1.2 Antidepressants

(1)

Dr. familar

Antidepressants

1.2

LEGENDS: IMPORTANT SIDENOTES

2 General Classifications of Antidepressants:

• Cyclic Antidepressants – most commonly used in practice • Monoamine Oxidase Inhibitors

PHARMACOLOGIC CLASS DRUG

CYCLIC ANTIDEPRESSANTS

Selective Serotonin

Reuptake Inhibitors (SSRI) Citalopram, Fluoxetine, Paroxetine, Escitalopram, Fluvoxamine, Sertraline Norepinephrine Dopamine

Reuptake Inhibitor (NDRI)

Bupropion Selective Serotonin- Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine, Desvenlafaxine, Duloxetine Serotonin-2 Agonist/Serotonin Reuptake Inhibitor (SARI) Trazodone, Nefazodone Serotonin-1A Agonist/

Serotonin Reuptake Inhibitor Vilazodone Noradrenergic/Specific

Serotonergic Agent (NaSSA)

Mirtazapine Nonselective Cyclic Agents

(Mixed Reuptake

Inhibitor/Receptor Blockers)

Desipramine, Amitriptyline, Nortriptyline, Imipramine

MONOAMINE OXIDASE INHIBITORS

Reversible MAO-A Inhibitor

(RIMA) Moclobemide Irreversible MAO (A & B

inhibitors) (MAOIs) Phenelzine, Tranylcypromine, Maprotiline Irreversible MAO-B Inhibitor Selegiline

Common MOA: reuptake inhibition of Serotonin Leads to accumulation of serotonin -> SEROTONIN SYNDROME

The specificity of the cyclic antidepressants’ reuptake of neurotransmitters somehow determines each drug’s spectrum of activity and adverse effects.

Therapeutic Effects of Antidepressants

• Elevated mood – most important effect

• Improved sleep & appetite

• Better memory (for pseudodementia in MDD) • Increased physical activity (for anhedonia,

bradykinesia, hypokinisia in MDD) • Improved clarity of thinking

• Decreased feelings of guilt, worthlessness, helplessness & inadequacy

• Decrease in delusional preoccupation & ambivalence

If it is MDD with psychotic features (i.e., with delusions of grandeur or paranoia), give antidepressants + antipsychotics

Overview

• In general, all antidepressants are equally efficacious

• Some antidepressants may apparently produce

restlessness or psychomotor agitation before any improvement in depressive symptom is seen • In children, adolescents and adults younger than

age 24, a small (2-3%) risk of suicidal ideation or hostility may be present in some who take

antidepressants

• Antidepressants from different classes may be combined if partial response or refractory cases are seen, but caution against serotonin syndrome resulting from drug interactions

• Tolerance to different antidepressants is seen in 10- 20% of patients in spite of compliance to treatment probably because of CNS adaptation, unrecognized rapid cycling or increase in severity of disorder.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI) Chemical class Generic name Trade

name Dosage forms & strength s Phthalene derivative

Citalopram Celexa Tab/cap 10, 20, 30, 40 mg Oral disintegr ating tab Oral solution Escitalopram (most common DOC for MDD) Lexapro Tab/cap 5, 10, 20 mg Oral solution Bicyclic Fluoxetine Prozac Capsule

10, 20, 40 mg Oral solution Fluoxetine/Olan zapine (Combination for MDD with psychotic features) Symbya x Caps 25/3, 6, 12 mg Caps 50/6, 12 mg Monocyclic Fluvoxamine Luvox Tabs 25,

50, 100 mg Phenylpiperidine Paroxetine Paxil Tabs 10,

20, 30, 40 mg Oral suspensi on Controlle d-release tab Tetrahydronaphthyl Sertraline Zoloft Cap/tab

(2)

100, 150, 200 mg Oral solution

All are in oral forms.

