Lectures 7-8: Antidepressants

tricyclic antidepressants inhibit

reuptake of both serotonin and norepinephrine

SNRIs inhibit

reuptake of both serotonin and norepinephrine

SSRIS

selectively inhibit reuptake of serotonin

Phenelzine inhibits

MAO

Mirtazepine increases

serotonin release

Tricyclic Antidepressants

Inhibit re-uptake of NE and 5HT

Anticholinergic/Antihistamine

Alpha1 blockade

Alpha2 stimulation in spinal cord

No euphoria/low abuse potential

Sedation

2-4 weeks to have effect

Metabolized in liver by CYP

Imipramine → Desipramine

Amitriptyline → Nortriptyline

Imipramine and Amitriptyline more sedating / anticholinergic/more 5-HT

Desipramine and Nortriptyline less sedating /anticholinergic/more NE

Analgesia- spinal cord action

Tricyclic Antidepressants Uses

Depression

Panic disorder

Chronic pain, nerve pain, headache

Fibromyalgia

Enuresis – imipramine

ADHD

Tricyclic Antidepressants Side Effects

Sedation

Impair memory/cognition- worse in elderly and children

Cardiac depression & increased irritability

imipramine, desipramine most cardiac effect

nortriptyline least cardiac effect

Torsades de pointes, esp in overdose

postural hypotension

reflex tachycardia

ventricular arrhythmias

Inverted T wave, inc. conduction time, myocardial depression

CAUTION in cardiac disease

Blurred vision, Dry mouth, Constipation, Urinary retention

CAUTION in benign prostatic hyperplasia

Switch to mania if bipolar

Weight gain

Decreased seizure threshold

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Sexual dysfunction

Muscle aches/malaise if stop abruptly

Suicide

Safe in pregnancy

Tricyclic Antidepressants Toxicity

cardiac arrhythmias- Torsades de pointes

severe hypotension, agitation, delirium, seizures, hyperpyrexia

coma, shock, metabolic acidosis

respiratory depression

Gastric lavage/charcoal and Restore acid-base balance

Mg, isoproterenol, cardiac pacing

Phenytoin, lidocaine, propranolol

Tricyclic Antidepressants Interactions

MAOIs- severe CNS toxicity, serotonin syndrome

Fluoxetine → increase TCA concentration, toxicity

Sympathomimetics, clonidine → Hypertension, arrhythmia

Alcohol and CNS depressants → increased sedation

Anticholinergics

Phenelzine

Monoamine Oxidase Inhibitors

Irreversibly inhibit MAO-A, which breaks down NE & 5HT, and MAO-B, which breaks down DA

Used for depression which doesn’t respond to other drugs, atypical depression

Effects of tyramine: severe hypertensive crisis!

Tyramine in foods: red wine, beer, aged cheese

Sympathomimetics (cold medicines) also cause HTx

Treat with alpha blocker (eg Phentolamine)

Phenelzine Side Effects and Interactions

Tremors, Sedation, excitation, insomnia, Orthostatic hypotension

Delayed ejaculation, Fatigue, Weight gain, skin rash

Muscarinic blockade

Suicide

Sympathomimetic amines (phenylephrine, ephedrine, amphetamine) → severe hypertension

Meperidine, dextromethorphan, TCAs, SSRIs: Hyperpyrexia and Serotonin syndrome

Buspirone → hypertension

Serotonin syndrome

Hypertension, tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus (muscle jerking), and hyperreflexia

Hyperthermia (temperature above 40 C), hyperactive bowel sounds, agitation, horizontal ocular clonus, hypervigilance, and pressure speech

Delirium and muscle rigidity

Complications include seizures, rhabdomyolysis, myoglobinuria, metabolic acidosis, renal failure, respiratory failure, coma, and death

Treatment: Cyproheptadine- serotonin receptor antagonist

Drugs that can cause Serotonin syndrome

Tricyclic Antidepressants

Phenelzine

SSRIs and SNRIs

Meperidine, tramadol, fentanyl, Dextromethorphan

St Johns’ Wort

Linezolid (antibiotic that also inhibits MAO)

