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Mood Disorders IV (Chapter 7) March 14, 2014 PSYC 2340: Abnormal Psychology Brett Deacon, Ph.D.

Mood Disorders IV (Chapter 7) March 14, 2014 PSYC 2340: Abnormal Psychology Brett Deacon, Ph.D. Or, Everything You Ever Wanted to Know about Antidepressant Medications, Part II. From Last Class. Psychotherapy vs. medication for depression: short-term benefits, long-term effects, attrition, cost

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Mood Disorders IV (Chapter 7) March 14, 2014 PSYC 2340: Abnormal Psychology Brett Deacon, Ph.D.

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  1. Mood Disorders IV(Chapter 7)March 14, 2014PSYC 2340: Abnormal PsychologyBrett Deacon, Ph.D.

  2. Or, Everything You Ever Wanted to Know about Antidepressant Medications, Part II

  3. From Last Class • Psychotherapy vs. medication for depression: short-term benefits, long-term effects, attrition, cost • Placebo effect in the antidepressant response (60 Minutes video clip) • FDA approval process

  4. Basis of Prozac’s FDA Approval • 3 trials showed a statistically significant advantage of Prozac vs. placebo; 2 did not • Averaged across all trials: • Average improvement with Prozac = 8.30 points on HAM-D • Average improvement with placebo = 7.34 points on HAM-D • 89% of drug effect duplicated with placebo • The FDA approved Prozac for adults in 1987

  5. Publication of Prozac Trials • 3 trials worked (p < .05), two did not • How did Eli Lilly choose to publish data from these clinical trials?

  6. Science or Marketing? Selective Publication of Prozac Trials in Adults Published Study FDA Trial = Positive Publication = Positive FDA trial = Negative FDA trial = Negative Publication Note: 7 of 9 published studies did not disclose industry funding for the study.

  7. Marketing Prozac Trials in Scientific Journals: Actual vs. Apparent Efficacy

  8. Submitted vs. Published Clinical Trials of Antidepressant Medications • Study published by Turner et al. (2008) in New England Journal of Medicine • Examined results of 74 studies submitted to FDA for 12 antidepressants • Question: how much more effective do newer generation antidepressants appear in the published literature than they actually are?

  9. Turner et al.’s Analysis of Submitted vs. Published Trials • Drug was significantly more effective than placebo in 51% of trials submitted to FDA • This despite biased trial design. • Drug was significantly more effective than placebo in 94% of published trials

  10. Turner et al.’s Analysis of Submitted vs. Published Trials • 37/38 (97.4%) positive trials submitted to the FDA were published • 14/36 (38.9%) questionable or negative trials submitted to the FDA were published • Of these 14, 11 were mischaracterized as demonstrating superiority of drug over placebo

  11. Questions about Antidepressants • Do they take several weeks to “take effect?” • Are higher doses more effective? • Are newer generation drugs more effective than older ones? • Are there major differences in the effectiveness of different antidepressants? • Does the drug’s action in the brain make any difference? • What are their adverse effects? • Does switching from one drug to another help if a person hasn’t responded to the first drug?

  12. Questions about Antidepressants: The STAR*D study • Sequenced Treatment Alternatives to Relieve Depression study (STAR*D) • Massive $35 million federally-funded study with 3,671 depressed patients enrolled • Enrollment criteria: Hamilton Depression Rating Scale at baseline > 14 • Designed to simulate real-world practice, sequential prescription of up to 4 antidepressants based on response

  13. Questions about Antidepressants: The STAR*D study • Goal: Remission, defined as > 50% reduction in Hamilton Depression Rating Scale score • Study results, according to the authors and NIMH: • http://www.nimh.nih.gov/science-news/2006/odds-of-beating-depression-diminish-as-additional-treatment-strategies-are-needed.shtml • % in remission after: • 1st drug: 37% • 2nd drug: additional 19% • 3rd drug: additional 6% • 4th drug: additional 5% • Total (eventual) response rate: 67%

  14. Lies, Damned Lies, and Statistics • Deception and “spin” in reporting of the study results • http://www.psychologytoday.com/blog/mad-in-america/201008/the-stard-scandal-new-paper-sums-it-all • http://www.psychologytoday.com/blog/mad-in-america/201005/update-the-stard-report • Researchers reported results from patients with baseline HDRS scores < 14 • In some cases, researchers calculated remission rates using other scales with better outcomes

