Wednesday, January 21, 2015

Antidepressant Efficacy: Hard to Prove

Antidepressants have not fared particularly well in clinical trials to determine efficacy. Placebo effect has gotten stronger over the years, resulting in many expensive failures of late-stage (Phase III) drug trials, with the result that most major drug makers have halted R&D programs aimed at developing new psychiatric drugs. Many of today's most popular drugs for depression barely achieved efficacy 30 years ago; if they had to jump through the same FDA hurdles today, most wouldn't make it.

The following table, from a 2003 Neuropsychopharmacology paper by Khan et al., shows the results of fixed-dose clinical trials (done for FDA approval) for a variety of antidepressants: fluoxetine (Prozac), nefazadone (Serzone), venlafaxine (Effexor), sertraline (Zoloft), bupropion (Wellbutrin), and citalopram (Celexa). Note that Serzone has since been pulled from the market over liver toxicity concerns. Trials in which the drug (at the dose shown) was superior to placebo are shown in bold. Remarkably, only a third of trials showed the drugs to be better than placebo.



Placebo
Antidepressant
Antidepressant: protocol
Duration of trial (weeks)
% symptom reduction
% symptom reduction
Dose (mg/day)
1. Fluoxetine: 62
6
23.5
39.7
20



39.8
40



29.8
60
2. Nefazadone: 03AOA-003
6
26.3
32.5
50–250



43.0
500
3. Venlafaxine: 600A-203
6
26.5
42.7
75



45.8
150–225



42.2
300–375
4. Sertraline: 103
6
30.0
42.7
50



39.4
100



35.8
200
5. Bupropion: 203
8
34.9
43.6
300
6. Bupropion: 205
8
35.5
38.1
300



38.4
400
7. Nefazadone: 030A2–0007
6
37.1
51.0
200



42.1
300
8. Mirtazapine: 003–008
6
37.2
29.2
15



26.7
30



32.0
60
9. Venlafaxine: 600A-313
6
37.4
42.6
50–75



46.1
150–200
10. Citalopram: 91206
6
37.8
40.6
20



50.0
40



49.4
60
11. Nefazadone: 03AOA-004A
6
37.9
35.8
150–300



40.3
300–600
12. Nefazadone: 03AOA-004B
6
38.0
40.2
100–300



50.0
300–600
13. Bupropion: 212
8
41.0
45.5
300





14. Citalopram: 89303
6
44.7
45.7
40
15. Venlafaxine ER: 367
8
49.2
57.8
20



58.9
75



53.9
150

How, then, did FDA decide to approve the drugs? Fixed-dose trials are not the only kind of trials used in drug approval. The drug makers also submit flexible-dose trials. Those are successful around 60% of the time. (See the Khan paper for data.)

Fixed-dose trials are typically done to establish dose-response relationships. Since weaker doses might not be as efficacious, it stands to reason that fixed-dose trials (which can be weighed down by weak-dose results) should fare worse than flexible-dose trials in terms of establishing efficacy. In theory, at least. In reality, that's not what Khan et al. found. When they looked at symptom reduction as a function of dose, they were unable to demonstrate a clear relationship ("paradoxically," in the investigators' words). Dose doesn't seem to matter much.

Looking at overall results, the average improvement in patient HAMD score was 35.8% for those who received placebo and 42.2% for those who got an antidepressant. One interpretation of this is that 85% (35.8 divided by 42.4) of the benefit of the drugs is due to placebo effect. But it's also possible that the only thing we're seeing here, in any of the results, is placebo effect. The greater "response" on drugs may be due to breaking of blind, as drug-takers realize (when side effects start to kick in) that they're not in the placebo group and begin thinking they're taking something powerful (when really it's just a different kind of placebo). This would also explain why dosage doesn't matter.

As you know (if you're a regular reader of this blog), I'm writing a mental illness memoir which is undergoing final proofing and formatting right now. Sample chapters will be available very soon. Add your name to the mailing list to be notified when samples are ready. Thanks!

