A number of recent studies have shown this. I've noted some important questions over how we ought to define "severe" in this context, and see the comments here for some other caveats, but I'm not aware of any studies that directly contradict this idea.
Until now. A new paper has just come out which seeks to challenge this dogma - not the author's term, but I think it's fair to say that the severity theory is becoming a dogma, even if it's an evidence-based one (but then, all dogmas start out seeming reasonable).
However, while the new paper is interesting, I think the dogma survives intact.
The authors went through the archives of all of the trials of antidepressants for depressive disorders conducted at the famous New York State Psychiatric Institute for the past 30 years. They excluded any patients who were severely depressed, and just looked at the milder cases. The drugs were mostly the older tricyclic antidepressants.
With a mean HAMD17 score of about 14, the patients they looked at were certainly mild. By comparison, most trials today have a mean of well over 20, and according to the main studies supporting the severity dogma, you need a score of about 25ish to benefit substantially:
So what happened? They reanalyzed 6 trials with over 800 patients. Overall there was a highly significant effect of antidepressants over placebo in mild depression, with an effect size d=0.52, or about 3.5 HAMD points. This is actually better than most other studies have found in "severe" depression. If valid, these results would torpedo the severity theory.
This seems very interesting... but. There's a big but (I cannot lie). Although the authors say they wanted to include all the relevant trials from the NYSPI, they only had access to the data from 6. There were another 6 projects, but they were "pharmaceutical company studies from which data were not released to the investigators."
This pretty much wrecks the whole deal. If those 6 studies all found no benefit of the drug, the overall average results would be much less impressive. We have no way of knowing what those studies found, but I'd wager that most of them were negative, because of publication bias - we know that drug companies tend to publish positive studies and bury negative ones. Or at least they did, at the time these studies took place (there are better regulations now).
By contrast, severity dogma classic Kirsch et al (2008) avoided publication bias by looking at unpublished data. Fournier et al (2010), the other major severity study, didn't but the data were very similar to Kirsch et al so it's not hard to believe them.
So in my view, until we know what happened in the other 6 trials, we can't really interpret these results, and the severity theory stands.
Stewart, J., Deliyannides, D., Hellerstein, D., McGrath, P., and Stewart, J. (2011). Can People With Nonsevere Major Depression Benefit From Antidepressant Medication? The Journal of Clinical Psychiatry DOI: 10.4088/JCP.10m06760
23 comments:
Thanks for the Sir Mix-a-Lot reference
There's another big but. Tricyclics have many more (and more serious) side effects than "modern" antidepressants. So the breaking of blind is obviously a much bigger problem than in RCT's of the latter.
That's why trials comparing tricyclics with an "active placebo" (v.gr. atropine) are so important. Moncrieff made a review of all the available trails of such kind. Results were pitiful.
rob: Thanks for getting it, I was worried no-one would...
A great post, as usual.
Really simple answer: The criteria for depression are an amalgamate of observational (i.e. unscientific) data garnered over time, used to create tests which are circle confirmed to be correct reinforcing the same mess that was there in the first place. Like most other disorders, syndromes and spectra in them.
With books like the DSM you can go anyway you want and always be right and wrong at the same time.
Solution is simple. Scrap the diagnostic criteria annuals and start from scratch.
I thank you so much for your continued writing about these subjects and sharing your expertese. I think there are many avenues of supporting people with mental illness that we have not done enough rigrous research on other than a pharmecuetical model of best treatment. THAT SAID-- many of those potential treatments would involve comprehensive support because people with mental illness often do not have the internal drive to keep up with lifestyle changes and the level of hands on professional support required is not currently cost effective.
I think we could change this and the investment would be worthwhile, but until we have more solid research on what sorts of environmental supports (I'm a believer in evidence based environmental enrichment, emotional support, diet, therapeutic activity, life functioning physical/cognitive/emotional assessment and therepeutic skill building of problem areas, and meditation/biofeedback/etc) it does not make sense to make the costly shifts without certainty that these would have the same level of success we see with meds EVEN IF those successes were entirely placebo based. (I doubt they are entirely placebo based but that doesn't mean they are the best solution long term). I am dissapointed in the lack of research anywhere on pharmaceutical effects over 20 to 30 years which many people are on these meds for. (Or more.) The difficulty with finding a way of comparing results of various interventions over 20 to 30 years is obviously firstly that 20 to 30 years studies are almost impossible to achieve, but also that there is no alternate treatment available for severe mental illness that we can reliably give to patients that wouldn't be putting them at risk of recieving inaddequate treatment-- i.e. the ethics of putting someone with severe mental illness on a 20-30 year treatment plan that is not evidence based are sketchy at best. That said because we DON'T HAVE such research, it's hard to figure out what is an effect of pharmeceuticals per se, vs the effect of the underlying condition even while on the drugs, vs how a non-pharmecuetical intevention program would compare over the long term.
