Transcript Antidepressants

ANTIDEPRESSANTS
1
OUTLINE
Part II
 Efficacy

 Cipriani

 STAR-D
(Lancet, 2009)
Side effect profile
 Drug to drug
interactions
 Comorbid anxiety

Treatment resistant
depression

(NEJM, 2009)
Special populations
 Pregnant
women
 Children

QTc
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OUTLINE

Part I
 SSRIs
 TCAs
 SNRIs
 NaSSAs
 MAOIs
 NDRIs
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SSRI
Prototype: Fluoxetine
 Paroxetine, Fluvoxamine, Sertraline,
Citalopram, Escitalopram

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SSRI: MOA

Deficiency of synaptic neurotransmitters
 5HT,

NE, DA
5HT
 Presynaptic
vesicles  synaptic cleft 
postsynaptic receptors  reuptake transporters
presynaptically
 Clinical efficacy is delayed a few weeks when
compared to other pharmacological action
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6
SSRI: MOA

Downstream effects
 Change
in receptor density
 Downregulation
of inhibitory presynaptic autoreceptors
 enhanced release of 5HT into synapse
 Reorganization
of neurons
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SSRI: PK, INDICATIONS, CONTRA

Usually long half-lives
 Fluoxetine
longest (because of norfluoxetine
metabolite)
Indications: MDD, OCD, GAD, Panic Disorder,
Bulimia
 Contraindications

 SSRI
+ MAOIs – need a washout 2 weeks when
switching
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SSRI: NOTES

Heterogenous group even though “SSRI”  not
interchangeable
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SSRI: NOTES
Citalopram – most serotonin selective, has H1
 Fluoxetine and Sertraline – have affinity for D2
receptors
 Paroxetine – has the most anticholinergic

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TCA
Prototype: amitriptyline
 Desipramine, imipramine, nortriptyline,
clomipramine, imipramine, doxepin, maprotiline

 Nortriptyline
is a metabolite of amitriptyline
 Desipramine is a metabolite of imipramine
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TCA: MOA
TCAs inhibit the reuptake of 5HT and NA into
the presynaptic cell body
 Antagonize many receptors: muscarinic,
histamine, adrenergic  lots of side effects

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TCA: MOA
Most serotonergic: clomipramine then
amitriptyline
 Most noradrenergic: desipramine then
nortriptyline
 Hits the most receptors and strongest:
amitriptyline
 Hits weakest: desipramine (least histaminic)
 Least α1: nortriptyline, desipramine

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Most 5HT
Clomipiramine Amitriptyline
Most NA
Nortriptyline
Desipramine
Least H2
Least α1
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TCA: NOTES
Group side effects by receptor profile
 Anticholinergic: hot as a hare, dry as a bone,
mad as a hatter, blind as a bat
 Orthostatic hypotension because of α1
 Antimuscarinic: avoid with urinary retention,
BPH, closed angle glaucoma, increased IOP

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TCA: NOTES

Cardiotoxic in overdose  wide QRS  heart
block often accompanied by hypotension
 Slowly
absorbed so may present in ER with fatal
dose that has yet to be absorbed
 Caution with suicidal patients

Cochrane 2007: As efficacious as SSRIs but
more side effects
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SNRI
Prototype: Venlafaxine
 Desvenlafaxine, duloxetine, milnacipran

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SNRI
MOA: same story
 PK: SNRIs shorter half-life compared to SSRI

 Venlafaxine
has extended release form
 Venlafaxine has an active metabolite, Odesmethylvenlafaxine. Both parent and metabolite
have lower clearance in liver and renal impairment
 Venlafaxine: CYP450, esp CYP2D6
 CYP2D6
is subject to polymorphisms  metabolism
variable
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SNRI

Taper gradually to avoid discontinuation
syndrome (more later)
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NASSA
Mirtazapine
 MOA:

 Autoreceptor
and heteroreceptor blockade
presynaptically
 5HT2 and 5HT3 antagonism postsynaptically
 Leads
to enhanced 5HT1
 5HT3 blockade explains less nausea and GI effects
 Low
affinity for muscarinic and dopaminergic
receptors
 High affinity for histaminic receptors
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MAOI

