1. antidepressants

2. outline Part II Treatment resistant depression Efficacy
STAR-D (NEJM, 2009)
Cipriani (Lancet, 2009)
Special populations
Side effect profile
Pregnant women
Drug to drug interactions
Children
QTc
Comorbid anxiety

3. outline
Part I
SSRIs
TCAs
SNRIs
NaSSAs
MAOIs
NDRIs

4. SSRI Prototype: Fluoxetine
Paroxetine, Fluvoxamine, Sertraline, Citalopram, Escitalopram

5. SSRI: MOA Deficiency of synaptic neurotransmitters 5HT 5HT, NE, DA
Presynaptic vesicles  synaptic cleft  postsynaptic receptors  reuptake transporters presynaptically
Clinical efficacy is delayed a few weeks when compared to other pharmacological action

7. SSRI: MOA Downstream effects Change in receptor density
Downregulation of inhibitory presynaptic autoreceptors  enhanced release of 5HT into synapse
Reorganization of neurons

8. 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
SSRIs increase serotonin
MAOIs inhibit breakdown of serotonin
QTc prolongation with thioridazine. Fluoxetine inhibits the metabolism of thioridazine. Thioridazine has been withdrawn in many markets
SSRI + Thioridzaine – washout of 5 weeks
SSRI + pimozine

9. SSRI: Notes
Heterogenous group even though “SSRI”  not interchangeable

10. SSRI: Notes Citalopram – most serotonin selective, has H1
Fluoxetine and Sertraline – have affinity for D2 receptors
Paroxetine – has the most anticholinergic

11. TCA Prototype: amitriptyline
Desipramine, imipramine, nortriptyline, clomipramine, imipramine, doxepin, maprotiline
Nortriptyline is a metabolite of amitriptyline
Desipramine is a metabolite of imipramine

12. 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

13. 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

14. Clomipiramine Amitriptyline Nortriptyline Desipramine
Most 5HT
Most NA
Clomipiramine Amitriptyline Nortriptyline Desipramine
Least H2
Least α1

15. 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

16. 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

17. SNRI
Prototype: Venlafaxine
Desvenlafaxine, duloxetine, milnacipran

18. 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

19. SNRI
Taper gradually to avoid discontinuation syndrome (more later)

20. 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
There is no reuptake inhibition

21. maoi MAO-A Degrades epi, norepi, serotonin, dopamine
Selective MAO-A inhibitor: Moclobemide

22. maoi MAO-B MAO-B is non-selective at high doses
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

23. maoi
Nonselective: Phenelzine

24. maoi
Drug interaction with sympathomimetics  hypertensive crisis

25. maoi Foods with tyramine  hypertensive crisis
Particularly with MAO-A inhibitors
MAO-A in the gut breaks down tyramine which stimulates norepi release

26. Maoi-A in the gut Can be by-passed by use of a patch
Norepinephrine release
Tyramine
MAO- A
MAO- A inhibitor
Can be by-passed by use of a patch

27. 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

28. ndri
Prototype: Bupropion
DA and NA
?Nicotinic receptor antagonist

29. 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

30. 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

32. 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

33. Efficacy We defi ned acute treatment as 8-week treatment for
both effi cacy and acceptability analyses.14 If 8-week data
were not available, we used data ranging between 6 and
12 weeks (we gave preference to the timepoint given in
the original study as the study endpoint). Response and
dropout rates were chosen as primary outcomes, being
the most consistently reported estimates of
acute-treatment effi cacy and acceptability. We defi ned
response as the proportion of patients who had a
reduction of at least 50% from the baseline score on the
Hamilton depression rating scale (HDRS) or
Montgomery–Åsberg depression rating scale (MADRS),
or who scored much improved or very much improved
on the clinical global impression (CGI) at 8 weeks.
When trials reported results from all three rating scales,
we used the HDRS results. Finally, we defi ned treatment
discontinuation (acceptability) as the number of patients
who terminated the study early for any reason during
the fi rst 8 weeks of treatment (dropouts).

34. Efficacy

35. efficacy VEMS: Venlefaxine, Escitalopram, Mirtazapine, Sertraline
Do not choose Reboxetine

