1. part ii efficacy cipriani (lancet, 2009) side effect profile drug to drug interactions ...
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ANTIDEPRESSANTS
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OUTLINE
Part II Efficacy
Cipriani (Lancet, 2009)
Side effect profile
Drug to drug interactions
Comorbid anxiety
Treatment resistant depression STAR-D (NEJM,
2009) Special
populations Pregnant women Children
QTc2
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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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, desipramine13
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Most 5HT Most NA
Least H2
Least α1
ClomipiramineAmitriptylineNortriptyline Desipramine
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, O-
desmethylvenlafaxine. Both parent and metabolite have lower clearance in liver and renal impairment
Venlafaxine: CYP450, esp CYP2D6 CYP2D6 is subject to polymorphisms
metabolism variable 18
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, D-amphetamine
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
Tyramine
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Norepinephrine release
MAO- A
MAO- A inhibitor
Can be by-passed by use of a patch
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 disturbances27
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 36
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 agents41
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 Beta-blockers Amiodarone Antiarrhythmics Diltiazem,
verapamil Sildenafil
HIV PI’s Tamoxifen Immune modulators Macrolides
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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: back to normal levels
Of 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
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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.
TRD: ADJUVANT SUMMARY
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Level 2 evidence to support efficacy of antidepressant combinations in non-responders to monotherapy
The best available evidence is for add-on treatment with mirtazapine/mianserin or bupropion
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 effect could not be ruled out
May be associated with neonatal complications
PPH Serotonergic overstimulation, withdrawal,
neurobehavioural effects (?long-term)
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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 has a higher risk estimate for
suicidality Best if AD is combined with CBT
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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
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QTC
Citalopram hERG blockade by metabolite didesmethyl-
citalopram (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
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QTC
Fluoxetine Also inhibits hERG But inhibits calcium channels = ?
Protective
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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
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