10 comments:

  1. We are known manufacturers of modern classic chair. The designs are so attractive that you will be confused among which one to buy. Our products are well appreciated by top interior designers, esteemed customers and architects. We not also supply our products to offices but also in many hospitals, schools, restaurants, auditorium and cafeterias.
    Chair Manufacturers in Mumbai
    Chair Supplier in Mumbai
    Office Chair Supplier in Mumbai
    Visitor Chair Supplier in Mumbai
    Chair Dealers in Mumbai

    ReplyDelete
  2. Relocation from one place to another is a common trend in this fast changing world. People often relocate to another city in hope of better lifestyle. However with house shifting comes a very challenging & critical activity of ensuring that all your household items are delivered on time and safely to your new destination.
    Movers and Packers in Mumbai
    Movers and Packers in Dadar
    Movers and Packers in Thane
    Movers and Packers in Panvel

    ReplyDelete
  3. Thanks for your stop at Indian Packers and Movers in Mumbai. We really know the intentions of the people who are moving their homes or offices in Mumbai. We are one of the best Packers And Movers in Mumbai that gives values to the suggestions and recommendations of the client. It is this heart reading and friendly packing and moving service that made us the most loved packers and movers in Mumbai to depend for professional local transport in Mumbai, courier services in Mumbai and relocation services Mumbai and more.
    Packers and Movers in Kamothe
    Movers and Packers in Vashi
    Movers and Packers in Chembur

    ReplyDelete
  4. You can forget your stress and anxiety with the help of best movers and packers in Hyderabad who take on the responsibility of shifting your household goods. They will perform all the laborious tasks of packing, loading, moving, unloading and even unpacking your items with much ease. And, they will also help you arrange all your things in the new house as required by you.
    Packers and Movers in Hyderabad
    Packers and Movers in Nampally
    Packers and Movers in Himayat Nagar
    Packers and Movers in Adarsh Nagar

    ReplyDelete
  5. A lesser known fact about packers and movers in India is the level of disorganization in the industry, which is the main reason there are so many unprofessional and fake movers who take up relocation jobs and either provide horrible service or vanish with the household items all together.
    Packers and Movers Hyderabad
    Packers and Movers in Kondapur
    Packers and Movers in Gachibowli
    Packers and Movers in KukatpallyPackers and Movers Hyderabad
    Packers and Movers in Kondapur
    Packers and Movers in Gachibowli

    ReplyDelete
  6. شركة نقل عفش بالرياض وجدة والدمام والخبر والجبيل اولقطيف والاحساء والرياض وجدة ومكة المدينة المنورة والخرج والطائف وخميس مشيط وبجدة افضل شركة نقل عفش بجدة نعرضها مجموعة الفا لنقل العفش بمكة والخرج والقصيم والطائف وتبوك وخميس مشيط ونجران وجيزان وبريدة والمدينة المنورة وينبع افضل شركات نقل الاثاث بالجبيل والطائف وخميس مشيط وبريدة وعنيزو وابها ونجران المدينة وينبع تبوك والقصيم الخرج حفر الباطن والظهران
    شركة نقل عفش بجدة
    شركة نقل عفش بالمدينة المنورة
    شركة نقل اثاث بالرياض
    شركة نقل عفش بالدمام
    شركة نقل عفش بالطائف
    شركة نقل عفش بمكة
    شركة نقل عفش بينبع

    ReplyDelete
  7. https://www.behance.net/gallery/46460639/_
    https://www.behance.net/gallery/46462575/_
    https://www.behance.net/gallery/46450923/_
    https://www.behance.net/gallery/46450419/_
    https://www.behance.net/gallery/46430977/-jumperadscom
    https://www.behance.net/gallery/42972037/_
    https://www.behance.net/gallery/40396873/Transfer-and-relocation-and-Furniture-in-Dammam
    https://www.behance.net/gallery/51576047/_

    ReplyDelete
  8. Hello Everyone !

    USA SSN Leads/Fullz available, along with Driving License/ID Number with good connectivity.

    All SSN's are Tested & Verified.

    **DETAILS IN LEADS/FULLZ**

    ->FULL NAME
    ->SSN
    ->DATE OF BIRTH
    ->DRIVING LICENSE NUMBER
    ->ADDRESS WITH ZIP
    ->PHONE NUMBER, EMAIL
    ->EMPLOYEE DETAILS

    *Price for SSN lead $2
    *You can ask for sample before any deal
    *If you buy in bulk, will give you discount
    *Sampling is just for serious buyers

    ->Hope for the long term business
    ->You can buy for your specific states too

    **Contact 24/7**

    Whatsapp > +923172721122

    Email > leads.sellers1212@gmail.com

    Telegram > @leadsupplier

    ICQ > 752822040

    ReplyDelete
  9. Are you in need of Best Writing Services? Then get connected with
    Law Assignment Help

    ReplyDelete

Add a comment. Registration required because trolls.