36. 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
Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with upper gastrointestinal haemorrhage (UGIH) but the magnitude and characteristics of this reaction and possible interaction with concurrent Non-Steroidal Anti-Inflammatory Drug (NSAID) therapy are unknown. Aim: To evaluate systematically the risk of UGIH with SSRIs, including interaction with NSAIDs. Methods: We searched PubMED, Science Citation Index, and trial registries for data on SSRIs, NSAIDs and UGIH. We evaluated spontaneous case reports from pharmacovigilance databases. Results: Random effects meta-analysis of four observational studies involving patients showed an odds ratio of 2.36 (95% CI: ; P = ) for SSRI associated UGIH. The odds ratio increased to 6.33 (95% CI: ; P < ) with concomitant NSAIDs. In patients aged above 50 years with no UGIH risk factors, the Number-Needed-to-Harm per year is 411 for SSRIs alone, and 106 with concomitant NSAIDs. Analysis of 101 spontaneous reports showed that UGIH occurred after a median of 25 weeks with SSRIs. Around 67% of these patients were on NSAIDs. Conclusions: Selective serotonin reuptake inhibitor use, alone and in combination with NSAIDs, substantially increases the risk of UGIH. Clinicians should consider this when managing patients at risk of, or presenting with UGIH
The random effects RR of fractures was 1.34 (95% CI 1.24, 1.45) for benzodiazepines (23 studies), 1.60 (95% CI 1.38, 1.86) for antidepressants (16 studies), 1.54 (95% CI 1.24, 1.93) for non-barbiturate antiepileptic drugs (13 studies), 2.17 (95% CI 1.35, 3.50) for barbiturate antiepileptic drugs (five studies), 1.59 (1.27, 1.98) for antipsychotics (12 studies), 1.15 (95% CI 0.94, 1.39) for hypnotics (13 studies) and 1.38 (95% CI 1.15, 1.66) for opioids (six studies). For non-specified psychotropic drugs (10 studies), the pooled RR was 1.48 (95% CI 1.41, 1.59).

37. Side effect profile
Slide from Dr. Raymond Lam’s lecture

38. Side effect profile Venlefaxine Escitalopram
Good: tremor, diarrhea, fatigue
Bad: nausea, insomnia, sedation, headache, dry mouth, sweating, constipation, anxiety
Escitalopram
Least side effects reported

39. Side effect profile Mirtazapine Sertraline
Bad: >50% sedation, dry mouth, constipation
Sertraline
Bad: headache, nausea, insomnia, sedation, tremor, dry mouth, diarrhea, fatigue, anxiety
Good: sweating, constipation

40. 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

41. 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

42. Side effect profile Focus on weight gain Most are weight neutral
Most weight gain with Mirtazapine and Paroxetine during long term treatment

43. Side effect profile Focus on sexual dysfunction >30% 10-30% <10%
Fluoxetine, fluvoxamine, paroxetine, sertraline
10-30%
Citalopram, duloxetine, escitalopram, milnacipran, venlefaxine
<10%
Agomelatine, bupropion, mirtazapine, moclobemide, reboxetine, selegeline
There is usually little or no spontaneous remission of antidepressant-induced sexual dysfunction and there is only a limited evidence base for management strategies (Taylor et al., 2005). Dose reduction, if possible, is sometimes beneficial. Many pharmacological antidotes have been proposed but relatively few have demonstrated efficacy. Adjunctive bupropion and sildenafil (for antidepressant-induced erectile dysfunction) have the best evidence (Taylor et al., 2005); combination treatment with mirtazapine is also sometimes beneficial. Many patients will require a switch to another antidepressant with less propensity for sexual dysfunction (Table 6).

44. Side effect profile Discontinuation syndrome HR, SBP
“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

45. 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

46. Drug to drug INTERACTIONS
Check if patient are on the following:
Sildenafil
Antiepileptics
HIV PI’s
Methadone
Tamoxifen
Olanzapine
Immune modulators
Quetiapine
Macrolides
Beta-blockers
Amiodarone
Antiarrhythmics
Diltiazem, verapamil

47. Comorbid anxiety
*Citalopram, escitalopram are effective but not Health Canada indicated in 2006 when guidelines were written.

48. Comorbid anxiety
Bupropion has not been adequately studied so not recommended for primary anxiety disorders but has been effective in depression with anxiety

49. 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

50. 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

51. Treatment resistant depression
30% discontinue in 30 days
40% in 90 days
Must increase adherence
Education, self-management, collaborative care
Therapeutic alliance

52. Treatment resistant depression
First line
Switch to an agent with evidence for superiority
VEMS, duloxetine, milnacipran
Add-on
Aripiprazole, Lithium, Olanzapine, Risperidone

53. 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

54. Treatment resistant depression
Third Line
Add-on
Buspirone, modafinil, stimulants, ziprasidone

55. 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
Remission rates with citalopram as the first step in
STAR*D were 28 to 33 percent, and response rates
averaged 47 percent

56. Treatment resistant depression
From Dr. Ray Lam

57. Treatment resistant depression
In summary, there is Level 1 evidence to support add-on treatment with lithium and atypical antipsychotics for TRD, and Level 2 support for T3. There is 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.
In summary, there is only 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.

