Treatment Resistant Depression [TRD] is a fictitious entity created by the KOL set to explain why the SSRIs weren’t wonder drugs. One of the most lucrative outcomes from TRD’s invention was the notion that adding atypical antipsychiotics would bring relief to the afflicted through some as yet unspecified mechanism. Spielmans et al poked a hole in that fantasy with their meta-analysis [and…] 
which showed statistical but little clinical efficacy for atypical antipsychiotic augmentation. In the middle of last night, the flying squirrels that have taken up residence in our in-need-of-repair roof system had their first [and hopefully last] annual nocturnal chariot races [while we await the roofers]. So I passed the time downstairs looking at the abstracts from the articles analyzed by Spielmans et al, and decided that what these authors said in the conclusions might be of general interest [I added the findings from Spielmans et al as a reminder].
These are all industry funded clinical trials published in peer-reviwed journals. I still have to pinch myself to accept that my colleagues wrote [or at least signed on to] all of these rah rah articles with such lackluster findings. In the comments, Dr. Carroll listed some of the KOLs who popularized atypical antipsychiotic augmentation [here], and I’ve added the links to the articles he mentioned to that comment that aren’t already listed below. This was a concerted campaign with all of the usual suspects participating in concert with their industry patrons. As you read through their conclusions, recall that this is the kind of rhetoric that practitioners had available to them. This is the kind of information peddled at medical meetings. This is what we heard at required C.M.E. presentations.
|
Apiprazole [Abilify]
|
|
The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study.
by Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK, and Khan A. Journal of Clinical Psychiatry. 2007 68(6):843-53. …In patients with MDD who showed an incomplete response to ADT, adjunctive aripiprazole was efficacious and well tolerated.
|
|
The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study
by Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, Trivedi MH, Thase ME, and Berman RM. Journal of Clinical Psychopharmacology. 2008 28[2]:156-65. …Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.
|
|
Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants.
by Berman RM, Fava M, Thase ME, Trivedi MH, Swanink R, McQuade RD, Carson WH, Adson D, Taylor L, Hazel J, and Marcus RN. CNS Spectrums. 2009 14[4]:197-206. …As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy.
|
|
Olanzapine + Fluoxetine [Zyprexa + Prozac]
|
|
OlanzapineA novel augmentation strategy for treating resistant major depression.
by Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, and Meltzer HY. American Journal of Psychiatry. 2001 158(1):131-4.
…An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features… Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.
|
|
Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.
by Shelton RC, Williamson DJ, Corya SA, Sanger TM, Van Campen LE, Case M, Briggs SD, and Tollefson GD. Journal of Clininical Psychiatry. 2005 66(10):1289-97. …This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination.
…The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization. |
|
A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression.
by Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, and Tollefson G. Depression and Anxiety. 2006 23(6):364-72. …Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (-14.6) versus olanzapine (-9.4, P<.001) versus fluoxetine (-10.7, P=.006) versus venlafaxine (-14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low-dose OFC all appeared to be similarly effective.
|
|
A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine in treatment-resistant major depressive disorder.
by Thase ME, Corya SA, Osuntokun O, Case M, Henley DB, Sanger TM, Watson SB, and Dubé S. Journal of Clinical Psychiatry. 2007 68[2]:224-36. …Patients with TRD [defined as treatment failure on 2 antidepressants] taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination> is an efficacious therapy for patients with TRD.
|
|
Quetiapine [Seroquel]
|
|
Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study.
by McIntyre A, Gendron A, and McIntyre A. Depression and Anxiety. 2007 24[7]:487-94. …Here quetiapine was shown to be effective as augmentation of SSRI/venlafaxine therapy in patients with major depression, comorbid anxiety, and residual depressive symptoms, with no unexpected tolerability issues. Further studies are warranted.
|
|
Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study.
by Bauer M, Pretorius HW, Constant EL, Earley WR, Szamosi J, and Brecher M. Journal of Clinical Psychiatry. 2009 Apr;70[4]:540-9. …Adjunctive quetiapine XR [150 mg/day and 300 mg/day] was effective in patients with MDD who had shown an inadequate response to antidepressant treatment. Significant reduction of depressive symptoms occurred as early as week 1. Findings were consistent with the known safety and tolerability profile of quetiapine.