Frustrating. Anyway thanks as usual for an interesting read.
Couldn't you get enough improvement to show positive results just from the fact that TCAs make you fat and sleepy? Thats a big chunk of the HAM-D right there.
Anonymous: Yes, that's a big concern, although actually in this case it's less likely to be the explanation than in severe depression.
If your baseline HAMD17 score is 14, it's unlikely that you'll have many points on the sleep items. There just aren't that many points to go round.
Whereas if youre HAMD17 is 25, you could have loads of sleep points and still have plenty left over for the other symptoms.
Thanks for another informative and useful post. I think we need all the tools we can have for mental illness, and I know that many people have been helped by antidepressants who may not have been "severely" depressed. Dysthymia can really disrupt a person's life. I don't mean to repeat a cliche here, but treatment saves lives. And we need all the information on available, viable treatments we can get.
@Tianeptino ; Are you a drug company rep. Your statement about Tricyclics is pharmaceutical company disinformation. A study of patients 65 and older in the UK published this summer in the BMJ compared the incidence of serious side effects between 3 groups: SSRIs, TCAs, other secong generation antidepressant using one year mortality as their measure of serious side effects. The group with lowest 1 yr mortality were those treated with TCAs. Many of the SSRIs, have high incidence of Torsade de Pointes which caused Celexa to require a black box warning. STAR D reveals the ineffectiveness of SSRIs. Anyone who understands research would never accept any drug trials by pharmaceutical companies. While there have numerous studies of TCAs by disinterested i.e. not working for a pharmaceutical which showed a 45-50% improvement of patients over the response to placebos. STAR D shows SSRIs when studied by researchers who aren't in bed or directly work for big Pharma Celexa and therefore all SSRIs are very likely at best barely more effective than placebo if studied objectively.
Anonymous, I'm not a drug rep. I'm a psychiatrist who won't see a drug rep or accept a pen from Pharma.
Maybe my English isn't good enough, or maybe you just got my post all wrong.
I'm aware of everything you're saying. And I know SSRIs have turned out to be just as (or even more) dangerous in old people as TCAs. I just meant that TCAs' adverse effects are far more common and evident than SSRIs' adverse effects. (If you have any doubt, try them both in the usual "antidepressant" doses).
That's why there's no such thing as a *double-blind* RCT of a TCA vs placebo. In such trials, everybody knows what they're taking, so the results are obviously not reliable. And this study reviewed by Neuroskeptic is mainly based in such kind of trials.
That's why I mention Moncrieff's review of trials of imipramine vs atropine (active placebo), which results are really sad news for TCA fans (at least in what is called "major depression", which is in my opinion a nosological aberration).
Am I making myself clear?
Regarding STAR*D, things have turned out to be much worse than many had thought...
http://www.psychologytoday.com/blog/mad-in-america/201008/the-stard-scandal-new-paper-sums-it-all
I hope you see where I come from now.
I think the placebo-controlled blah blah trial is the wrong paradigm to study any drugs designed to have an effect on mental life. It's been well borne out that anti-depressants and anti psychotics etc can have different effects on different people in different doses without much reference to severity in the first place. I won't bother to quote here, but I could do a whole blog on it! Secondly, questionnaires about symptoms can be OK for the first or a few times, but repeated administration tends to make people more random or more extreme in attempts to try and differentiate amongst the occasions they have been asked. As both a depression sufferer and a mental health researcher I've seen this from both sides of the fence. Much better measures would ask about daily functioning, and where possible, include some observational items completed by others. Individuals feel depression in many different ways- some feel "empty", others feel "thwarted" and others feel "not wanting to exist", others just "overwhelming sadness & crying". However, we all have to function to achieve continued life and the degree to which we can get up, stay clean, prepare food, eat, excrete, get out of the house, keep our home environment acceptable for living and interact with others is the real measure of our lives, no matter how we describe our feelings.
I would recommend that anyone who fulfills the current criteria for even mild depression who does not improve with social contacts/several talking appointments should be offered a medication. THEN the chase begins to find a drug and a dose that starts to work.
