Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs) Notes: Increased risk of suicide in 0-24 y/o upon initiation (black box) More gestures and Ideations, no more completions Decreased risk of suicide in ≥65 y/o upon initiation (white men) Drug Interactions: Paroxetine ≥ Sertraline ≥ Citalopram Also helpful for anxiety associated depression SE (General): Sexual dysfunction is the MCC of noncompliance and MC SE (50-80%) Akathisia Early: HA/Nausea, dizziness, insomnia, anxiety Nonspecific: Flu-like, GI upset, Psych symptoms Late: sexual dysfunction and weight gain Citalopram (Celexa) Dose: 20mg up to 20-40mg daily (40mg max effective) Weak CYP2D6 inhibitor Use: Treats anxiety symptoms better than other SSRIs Least likely to have drug interaction Low P450 SE: More cardiotoxic, May Prolong Qt interval (blockade of KCNH2 gene potassium channel) 20mg: 8.5ms, 40mg: 12.6ms, 60mg: 18.5ms Use 20mg if ≥60 or hepatic dysfunction Escitalopram (Lexapro) Dose: 10mg up to 10-20mg daily (10mg max effective) Most serotonin specific of SSRIs Most potent SSRI Use: Paraphilias, GAD, Chronic pain Post-MI depression due to low drug reaction potential Low p450, fewer SE than citalopram, rapid SE: QTc Prolongation: 10mg: 4.5ms, 20mg: 6.6ms, 30mg: 10.7ms Fluoxetine (Prozac) Dose: 20mg up to 20-80mg daily Potent CYP2D6 inhibitor Use: OCD, Bulimia, Panic Disorder Can be used with olanzapine for acute bipolar depression Doesn't need to be tapered when stopping, long half-life SE: May cause agitation/anxiety and insomnia initially, sexual dysfunction, may cause weight loss Nausea, vomiting, diarrhea QTc prolongation (4.5ms) Fluvoxamine (Luvox) 50mg daily, max 300mg divided daily CYP3A4, 2C10, 1A2 inhibitor Most drug interations Use: OCD only No QTc Prolongation (-5.0ms) Paroxetine (Paxil) Dose: 20mg up to 20-60mg daily (50mg max effective) Potent CYP2D6 inhibitor Use: Premature ejaculation, Body dysmorphic disorder, SAD, OCD, PTSD Potent CYP2D6 inhibitor No QTc prolongation SE: Most likely to have side effects, Dizziness, most sedating and anticholinergic SSRI, highest rate of sexual dysfunction, higher rate of weight gain (30%), highest rate of discontinuation syndrome, sedating, constipation Cardiac septal defects in kids (pulm htn) Sertraline (Zoloft) Dose: 50mg up to 50-200mg daily Increased absorption with food Weak CYP2D6 Use: PMDD, PTSD, SAD, OCD, Post-MI Best for breastfeeding SE: delayed ejaculation, QTc Prolongation, Bruxism (better with buspirone), generic may be activating, bruising, hair loss 3.0ms Most likely to cause GI upset (Nausea ≥ Diarrhea) May displace warfarin increasing PTT Selective Norepinephrine Reuptake Inhibitors (SNRIs) Notes: Nausea (MC), Sexual dysfunction, Hypertension (not duloxetine), Pseudo-anticholinergic effects (constipation, dizziness, dry mouth, sweating, agitation, anxiety, tachycardia) due to increased synaptic NE Duloxetine (Cymbalta) Dose: 20 mg up to 60mg daily (BID dosing may decrease SE) Aka Yantreve MOA: 5HT = NE at all doses Moderate CYP2D6 Use: MDD, stress incontinence, panic disorder FDA approved for diabetic neuropathy, fibromyalgia Pain with depression Useful in diabetics with peripheral neuropathic pain Rapid symptom relief, few side effects Only SNRI w/o BP effects SE: Avoid in renal failure, Hepatic failure in liver disease, may increase HbA1c, Insomnia Nausea, dry mouth, constipation Prompt discontinuation due to side effects Less likely to cause HTN Desvenlafaxine (Pristiq) Dose: 50mg daily MOA: Inhibits 5HT and NE Active metabolite of venlafaxine and levo-milnacipran Avoids hepatic CYP2D6 metabolism Less likely to increase BP than Effexor Use: MDD, GAD, Panic Disorder, Menopause, Cocaine dependence Rapid, few side effects, low cytochrome P-450 effects No Weight gain Milnacipran Racemic mixture of levo- and dextro-milnacipran Use: Fibromyalgia (FDA) No CYP450 interaction, NET ≥SERT selectivity SE: HTN, Tachycardia, GI symptoms, hyperhidrosis, ED Levo-Milnacipran (Fetzima) 20mg; max 40-120mg daily Use: MDD More potent enantiomer of milnacipran Inhibits BACE-1 (B-amyloid plaques) SE: HTN, Tachycardia, GI symptoms, hyperhidrosis, ED Venlafaxine (Effexor) Dose: 37.5mg up to 75-375mg daily XR MOA: Inhibits 5HT ≥ NE low dose, NE ≥ 5HT at high dose Inhibits CYP2D6 Use: MDD, GAD, Panic Disorder, Menopause, Cocaine dependence Rapid, few side effects, low cytochrome P-450 effects No Weight gain SE: May cause diastolic hypertension, activating, "stimulant effect", Increases diastolic BP, most cardiotoxic SNRI, headache, constipation, sweating, Anxiety and HTN in high doses, discontinuation syndrome Nausea and sexual side effects in 30% due to NE not 5HT May have withdrawal Atypical Antidepressants Bupropion (Wellbutrin) Dose: 150mg up to 300-450mg daily MOA: NE and Dopamine reuptake inhibitor, increasing activity Metabolized by CYP2B6 to hydroxy- which is a moderate CYP2D6 inhibitor CYP2B6 substrate Use: Smoking cessation, MDD w/seasonal pattern, Adult ADHD, Obesity Good for weight loss, hypersomnia, smoking cessation, no sexual side effects Not good for anxious patients SE: Agitation, insomnia, anorexia, sweating, false positive for amphetamines on UDS, headache, tremor, dry mouth, psychosis Avoid in pregnancy CI: Seizures, Bulimia and Anorexia Nervosa, epilepsy Check for hypokalemic, hypochloremic metabolic alkalosis (self-induced vomiting seen in Bulimia Nervosa) prior to initiating Seizure risk is 2% at 600mg, 0.1% with 300-450mg, almost same as other antidepressants (0.05%) Mirtazapine (Remeron) Dose: 7.5mg up to 15-45mg daily \<30mg = sedation ≥30mg = activating (more NE) MOA: Presynaptic Alpha-2 antagonist Increased NE and 5-HT release Selective postsynaptic 5-HT receptor antagonist Increased 5-HT1 receptor neurotransmission, antagonist at 5-HT2 and 5-HT3 receptor Antagonizes H1 receptors Clearance impaired in liver disease by 30%, 50% in renal disease, elderly (males 40%, females 10%) Use: Insomnia Sleep, Depression, Hunger (Weight Gain) Don't break it in half, sedative already Additive effects with alcohol and benzos (substrate) Increases appetite, weight gain, increases mood, sleep Lacks sexual side effects SE: Drowsiness (54%), Xerostomia (25%), Weight Gain (12%), Sedation, Thrombocytopenia, Bone marrow suppression and neutropenia, hypertriglyceridemia, increase in appetite, constipation (13%), Disorientation and tachycardia, increased cholesterol, decreased ANC Maprotiline (Ludiomil) D2 blocker (NET ≥SERT inhibition) TCA like adverse effects, seizures, high NET affinity Use: Anxiety with depressive features Nefazodone (Serzone) 50mg BID up to 300mg BID 5-HT2A antagonists (relatively selective), Alpha1 receptor blockade, CYP3A4 inhibitor, weak Serotonin reuptake inhibitor (antagonist and agonist of serotonin receptor) Sedation, dose related GI effects \< SSRIs Rare sexual effects, hypotension Short half life Use: Insomnia Black Box Warning: Fulminant liver failure Trazodone (Desyrel) MOA: 5-HT2A antagonist (relatively selective), Alpha-1 receptor blockade, CYP3A4 substrate, 5HT2C receptor agonist Vasodilation, Short half life Use: Insomnia in depression Depression: 150mg up to 150-600mg daily Sleep: 25-50mg qPM Pronounced sedation, dose related GI effects \< SSRIs SE: Rare sexual effects, priapism (\<1%), hypotension, sedation Vilazodone (Viibryd) Dose: 10mg daily, goal 40mg daily, 10mg per week increase SSRI + 5HT1 partial agonist (MDD + GAD) CYP3A4 Use: Less Sexual and Weight gain SE SE: Nausea and Diarrhea ≥ SSRIs, discontinuation syndrome Vortioxetine (Trintellix) Serotonergic, nausea, Sexual side effects Processing speed increase SSRI + 5HT1A full agonist/5HT1B partial agonist, 5-HT3/7/1D antagonist