1. part ii efficacy cipriani (lancet, 2009) side effect profile drug to drug interactions ...

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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