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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 2 OUTLINE Part I SSRIs TCAs SNRIs NaSSAs MAOIs NDRIs 3 SSRI Prototype: Fluoxetine Paroxetine, Fluvoxamine, Sertraline, Citalopram, Escitalopram 4 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 5 6 SSRI: MOA Downstream effects Change in receptor density Downregulation of inhibitory presynaptic autoreceptors enhanced release of 5HT into synapse Reorganization of neurons 7 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 8 SSRI: NOTES Heterogenous group even though “SSRI” not interchangeable 9 SSRI: NOTES Citalopram – most serotonin selective, has H1 Fluoxetine and Sertraline – have affinity for D2 receptors Paroxetine – has the most anticholinergic 10 TCA Prototype: amitriptyline Desipramine, imipramine, nortriptyline, clomipramine, imipramine, doxepin, maprotiline Nortriptyline is a metabolite of amitriptyline Desipramine is a metabolite of imipramine 11 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 12 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 13 Most 5HT Clomipiramine Amitriptyline Most NA Nortriptyline Desipramine Least H2 Least α1 14 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 15 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 16 SNRI Prototype: Venlafaxine Desvenlafaxine, duloxetine, milnacipran 17 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 18 SNRI Taper gradually to avoid discontinuation syndrome (more later) 19 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 20 MAOI MAO-A Degrades epi, norepi, serotonin, dopamine Selective MAO-A inhibitor: Moclobemide 21 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 22 MAOI Nonselective: Phenelzine 23 MAOI Drug interaction with sympathomimetics hypertensive crisis 24 MAOI Foods with tyramine hypertensive crisis Particularly with MAO-A inhibitors MAO-A in the gut breaks down tyramine which stimulates norepi release 25 MAOI-A IN THE GUT Norepinephrine release Tyramine MAO- A MAO- A inhibitor Can be by-passed by use of a patch 26 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 27 NDRI Prototype: Bupropion DA and NA ?Nicotinic receptor antagonist 28 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 29 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 30 31 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 32 EFFICACY 33 EFFICACY 34 EFFICACY VEMS: Venlefaxine, Escitalopram, Mirtazapine, Sertraline Do not choose Reboxetine 35 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 37 SIDE EFFECT PROFILE Venlefaxine Good: tremor, diarrhea, fatigue Bad: nausea, insomnia, sedation, headache, dry mouth, sweating, constipation, anxiety Escitalopram Least side effects reported 38 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 39 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 40 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 41 SIDE EFFECT PROFILE Focus on weight gain Most are weight neutral Most weight gain with Mirtazapine and Paroxetine during long term treatment 42 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 43 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 44 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 45 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 46 COMORBID ANXIETY *Citalopram, escitalopram are effective but not Health Canada indicated in 2006 when guidelines were written. 47 COMORBID ANXIETY Bupropion has not been adequately studied so not recommended for primary anxiety disorders but has been effective in depression with anxiety 48 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 49 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 50 TREATMENT RESISTANT DEPRESSION 30% discontinue in 30 days 40% in 90 days Must increase adherence Education, self-management, collaborative care Therapeutic alliance 51 TREATMENT RESISTANT DEPRESSION First line Switch to an agent with evidence for superiority VEMS, duloxetine, milnacipran Add-on Aripiprazole, Lithium, Olanzapine, Risperidone 52 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 53 TREATMENT RESISTANT DEPRESSION Third Line Add-on Buspirone, modafinil, stimulants, ziprasidone 54 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 55 TREATMENT RESISTANT DEPRESSION 56 TREATMENT RESISTANT DEPRESSION 57 TREATMENT RESISTANT DEPRESSION Number needed to treat is about 1:9 to 1:7, therefore, reasonable 58 TREATMENT RESISTANT DEPRESSION 59 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. 60 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 61 RISK FACTORS SUPPORTING LONG TERM Older age Recurrent episodes (3 or more) Chronic episodes Psychotic episodes Severe episodes Difficult to treat episodes 62 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 63 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 64 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 66 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 67 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. 69 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