  15. Questions about Antidepressants: The STAR*D study • Actual findings: • 3,110 patients met enrollment criteria (HDRS > 14) • Of these, 1,192 (38%) achieved remission at some point during the study • The other 62% either dropped out or did not achieve remission • Reported here: http://psychrights.org/research/Digest/AntiDepressants/STARDTaleandTrailofBiasPiggot2011.pdf

  16. Questions about Antidepressants: The STAR*D study • Actual findings: • Approximately 3% of study patients achieved sustained remission for 12 months and remained enrolled in the study • Some scientists have called for the primary STAR*D publication to be retracted

  17. Adverse Effects of Antidepressants • Increased risk of birth defects when taken during pregnancy, especially first trimester, as well as increased risk of subsequent autism in child • Acts of violence toward others, as reported to the FDA http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015337 • Sexual dysfunction

  18. Sexual Effects of Antidepressants in Patients with Previously Normal Sexual Function (Montejo et al., 2001; N = 1022) http://www.ncbi.nlm.nih.gov/pubmed/?term=Montejo+2001+antidepressant+sexual

  19. Adverse Effects of Antidepressants (Read, Cartwright, & Gibson, in press; N = 1829) 36% were not informed about any adverse effects by their prescriber. 8.7% were informed about sexual dysfunction. 4.6% were informed about suicidality.

  20. Antidepressants’ Black Box Warning “Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders. Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.” -U.S. Food and Drug Administration website

  21. Overall Suicide Risk with SSRIs • Completed suicides are rare, so scientists often study suicidal ideation and suicide attempts • In a review of 372 placebo-controlled antidepressant trials conducted with 99,321 patients submitted to the FDA, SSRIs raised the risk of suicide attempts from 1.1 per 1000 to 2.7 per 1000 (Stone et al., 2009) http://www.ncbi.nlm.nih.gov/pubmed/19671933Z • SSRIs increased suicidal ideation and attempts markedly in people younger than age 25, had no effect in adults, and lowered it in older adults • What exactly is the risk in young people?

  22. The Treatment for Adolescents with Depression (TADS) Study • Depressed adolescents (N = 439) were randomly assigned to receive: • Fluoxetine (Prozac) • CBT (15 therapy sessions over 12 weeks) • Combined treatment (Prozac + CBT) • Pill placebo • 36 weeks of treatment, naturalistic one-year follow-up after treatment discontinuation • Funded by NIMH, not a drug company • Brief note on the logic of randomized, controlled trials and their role in understanding drug-induced suicidal events TADS Team, 2004, 2007, 2009

  23. Major Findings of the TADS Study • All active treatments were effective in reducing symptoms of depression, with combined treatment showing the largest benefit • All active treatments were effective in reducing overall suicidal thinking, with combined treatment showing the largest benefit • Treatment gains were generally maintained over time, even after treatments were discontinued TADS Team, 2004, 2007, 2009

  24. TADS Study: Findings During Ongoing Medication Treatment CBT ended here TADS Team, 2007

  25. TADS Study: Final Outcomes Following One Year of No Treatment TADS Team, 2007

  26. TADS Study: Suicidal Events • The “real” suicide data are published here, not in the original TADS reports: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702701/pdf/nihms101259.pdf • No patients committed suicide • Through 36 weeks, there were 44 suicidal events (suicidal ideation or suicide attempt) • 36 of 44 (82%) suicidal events occurred in patients taking Prozac • 17 of 18 (94.4%) suicide attempts occurred in patients taking Prozac

  27. TADS Study: Suicidal Events http://www.madinamerica.com/2012/02/the-real-suicide-data-from-the-tads-study-comes-to-light/ http://www.madinamerica.com/wp-content/uploads/2012/02/Tads-Suicide-data.pdf http://davidhealy.org/coincidence-a-fine-thing

  28. TADS Study: Suicidal Events • For adolescents who received Prozac (alone or in combination with CBT*)… • 19 had suicidal ideation = 8.8% • 17 attempted suicide = 7.9% • Overall rate of suicidal events = 16.7% • For adolescents who received pill placebo or CBT… • 7 had suicidal ideation = 3.1% • 1 attempted suicide = 0.4% • Overall rate of suicidal events = 3.5% *Note: Suicidal events were much higher for Prozac alone (22%) vs. Prozac + CBT (8%)

