Depression

1. Depression G. Michael Allan Assoc. Prof, Family Med, U of A

2. Conflict of Interest Family Doctor for 12+ yrs Academic 8 years Pay from U of A and Alberta Health Research and Speaking Fees Non-Profit Sources (E.g Canadian Expert Drug Advisory Committee, Alberta College of Family Physicians, etc) No funding from Industry

3. Objectives • History and Context • Screening and Diagnosis • Challenges with Anti-Depressant Evidence • Do Antidepressants work? • What about pediatric (& adolescent) patients? • Safety in Pregnancy • How long do they take work? • Which is the best • Are older worse than newer? • Is one 2nd Generation better than another? • Specific Topics • What is the evidence for dose or dose adjustment? • What if the first doesn’t work? • When can we stop them?

4. Sad Truth of Anti-depressants • Your student just saw Mrs Misery (41 y.o.). She is feeling down for 4 months, doesn’t enjoy anything, cries without cause, can’t get or stay asleep, has no energy, and can’t stay focused. She has lost 10 lbs (she is glad for that at least). • She has no thoughts of self-harm • As you write a script for an anti-depressant, the students asks, “But I thought they didn’t work?”

5. Sad Truth of Anti-depressants • Do Anti-depressants Work? • They work but • Not as well as we thought • It varies in some groups • Psychiatry provides the best examples of bias in the literature. • Let’s review some of those bias

6. Poor Quality in Anti-depressants • In a series of 46 RCT1 • 91% fair quality – 9% good (poor quality excluded) • 85% industry funded (11% affiliated, 4% not reported) • In a series of 50 RCT2 • Intention to treat used only 54% • In a series of 11 RCT3 • Allocation Concealed (assured randomization) in 9% 1) Ann Intern Med. 2005;143 :415-26. 2) Arch Gen Psychiatry 2006; 63: 1217-23. 3) Lancet 2004;363:1341-5

7. Other Specific Biases • Subjective: • Clinicians report/score benefit > pts • E.g.: In one series clinicians found benefit in 33% of scales but patients report benefit in 0% • Scales: • ↑ numbers (esp big scales) • Easier to find statistical significant • But not clinical significant • E.g. Improving 2.7 on a 113 scale. Lancet 2004;363:1341-5. & BMJ 2004;328:879-83.

8. Hiding the Bad: Part 1 • Selective Publication of Anti-depressant Trials • FDA records of 12 SSRI/SNRI’s vs Published • 74 Trials: • 38 Positive: 37 published, 1 not published. • 36 Negative: 3 published as negative, 11 published as positive, 22 not published. • Positive = 94% published vs 51% FDA • Effect (benefit): Published (0.41) > FDA (0.31) NEJM 2008; 358: 252.

9. Hiding the Bad:Part 2 • Single Trails Pub: • if trial +ve = 90% • if trial –ve = 29% • What Actually happens to SSRI trials? • Hiding “Bad” trials • Multiple pub. “Good” Melander. et al, BMJ, 2003; 326: 1171-73

10. Hiding the Bad: Part 2 • What Actually happens to SSRI trials? • +ve trials published 4.4x each (vs 1.3) Melander. et al, BMJ, 2003; 326: 1171-73

11. Getting the most of a small effect • Initial Severity and Anti-depressant Benefits • 35 RCT’s of 4 SSRI/SNRI’s • No diff. between Anti-depressants • Overall, Statistical Sign common BUT,… • Clinical Significance less clear • Ham D scores range between 17-30.5 • Mean Change was 9.6 for med & 7.8 for placebo • Mean difference was 1.8 HRSD • Therefore, 81.5% of the improve seen on anti-depressants is from “placebo” PLOS Med 2008; 5(2): 0260.

12. These are basically scatter plots with regression analysis. • Putting on mean outcomes for placebo and drug from each trial and drawing a best fit line for the effect of placebo and drug. • You then figure out when the two separate to predefined level. • This uses effect sizes, which is common in summary statistics for scales (like depression or pain) • In this case, they used 0.5 which they got from NICE. • It separates at green, about HSRD 27 • Note: If they used an easier clinical sign (let’s say 0.2, like in OA), separation would be earlier (around 24 in the OA case). Effect size

13. Getting the most of a small effect • Differences Only reach Clinical Significance when Depression Severe • The actual number varies by graph but seems like HSRD 26 (from figure 4), 27 (from figure 3) and 28 (from figure 2) • Maybe lower (perhaps Moderate) if “clinical significance” defined more liberally • Example: 0.2 is defined as the minimum effect size in OA • Bottom-line: drug effect stable but placebo less effective as depression worsens • Meaning, benefit of drug over placebo greater with worsening depression. PLOS Med 2008; 5(2): 0260.