|
|
Extended-release quetiapine fumarate [quetiapine XR] as adjunctive therapy in major depressive disorder [MDD] in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study.
by El-Khalili N, Joyce M, Atkinson S, Buynak RJ, Datto C, Lindgren P, and Eriksson H. International Journal of Neuropsychopharmacology. 2010 13[7]:917-32. …In this study, quetiapine XR 300 mg/d as adjunctive therapy in patients with MDD with an inadequate response to ongoing antidepressant treatment was effective at week 6. However, the difference from placebo for quetiapine XR 150 mg/d at week 6 was not statistically significant. Both doses studied [150 and 300 mg/d] were effective at week 1 and generally well tolerated.
|
|
Risperidone [Risperdal]
|
|
Risperidone for treatment-refractory major depressive disorder: a randomized trial.
by Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, and Gharabawi-Garibaldi GM. Annals of Internal Medicine. 2007 147(9):593-602. …Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures.
|
|
Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study.
by Reeves H, Batra S, May RS, Zhang R, Dahl DC, and Li X. Journal of Clinical Psychiatry. 2008 69[8]:1228-336. …Data from this pilot study suggest that risperidone is beneficial as an augmenting treatment in MDD patients who have developed high-risk suicidal ideation during a depressive episode. The antisuicidality effect of risperidone is especially valuable in the acute management of severe depressive symptoms. Although the pilot study is limited by small sample size, the promising results warrant further larger scale investigation in the efficacy of atypical antipsychotics in the treatment of severe depression with suicidality.
|
|
A randomized, placebo-controlled trial of risperidone augmentation for patients with difficult-to-treat unipolar, non-psychotic major depression.
by Keitner GI, Garlow SJ, Ryan CE, Ninan PT, Solomon DA, Nemeroff CB, and Keller MB. Journal of Psychiatric Research. 2009 43(3):205-14. …Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life.
|
I would be interested to know how long the Keitner et al RCT was – as this enabled them to conclude so confidently that: “Augmentation of an antidepressant with risperidone for patients with difficult-to-treat depression leads to more rapid response and a higher remission rate and better quality-of-life. Some claim, presumably based on a few weeks?
Mick,
4 weeks!
Dear Mickey,
This is somewhat off topic, but I came across it a few days ago.
http://www.nytimes.com/2013/03/14/health/fda-to-ease-alzheimers-drug-approval-rules.html?pagewanted=all&_r=1&
If i had to guess, I’d say bribes were probably involved, and it may be an attempt to prevent drugs that may actually work from taking away the psychotropic drug market. It is disturbing that the FDA’s change in requirements for clinical trials means we should expect to see amphetamines and other psycho-stimulants get approved for Alzheimers in the near future, if this goes through.
If psychiatrists, and all others that prescribe psychoactive drugs (and drugs that aren’t used to treat psychiatric problems, but can have psychiatric effects) were properly educated and honest about the effects of those drugs, were vigilant toward the effects of drugs on their patients, encouraged the patients to report effects, and informed the patient about all of this clearly and honestly; then it would be perfectly o.k., in my opinion, for them to tell a patient something like
I see that you’re overwhelmed right now and are having trouble getting needs met for yourself and those you are responsible for; we could try ______________ to turn those feelings down so that you can function well enough to keep from the kind of ground that could have a catastrophic impact on you and your family— losing a job, inability to adequately care for yourself and your charges, etc.
I also recommend that you see a counselor, and perhaps a social worker to help you get back on top of things. I’d be happy to give you some referrals.
Ideally, the patient would see a general practitioner first to rule out common conditions that can be mistaken for depression or mood swings.
Discuss the risks of the drug, and how to get off of the drug, before the patient makes a choice. Make appointments to track this patient’s experiences on the drugs. DO NOT GIVE A PATIENT AN INDELIBLE LABEL AFTER ONE VISIT (or ten, unless the patient clearly needs hospitalization and has no to very little capacity for self-care or to be sufficiently lucid to function).
