Combating Five Myths on Psychotropic Medication Treatments

1. Combating Five Myths on Psychotropic Medication Treatments Julie M. Zito, PhD Professor Emerita of Pharmacy and Psychiatry University of Maryland, Baltimore National Association for Rights Protection & Advocacy Sept 19, 2019 East Hartford, CT

2. Objectives A. List five myths on psychopharmacologic treatments • New drugs are better and safer • Clinical trial effectiveness data are enough • Better post-marketing data aren’t needed • 21st Century Cures Act will improve treatments • Children are just little adults B. Your turn to comment and challenge C. Identify a target for advocacy?

3. Myth #1New drugs are better and safer

4. FDA explains innovation initiative “…It aims to make sure our regulatory processes are modern and efficient, so that safe and effective new technologies can reach patients in a timely fashion. We need to make sure that our regulatory principles are efficient and informed by the most up to date science. We don’t want to present regulatory barriers to beneficial new medical innovations that add to the time, cost, and uncertainty of bringing these technologies forward if they don’t add to our understanding of the product’s safety and benefits." —Scott Gottlieb, M.D., Commissioner of Food and Drugs, December 2017

5. Esketamine for treatment resistant depression: An innovative new drug? • Designated ‘breakthrough therapy’, a category of innovation initiative: lower evidence standard than for other prescription drugs • FDA panel of experts approved drug 14 to 2 (Feb 2019) • Weak evidence of benefit: • Design issues: added esketamine to randomly assigned marketed oral ATD; does not rule out oral ATD’s effect; nasal rather than IV • Weak definition of treatment resistant depression: failed ≥2 ATDs • Weekly dosing for 4 weeks is an unusually short depression trial • Only 1 of 3 short-term studies was positive: 50% improvement over baseline symptoms: -18.2 Drug-treated vs. -14.9 Placebo/ATD-treated • 3 suicides and possible fourth were ALL in the active drug group • 6 deaths all in esketamine group; none in placebo group • Serious safety concerns: • Dissociative (out of body) experiences; Blood pressure 5

6. More Esketamine Concerns • list price = $590 to $885 per treatment session, depending on dosing and number of sessions, which can vary by patient; $6,000 + $742/wk • NMDA (N-Methyl-D-Aspartate Antagonist): increases glutamate effects similar to opioids • Ketamine Abusers: bladder toxicity with long term use; opioid-like addiction not seen with esketamine tx (yet)

7. Myth #2Clinical trial data are enough

8. FDA Drug Approval Process

9. Facts about clinical trials (CTs) • Most CTs are conducted in adults, leaving youth and elders with less scientific rx info • CT findings do not tell us how well a drug works in community-treated populations • Many medication uses are ‘off-label’---- without an indication (reason for use) in the age group or for the condition treated • Off-label prescribing is legalbut is it ethical?

10. Examples of Off-label Use • Risperidone, a second generation antipsychotic for non-psychotic behavior problems; • Lamotrigine, an anticonvulsant used as a ‘mood stabilizer’ in youth with behavior problems: serious risks! • Fluoxetine (Prozac), a second generation antidepressant used for depression and anxiety in children less than 6 or 8 years old

11. Adoption of Antipsychotics after Marketing AGGREGATE USE OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS, 1995-2008.* *Source: IMS Health National Disease and Therapeutic Index™, 1995-2008

12. Evidence changes over time

13. Myth of Antidepressant Effectiveness Dies Slowly • Two meta-analyses used FDA data and now don’t support individual trial findings • Biased reporting: 60% of negative clinical trials were never published; 31% misleading interpretation • Statistical vs. clinical significance • Limited study design, measures & selection of study subjects 13

14. Supporting Scientific Myths • Mental illness as a chemical imbalance • Depression as a serotonin deficiency disease • Bipolar disorder as a lithium deficiency disease • Schizophrenia as a dopamine excess disease • These theories use the mechanism of drug action to explain the disease! When, actually it is exploiting the side effects (fatigue from risperidone) or from anticonvulsant) • Mental illness as a brain disease vs biopsychosocial treatment model

15. Myth #3 Better post-marketing data aren’t needed because safety data from clinical trials are enough

16. Aaaaaa

17. Why Clinical Trial Findings on Psychotropic Medications Aren’t Enough Safety research lags behind effectiveness because: • CTs are too short • CTs are too simple • CTs are too small • CTs are too median aged • CTs are too narrowly focused

18. PMS safety study of antidepressant treatment of youth: Beyond clinical trials • Large claims datasets • ‘Real world’ data for ‘real world evidence’ • Addresses questions on benefit and risk in community-treated populations • Improve measures of outcome 18

19. Myth #421st century cures act will improve mental health treatments

20. History on Clinical Trials and Regulatory Change • Streptomycin for TB – 1948 • 1962 Response to thalidomide epidemic • RDBCCT to demonstrate efficacy • 1997 PDUFA • 2007 FDAAA - BPCA; PREA; REMS • 2016 21st Century Cures Act 20

21. 21st Century Cures Act • Bipartisan passage Dec. 2016 • Assumes FDA is not efficient in approving drugs for marketing • Uses ‘innovative drug’ or breakthrough therapy designation to fast-track new drugs despite weakened evidence • Emphasizes big data to find new indications for existing drugs: data mining!

22. Myth #5 Children are just little adults 22

23. Where do we go from here? 23

24. Reduce the Effectiveness Gap between pre- and post-marketing populations, e.g. urge large cohorts in public university health systems with electronic health records to form PMS networks • Encourage post-marketing research in community populations to: • Discourage polypharmacy unless its use is supported by evidence • Discourage off-label use unless its use is supported by evidence 24

25. Advocacy Possibilities • Join ‘Mad in America’ to keep abreast of major concerns newsletter=madinamerica.com@mail194.atl271.mcdlv.net • Get involved in your community to help young, poor and under-resourced families, e.g. become a ‘navigator’ • Work to reduce corruption in the pharmaceutical industry and in the health care delivery system in the U.S. • Write to your congress people with stories of mishaps and suggestions to avoid future errors. FDA listens to congress! 25

26. Now it’s your turn… jzito@rx.umaryland.edu