The psychiatrist's standard method of choosing a drug they think suitable and pushing the dose to the maximum seeking an effect, is as good as any. Primary care doctors who only try the recommended usual dose and then switch are not doing much good. They need to quickly push to the maximum they are allowed to prescribe and then refer if a significant improvement has not yet occurred. IF the main care provider is a psychologist, ideally they need to set functional criteria for their client and refer for medication assessment if mood is unresponsive or sub-optimal. Most medically trained people these days seem to recognise that talking therapy to supplement medication can be just as well delivered by a clinical psychologist.
Therefore, I'm ignoring the "anti depressants only good for severe depression" crowd and voting with my intuition!
Murfomurf: I completely agree about the problems with quantifying depression. I think some kind of "functional" measure would be a very useful addition to the current symptomatic measures; but it would be difficult to make a good one.
It's easy to make a bad functional measure - "Did you go to work today YES/NO", that kind of thing. But that misses all the subtleties.
Murfomurf, I could write a whole blog about doctors who don't give a crap about evidence and do whatever they just feel like doing ("intuition").
petrossa ,
Thanks for what you wrote commenting that post.
Murfomuf,
Not only neuroskeptic chooses wisely his subject of posts and writes out beautifully for a very vast audience his well informed and prepared mind
but reading his generous work makes one discover interesting blogs like yours.
Still, I hope it didn't escape you that doing some kind of physical exercice is recognized by competent physicians as the first treatment for depression as the NICE recommandations showed.
Of course, I know the objection the psychologists used frequently against exercice therapy -they use the same with mindfullness: not practical with severely depressed people.
I heard a very clever and nice well informed British GP depression sufferer telling an audience of psychologists and psychiatrists and some clients interesting or working "in recovery " that for her to cross the street to go and buy a coffee from Starbuck was a challenge when depressed.
To that kind of objection I had - in the times where an academic husband working in intensive care agreed to sign my prescriptions on his prescription pads -a trick who was to prescribe physiotherapy three times a week with a letter asking the physiotherapis to obtain as much sweat and muscular work as possible.
This exercice approach can work sometimes beautifully even with a severely depressed person providing you have family members and/or significant other able to protect your client and yourself from suicidal attempt.
Often enough homeopathy also works and it is not "severity of symptoms related" in my experience.
I cannot figure out why academics do not start to follow the lead of Pr Nemeroff and do their best to study different kind of depressed people to make groups for drugs and other treatment trials.
What he says to believe and test is that depression in persons with a big childhood trauma story is not rezsponding to drugs but only to psychoatherapy.
NB: I do not know personaly Pr Nemeroff and I am fully aware that Pr Nemeroff is no saint and has been in trouble at Emory for making a lot of money from Big Pharma. I know that I am not immune to his considerable personal charm-who can be?
Neuroskeptic,
I hope that your psychiatrist and GP insist at each visit about your moving more muscles than the forearm muscles needed to work your computers and noisy machinery
and the little muscles exercise needed for bodily maintenance (like for example eating) plus moving around town to go to work and to amuse yourself.
- since you told us about your psychiatrist or GP is insisting on seeing you every month as you wrote complaining about the fact that the prescriptions of your two beloved antidepressant drugs are only for one month duration although you do not plan to change itin the years to come… - Bless your psychiatrist and beware neuroskeptic that you are a very respected person and a role model for many people outhere I am sure!
I would also dearly like to know if it is possible- outside France- for physicians to prescribe physiotherapy at the client's home with private practice physiotherapists able to visit the clients' home until the physician decide that the client has to visit the physiotherapist at the private practice premises of that physiotherapist unless the MD civil servants working for the French social security services had written to the physician prescriber of physiotherapy that it is not a psychiatrist business to prescribe physiotherapy or that a GP has made the French social security to spend too much on physiotherapy.
(-in France the social security system is giving back to the client most of the money involved in paying the private physiotherapist coming to the client's home and the private practice GP or psychiatrist or whatever fees but as soon as possible the physiotherapist will ask you to prescribe that the client has to go to the physiotherapist private practice premises because the social security gives ludicrous little money for physicians or physiotherapists or whatever visiting the clients ‘homes)
Unfortunatly, the French medical gestapo never ever accepted that I could be getting continous medical education in GB and America or wherever outside of France. They are trusting the psychonalysts about the mental health of their nation. Do not get me wrong then and assume that the French labeled depressed people by physicans get free and safe physical exeecice at home if needed from physiotherapists.
Also, may I remember everyone that hormones are playing a big role in moods and that testosterone can in some persons be very active in relieving -in men and women- lack of libido.
For those interested the Royal college od psychiatrists and the RC of ostretricians and gynecoloigists (whatever how you spell that professions) had the very nice idea to make a joint effort in a:
"" Hormones and Mood Disorders in Women Conference ""
Joint RCOG/RCPSYCH Meeting to be held at the RCOG place on the 26th of January 2012.