MAO-A
 Degrades
epi, norepi, serotonin, dopamine
 Selective MAO-A inhibitor: Moclobemide
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MAOI

MAO-B
 Degrades
phenylethylamine, dopamine
 Selective MAO-B inhibitor: Selegiline
 Metabolites
of selegiline: L-amphetamine, Damphetamine
 Parkinson’s

disease
MAO-B is non-selective at high doses
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MAOI

Nonselective: Phenelzine
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MAOI

Drug interaction with sympathomimetics 
hypertensive crisis
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MAOI

Foods with tyramine  hypertensive crisis
 Particularly
with MAO-A inhibitors
 MAO-A in the gut breaks down tyramine which
stimulates norepi release
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MAOI-A IN THE GUT
Norepinephrine
release
Tyramine
MAO- A
MAO- A inhibitor
Can be by-passed by use of a patch
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MAOI
Drug interaction with sympathomimetics 
hypertensive crisis
 Foods with tyramine  hypertensive crisis

 Particularly
with MAO-A inhibitors
 MAO-A in the gut breaks down tyramine which
stimulates norepi release

Disturbed REM, weight gain, postural
hypotension, sexual disturbances
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NDRI
Prototype: Bupropion
 DA and NA
 ?Nicotinic receptor antagonist

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NDRI
Contraindications: seizure, MAOI’s, thioridazine
 DA: smoking cessation
 No 5HT: less sexual dysfunction
 Wellbutrin vs Zyban
 OR 1.9 vs placebo for smoking cessation
 About Varenicline

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PRINCIPLES OF PHARMACOTHERAPY

Thorough assessment
 Suicidality, bipolarity, comorbidity, meds, features
(psychosis, atypicality, seasonality)
 Laboratory assessment as indicated
 Increase adherence
 1-2 weeks initially, then every 2-4 weeks
 Monitoring should include the use of validated scales
 Choose according to sx profile, comorbidity, tolerability,
previous response, drug-drug interaction, cost, patient
preference
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EFFICACY
SSRIs, SNRIs are safer and more tolerable than
TCAs and MAOIs
 TCAs are second line
 MAOIs are third line
 NB:




Trazodone second-line – very sedating
Selegeline (MAO-Bi)- more tolerable but there are dietary restrictions
Quetiapine XR – good Level 1 evidence, but second line because of
tolerability and less data compared to SSRI’s
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EFFICACY
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EFFICACY
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EFFICACY
VEMS:
Venlefaxine,
Escitalopram,
Mirtazapine,
Sertraline
 Do not choose
Reboxetine

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SIDE EFFECTS: SERIOUS ADVERSE EVENTS
Serotonin syndrome when SSRIs/SNRIs are
coadministered with MAOi
 Increased risk of UGIB especially with NSAIDS
 Osteoporosis and fractures in the elderly
 Hyponatremia and agranulocytosis
 Seizures

 SSRIs

~0.4% compared to TCAs ~1.2%
Venlefaxine cardiotoxic in overdose
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SIDE EFFECT PROFILE
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SIDE EFFECT PROFILE

Venlefaxine
 Good:
tremor, diarrhea, fatigue
 Bad: nausea, insomnia, sedation, headache, dry
mouth, sweating, constipation, anxiety

Escitalopram
 Least
side effects reported
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SIDE EFFECT PROFILE

Mirtazapine
 Bad:

>50% sedation, dry mouth, constipation
Sertraline
 Bad:
headache, nausea, insomnia, sedation,
tremor, dry mouth, diarrhea, fatigue, anxiety
 Good: sweating, constipation
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SIDE EFFECT PROFILE

Focus on insomnia/CNS
 Sleep
promoting: agomelatine, mirtazapine,
trazodone
 Short-term BDZ or non-BDZ hypnotics in carefully
selected patients
 May
also reduce nervousness and activation associated
with initiation of SSRI/SNRI antidepressants
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SIDE EFFECT PROFILE