SSRI Indications • Mood Disorders

Ø MDD

Ø MDD, recurrent, prophylaxis

Ø Depression in bipolar I & treatment-resistant depression

Ø Premenstrual dysphoric disorder Ø Dysthymia

Ø Atypical depression

Ø MDD in medical or other psychiatric disorders Ø Postpartum depression

• Eating Disorders

Ø Bulimia nervosa Ø Binge-eating disorder

• Anxiety & Related Disorders

Ø Panic disorder with or without agoraphobia Ø Social phobia Ø GAD Ø OCD Ø PTSD • Others Ø Pain management Ø Trichotillomania Ø Premature ejaculation Ø Body dysmorphic disorder

Ø Schizophrenia, negative symptoms Ø Tardive dyskinesia

Currently approved indications of SSRIs in US/Canada Disor

der xetinFluo e Fluvo xamin e Paro xetin e Sertr aline Citalopra

m

Escital opram

MDD A/P - A A A A GAD - - A - - A OCD A/P A/P A A/P - A Panic disord er A - A A - - PTSD - - A A - - Social anxiet y disord er A - A A - - Bulimi a nervo sa A - - A - - Prem entru al Dysp horic Dso. A - A A - -

Pediatric indications for: MDD - Fluoxetine

OCD – Fluoxetine, Fluvoxamine, Sertraline

Mechanism of Action of SSRIs

• Exact MOA is unknown

• Inhibition of serotonin reuptake

• Increased concentration of serotonin in the synapse • Downregulation of postsynaptic receptors

Some SSRIs can also affect other neurotransmitters

SSRI Other actions

Citalopram &

Escitalopram Most selective serotonin reuptake inhibitor

Fluoxetine Weakly inhibits

norepinephrine reuptake and binds to 5-HT2c receptors

Sertraline Weakly inhibits

norepinephrine & dopamine reuptake

Paroxetine Significant anticholinergic activity at higher doses

Pharmacokinetics of SSRIs

• Absorbed relatively slowly but completely • Time to peak plasma concentration 3-8 hours • Undergo little first-pass effect

• Highly bound to plasma protein and may even displace other drugs from protein binding but this is

not clinically significant: FLUOXETINE, PAROXETINE, SERTRALINE

• Metabolism primarily by the liver

Ø All affect CYP450 and will affect metabolism of other drugs metabolized by this system

Ø Least: CITALOPRAM and ESCITALOPRAM

Ø Clearance of ALL SSRIs is reduced in patients with cirrhosis

• FLUOXETINE and PAROXETINE decrease their own metabolism

• FLUOXETINE, as well as its active metabolite,

NORFLUOXETINE, have the longest half-lives (70 and 330 hours, resp.)

Ø Peak plasma concentration of SERTRALINE is

30% higher when taken with food, as first pass metabolism is reduced

• The most important drug-to-drug interactions involving the SSRIs occur as a result of inhibition or slowing by the SSRI of the metabolism of co- administered medications. Drug Characteristi c Interaction with Thro ugh Fluvoxamine Most notorious – marked effect on several CYP enzymes Theophylline CYP 1A2 Clozapine CYP 1A2 Alprazolam/Clo nazepam CYP3A4 Fluoxetine &

Paroxetine Significant effects Opiates such as codeine & hydrocodone by blocking conversion into their active forms CYP 2D6 Sertraline/ Citalopram/ Escitalopram Least likely for interaction

(3)

Drug Bioavaila bility (%) Prot ein bindi ng (%) Pea k plas ma level (%) Elimina tion half-life (%) Therap eutic dose range (mg) Citalopr am 80 80 4 23-45 10-40 Escitalo pram 80 54 4-5 27-32 10-20 Fluoxeti ne 72-85 94 4-8 24-144 (parent) 200- 330 (metab olite) 10-80 Fluvoxa mine 60 77-80 2.5-4 9-28 50-300 Paroxeti ne >90 95 5.2 3-65 10-60 Sertralin e 70 96 6 22-36 (parent) 62-104 (metab olite) 50-200

Onset & Duration of Action of SSRIs • Long acting

Ø Can be given in single daily dose, usually in morning

Ø Fluvoxamine and sertraline may cause sedation and may have to be given at night

• Adequate clinical activity and saturation of the transporters

Ø Most patients with depression respond to the initial dose

Ø As a rule, higher dosages do not increase antidepressant effect but may increase the risk of adverse effects