Also worth reading:
Bianchi M et Baulieu EE.3ßMethoxypregnenolone
(MAP4343) as an innovative
therapeutic approach for depressive
disorders. Proc Natl Acad Sci USA (2012).
Pr Étienne-Émile Baulieu is a great scientist-the discover of RU-486 used as a post-coital contraception , a tumor treatment. He is involved in research on neurosteroid now. This publication suggest new approaches to hormonal treatment of depression. Using MAP4343 (3ß-Methoxy-pregnenolone), a neurosteroid acting on MAP2
(Microtubule Associated Protein) and beware for those who believe in the hippocampus dogma for depression that modifications of the MAP2 expression in the hippocampus has been advanced in the mechanism of depression! And no in vitro affinity of MAP4343 for the neurotransmitters involved in the simplistic Big Pharma propaganda about antidepressant drugs activity dogma. Massimiliano Bianchi and Pr Étienne- Émile Baulieu (Mapreg SAS, Le Kremlin-Bicètre) injected once Sprague-Dawley adult rats groups with either MAP4343 at a dosage of 4, 10 or 15 mg/kg, or fluoxétine (an ISRS antidepressant Big Pharma drug better known as Prozac, Sarafem, Fontex) 10 mg/kg or a placebo injection.
Their published rats results using the forced swimming test with MAP4343 working as well as fluoxetine at 4mlg and 10mg/kg but not for MAP4343 at 15mg/kg. More interestingly to my mind they also used the Rat Isolation-Rearing-Model and found their MAPP4343 giving more long lasting results in NOR test (exploring some memory) than fluoxetine and they found their MAP43473 to give more benefits on anxiety.
Of course Pr Beaulieu is not young man and many people will use that to despise his work and it is only a rat study but worth reading by people more competent than poor I about rats study.
I wish neuroskeptic will do a post on it.
Please –especially physicians readers of neuroskeptic - keep present also that a loss of libido might be cured sometimes in male and female persons with testosterone only- no matter how effective you might have been on other depressive symptoms complaints with estrogen therapy in some post-menopausal women.
For those interested , some of you might make it to attend the
“Hormones and Mood Disorders in Women” conference
to be held on the 26th of January in London by the Joint effort of the Royal College of Obstetricians and Gynaecologists and the RCPSYCH.
Also, last but not least, worth reading:
Bianchi M et Baulieu EE. 3ß-Methoxypregnenolone(MAP4343) as an innovative therapeutic approach for depressive disorders. Proc Natl Acad Sci USA (2012)
Pr Étienne- Émile Baulieu published recently suggesting a possible new approaches to hormonal treatment of depression. Using MAP4343 (3ß-Methoxy-pregnenolone), a neurosteroid acting on MAP2
(Microtubule Associated Protein) and beware for those who believe in the hippocampus dogma for depression that modifications of the MAP2 expression in the hippocampus has been advanced in the mechanism of depression! And no in vitro affinity of MAP4343 for the neurotransmitters involved in the simplistic Big Pharma propaganda about antidepressant drugs activity dogma. Massimiliano Bianchi and Pr Étienne- Émile Baulieu (Mapreg SAS, Le Kremlin-Bicètre) injected once Sprague-Dawley adult rats groups with either MAP4343 at a dosage of 4, 10 or 15 mg/kg, or fluoxétine (an ISRS antidepressant Big Pharma drug better known as Prozac, Sarafem, Fontex) 10 mg/kg or a placebo injection.
Their published rats results show on the forced swimming test MAP4343 working as well as fluoxetine at 4mlg and 10mg/kg but not at 15mg/kg. More interestingly -to my mind -they also used the Rat Isolation-Rearing-Model and found their MAPP4343 giving more long lasting results in NOR test (exploring some memory) than fluoxetine and they found their MAP43473 to give more benefits on anxiety.
neuroskeptic,
Please cancel one of those 21 01 12 comments of mine: I wrote it twice because I thought I was the victim of "selective spammage" as you put it previously to another commentator.
Please choose for me the one to cancel I trust your English and kindness for that choice .
From a bright boy who gives first hand testimony about many drug treatments (including antidepressants neuroskeptic):
Twelve-year-old Ke’onte Cook Testifies in US Senate Hearing
Americahttp:
//d1078319.site.myhosting.com/?p=3079
This blog is NEUROSHIT
Hmmm. Not bad. Got a certain elegance to it. Not as good as "neuroseptic" or "neuroskepdick" though.
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