Skip to comments.Antidepressants Beat Placebo Only for Very Severe Disease
Posted on 02/10/2010 5:15:40 PM PST by neverdem
The efficacy of antidepressant treatment over placebo for major depressive disorder varies considerably, depending upon symptom severity, according to a meta-analysis.
Only patients whose depression is classified as very severe appear to have a greater benefit from antidepressants than from placebo pills, according to the study by Jay C. Fournier of the University of Pennsylvania, Philadelphia, and his colleagues (JAMA 2010;303:4753).
Most placebo-controlled studies of antidepressants specifically exclude individuals who score below 23 on the Hamilton Depression Rating Scale (HDRS). HDRS scores of 813 indicate mild depression, scores of 1418 indicate moderate depression, scores of 1922 indicate severe depression, and scores of 23 or above indicate very severe depression.
In addition, many antidepressant studies include a placebo washout period in which all patients receive placebo pills for several days to 2 weeks before randomization. Often, patients who improve by 20% or more in the HDRS are excluded from the trial. Removing known placebo responders at the outset is thought to enhance the statistical power of the antidepressant-placebo comparison. This design feature severely limits the ability to generate accurate estimates of the placebo response rate, wrote Mr. Fournier and his colleagues, noting that the true rate of placebo response may be underestimated in trials that use this feature.
To determine the true placebo response rate across the entire range of depression severity, the investigators combed the literature for randomized, controlled studies of minor depressive disorder that did not include a placebo washout period.
Of the 2,146 randomized controlled trials of depressants published in English from January 1980 to March 2009, only 23 studies met those criteria. But only six of those studies could provide patient-level data to the investigators. It was those six studies, comprising 434 patients in antidepressant groups and 284 patients in placebo groups, that were the subject of the meta-analysis.
Actually, most meta-analyses include only group-level data. A study such as this one that includes patient-level data is called a mega-analysis. This approach allows investigators to conduct a more fine-grained multivariate analysis.
Three of the six studies used imipramine, a tricyclic antidepressant, and the other three used paroxetine, a selective serotonin reuptake inhibitor. The mean baseline HDRS score in the studies ranged from 14 to 24.
As expected, the higher the patient's baseline HDRS score, the more improvement was seen with both the active drug and the placebo. A difference of 3 points or more on the HDRS is considered clinically significant. It was only at HDRS baseline levels of 25 and above that active drug was both statistically and clinically better than placebo. This finding was the same for imipramine and paroxetine.
The investigators wrote that in marketing antidepressants, pharmaceutical manufacturers rarely mention that most efficacy studies specifically exclude patients who derive little benefit from their medications.
Commenting on the meta-analysis, Dr. Eric G. Tangalos emphasized that conclusions based on studies published as early as 1980 might not be relevant to current medical practice. Papers published in the 1980s took their data from clinical practice in the 1970s, and papers in the 1990s took their information from the 1980s. SSRIs, which are the current mainstay of therapy, did not emerge until the 1990s. Prior to the advent of SSRIs, physicians were reluctant to even identify depression because the available treatments (MAO inhibitors and, later, tricyclics) carried so many serious side effects, said Dr. Tangalos, professor of medicine at the Mayo Clinic in Rochester, Minn. He reported no relevant conflicts of interest.
The National Institute of Mental Health funded the study. Mr. Fournier stated that he had no relevant financial conflicts. Several of the other investigators did report financial relationships with several pharmaceutical companies.
Antidepressant Drug Effects and Depression Severity
The study illustrates a common difficulty in extrapolating the results of randomized controlled trials to real-world practice. RCTs are designed to focus in on narrow populations to prove the effectiveness of a method or intervention, yet the results are generalized (in part by clinical need and in part by pharmaceutical company marketing efforts) to larger populations, such as patients with milder types of depression not represented in studies.
Patients in antidepressant studies are often not representative of all the patients we treat in family medicine. Study patients are volunteers and are generally more treatment motivated and may be more likely to respond to placebo. Placebo patients get a lot of attention and frequent follow-up and monitoring. This is typically much more attention than patients receiving no treatment in real-world practice.
Publication bias in antidepressant studies is known to exist. Two studies published in 2008 (by Turner and Kirsch) demonstrated how the exclusion of unpublished trials in analyses and the emphasis on positive studies rather than negative ones, resulted in an overestimation of antidepressant effectiveness. The current JAMA study adds weight to this concern.
Despite these limitations, I still believe that antidepressants are reasonable choices for family physicians to consider. The Fournier analysis concluded that the number needed to treat with antidepressants to achieve one additional remission compared with placebo ranged from 4 for very severe depression to 16 for milder depression. A NNT of 16 is consistent with other studies' estimates of antidepressant treatment effectiveness and is in the ballpark for treatments of other conditions.
The preponderance of evidence (supported by the Fournier analysis) shows that antidepressants are effective for severe depression. In fact, combining antidepressants and psychotherapy is most effective in severely depressed patients. None of the studies in the Fournier analysis compared antidepressants to psychotherapy.
Our Kaiser Permanente national guideline systematic review found that psychotherapy and antidepressants are equally effective for mild to moderate depression. Patients may not have access to trained therapists, or might not choose psychotherapy if offered. However, shared decision-making studies show that we tend to overestimate our patients' preference for medication.
Many patients, especially those from different cultural or ethnic backgrounds, will choose or prefer psychotherapy if offered, so one of the lessons from this study is to ask the patient before whipping out the prescription pad.
DR. DAVID PRICE is depression clinical lead for Kaiser Permanente's Care Management Institute in Oakland, Calif., and professor of family medicine at the University of Colorado, Denver. He reports having no conflicts of interest.
(The 'My Take' section commentary came with source article. I separated it for clarity.)