• Therapeutic effect seen in about 28 days but some may respond sooner

• Tolerance to effects may be seen after months of treatment -> may lead to serotonin syndrome

Adverse Effects of SSRIs

• Incidence may be greater in the early days of treatment

• Patients may adapt to them over time

• If there is intake of a previous drug, may have to rule out withdrawal from that drug

• CNS EFFECTS: Ø Headache is common

§ From FLUOXETINE mainly Ø Or a worsening of migraines

§ Generally effective prophylaxis for migraine & tension headache

Ø Seizure episodes in those previously diagnosed § More frequent at the highest doses of the drug

Ø Sedation or wakefulness

§ Improved sleep is the major effect but 25% report trouble sleeping or excessive sleepiness

Drug Effect on sleep

Fluoxetine Insomnia

Sertraline/Fluvoxamine Insomnia <-> Somnolence

Citalopram/Paroxetine Somnolence

Escitalopram More likely insomnia

• Case reports of cognitive impairment (short-term memory and attention affected)

Ø Rarely tremor, EPS, and fine tremor

• Anticholinergic effects

Ø Mild dose-dependent dry mouth, constipation and sedation: PAROXETINE

• Hematologic effects

Ø Easy bruising, excess or prolonged bleeding without reduced platelet count

Ø Caution with concomitant use of aspirin and NSAIDs

• Sexual dysfunction

Ø Most common side effect caused by all SSRIs, associated with long-term treatment

Ø Result of increased serotonergic transmission through 5-HT2c receptor that results in reduced

dopaminergic transmission and acetylcholine blockade

Ø Affects all phases of sexual cycle

Ø Reducing dose may help in some, Sildenafil has helped some, too

• GI effects

Ø Very common, resulting from activation of 5-HT2

receptors

Ø Nausea, vomiting, diarrhea, anorexia, flatulence, and dyspepsia

Ø Most severe symptoms are caused by

SERTRALINE & FLUVOXAMINE

Ø Up to one-third of patients may gain weight that happens gradually and is resistant to diet and exercise

Ø Most weight gain is caused by PAROXETINE

• Glucose disturbance

Ø Acute decrease in glucose, so caution to diabetics Ø Long-term use may increase glucose levels

• CV effects

Ø All SSRIs can lengthen QT interval and cause QT syndrome even in the healthy, when taken in overdose especially CITALOPRAM

§ Poses the greatest risk

§ Dose should not exceed 40 mg/day or 20 mg/day for those over 45, with liver failure, if combined with CYP2C19 inhibitors or if taking Cimetidine § Do not give to those with congenital long QT

syndrome

§ Monitor ECG and serum electrolytes and correct abnormal levels before prescribing

• Serotonin syndrome

Ø Serious and possibly fatal syndrome of serotonin overstimulation

Ø With concurrent use of SSRI and MAOI or lithium or L-tryptophan

(4)

Ø Symptoms appear in the following order, till it worsens:

§ Diarrhea § Restlessness

§ Extreme agitation, hyperreflexia & autonomic instability with fluctuation in vital signs § Myoclonus, seizures, hyperthermia,

uncontrollable shivering, and rigidity

§ Delirium, coma, status epilepticus, cardiovascular collapse, and death

• Withdrawal

Ø Abrupt discontinuation of an SSRI with a shorter half-life such as Paroxetine or Fluvoxamine may lead to dizziness, weakness, nausea, headache, rebound depression, anxiety, insomnia, poor concentration, upper respiratory symptoms, paresthesias, and migraine-like symptoms

Ø May occur only after at least 6 weeks of treatment, and disappears in 3 weeks spontaneously

• Endocrine and allergic reactions

Ø Increased prolactin levels caused by SSRIs can produce galactorrhea in both men and women Ø Rashes in some patients may generalize to involve

the pulmonary system, resulting in rare fibrotic damage and dyspnea

Ø Discontinue if with drug-related rashes

In children & adolescents – no SSRI is approved for clinical use in Canada

Drug MDD OCD

Fluoxetine Age 8-17 Age 7-17 Fluvoxamine No data >age 7 Sertraline Efficacy not

demonstrated in clinical trials

>age 6 Paroxetine Efficacy not

? Citalopram Efficacy not

? Escitalopram No data ?