Lithium

Psychostimulants

Triptans (for migraine)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine

Sertraline

Paroxetine

Citalopram

Escitalopram

Vortioxetine

Vilazodone

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Venlafaxine

Desvenlafaxine

Duloxetine

Levomilnacipran

Milnacipran

Fluoxetine

Inhibits NE uptake slightly, useful in chronic pain

Slow onset of effect

Late side effects

Long half life

Active metabolite

Fluoxetine and paroxetine inhibit CYP2D6 + effect on hepatic enzymes

SSRIs Uses

Depression

Panic disorder

Obsessive-compulsive disorder

Social anxiety

Bulimia

PMDD

Alcoholism

Premature ejaculation

Children/Adolescents

Elderly: Anxiety, Depression, OCD

SSRIs Side Effects

Nausea, loss of appetite

Weight loss initially, but weight gain with long-term use

Anxiety, insomnia, or sedation

Sexual disinterest/dysfunction

Delayed ejaculation

Headache, rash, sweating

Photosensitivity

Suicide

SSRIs Interactions

Inhibit TCA metabolism → toxicity

Inhibition of metabolism by fluoxetine: Warfarin, Phenytoin, carbamazepine, ß-blockers, Ca channel blockers, Tamoxifen, Opioids

Seizures with tramadol

MAOIs, St John’s Wort, Amphetamines → Serotonin syndrome

Sertraline

Fewer drug interactions + shorter ½ life than fluoxetine

Paroxetine

Fluoxetine and paroxetine inhibit CYP2D6 + effect on hepatic enzymes

OCD

Social anxiety

Slightly sedating

GI effects common

Do not use in pregnancy → cardiac defects

Citalopram and Escitalopram

Few side effects

Few drug interactions

Hot flashes

Vortioxetine and Vilazodone

SSRIs that blocks some 5HT receptors

Agonist activity on 5-HT1A

Increase serotonin levels, but then have selective receptor effects based on blockade or stimulation of specific receptors

Side effects similar to SSRIs

Venlafaxine and Desvenlafaxine

Block both 5-HT and NE re-uptake

Good in chronic pain

Hot flashes

Long duration of action

Side effects greater than SSRIs

SIADH

Increase blood pressure

Duloxetine

Inhibits reuptake of 5-HT and NE

Depression-associated pain

Moderate inhibition of CYP2D6

Metabolized by CYP450

Long half-life

Increase liver enzymes

Caution in liver disease

Milnacipran and Levomilnacipran

Fibromyalgia

Bupropion

Inhibits DA + NE re-uptake

Extended release for quitting smoking

Few sexual side effects- sometimes combined with SSRIs to improve sexual function

ADHD, Alcoholism, night eating (decreases craving)

Side Effects:

Anxiety, insomnia, restlessness, tremor

Psychosis, Seizures

Do not give to patients with history of seizure or head trauma, or with drugs that decrease seizure threshold

Tachycardia

Rash- discontinue

Mirtazapine

blocks presynaptic α2 receptors

increases release of NE and 5-HT

blocks 5-HT2A and 5-HT3A receptors

Reduces anxiety, insomnia, nausea, sexual problems

Antihistamine - sedation

Effects similar to TCAs, without cardiac toxicity

Causes significant weight gain

Esketamine

Ketamine in treatment resistant depression

nasal form of ketamine

Administered in a health care setting and patients must be monitored for 2 hours post treatment and avoid driving the next day

Atomoxetine

NE Reuptake Inhibitors

ADHD

GI distress and insomnia

Liver toxicity

Amoxapine

Inhibits 5HT/NE reuptake and Blocks DA receptors

Some antipsychotic effects and similar side effects

Sedation

Maprotiline

Inhibits NE reuptake

Cardiac side effects

Seizures

Trazodone

Partial agonist at 5HT1A receptor

Blocks 5HT2A receptors

Short onset of action

Sedation

Not a very good antidepressant

Widely used for insomnia and pain management

Hypotension, dizziness, nausea

Priapism

St John’s Wort

Mild depression

Photosensitivity

DO NOT combine with other antidepressants

Prolong anesthesia

Efficacy of protease inhibitors, oral contraceptives, digoxin, warfarin reduced

Induces CYP450

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Antidepressant use

ADH increases water reabsorption

If intake exceeds reduced output, patient develops water retention and hyponatremia in blood

→ Mental status changes, inc. urine Na

Treated by restricting fluid intake

Metabolized by CYP450

Tricyclic antidepressants

Duloxetine