58. Treatment resistant depression
Number needed to treat is about 1:9 to 1:7, therefore, reasonable
Slide from Dr. Ray Lam’s lecture
In summary, there is Level 1 evidence to support add-on treatment with lithium and atypical antipsychotics for TRD, and Level 2 support for T3. There is 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.

59. Treatment resistant depression
Slide from Dr. Ray Lam’s lecture

60. 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.
Slide from Dr. Ray Lam’s lecture

61. TRD: ADJUVANT Summary
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
Slide from Dr. Ray Lam’s lecture

62. Risk factors supporting long term
Older age
Recurrent episodes (3 or more)
Chronic episodes
Psychotic episodes
Severe episodes
Difficult to treat episodes
(2 years to lifetime) antidepressant maintenance.

63. 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
Many RCTs and meta-analyses have shown that maintenance medication effectively prevents recurrence of symptoms with effects lasting from 6 months through 5 years. Two meta-analyses have examined predictors of the maintenance effect, and both had similar results: the effect size was not dependent on the risk factors for relapse (as well as could be determined), the duration of antidepressant treatment prior to randomization, nor the time of the randomized follow up period (Geddes et al., 2003 and Hansen et al., 2008). One meta-analysis confirmed that maintenance doses should be the same as the dose that got people better, as those randomized to dose reduction had higher relapse/recurrence rates than those continuing on the same dose (Papakostas et al., 2007b). Only 1 RCT involving newer agents has prospectively examined the length of time for maintenance. The PREVENT trial entered patients with recurrent depression (defined as 3 or more episodes, two of which were in the past 5 years) who were treated to remission with venlafaxine for 6 months. They were then randomized to maintenance venlafaxine or placebo for 12 months, after which sustained remitters in the venlafaxine arm were re-randomized for another 12 months (Keller et al., 2007). The recurrence rate was significantly lower in the venlafaxine-treated patients compared to placebo after both follow up periods, indicating that maintenance treatment for at least 2 years is beneficial for recurrent depression [Level 2].

64. 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

65. 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)

66. 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

67. 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

68. 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
In regards to risks, independent meta-analyses (Bridge et al., 2007, Dubicka et al., 2006 and Hetrick et al., 2007) have replicated the meta-analyses from the U.S. Food and Drug Administration (FDA) (Hammad et al., 2006a and Mosholder and Willy, 2006) showing a 1.5 to 2 fold risk of increasing suicidal thoughts/behaviours associated with newer antidepressants compared to placebo. Of note, there were no completed suicides in the clinical trial database. The absolute risks are quite small, however, with a recent estimated risk difference of 0.7%, corresponding to a number needed to harm (NNH) of 143 (Bridge et al., 2007). The only individual antidepressant associated with a significantly higher risk estimate is venlafaxine (Bridge et al., 2007 and Hammad et al., 2006a). Some trials have shown that CBT can reduce the risk of suicidality associated with SSRIs (Emslie et al., 2006) while others have not (Goodyer et al., 2007). In addition, results of meta-analyses should be supplemented by real-world evidence, such as that from pharmacoepidemiology studies and forensic toxicology studies (Bridge and Axelson, 2008). These studies have shown only mixed evidence that suicidality is associated with antidepressant use in youth.

69. 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.
In regards to risks, independent meta-analyses (Bridge et al., 2007, Dubicka et al., 2006 and Hetrick et al., 2007) have replicated the meta-analyses from the U.S. Food and Drug Administration (FDA) (Hammad et al., 2006a and Mosholder and Willy, 2006) showing a 1.5 to 2 fold risk of increasing suicidal thoughts/behaviours associated with newer antidepressants compared to placebo. Of note, there were no completed suicides in the clinical trial database. The absolute risks are quite small, however, with a recent estimated risk difference of 0.7%, corresponding to a number needed to harm (NNH) of 143 (Bridge et al., 2007). The only individual antidepressant associated with a significantly higher risk estimate is venlafaxine (Bridge et al., 2007 and Hammad et al., 2006a). Some trials have shown that CBT can reduce the risk of suicidality associated with SSRIs (Emslie et al., 2006) while others have not (Goodyer et al., 2007). In addition, results of meta-analyses should be supplemented by real-world evidence, such as that from pharmacoepidemiology studies and forensic toxicology studies (Bridge and Axelson, 2008). These studies have shown only mixed evidence that suicidality is associated with antidepressant use in youth.

70. QTc
Slide from Dr. Ray Lam’s lecture

71. 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
Slide from Dr. Ray Lam’s lecture

72. QTc Fluoxetine Also inhibits hERG
But inhibits calcium channels = ? Protective
Slide from Dr. Ray Lam’s lecture

73. 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
Slide from Dr. Ray Lam’s lecture