14. Getting the most: NEW • Meta-analysis of 6 trials: with patient level data! • Searched 3 databases (pubmed, Psychinfo & cochrane). • RCT, Adult, ≥ 6 wks, Ham D, pt level data. • 6 studies (3 imipramine, 3 Paroxetine), 6-11 weeks (median 8), baseline Ham D= 14-23. • Results: Same as before, severe,  benefit • Clin Sign Diff (NICE definition (diff 3 on Ham-D) at Ham-D 25

15. Getting the most: NEW • Continued results: used 3 categories • Mild/mod (Ham-D ≤18), severe (19-22), very severe (≥23) • Using effect size (measuring diff from comparator): both mild/mod & severe never got better 0.20. At very severe 0.47. • NNT (for better outcome): 16, 11 and 4 (mild/mod, severe, very severe). JAMA. 2010;303(1):47-53

16. Getting to the Actual Numbers • Paroxetine is well studied and a meta-analysis of the drug helps see the individual outcomes • Standard Mean difference was -0.31, -0.40 to -0.22) • Actual numbers that get ≥50% of improvement; If you treat 100 pts with paroxetine • 53% taking paroxetine • 42% with placebo • Difference is 11% (or NNT 9) • If you look at other outcomes • Those who discontinue for any reason: no difference • Adverse events: reporting (NNH 9), discontinuing due to (NNH 17) • Experience Suicidal tendencies (NNH 142).* CMAJ 2008;178(3):296-305

17. Bottom-line • Antidepressants help reduce symptoms of (moderate to severe) depression in up to 70% of patients • (but likely lower & maybe a lot lower) • Remission Less. • In mild Depression, 90% of that effect is from “Placebo” • As the Depression is more severe, the drug gives more of that effect (compared to placebo).

18. Best Anti-depressant • A 27 year old woman has been slipping into depression for 4 months and non-medicinal measures have been ineffective. She is now clearly depressed (not suicidal). You have heard from psychiatrists and different drug reps certain meds are better.

19. Best Anti-depressant • Which was better in a well-designed meta-analysis? • Venlafaxine • Buproprion • Esocitalopram • Citalopram • They’re all the same • None Ever Work (Dr Thomas Cruise)

20. Best Anti-Depressant = Any • They are all about the same • 46 RCT’s (11.5 K pts), ≥3 months • No Diff Quality of Life (& for Ham D) • Venlafaxine > Fluoxentine: RB 1.12 (1.02-1.23) & NNT16 • Sertraline > Fluoxetine: RB 1.1 (1.01-1.2) & NNT 17 • SE similar (? Venlafaxine N&V), rapidity of response No diff. • Benefit = always 5% in favour of sponsored drug (NNT 20) • SE similar (? Venlafaxine N&V), rapidity of response No diff. Ann Intern Med. 2005;143 :415-26.

21. Best Anti-Depressant = Any • Added since 2005 • Meta-analysis1: 203 studies (171 RCT’s) – using some indirect comparisons • Effectiveness similar. Few stat sign relative benefit, but • None clinically significant E.g. MADRS 60 pt scale: esocitalopram 1.13 > citalopram (min clinically important diff=2) • Sponsorship may play a role in these subtle differences • Adverse Events similar in amount (61% of patients had ≥1) but types varied • E.g. Venlafaxine 11% more nausea & vomiting, Sertraline 3% more diarrhea, 1. Ann Intern Med. 2008;149:734-750. 2. Lancet 2009; 373: 746–58

22. Best Anti-Depressant = Any • Meta-analysis2 (117 RCTs), examined response to treatment and withdrawal, used indirect methods • Identified some small differences • Efficacy Top 4: mirtazapine, escitalopram, venlafaxine, sertraline • Acceptability Top 4: escitalopram, sertraline, bupropion, citalopram • Used Odds Ratios, treated scales as =, Funding bias • Interpret in context 1) Antidepressant research suffers significant bias, 2) ≤10% of studies are high quality • Bottom-line: Similar Effectiveness, different AE 1. Ann Intern Med. 2008;149:734-750. 2. Lancet 2009; 373: 746–58

23. Best Antidepressant = Any: Quality Concerns • Other reviews have attempted to determine if one antidepressant is superior but the results are inconsistent.1 • The 2009 review2 has important concerns regarding validity including, • They treated all depression scales as the same (and they are not), • Using odds ratios exaggerated the differences they found, • Importantly, when they tried to account for sponsorship bias, the differences between the drugs were reduced. • Both reviews2,3 did some indirect comparison of drugs from different studies, which is less reliable than direct comparison in the same study. • The 2008 review3 did not have quite as many concerns with validity. 1) Cochrane 2005;(4): CD004185. Curr Med Res Opin. 2009; 25 :161-75. Cochrane 2009;(2): CD006117. Ann Intern Med. 2005;143 :415-26. 2) Lancet 2009; 373: 746–58. 3) Ann Intern Med. 2008;149: 734-750.