The both/and isn't discussed here, oddly. Many patients get a combination of counseling and medications.
The placebos however don’t have the benefit of turning you into a drug addicted mass murderer like the real thing.
Also, is Tofranil and Paxil the best they could do? The old tricyclics had a reputation of being weaker than the even older (but hypertension risky) MAO inhibitors, and SSRIs often generate unacceptable side effects.
But they can rot your teeth :-)
Except for rare situations, antidepressants should only be used short term, followed by clinically monitored withdrawal. Long term kneejerk use has literally created a passive, hypocritical society of zombies unable to feel anything other than their own immediate desires, who erupt with murderous rage the moment they are thwarted in the smallest thing. For this reason, the street name for antidepressants are “soul suckers.”
These clinical aspects also, however, perfectly explain liberal behavior - and virtually all liberals are on antidepressants.
This guy at work just missed his meds one day and got fired. Modern “Meds” are truly mind altering in a bad way.
At a party, I went through a window 4 stories up, while holding a small African green monkey, we both landed on this guys hot dog cart...Both survived.
I agree. I tried them, and I hated the way I felt on them. They make you not give a damn more than they make you happy, and if modern society gives a damn a little less than it does already, we’re all in trouble. I know a few people who are on both anti-anxiety meds and anti-depressants, and they’re these devil may care, shallow, platitude spouting fluff heads, who don’t give a tinker’s damn about personal responsibility in their life anymore. Their life’s not any less screwed up, it just doesn’t bother them anymore.
I would prescribe skydiving or some other extreme sport for depression. It is pretty hard to be depressed when your life is on the line and it is completely up to you to ensure you survive. And even if you fail, you will have cured your depression. Its a win win treatment.
It's an absolute joke to call this study a "meta-analysis" or to attempt to draw any conclusions from it about "antidepressants" in general. This study ended up considering only 6 of 2134 randomized controlled studies published over the past 30 years, and these 6 studies only represented 2 of the many antidepressant drugs currently in use, which happen to be the 6th and 13th most frequently prescribed (paroxetine is 6th and imipramine 13th). Together these drugs represent less than 10% of antidepressant prescriptions (2007).
And as the article notes, some of the data (particularly on imipramine, which was what 3 of the studies used) is probably from the 1970s or 1980s, before the newer antidepressants were available. To the extent that any of these studies were recent, they almost certainly were heavily weighted with patients who had already tried and failed other antidepressants -- normally the only reason a doctor would prescribe a rarely used antidepressant is when the more commonly prescribed ones have already been tried and failed for the patient in question. If any of these studies actually screened out such patients and were also done in recent history, then the doctors doing the prescribing were real oddballs, whose ability to diagnose depression accurately would be in question.
This is junk science, but it's hardly the first time JAMA has published junk science. I'm sure there is a significant placebo effect from antidepressants (as there is from most drugs), but this sloppy study doesn't illustrate anything of the sort.
Exercise is usually very effective for depression, but there are a lot of people who can’t do it in any meaningful way, due to other medical conditions/injuries. In a lot of cases, the inability to exercise as one used to is at the root of the depression.
My SIL is addicted to Zanax. She freaks out if she thinks she may have to go one day without. 30+ years of the stuff, non stop.
Irony is that my wife has shown her the literature on physical side effects from long term addiction. And she suffers from a bunch of them. She refuses to believe that all these other problems can be tied to the Zanax, she is convinced she will literally die without the drug.
Sad thing is, her life totally sucks (unnecessarily, pretty much all of her own doing). A month in her shoes and I’d be suicidal. But she refuses to do anything for herself, just give me my Zanax and leave me alone. It’s depressing just being around her.
PS: One of the best ways to evaluate the non-placebo effects of drugs is to see how they work in animals. I can personally attest to the efficacy of amitriptyline (9th most frequently prescribed antidepressant in the US in 2007) in cats. Many years ago, I had a dear little kitty who had, um, “issues”. The manifestation of these issues which prompted intervention with psychoactive drugs was a habit of peeing on things to get attention — even though he knew full well the attention would be in the form of getting walloped, and to express anger (ditto on the consequences). This cat would pee on the coffee-maker (only when someone was making coffee), pee on the sugar bowl (only when someone was eating at the table upon which the sugar bowl sat), pee on the cable box on top of the TV (only when someone was watching the TV), and would also pee on any object left where it didn’t belong (that one didn’t bother me at all — made for a tidy house, since people quickly learned not to leave backpacks lying on the living room floor, etc). If somebody shut him out of their bedroom at night, he’d leave a giant puddle right in front of their door.
ALL of this behavior stopped immediately when he was put on amitriptyline, which apparently relieved whatever kitty depressions and anxieties were triggering the non-stop pee-assaults. Unless the kitty managed to understand the conversation between me and the vet, and thus understood what the thing getting pushed down his throat every day was *supposed* to do, and also *wanted* to achieve this effect (even less likely than understanding the conversation and the effects the humans were hoping for), then this wasn’t a placebo effect.
The elimination of placebo responders in the test sample is not wrong; it is an attempt to reduce error in the data set, as is the truncation of Hamilton scores. The mushy middle never proves anything, and only promulgates error in the literature.
Good research is hard, and shouldn't be tried at home by amateurs.
Atypical antidepressants, like Wellbutrin, have very low side effect profiles and efficacy comparable to the SSRI's.
Anyway, I know what it's for. Xanax is used to treat anxiety disorders, panic disorders, and anxiety caused by depression. All of which she appears to have. And more.
Unfortunately, any doctors that suggest a more reasoned/balanced approach to her mental problems are ditched ASAP.
What’s worse, giving damns about the wrong things, or not giving damns at all.
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