Focus on nausea/GI
 Higher
with SSRIs/SNRIs that do not primarily inhibi
the serotonin reuptake transporter
 Bupropion,
Mirtazapine, Moclobemide, Agomelatine
 ER
is better than IR formulations
 Most severe in first 2 weeks, then tolerance
 Coadminister with ood, HS dosing, use of gastric
motility agents
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SIDE EFFECT PROFILE

Focus on weight gain
 Most
are weight neutral
 Most weight gain with Mirtazapine and Paroxetine
during long term treatment
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SIDE EFFECT PROFILE
Focus on sexual dysfunction
 >30%

 Fluoxetine,

fluvoxamine, paroxetine, sertraline
10-30%
 Citalopram,
duloxetine, escitalopram, milnacipran,
venlefaxine

<10%
 Agomelatine,
bupropion, mirtazapine,
moclobemide, reboxetine, selegeline
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SIDE EFFECT PROFILE

Discontinuation syndrome
 “FINISH”:
Flu-like symptoms, Insomnia, Nausea,
Imbalance, Sensory disturbances, and
Hyperarousal (anxiety/agitation)
 Paroxetine, Venlafaxine

HR, SBP
 Noradrenergic

blockade
LFT rise often not clinically relevant
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DRUG TO DRUG INTERACTIONS

Highlights only. Table 7 of CanMAT on
pharmacotherapy.
 Rifampin
may reduce AD efficacy (2C9, 2C19, 2D6)
 Cipro and other fluoroquinolones may increase
duloxetine (1A2 inhibition)
 Fluoxetine and paroxetine inhibit 2D6: codeine less
effective. Paroxetine increases propranolol.
 Fluvoxamine increases warfarin and statins
(bleeding and rhabdo, respectively). 1A2. 2C19,
3A4
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DRUG TO DRUG INTERACTIONS
 Check
if patient are on
the following:
 Antiepileptics
 Methadone
 Olanzapine
 Quetiapine
 Sildenafil
 HIV
PI’s
 Tamoxifen
 Immune modulators
 Macrolides
 Beta-blockers
 Amiodarone
 Antiarrhythmics
 Diltiazem,
verapamil
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COMORBID ANXIETY

*Citalopram, escitalopram are effective but not Health Canada indicated in
2006 when guidelines were written.
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COMORBID ANXIETY

Bupropion has not
been adequately
studied so not
recommended for
primary anxiety
disorders but has
been effective in
depression with
anxiety
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TREATMENT RESISTANT DEPRESSION
Clinical lore: 2-4 weeks for tx effect
 Studies: onset of response in 1-2 weeks
 Patients with <20% improvement after 2 weeks
should have a change in tx such as a dose
increase
 OSAC: optimise, switch, augment, combine

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TREATMENT RESISTANT DEPRESSION
Ensure adherence
 Re-evaluate diagnosis (bipolar II, psychotic
depression)
 Re-assess comorbidity (anxiety, substance,
personality, medical conditions, chronic social
stressors)
 Partial or no response – importance of scales

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TREATMENT RESISTANT DEPRESSION
30% discontinue in 30 days
 40% in 90 days
 Must increase adherence

 Education,
self-management, collaborative care
 Therapeutic alliance
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TREATMENT RESISTANT DEPRESSION

First line
 Switch
to an agent with evidence for superiority
 VEMS,
duloxetine, milnacipran
 Add-on
 Aripiprazole,
Lithium, Olanzapine, Risperidone
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TREATMENT RESISTANT DEPRESSION

Second line
 Add-on
 Bupropion,
Mirtazapine, quetiapine, T3, another
antidepressant
 Switch
for agents with superiority but side-effect
limitation
 Amitriptyline,
clomipramine, MAOi
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TREATMENT RESISTANT DEPRESSION

Third Line
 Add-on
 Buspirone,
modafinil, stimulants, ziprasidone
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TREATMENT RESISTANT DEPRESSION

