propranolol levels) & 3A4 (arrithmias with  astemizole (hismanal) & terfenadine (seldane), cisapride (propulsid) • Prozac 2D6, 3A4, 2C19 • Paxil 2D6

  9. SSRIs Dosage • Fluoxetine [Prozac] 10-80 mg/d • Paroxetine [Paxil] 10-50 mg/d • Sertraline [Zoloft] 25-200 mg/d • Fluvoxamine [Luvox] 50-300 mg/d • Citalopram [Celexa] 20-50 mg/d • Initial response 2-4 wks, if not better after 3-4 wks dose

  10. SNRIs: Venlafaxine [Effexor] • XR & Regular (t1/2=5 hrs) available • Potent 5-HT, NE uptake inh. • Prot. Binding (27%), low p450 problems • SE SRI-like: N/V, dizziness, sedation • Dosage: • 37.5 bid, optimal dose 175-225 • XR 37.5 qd 5-7 d., 75 qd, 150 qd after wk 3 • Monitor Blood Pressure

  11. Bupropion [Wellbutrin] • DA Agonist • Structure similar to amphetamine • decrease sleep & appetite, Tx ADHD • Liver metab, kidney excreted • t1/2: 8-12 hrs (bid, tid) • Indications: Depression & ADHD • Risk of Seizures @ 450-600 mg/d • Single dose <150, >4hrs apart • Max dose 400 mg/d

  12. Bupropion: SE • N, V, sleep, restlessness, irritab, agit • No sexual SE • Do not use with MAOI • Delirium, psychosis, dyskinesias combined w DA agonists (amantadine, L-dopa, bromocriptine) • Risk of Seizures • Contraind. Hx HI, brain tumor, Sz threshold

  13. Trazodone [Desyrel] • Blocks 5-HT 2 & 1 receptors • Weak inhibitor 5-HT reuptake • Helpful for sleep • GI absorbed, t1/2 3-9 hrs • Dose: 150 mg/day divided doses, max 400 • SE: • Sedation, occasional orthostasis • Rare: Priapism (1 in 6,000) (alpha-1 block)

  14. Nefazadone [Serzone] • Similar to Trazodone [Desyrel] • less sedating, no priapism • 5-HT2 antagonist: little sexual SE • Mild inhibition 5-HT, NE reuptake • t1/2 18-24 hrs: (hs, bid SE) • Metabol p450 3A4: • interaction: alprazolam, ketokonazole, terfenadine, astemizole, cisapride

  15. Mirtazapine [Remeron] • Presynaptic alpha2 blockade • (blocks feedback that release of NE, 5-HT) • Postsynap 5-HT2 block: sexual SE • Postsynap 5-HT3 block: N,V,HA • 5-HT to 5-HT1antidepressant effect) • SE: Sedation, Constipation, Wt gain • Dose: 15 mg/ hs, max 45 mg/d

  16. Tricyclics, Tetracyclics (TCA) • Secondary Amines: • Desipramine [Norpramin], Nortryptiline [Pamelor], protryptiline [Vivactil] • Tertiary Amines: • IMI [Tofranil], Amitriptiline [Elavil], Doxepin [Sinequan], Clomipramine [Anafranil (SRI)] • Tetracyclic: Amoxapine [Asendin]

  17. TCAs • Action: Blockade of • reuptake of NE & 5-HT • Muscarinic, Histamine, Alpha Adrenergic • 2nd amines safer & better tolerated • Clomipramine most SRI, Doxepine most anticholinergic • Start & Stop slowly • Monitor plasma levels

  18. TCAs: Indications • Depression • Panic DO (low dose IMI) • GAD (Doxepine) • OCD (Clomipramine) • Anorex, Bulimia • Enuresis (IMI), ADHD • Narcolepsy, sleep walking, sleep terrors

  19. TCA: Side Effects • Anticholinergic • Alpha 1 blockade: • Autonomic: Orthostasis • Cardiac: arrithmias, long QT, depr ST • Histamine: Sedation, Wt Gain, Sexual SE • Amoxapine: EPS, akathisia (DA Block) • Clomipr, Amoxapine lower Sz Treshold • OD: Serious, often fatal. Delirium, Sz, BP & Temp dysregulation,

  20. TCAs: Interactions • P450 2D6 • Cimetidine, Quinidine, SsRI, antipsychotics, antiarrithmics TCA • Smoking, Li, Cl Hydrate TCA levels • Additive effects CNS depressants: • EtOH, benzos, opioids, hypnotics, OTC decongestants

  21. MAO-inhibitors (MAOIs)Phenelzine [Nardil], Trancypromine [Parnate] • Must: LOW TYRAMINE DIET: no cheese, smoked/aged meats, wine, beans, liver • Avoid: • OTC decongestants (OK ASA, tylenol, ibuprofen, benadryl, plain robotussin) • Diet pills (ephedrine) • DA agonists (Bupropion) • SSRIs, Venlafaxine, most TCAs • L-Tryptophan • Antihypertensives & Diuretics • Narcotics

  22. MAOIs • Tyramine (BP) metabolized GI MAO • Hypertensive Crisis: • headache, N, V, stiff neck, photophobia, diaphoresis, palpitations • Serotonin Syndrome: • autonomic instability, hyperthermia, myoclonus, confusion, delilrium, coma • No longer first line, but very effective • SE: orthostasis, sedation, sex dysfx,wt

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