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Psychiatry 3 Dr. familar Antidepressants 1.2 LEGENDS: IMPORTANT
Psychiatry 3
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

Trazodone, Nefazodone

Agonist/Serotonin Reuptake Inhibitor (SARI)

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 at reducing the symptoms of depression

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

Dosage

name

forms &

strength

s

Phthalene

Citalopram

Celexa

Tab/cap

derivative

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

Symbya

Caps

zapine

x

25/3, 6,

(Combination for

12

mg

MDD with

Caps

psychotic

50/6, 12

features)

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

methylamine

25, 50,

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100, 150,

Mechanism of Action of SSRIs

200 mg

Exact MOA is unknown

Oral

Inhibition of serotonin reuptake

solution

Increased concentration of serotonin in the synapse

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

Fluo

Fluvo

Paro

Sertr

Cital

Escital

der

xetin

xamin

xetin

aline

opra

opram

e

e

e

m

MDD

A/P

-

A

A

A

A

GAD

-

-

A

-

-

A

OCD

A/P

A/P

A

A/P

-

A

Panic

A

- A

 

A

-

-

disord

er

PTSD

-

- A

 

A

-

-

Social

A

- A

 

A

-

-

anxiet

y

disord

er

Bulimi

A

- -

 

A

-

-

a

nervo

sa

Prem

A

- A

 

A

-

-

entru

al

Dysp

horic

Dso.

Pediatric indications for:

MDD - Fluoxetine OCD – Fluoxetine, Fluvoxamine, Sertraline

Downregulation of postsynaptic receptors

Some SSRIs can also affect other neurotransmitters

SSRI

Other actions

Citalopram &

Most selective serotonin reuptake inhibitor

Escitalopram

Fluoxetine

Weakly inhibits norepinephrine reuptake and binds to 5-HT 2 c 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

Interaction

Thro

c

with

ugh

Fluvoxamine

Most

Theophylline

CYP

notorious

1A2

marked effect

Clozapine

CYP

on several

1A2

CYP enzymes

Alprazolam/Clo

CYP

nazepam

3A4

Fluoxetine &

Significant

Opiates such as codeine & hydrocodone by blocking conversion into their active forms

CYP

Paroxetine

effects

2D6

Sertraline/

Least likely

   

Citalopram/

for

Escitalopram

interaction

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Drug

Bioavaila

Prot

Pea

Elimina

Therap

bility (%)

ein

k

tion

eutic

bindi

plas

half-life

dose

ng

ma

(%)

range

(%)

level

(mg)

(%)

Citalopr

80

80

4

23-45

10-40

am

Escitalo

80

54

4-5

27-32

10-20

pram

Fluoxeti

72-85

94

4-8

24-144

10-80

ne

(parent)

200-

330

(metab

olite)

Fluvoxa

60

77-

2.5-4

9-28

50-300

mine

80

Paroxeti

>90

95

5.2

3-65

10-60

ne

Sertralin

70

96

6

22-36

50-200

e

(parent)

62-104

(metab

olite)

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-HT 2 c 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-HT 2 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

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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

>age 6

demonstrated in

clinical trials

Paroxetine

Efficacy not

?

demonstrated in

clinical trials

Citalopram

Efficacy not

?

demonstrated in

clinical trials

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

Drug name

Trade

Dosage

class

name

forms &

strengths

Bicyclic

Venlafaxine

Effexor

Tab 25, 37.5, 50, 75, 100 mg

agent

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

Bioava

Pro

Pea

Elimi

Metab

peuti

ilability

tein

k

natio

olizin

c

(%)

bin

pla

n

g

dose

din

sm

half-

enzym

(mg)

g

a

life

es

(%)

lev

el

(%)

Venlafa

75-

11

27

2

5-7

1D6,

xine

375

(pare

3A4,

nt)

2C9,

8-13

2C19

(meta

bolite)

Desven

50-

80

30

7.5

11

UGT

lafaxine

100

1A4

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Duloxet

60-

70

25

6

6-19

1A2,

Panic disorder, GAD, social anxiety disorder

ine

120

2D6

Sexual dysfunction, SSRI-induced

 

Serotonin syndrome

 

Desvenlafaxine is the major active metabolite of venlafaxine which is not metabolized by CYP2D6.

Mechanism of Action of NaSSA

This may result in its reduced risk of interaction with other drugs.

Antagonism of central presynaptic α 2 -adrenergic receptors – increased firing of norepinephrine and serotonin neurons

Blockade of post synaptic serotonin 5 HT 2 and 5 HT 2 receptors – decrease anxiety, relieve insomnia, and stimulate appetite

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.

Potent antagonism of H 1 receptors and moderate antagonism of α 1 adrenergic and muscarinic cholinergic receptors

Reduces sleep latency and prolongs sleep duration due to H 1 and 5-HT 2 A/C blockade

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

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

Dizziness

Dry mouth

Sweating

Incoordination

Lethargy

Diarrhea

Chills

Insomnia

Side effects of NaSSA

Nausea

Headache

Malaise

Nervousness

Side effect

Percentage affected

Vomiting

Fever

Anorexia

Sensory

Somnolence

54

disturbances

Dry mouth

25

 

Increased appetite

17

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

Constipation

13

Weight gain

12

 

Dizziness

7

NORADRENERGIC/SPECIFIC SEROTONERGIC ANTIDEPRESSANT (NaSSA)

Myalgias

5

Disturbing dreams

4

Chemical

Drug name

Trade

Dosage

class

name

form &

strengths

Hypotension, hypertension, tachycardia and palpitations are rare

No significant ECG changes

Sexual dysfunction occurs occasionally

Tetracyclic

Mirtazapine

Remeron

Tab 7.5, 15, 30, 45 mg

agent

Remeron

Soltab

Oral disintegrating tab 15, 30, 45 mg

 
 

Risk increased with age, higher doses and concomitant medications

Monitor all patients for worsening depression and suicidal thoughts with treatment

 

Indications of NaSSA

MDD (with or without comorbid anxiety)

Low liability for toxicity in overdose if taken alone

May induce manic reactions in those with bipolar disorder

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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

Drug name

Trade

Dosage

class

name

form &

strength

Monocyclic

Bupropion

Wellbutrin

Tabs 75,

agent

100

mg

(aminoketone)

Wellbutrin

Sustained

SR

release tab

100, 150,

200

mg

Wellbutrin

Extended

XL

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

Dosage

name

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 H 1 receptors and α 1 adrenoceptors

Occur frequently

Drowsiness: most common

Weakness, lethargy, fatigue

Anticholinergic: Result of antagonism by muscarinic receptors

Dry eyes, blurred vision, constipation, and dry mouth

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CV: Result of antagosim at α 1 adrenoreceptors, muscarinic, 5-HT 2 AC and H 1 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 M 1 receptor antagonism

Peculiar taste, glossitis

Beware of discontinuation syndrome

Use caution in combination with drugs prolonging QT interval

------------------------------------------------------------------------------------

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 pro ductive.

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 H 1 and 5 - HT 2 A/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 .

A nswer if patient is not yet term:

ANY DRUG EXCEPT MIRTAZAPINE (NaSSA) because it causes spontaneous abortion and preterm delivery.

DRUG EXCEPT MIRTAZAPINE (NaSSA) because it causes spontaneous abortion and preterm delivery. Transcribed by: orquia, pat