24. Miscellaneous Management Issues

25. Is Bigger Better? • Mrs Low (31 year old) is in. 2 weeks ago she was diagnosed with moderate depression. She is now ready to trial a medication. • Your resident says he heard (from an expert) that “primary care doctors always under-treat depression” • As you write the script, he wants to know what your target dose is.

26. Is Bigger Better • Based on two literatures reviews, you can say; • Moderate dose SSRI (e.g. 30-40) is the general target • Starting low (10mg) is reasonable • Increases into high doses (>20mg) may not be much help. • Forget the prescription, send her to this know it all expert.

27. Bigger Is NOT Better • Low doses of anti-depressants seem as effective as high doses. • Flouxetine (5 vs 20 vs 40mg)1 • Tricyclics (50-100 vs >100mg)2 • Increasing doses in non- responsive patients doesn’t seem to help much.3 • At least not until 8 weeks have past. 1) Psychopharm Bull 1988; 24: 183-8. 2) BMJ. 2002;325:991-5. 3) Br J Psychiatry 2006;189:309–16.

28. Switching Quick: New What constitutes a reasonable trial? When should we say, “this isn’t working, lets’ try another instead.” Only three studies have looked at this and can’t see a difference in switching after 6-7 weeks and not. Note STAR*D waited a mean of 12 weeks Acta Psychiatr Scand 2010;121:174–9.

29. New: Combination • Combined regular anti-depressants at the start may be helpful, • RCT of 105 pts x 6 weeks, Fluoxetine (20) vs Mirtazapine (30) plus Fuoxetine (20) or Venlafaxine (225) or Bupropion (150) • Remission = Ham D ≤7 (mean start =22) • Fluox 25%, Fluox+M 52%, Ven+M 58%, Bup+M 46% (all comb stat sign (p=0.01) vs Fluox alone); NNT 4 • AE common but No diff in AE quiting • Few other studies also find (nothing big yet though). Am J Psychiatry 2010; 167:281–288

30. Waiting for the World to Change • Mrs low is back 7 days later. She is on Fluoxetine 10mg. She reports she is feeling a little better (more energy concentration). • She read that it should take 2-4 weeks to work so wants to know how this can be helping? • How fast do anti-depressants work?

31. Waiting for the World to Change • They work as fast as 7 days: • From a meta-analysis1 of 50 trials (10,121 depressed patients) looking at response to SSRI medications, compared to placebo, at a series of time intervals. • On average, 1/3 of the total benefit occurs in the first 7 days (whole effect by 6 weeks). • For every 25 people treated, one more will be 50% improved over placebo at 7 days. • Hard to find because the “n” needed to show a benefit is 9x bigger that most trials! • The results of the meta-analysis above confirm those of another meta-analysis2 • That study also found antidepressants result in statistically significant improvement in clinically important outcomes within the first week. 1) Arch Gen Psychiatry 2006; 63: 1217-23. 2) J Clin Psychopharmacol 2006;26:56–60.

32. A Trial of Separation? • Mrs Low is now 6 months on Anti-depressants and has done well. This was her first case of depression. She wants to know if she can stop? • What if this was her 2nd or 3rd case?

33. A Trial of Separation? • In Meta-analysis of 31 RCT (of all types)1 • Meds stopped after 4-28 weeks (most 6-16) • Relapse at 12 months: 41% Placebo vs 18% • NNT 5. • Dose reduction similar (5 RCT)2 • 25.3% low dose vs 15.1% in previous dose • Recurrence (hard to separate out one)3 • From a cohort of 318 depressed pts, 60% had previous depression • After 1 yr, 25% of the cohort had a recurrence • If second, 41% in 1 year. • Add 16% for each subsequent episode, but some repeaters • 36% did not have a recurrence in 5 years. 1) Lancet 2003; 361: 653–51. 2) Psychother Psychosom. 2007;76(5):266-70 3) Am J Psychiatry 2000; 157:229–233

34. Missing the Diagnosis • Ms V Blue is a 25 year old female coming for her complete medical. She is mentions she is a little more fatigued of late. • You want to screen for depression. • Is there a quick screen?

35. 2 Question Screen • During the past month have you often been bothered by, • Feeling down, depressed, or hopeless? • Little interest or pleasure in doing things? • No to both: virtually rules out depression • LR 0.05 (Sensitivity 97%) • Yes to either: go through full depression questions • Not specific (can’t make Dx, many false positives) • Another study of these found same (LR 0.07) BMJ 2003; 327:1144-46.J Gen Intern Med. 1997;12:439-45.