• SSRIs have been associated with increased suicidal

ideation, hostility and psychomotor agitation in clinical trials involving children, adolescents and young adults, which was not seen in those aged 24- 65

• They may even be protective for those over 65 • Monitor all patients for worsening of depression and

suicidal thinking

In the Elderly

• Initiate lower dose and increase more slowly • Elderly may take longer to respond and may need

trials of at least 12 weeks before treatment response is noted.

• Higher doses of fluoxetine have been associated with delirium

• SSRIs generally have low risk of CNS, anticholinergic and cardiovascular effects

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITOR (SNRI)

Chemical

class Drug name Trade name Dosage forms & strengths

Bicyclic agent

Venlafaxine Effexor Tab 25, 37.5, 50, 75, 100 mg Effexor XR Extended release tab/cap 37.5, 75, 150, 225 mg Duloxetine Cymbalta Delayed-

release cap 20, 30, 60 mg Desvenlafaxine Pristiq Extended

release tab 50, 100 mg

• Potent reuptake inhibitors of serotonin and norepinephrine

• Venlafaxine inhibits norepinephrine reuptake at

doses above 150 mg

• Duloxetine has equal affinity to both serotonin and NE receptors

Indications of SNRIs

Venlafaxine Duloxetine Desvenlafaxine

MDD √ √ √ GAD √ √ - Social Phobia √ - - Panic Disorder √ - - • Other indications Ø Neuropathic pain Ø Pain from fibromyalgia Ø Chronic musculoskeletal pain Ø Pain due to osteoarthritis

Ø Bipolar disorder: depressed phase

Ø Treatment resistant depression, dysthymia, postpartum depression and melancholic depression Ø OCD

Dosing and Pharmacokinetics

Drug Thera peuti c dose (mg) Bioava ilability (%) Pro tein bin din g (%) Pea k pla sm a lev el (%) Elimi natio n half- life Metab olizin g enzym es Venlafa xine 75- 375 11 27 2 5-7 (pare nt) 8-13 (meta bolite) 1D6, 3A4, 2C9, 2C19 Desven

(5)

Duloxet

ine 120 60- 70 25 6 6-19 1A2, 2D6

• Desvenlafaxine is the major active metabolite of venlafaxine which is not metabolized by CYP2D6. • This may result in its reduced risk of interaction with

other drugs.

• Venlafaxine & desvenlafaxine are well absorbed from GIT and food has no effect on absorption

• Duloxetine may or may not be given with meals • Therapeutic effect typically seen after 28 days or

sooner in some

• Clinical trials among children have shown associated

increased suicidal ideation, and psychomotor agitation;; close monitoring needed if depression worsens and suicidal thoughts are noted.

Side Effects of SNRIs

• Generally dose-dependent

• Safety and tolerability of Venlafaxine is similar to the SSRIs

• Nausea is most common;; headache, too

• Other common ones include dry mouth, dizziness, somnolence, constipation and sweating

• Rise in BP noted with higher doses of venlafaxine;; duloxetine, too

• For those with diabetes or are high risks, increase in blood sugar and hemoglobin A1C levels are noted with long-term treatment

• Hepatic problems may ensue with duloxetine use, so avoid giving to those who abuse alcohol

• Fatal overdoses have been documented with venlafaxine in combination with alcohol, other drugs or both

• Avoid duloxetine in those with severe renal insufficiency and liver disease

• Do not use SNRI in those with uncontrolled hypertension

• Serotonin syndrome may occur

• May induce mania in those with bipolar disorder

Discontinuation syndrome manifesting as

Dizziness Dry mouth Sweating Incoordination Lethargy Diarrhea Chills Insomnia Nausea Headache Malaise Nervousness Vomiting Fever Anorexia Sensory

disturbances

• These medications should be withdrawn gradually over several weeks after prolonged use!!!