STAR*D
 Open
label citalopram for 12 weeks, then switch
and combination arms
 Response: 50% improvement
 Of
those who responded, 56% in 8 weeks
 Remission:
 Of
back to normal levels
those with remission, 40% in 8 weeks
 Thus
if improvement is minimal (>20%) after 4-6
weeks, continue for another 2-4 weeks before
considering other strategies
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TREATMENT RESISTANT DEPRESSION
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TREATMENT RESISTANT DEPRESSION
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TREATMENT RESISTANT DEPRESSION

Number
needed to treat
is about 1:9 to
1:7, therefore,
reasonable
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TREATMENT RESISTANT DEPRESSION
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TRD ADD-ON SUMMARY
Level 1 evidence to support add-on treatment
with lithium and atypical antipsychotics for TRD
 Level 2 support for T3
 Level 3 evidence but also negative studies with
buspirone, methylphenidate, modafinil and
pindolol, so these agents are not
recommended as first or second-line
treatments.

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TRD: ADJUVANT SUMMARY
Level 2 evidence to support efficacy of
antidepressant combinations in nonresponders to monotherapy
 The best available evidence is for add-on
treatment with mirtazapine/mianserin or
bupropion

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RISK FACTORS SUPPORTING LONG TERM
Older age
 Recurrent episodes (3 or more)
 Chronic episodes
 Psychotic episodes
 Severe episodes
 Difficult to treat episodes

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RISK FACTORS SUPPORTING LONG TERM
Significant comorbidity (psychiatric or medical)
 Residual symptoms (lack of remission) during
current episode
 History of recurrence during discontinuation of
antidepressants

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SPECIAL POPULATIONS
Pregnant women
 See CanMAT

 ADs
do not appear to be major teratogens
 1st
trimester use of paroxetine increased risk of cardiac
malformations
 1st trimester use of fluoxetine not associated with
teratogenicity
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SPECIAL POPULATIONS
Pregnant women
 See CanMAT

 ?Increased
risk of spontaneous abortions
 Depression
 May
effect could not be ruled out
be associated with neonatal complications
 PPH
 Serotonergic
overstimulation, withdrawal,
neurobehavioural effects (?long-term)
65
SPECIAL POPULATIONS

Mom in the postpartum
 Paroxetine
better than placebo for remission
 Sertraline had a preventatitve effect in women with
prior hx of postpartum depression
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SPECIAL POPULATIONS

Lactation
 ADs
are in breast milk in usually small amounts
 Nortripltyline, sertraline, paroxetine not detected in
infant serum levels
 Fluoxetine higher risk of elevated serum levels
 Citalopram – very little; equivocal studies
 No effect on infant weight up to 18 mos
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SPECIAL POPULATIONS

Children
 TCAs
not effective in children
 Citalopram and fluoxetine are favourable but effect
sizes are modest (NNT: 10)
 Increased suicidal ideation/behaviours but NNH is
143
 Venlafaxine
 Best
has a higher risk estimate for suicidality
if AD is combined with CBT
68
SPECIAL POPULATIONS

Children and suicidality
 In
summary, there is Level 1 evidence to support
modest efficacy of SSRI and SNRI antidepressants
in this age group, with most evidence for fluoxetine
and citalopram, and only a very small risk of
increased suicidality
 Regardless, close monitoring is required when
using antidepressants in youth and young adults.
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QTC
70
QTC

Citalopram
 hERG
blockade by metabolite didesmethylcitalopram (DDCT)
 Seen
in beagles, thought to be minor in humans
 However,
2% of the US are cytochrome P450 2D6
ultrarapid and could have more DDCT
71
QTC

Fluoxetine
 Also
inhibits hERG
 But inhibits calcium channels = ? Protective
72
QTC

Though case reports have linked other SSRIs
with QTc prolongation, no prospective studies
have shown such agents to have a statistically
significant effect on the QTc
 Overdose
reports
 Few therapeutic dose studies

8 fluoxetine studies, 5 paroxetine studies = no
QTc prolongation
73