Monoamine Oxidase Inhibitors (MAOIs) Avoid: beer, wine, aged cheese, soy sauce, bananas, smoked meat SE: MCly Orthostatic hypotension and weight gain, paresthesia (from B6 deficiency), mania highest rates of sexual dysfunction of all antidepressants, Anorgasmia Activation, insomnia, and restlessness Confusion at higher doses Hypertensive Crisis (0.02%) Delirium-like discontinuation with psychosis, excitement, and confusion Meperidine is specifically contraindicated Need 2-week washout Nonselective MOA: Irreversibly inhibit MAOA/B Isocarboxazid (Marplan) 10mg BID, max 60mg daily Use: Geriatric Depression Tranylcypromine (Parnate) 30mg daily to 60mg in divided doses Use: Atypical Depression Phenelzine (Nardil) 15mg TID to 90mg TID Non-selective blockade of MAO More sedating than selegiline and tranylcypromine Pain, Eating, Panic disorders Selective Selegiline (Emsam) Dose: 6mg-12mg transdermal patch (24hr) MOA: MAO-B irreversible inhibition at low doses Increased dopamine MAO-A inhibition if given transdermally Use: Parkinson's drug No dietary restriction if used in low dosages SE: Orthostatic hypotension Rasagiline Tricyclic Antidepressants (TCAs) General MOA: Block NE and serotonin reuptake at synapse, some block Dopamine reuptake Inhibition of NE and 5-HT can trigger convulsions/seizures Also block muscarinic acetylcholine receptors Orthostatic hypotension due to alpha blockade H1 receptors also blocked Class 1A Antiarrhythmic agents at low doses, arrhythmic agents at high doses 2nd MCC of lethal OD in US (amitriptyline ≥ rest combined), death in 8.5/1000 OD SE: Convulsions, Coma, Cardiotoxicity, Respiratory Depression, Hyperpyrexia, Prolonged QRS, weight gain, sedation Cholinergic rebound on discontinuation (flu like) Delirium (amitriptyline) Seizures (2% clomipramine) Acute Hepatitis (0.1%) CI: Narrow-angle Glaucoma Secondary Amines General High affinity for blocking NE reuptake (NE ≥ 5HT) Fever, anticholinergic effects, weight gain Desipramine (Norpramin) Dose: 25-50mg daily up to 100-300mg daily Least sedating TCA (most noradrenergic) SE: LFT elevation (AST≥≥≥ALT) Maprotiline (Ludiomil) Dose: 25mg TID, max 225mg daily Lacks 5HT reuptake inhibition (mainly NE reuptake) SE: Sedating Nortriptyline (Pamelor) Dose: 25-50mg daily up to 150-200mg daily Use: Elderly depression, cardiac diseases, pruritus, smoking cessation, QTc Prolongation Least likely to cause orthostatic hypotension (low acnticholinergic) Tertiary Amines Notes: 5HT ≥ NE Have more anticholinergic side effects and sedation Agitation, blurry vision, fever, constipation, urinary retention, confusion Myotonic jerking, delirium, sedation, coma Amitriptyline (Elavil) Dose: 25-50mg daily up to 100-200mg daily Use: Depression w/insomnia, chronic pain SE: Orthostatic hypotension (causing falls), Sedating Semiannual EKG due to risk of QT prolongation Most anticholinergic Amoxapine (Asendin) Dose: 50mg BID, max 400mg daily MOA: D2 blocker (5HT = NE, weak DA) Blockade of NE and 5-HT reuptake Use: MDD w/Psychotic Features Dopamine receptor blockade (antidepressant) Anti-dopaminergic effects (Parkinson's, ED) Unique to drug in class (may cause EPS) SE: higher seizure risk, TD Most dangerous in overdose Clomipramine (Anafranil) Dose: 25mg daily, max 250mg daily Most serotoninergic, most sexual effects Use: OCD Doxepin (Sinequan) Dose: 25-75mg daily up to 100-300mg daily MOA: 5HT = NE, highly sedation Use: GAD, PUD, pruritis SE: Sedating, antihistaminergic, anticholinergic Imipramine (Tofranil) Dose: 25-50mg daily up to 100-200mg daily MOA: 5HT = NE Use: Panic disorder with agoraphobia, enuresis, eating disorders, but has a high relapse rate SE: Orthostatic hypotension, prolonged QT, LFT elevation (AST≥≥≥ALT) Protriptyline (Vivactil) Less sedating than doxepin, nor/amitriptyline, imipramine Good for job alertness