36. Patients Like Ours? Shooting Stars: Fall to Earth • So what really happens to the average patient seen for depression?

37. Shooting STAR*D: Findings • 2876 people were put on Citalopram • More like real patients • (mix of general and specialty) • 80% had chronic or recurrent depression • Many complicating Psychiatric conditions. • 18% had attempted suicide. • Mean HRSD = 21.8 • Mean exit dose of citalopram = 42 mg/day

38. Shooting STAR*D: Findings • Citalopram remission rates • HRSD = 27.5% and QIDS-SRTreatment 33% • Response rate = 47% • Similar rates between GP’s and specialists • If a patient hadn’t attained remission, they were offered to continue. • 2086 patients were offered to continue. Am J Psychiatry 2006; 163:28–40

39. Shooting STAR*D: 2 Findings • Substituting 727 patients • Drop Citalopram and immediate start: • Bupropion-SR, Sertraline, or Venlafaxine-XR • Remission rates about 25% across the board (for both tools & all 3 meds). • Tolerability and adverse events similar. N Engl J Med 2006;354:1231-42.

40. Shooting STAR*D: 2 Findings • Augmenting 565 patients • Drop Citalopram continue and add: • Bupropion or Buspirone • HSRD Remission rates around 30% for both. • QIDS-SR-16: Buproprion > than buspirone • Reduction 25% vs 17% • Lower end score 8 vs 9 • Lower intolerance drop-out rate 12.5% vs 20.6 N Engl J Med 2006;354:1243-52.

41. Shooting STAR*D: 3 Findings • Augmenting 142 patients • Add: Lithium or triiodothyronine (T3) • Remission rates around 20% for both. • Substituting 234 patients • Switch: nortriptyline or mirtazapine • Remission rates between 10-20% for both EBMH November 2008; 11(4): 97-9.

42. Shooting STAR*D: Summary • Perhaps trials reporting the ideal response 70% (or more “realistic” 53% from the paroxetine study) are actually an exaggeration • Efficacy population = 51.6% response versus 39.1% in effectiveness or pragmatic STAR*D population. • Maybe choosing the type of alternative antidep doesn’t matter (they seem the same). • Maybe specialist care is not a lot different from GP • Choice of augmentation uncertain (guidelines2 put lithium and olanzapine ahead of the first choices here). Am J Psychiatry 2009; 166:599–607. 2. J Psychopharmacol 2008;22:343–96.

43. Related to STAR*D: New • Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007954. • J Clin Psychiatry. 2006 Dec;67(12):1836-55. • Some related citations • Treating Depression in Primary Care does work1 • Treatment response NNT 7-9, • Withdrawal due to AE (4-30 TCA or 20-90 SSRI) • If you need to switch,2 • it doesn’t matter which one • The more previous treatments, the higher the chance of a poor outcomes.

44. What About the Children?

45. Pediatric Depression: Meds or not You are seeing a 12 year old boy whom a has many symptoms of depression. This is new for him (last 6 weeks). His mother worried and wonders if antidepressants might help (she has been successfully treated in the past). In addition to possible referral, looking into contributing factors, etc: What can we say about antidepressants in pediatrics.

46. Pediatric Depression: Meds or not • What can we say: • There are concerns that the drugs are ineffective. • There are concerns that the drugs are not safe. • There is some evidence that perhaps fluoxetine may be a reasonable choice. • SR/Met: 5 Databases + refs & authors, 6 drugs (5 pub, 6 unpub from 5000+), f/u 42-96 days F/U poor (54-83%). (BMJ= 4 drugs, 6 published trials) Lancet 2004;363:1341-5 (BMJ 2004;328:879-83)

47. Pediatric Depression: Meds or not New anti-depressants vs placebo Results: see table Good use of unpublished data, excellent combo, but poor f/u, short duration Industry bias (under-reporting SE & Hiding trials). Fluoxetine only (for now) & Some question it’s benefit. Lancet 2004;363:1341-5 (BMJ 2004;328:879-83)

48. Study 1 & 2: SSRIs in childhood dep,… & Efficacy & safety of anti-depressants,... In 6 trials, 42 measures used but only 14 showed any improve (0/10 patient/parent measures. Scales clinically questionable (Improving 2.7 on a 113 scale ?)

49. Suicide • Adolescents: Odds ratio 1.92 (1.51-2.44) • Adults: 0.57 (0.47-0.70) • Elderly: 0.46 (0.27-0.79) • Absolute numbers not given (but likely low). CMAJ. 2009;180:291-7.

50. Questions