Antidepressants Study Notes

Antidepressants

Introduction to Antidepressants

  • Antidepressants are chemical agents used to treat various forms of depression and mood disorders.

Tricyclic Antidepressants (TCA)

  • Development Origin:

    • Tricyclic antidepressants (TCA’s) were developed from phenothiazine anti-psychotic agents.

    • Structure includes a nitrogen and chlorine atom (represented in diagrams as: N S N Cl N N).

  • Chemical Modifications of TCAs:

    • Replacement of Sulfur with Ethylene Group:

    • This alteration results in a compound that loses dopamine antagonist activity.

    • Instead, the compound becomes an inhibitor of serotonin (5HT) and norepinephrine (NE) reuptake.

    • Retains anti-acetylcholine, anti-histamine, and anti-alpha activity from its predecessor.

    • Reduction of Double Bond:

    • Enhances potency as a reuptake inhibitor.

    • This modification led to the development of a commonly used antidepressant, Imipramine (chemical structure: N N N N).

    • Ring Structure Modifications:

    • Nitrogen in the ring can be replaced with a double bond, seen in Amitriptyline (chemical structure: N N N).

    • Chlorine Addition:

    • Chlorine added to the imipramine ring creates Clomipramine which shows enhanced serotonin reuptake inhibition compared to norepinephrine.

    • Chemical structure: N N Cl N N.

  • General Aspects of TCAs:

    • Dimethyl Compounds:

    • Examples include Amitriptyline and Imipramine.

    • These compounds tend to affect serotonin more than norepinephrine.

    • Chloro Substitution:

    • Enhances serotonin reuptake inhibition over norepinephrine (clomipramine highlighted).

    • Mono Methyl Compounds:

    • Greater effect on norepinephrine than serotonin, exemplified by Desipramine (21) and Nortriptyline (5).

    • Ratios represent the comparative inhibitory effects on serotonin to norepinephrine.

  • Side Effects of TCAs:

    • Common side effects not encountered with selective serotonin reuptake inhibitors (SSRIs):

    • Anticholinergic effects

    • Sedation

    • Hypotension

    • Cardiotoxicity

    • Due to these side effects, TCAs have fallen out of favor for depression treatment.

Transition to SSRIs

  • Clomipramine's enhanced serotonin reuptake inhibition prompted a reevaluation of other compounds for similar activity.

    • Compounds like Chlorpheniramine and Diphenhydramine were noted for their serotonin reuptake inhibition.

  • Development of the First SSRI:

    • Zimeldine (structurally akin to triprolidine) was marketed in Europe but withdrawn due to toxicity.

    • Chemical structure: N N H3C CH3 Cl O N CH3 CH3 N H N H3C CH3 Br.

  • Following Zimeldine's discovery, Fluoxetine was designed, leading to the development of SSRIs and norepinephrine reuptake inhibitors (NERIs).

    • Chemical structure: O HN CH3 CF3.

  • Activity of Fluoxetine:

    • The role of oxygen in the activity is significant due to the potential for hydrogen bonding with the protonated amine, leading to cyclic structure formation that interacts with the serotonin transporter.

  • Structure Comparison:

    • Examples include cyclic structures of Fluoxetine, Chlorpheniramine, and Zimeldine.

Important Structural Features of SSRIs

  • The para electron-withdrawing group (EWG) is crucial for SSRI activity.

  • Ortho substitution either as EWG or electron-donating group (EDG) leads to compounds with mixed NERI activity (e.g. Atomoxetine).

Specific SSRIs and Their Properties

  • Fluoxetine (Prozac):

    • Uses: Major depression, OCD, premenstrual dysphoric disorder (PMDD), panic disorder (with and without agoraphobia).

    • Metabolism: By cytochrome P450 enzymes 2C8/9 and 2D6 (Fluoxetine acts as an inhibitor).