NORADRENERGIC/SPECIFIC SEROTONERGIC ANTIDEPRESSANT (NaSSA)

Chemical class

Drug name Trade name Dosage form & strengths Tetracyclic agent

Mirtazapine Remeron Tab 7.5, 15, 30, 45 mg Remeron Soltab Oral disintegrating tab 15, 30, 45 mg

Indications of NaSSA

• MDD (with or without comorbid anxiety)

• Panic disorder, GAD, social anxiety disorder • Sexual dysfunction, SSRI-induced

• Serotonin syndrome

Mechanism of Action of NaSSA

• Antagonism of central presynaptic α2-adrenergic

receptors – increased firing of norepinephrine and serotonin neurons

• Blockade of post synaptic serotonin 5 HT2 and 5 HT2

receptors – decrease anxiety, relieve insomnia, and stimulate appetite

• Potent antagonism of H1 receptors and moderate

antagonism of α1 adrenergic and muscarinic

cholinergic receptors

• Reduces sleep latency and prolongs sleep duration due to H1 and 5-HT2A/C blockade

• This may be helpful in treating depression with

prominent insomnia or agitation • Has mild anxiolytic effect at low doses

• Increases both norepinephrine and serotonin through a mechanism other than reuptake blockade (as in the case of SSRI and TCA), or monoamine oxidase inhibition (as in the case of phenelzine or moclobemide)

Pharmacologic Actions of NaSSA

• Orally administered

• Rapidly and completely absorbed • Half-life of about 20-40 hours

• Peak concentration in 2 hours of ingestion • Steady state after 6 days

• Plasma clearance impaired by liver disease and renal disease

• Plasma clearance slowed in the elderly • Food slightly decreases absorption rate • Protein binding about 85%

• Extensively metabolized by CYP1A2, 2D6, and 3A4

• Therapeutic effect seen after 28 days but effects on sleep and appetite are seen sooner

• Remeron SolTabs dissolve on tongue within 30 seconds and can be swallowed with or without water, chewed or allowed to dissolve

Side effects of NaSSA

Side effect Percentage affected

Somnolence 54 Dry mouth 25 Increased appetite 17 Constipation 13 Weight gain 12 Dizziness 7 Myalgias 5 Disturbing dreams 4

• Hypotension, hypertension, tachycardia and palpitations are rare

• No significant ECG changes

• Sexual dysfunction occurs occasionally • Risk increased with age, higher doses and

concomitant medications

• Monitor all patients for worsening depression and suicidal thoughts with treatment

• Low liability for toxicity in overdose if taken alone • May induce manic reactions in those with bipolar

(6)

• Early data suggests no teratogenic effects in humans

• Higher rate of spontaneous abortions and preterm births reported

• Secreted into breast milk in low concentrations

Discontinuation syndrome

• Withdraw gradually after prolonged use because of manifestations of dizziness, lethargy, nausea, vomiting, diarrhea, headache, fever, sweating, chills, incoordination, and others

NOREPINEPHRINE DOPAMINE REUPTAKE INHIBITOR (NDRI)

Chemical class

Drug name Trade name Dosage form & strength Monocyclic agent (aminoketone)

Bupropion Wellbutrin Tabs 75, 100 mg Wellbutrin SR Sustained release tab 100, 150, 200 mg Wellbutrin XL Extended release tab 150, 300, 450 mg

Indications of NDRI

• MDD

• Prophylaxis for recurrent MDD • Bipolar disorder, depressed phase

• Smoking cessation (Zyban, extended-release tablet) • Seasonal affective disorder

Mechanism of action of NDRI

• Inhibits reuptake of primarily norepinephrine and to a lesser extent, dopamine, into the presynaptic neurons

• Hydroxybupropion, the major metabolite, is 10- to 20-fold higher than bupropion and blocks only norepinephrine reuptake

• May have lower switch rate to mania or hypomania than other antidepressants

• May enhance energy and motivation early in treatment due to effects on norepinephrine and dopamine

• Reported to improve neurocognitive function in patients with depression

• Does not potentiate the sedative effects of alcohol

• Least likely of all antidepressants to impair sexual functioning

Pharmacologic action of NDRI

• Rapid absorption: peak concentration in 3 hours • Protein binding 80-85%

• Metabolism primarily by liver, through CYP2B6 • Both bupropion and hydroxybupropion inhibit