  29. TADS Study: Estimating the Rate of Suicidal Events Caused by Prozac • We can estimate the rate of Prozac-induced suicidal events by subtracting the rate from patients who did not take Prozac from the rate of patients who did take Prozac (alone or with CBT) • Suicidal ideation: 8.8% (Prozac) – 3.1% (no Prozac) = 5.7% • Suicidal attempts: 7.9% (Prozac) – 0.4% (no Prozac) = 7.5% • 13.2% of patients in this study experienced a Prozac-induced suicidal event • Approximately 1 of 7 adolescents who took Prozac

  30. Important Caveats • It is unclear to what extent the rate of drug-induced suicidal events in the TADS study generalizes to routine real-world clinical practice. • As a group, TADS patients were probably more depressed than most depressed adolescents who receive treatment in the real world • TADS patients received far more attention and support than most patients in the real world • Patients receiving Prozac met with their prescriber for bi-weekly 20-30 minute sessions

  31. Clinical Implications of the TADS Study • Letter to the Editor by David Antonuccio (2008), “Tailoring Treatment to Parental Values: A Comment on TADS” • “When considering efficacy, the Treatment for Adolescents With Depression Study (TADS),in my view the best comparative study ever done in children with depression, ranks the acute outcome of the treatments from best to worst this way: combination treatment, followed by [Prozac] alone, followed by cognitive behavior therapy (CBT) alone, followed by placebo. Analysis of longer-term efficacy suggests that CBT caught up with fluoxetine therapy at the 18-week follow-up and CBT caught up with the combination treatment at the 36-week follow-up…When considering safety, the acute treatment rankings from best to worst were entirely different: CBT alone was best, followed by placebo, followed by combination treatment, followed by [Prozac] alone…What’s a clinician to do? One possibility is to empower parents to make informed choices about treatment consistent with their own values by giving them this information on risk and benefit and letting them decide…. A legitimate question is ‘How many children should benefit from an antidepressant to justify 1 extra child harmed by an antidepressant?’ Parents could be armed with the data so they can answer this question themselves.” (pp. 723-724)

  32. Clinical Implications of the TADS Study • Reply to David Antonuccio’s letter by John March, M.D., on behalf of TADS Team (2008) • “Taking both risks and benefits into account, the TADS strongly suggests that [Prozac + CBT] COMB should be the first-choice treatment for the average teen with depression….Even more worrisome, the decrease in prescriptions for antidepressants that followed the Food and Drug Administration warning may have deprived many youth of the benefits of medical management and perhaps led to a rise in death by suicide.” (p. 724)

  33. Clinical Implications of the TADS Study • Should we be concerned about the public health implications of the FDA’s “Black Box” warning causing too few depressed young people to take SSRIs, and experience improvement in their depressive symptoms, because of safety concerns? • Or should we be concerned about the public health implications of too many depressed young people taking SSRIs because of the increased suicide risk? • What are treatment providers, patients, and parents to do?

  34. Effect of SSRIs on National Suicide Rates? • Based on the data discussed thus far, what trends do you expect to see in suicide rates among young people in the United States? • How do you think the extraordinary increase in use of SSRIs among young people in recent decades has affected the suicide rate?

  35. Trends in National Suicide Rates http://www.cdc.gov/injury/wisqars/index.html • Actual suicides have not increased over time • From 1985 to 2004, the suicide rate decreased by about 13% www.hsph.harvard.edu/means-matter/files/SuicideTrends.ppt • The rate among 15-24-year-olds dropped from about 13/1000 to about 10/1000 • The rate of suicide attempts remained stable during the introduction and widespread adoption of SSRIs • Rate from 1990-1992: 0.7% • Rate from 2001-2003: 0.8%

  36. Effect of SSRIs on National Suicide Rates? • Following the FDA’s “Black Box” warning, SSRI prescriptions declined • The suicide rate did not change • SSRIs have likely decreased the number of suicidal events among depressed individuals, as a group, by effectively treating depressive symptoms • SSRIs have likely increased suicidal events in a subset of individuals, and have directly caused numerous suicides • Is it possible that SSRIs have been simultaneously preventing and causing suicidal events? • Implications for patient care?

  37. Trends in National Suicide Rates • Why are completed suicides, but not attempted suicides, declining? • No change in rates of suicide by suffocation, poison, and other means • However, suicide due to firearms has declined • Gun availability has gradually declined over time • Suicidal events often occur during a crisis and are impulsive • Compared to firearms, all other suicidal methods are less lethal

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