Drugs used judiciously and voluntarily with truly informed consent can help immensely.
I think what we’re all seeing in these studies is that almost everything that the institution of bio-psychiatry KNOWS about treating “mental illness” is false.
One. big. epistemic. failure.
Thanks for that Mickey. After just 4 weeks. Absurd.
Do you know when “Treatment Resistant Depression” was first used and by whom?
The documentary Mea maxima culpa: Silence in the House of God, about sexual abuse of children by pedophile priests in the Catholic church, priests protected by the Vatican, is a reminder of how easily hierarcical systems of authority and power may suppress crimes perpetrated by the mighty against the young and the vulnerable. The parallells to Big Pharma fraud and the church of Kreapelinian biopsychiatric wrongs are obvious, as remedies of public protest, exposure and strategic litigation, advocated by Alaska lawyer of Zyprexa trial fame Jim Gottstein.
To the question of when the term treatment resistant depression originated: it’s been around for over 50 years. The first publication I could locate appeared in 1959, followed by half a dozen or so in the 1970s. Sometimes it was termed refractory depression. So today’s KOLs didn’t invent the term – they just ran with it in selling experimercials. Charles Nemeroff is on record at one point in opining that 40% – 50% of depressed patients have treatment resistance. He looked to the STAR*D study for support. As I have said before, evidence based medicine needs medicine based evidence – and STAR*D isn’t it.
A few questions here:
1. How did the choice of Celexa for STAR*D be made as the first line of treatment when it is now being vilified by the FDA for dosages above 40mg? Oh, and how did Lexapro escape any mention as a sister med for all these cardiac arrhythmia matters? Wow, what a dump that turned out to be.
2. Treatment Resistance is defined solely by mood symptoms, or, just conveniently minimizing or ignoring comorbid factors, like, Axis 2? And resistance is defined solely by lack of response to medication?
3. Why has the protocol of using traditional antipsychotics in mood disorders past like Haldol, Navane, Stelazine gotten lost with the novel ones when the plan was to wean and discontinue such antipsychotics when psychotic features dissipated?
The fourth question I have asked repeatedly since first commenting at blogs: why do psychiatrists tolerate corruption? Oh yeah, hard to look away from that mirror.
Still want to know, did I miss the introductory lecture in residency that told every new group that paternalism, arrogance, and intolerance of alternative ideology are the standards of behavior and choice in becoming a psychiatrist in general? If this is true, glad I came late to the program! Unfortunately, too late to make a difference either!
… too late to make a difference, dr Hassman?
I see it differently. Any honest, careful person/doctor/therapeut sincerely trying to connect with her/his patients may make a difference. Kindness, understanding, humility, faced with the many ills of mankind, do make a difference!
Arrogance and paternalism are signs of insecur power, I think.
Thanks Bernard Carroll for answering my question!
Treating Alzheimer’s is the new pharma gold rush. Who wouldn’t take a neuroactive medication daily for years to reduce the risk of this dread disease by a percentage point or two?
Ninan PT (Philip Ninan), a co-author of the Keitner, 2009 risperdone paper, was then Vice President of Wyeth Medical Affairs, Neuroscience. He also shepherded Pristiq through the FDA approval process — Pristiq, coated time-release desvenlafaxine that comes in only two dosages, 50mg and 100mg, affording no way to taper off.
Ninan knew full well the hazards of going off Pristiq, Effexor’s sibling. In this 2008 interview: http://psychcentral.com/blog/archives/2008/06/23/wyeths-dr-phil-ninan-on-pristiq/
Hi,
I totally agree that every new habit begins with mental shifts, Best Practices, LLC is a research consulting firm, leading in the field of business benchmarking services, we focus mainly on pharmaceutical, medical device health care industries If you want to know more about it then please Follow the link http://www.best-in-class.com/bestp/domrep.nsf/products/700DEAC70570BE208525751A0055636A!OpenDocument