CYP2D6 isoenzyme

• Elimination half-life 11-14 hours;; longer with chronic dosing

• Decreased clearance reported in elderly

• Therapeutic effect usually after 28 days

• Caution with use in those with hepatic and renal impairment

• May lower seizure threshold

• Contraindicated in patients with history of anorexia or bulimia, undergoing alcohol or benzodiazepine withdrawal

Adverse effects of NDRI

• Primarily a result of effects on dopamine and norepinephrine

• Insomnia, headache, tremor, nausea, dry mouth are most common

• Vivid dreams and nightmares • Agitation, anxiety, irritability

• Can exacerbate psychotic symptoms • Reported to exacerbate symptoms of OCD • Seizures with abrupt dose increases or high daily

dose above 450 mg

• Most notable in the absence of significant drug- induced orthostatic hypotension, weight gain, daytime drowsiness and anticholinergic effects

SEROTONIN-2 ANTAGONIST/REUPTAKE INHIBITORS (SARI)

Chemical class Drug name Trade

name Dosage form & strength

Phenylpiperidine Nefazodone Serzone Tabs 50, 100, 150, 200, 250 mg Triazolopyridine Trazodone Desyrel Tabs 50,

68.25, 100, 150, 300 mg Oleptro Extended release tab 150, 300 mg

Indications of SARI

• MDD

• MDD, recurrent, prophylaxis • Bipolar disorder, depressed phase • Agoraphobia with panic disorder • Dysthymia

• Social phobia • PTSD

Mechanism of action of SARI

• Exact MOA is unknown

• Cause downregulation of β-adrenergic neurons

• Trazodone inhibits reuptake of serotonin and induces changes in 5-HT presynaptic receptor adrenoceptors

• Nefazodone inhibits neuronal reuptake of serotonin and norepinephrine

Adverse effects of SARI

• CNS: Result of antagonism at histamine H1 receptors

and α1 adrenoceptors

• Occur frequently

• Drowsiness: most common • Weakness, lethargy, fatigue

• Anticholinergic: Result of antagonism by muscarinic receptors

(7)

• CV: Result of antagosim at α1 adrenoreceptors,

muscarinic, 5-HT2AC and H1 receptors, and inhibition

of sodium fast channels • More common in elderly

• Dizziness, orthostatic hypotension, and syncope

• Bradycardia: Nefazodone

• Exacerbate transient ischemic attacks • GI: Result of inhibition of 5-HT uptake and M1

receptor antagonism • Peculiar taste, glossitis

• Beware of discontinuation syndrome

• Use caution in combination with drugs prolonging QT interval

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SHORT QUIZ RECALLS (NON-VERBATIM)

CASE A:

Ate gurl suffers from insomnia and MDD, unable to take care of her child and was fired from her job because she’s no longer productive.

DOC, justification and what would you advise the patient/cautionary use:

a. Paroxetine (SSRI)

Justification: AE includes somnolence, so it would normalize the sleep-‐wake cycle of the patient

Caution: Take note of her diet because it causes weight gain and she may feel anti-‐cholinergic AEs (dry mouth, constipation, etc.)

b. Citalopram (SSRI)

Justification: SAME

Caution: may cause CV problems (QT prolongation)

c. Mirtazapine (NaSSA)

• Justification: reduces sleep latency and prolongs sleep duration due to H1 and 5-‐HT2A/C blockade, SAME

Caution: may cause dry mouth, increased appetite, etc.

CASE B:

Manong suffers from MDD and has a history of hypertension and angina attacks.

DOC:

ANY DRUG EXCEPT CITALOPRAM because it causes CV problems (QT

prolongation).

Don’t know the details of the other cases.

CASE C:

Surgeon yada yada with insomnia.

DOC, justification:

PLEASE FOLLOW CASE A ANSWERS.

CASE D:

Preggers near term yada yada.

According to Doc Familiar, ANY DRUG WILL DO.

Answer if patient is not yet term:

ANY DRUG EXCEPT MIRTAZAPINE (NaSSA) because it causes

spontaneous abortion and preterm delivery.