    • Adverse Reactions (ADR): Insomnia, drowsiness, nausea, diarrhea, anorexia, dry mouth, weakness, and yawning.

    • Converted to Norfluoxetine, active with a half-life of 10 days; this results in prolonged therapeutic effect (once weekly dosing).

  • Fluvoxamine:

    • Structural features include absence of a second aromatic ring and presence of a primary amine.

    • Uses: OCD, unlabeled for major depression and panic disorder.

    • Metabolism: By enzymes 1A2 and 2D6, also inhibits 1A2.

    • ADR: Drowsiness, insomnia, nausea, dry mouth, diarrhea, weakness.

  • Citalopram (R and S):

    • Uses: Depression, unlabeled (dementia, smoking cessation, ethanol abuse, OCD, diabetic neuropathy).

    • Metabolism: By enzymes 2C19 and 3A4.

    • ADR: Drowsiness, insomnia, nausea, dry mouth, sweating.

  • Escitalopram:

    • The S isomer is the active form of Citalopram.

    • Metabolism: Converted to active desmethyl form (1/7th as active) with a half-life of 59 hours.

    • Side effects: Same as Citalopram.

  • Paroxetine:

    • Uses: Depression, panic disorder, OCD, social anxiety, PMDD, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD).

    • Most potent SSRI, metabolized by 2D6, no active metabolites.

    • ADR: Drowsiness, insomnia, nausea, dry mouth, constipation, diarrhea, weakness, sweating.

  • Sertraline:

    • Structurally unique compared to other SSRIs, particularly during the middle structural configurations.

    • Uses: Depression, OCD, panic disorder, PTSD, PMDD, social anxiety (unlabeled for eating disorders, GAD, impulse control disorder).

    • Metabolism: By 2C19 and 2D6, moderate inhibitor of 3A4.

    • Half-life: Parent 26 hours, desmethyl active metabolite 66 hours.

    • ADR: Similar to aforementioned SSRIs.

  • Venlafaxine:

    • A mixed reuptake inhibitor of serotonin (5HT), norepinephrine (NE), and weak dopamine (DA).

    • Uses: Depression, GAD, social anxiety, panic disorder (unlabeled for OCD, hot flashes, neuropathic pain, ADHD).

    • Metabolism: By 2D6 and 3A4; produces an active metabolite (desvenlafaxine/Pristiq).

    • ADR: Similar to previous agents.

  • Duloxetine:

    • Another mixed reuptake inhibitor (5HT, NE, weak DA); structurally similar to Fluoxetine (no EWG).

    • Uses: Depression, GAD, diabetic neuropathy, chronic pain, fibromyalgia management (unlabeled stress incontinence).

    • Metabolism: By 1A2 and 2D6, inhibits 2D6.

    • ADR: Similar to others mentioned.

  • Milnacipran (Savella®):

    • A selective 5-HT and NE reuptake inhibitor (1:3 ratio).

    • Primary use: Management of fibromyalgia only.

    • Mechanism: Some cytochrome P450 metabolism present; not a CP450 inhibitor, involved in glucuronide formation, renally excreted.

    • Active isomer has a longer half-life than the negative isomer.

  • Levomilnacipran (Fetzima®):

    • Selective 5-HT and NE reuptake inhibitor (1:3 ratio).

    • Approved for treatment of major depression only.

    • Extended-release formulation utilizing beads in capsules.

    • Half-life: 12 hours, bioavailability: 92%.

    • Metabolism: By 3A4 (desethyl) and also involves hydroxylation and glucuronidation.

    • ADR: Nausea and tachycardia (low incidence) with slight weight loss.

  • Vilazodone (Viibryd®):

    • Newly classified as a 5-HT modulator and stimulator.

    • Mechanism: Binds to 5-HT reuptake pump and acts as a partial agonist at 5-HT1A.

    • Half-life: 25 hours, absorption 72% with food; decreases without food.

    • Protein binding: 92% with 3A4 as a major metabolic route and minor pathways through 2C19 and 2D6.

    • ADR: Nausea and diarrhea (low incidence), insomnia.

  • Vortioxetine (Brintellix®):

    • Mechanism: Inhibits 5-HT reuptake, agonist/partial agonist at 5-HT1A, and 5-HT3 antagonist.

    • Bioavailability: 75%, minimal food effect.

    • Protein binding: 98%.

    • Metabolism: By pathway including 2D6 (primary), 3A4 and 2C19, also undergoes glucuronidation; major carboxylic acid metabolite present.

    • Note: Poor metabolizers exhibit 2X plasma levels.

    • ADR: Increases QT and associated nausea.

  • Atomoxetine (originally known as Tomoxetine):

    • Mechanism: NERI; ortho substitution induces activity switch (analogue of Fluoxetine).

    • Use: Treatment of ADHD.

    • Metabolism involves cytochrome P450 2D6 to form 4-OH (equally active with 8-hour half-life) and desmethyl (weakly active).

    • ADR: Cough, insomnia, dry mouth, nausea.

  • Bupropion:

    • Mechanism: Primarily a dopamine reuptake inhibitor, with a metabolite showing norepinephrine reuptake inhibition.

    • Uses: Depression and smoking cessation; unlabeled for ADHD.

    • Metabolism by 2B6; hydroxy bupropion and hydrobupropion are key variants.

    • ADR: Insomnia, nausea, dry mouth, sore throat, seizures at doses >300 mg/day (non-SR or XL form).

    • Features a new 450 mg XL formulation (Forfivo XL).

  • Trazodone:

    • Characterized as an atypical antidepressant.

    • Mechanism: Weakly inhibits 5-HT reuptake.

    • Features considerable sedative properties; hypotensive effects also noted (N N N CH2 CH2 CH2 N N O Cl N NHCl).

  • Nefazodone:

    • Another atypical antidepressant closely related to Trazodone.

    • Shares similar mechanisms with weak 5-HT reuptake inhibition and 5-HT1 agonism from parent compound and metabolites.

    • Significant sedative property, less hypotension compared to Trazodone.

    • Withdrawn in 2003 due to hepatotoxicity concerns; available as generic.

Monoamine Oxidase Inhibitors (MAOIs)

  • MAO inhibitors:

    • Non-selective MAO inhibitors: Phenelzine and Tranylcypromine, affecting both MAO A and B.

    • Generally reserved for atypical depression that hasn't responded to other treatments.

    • Selegiline:

    • Selective for MAO-B and available as a once-daily transdermal patch (Emsam®).

  • Phenelzine (Nardil®):

    • Type: Hydrazine-based MAO inhibitor.

    • Metabolic pathway: Converts via MAO to phenylacetaldehyde and subsequently to phenylacetic acid.

    • Inhibition mechanism: A reactive intermediate formed can covalently bind to functional groups in the enzyme.

    • Major side effect includes risk of hypertensive crisis from dietary tyramine.

  • Tranylcypromine (Parnate®):

    • Type: Cyclopropane derivative.

    • Mechanism: Upon oxidation, becomes reactive with enzyme groups to cause MAO inactivation.

    • Similar side effect risk of hypertensive crisis due to interaction with tyramine-rich foods.

  • Toxic Effects of MAOIs:

    • Hypertensive crisis is a serious risk associated with both drug and food interactions.

    • Tyramine-Rich Foods:

    • Certain foods like aged cheese (particularly those 1° aged), beer, wines, pickled herring, snails, chicken livers, yeast products, and various fruits can lead to dangerously high blood pressure when consumed with MAOIs due to tyramine's inability to be properly metabolized.

    • Notably dangerous foods include aged cheeses and yeast products used as food supplements.

    • Use of sympathomimetic amines (e.g., ephedrine, phenylpropanolamine, pseudoephedrine, phenylephrine) in cold medications is also a concern for patients on MAOIs.