New Study Shows Antidepressant Medication Fails to Help Most Depressed Patients

A very interesting study recently published in the Journal of the American Medical Association (JAMA) demonstrated very clearly that when it comes to antidepressant medication, the Emperor is wearing few if any clothes! The researchers did what is called a meta-study or meta-analysis. They searched the research literature for all studies that were placebo-controlled studies of antidepressants when used for depression. That means the studies had to include random assignment to either a medication group or a placebo (sugar pill) group. They eliminated some studies which use a placebo washout condition. (This means the studies first gave patients a placebo, and then eliminated all patients who had a 20% or greater improvement while taking placebo.) When they eliminated all studies that didn’t meet their criteria, they were left with 6 studies of 738 people.

Based on scores on the Hamilton Depression Rating Scale (HDRS), the researchers divided the patients into mild to moderately depressed, severely depressed, and very severely depressed. This is a 17 item scale that is filled out by a psychologist or psychiatrist, and measures various aspects of depression. It is used in most studies of depression. They then analyzed the response to antidepressant medication based on how severe the initial depression was.

The two antidepressants studied were imipramine and paroxetine (Paxil). Imipramine is an older, tricyclic antidepressant, and Paxil is a more modern SSRI antidepressant.

What did they find? They were looking at the size of the difference between the medication groups and the placebo groups. Rather than do the typical thing of just looking at statistical significance, which is simply a measure of whether the difference could be explained by chance, they looked at clinical significance. They used the definition used by NICE (National Institute of Clinical Excellence in England), which was an effect size of 0.50 or a difference of 3 points on the HDRS. This is defined as a medium effect size.

What they found was very disheartening to those who use antidepressant medications in their practices. They divided the patients into three groups based on their initial HDRS scores: mild to moderate depression (HDRS 18 or less), severe depression (HDRS 19 to 22), and very severe depression (HDRS 23 or greater).

For the mild to moderately depressed patients, the effect size was d=0.11, and for severely depressed patients the effect size was d = 0.17. Both of these effect sizes are below the standard description of a small effect which is 0.20. For the patients in the very severe group, the effect size was 0.47 which is just below the accepted value of 0.50 for a medium effect size.

When they did further statistical analysis, they found that in order to meet the NICE criteria of effect size of a 3 points difference, patients had to have an initial HDRS score of 25 or above.  To meet the criteria of an effect size of .50, or medium effect size, they had to have a score of 25 or above, and to have a large effect size, 27 or above.

What does this all mean for patient care? It means that for the vast majority of clinically depressed patients who fall below the very severely depressed range, antidepressant medications most likely won’t help. The sadder news is that even for the very severely depressed, medications have a very modest effect. Looking at the scoring of the HDRS, the normal, undepressed range is 0 to 7. The very severely depressed patients had scores of 25 or above, and a medium effect size was a drop in scores of 3 or more points compared to placebo patients. Looking at the one graph in the paper that show the actual drops in HDRS scores, the medication group had a mean drop of 12 points when their initial score was 25. That means they went from 25 to 13, which is still in the depressed range, although only mildly depressed. Patients who initially were at 38 dropped by roughly 20 points, ending at 18, which is still pretty depressed. And the placebo group had only slightly worse results.

One interesting thing is how strong the placebo effects are in these studies. It seems that for depressions less serious than very severe, placebo pills work as well as antidepressant medication.  Is this because antidepressants don’t work very well, or because placebos work too well? It’s hard to know. Maybe doctors should give their patients sugar pills, and call the new drug Eliftimood!

So in summary, here are the main observations I make from this study.

  • If you are very severely depressed, antidepressants may help, and are worth trying.
  • If you are mildly, moderately, or even severely depressed, there is little evidence that antidepressants will help better than a placebo. You would be better off with CBT (Cognitive Behavioral Therapy), which has a proven track record with less severe depressions, and which has no side effects.
  • Interestingly, CBT is less effective for the most severe depressions, so for these kinds of depressions medication treatment makes a lot of sense.
  • If you are taking antidepressants and having good results, don’t change what you are doing. You may be wired in such a way that you are a good responder to antidepressants.
  • If you have been taking antidepressants for mild to severe (but not very severe) depression, and not getting very good results, this is consistent with the research, and you might want to discuss alternative treatments such as CBT with your doctor. Don’t just stop the medications, as this can produce withdrawal symptoms, work with your doctor to taper off them.
  • Even in very severely depressed patients, for whom antidepressants have some effects, they may only get the patient to a state of moderate depression, but not to “cure”. To get to an undepressed, normal state, behavioral therapy may be necessary in addition to medications.
  • How do you find out how depressed you are? Unfortunately there is no online version of the HDRS for direct comparison. You may want to see a professional psychologist or psychiatrist if you think you might be depressed, and ask them to administer the HDRS to you.  There are also online depression tests, such as here and here. If you score in the highest ranges you might want to consider trying antidepressant medications, if you score lower you might want to first try CBT.
  • The most important thing is not to ignore depression, as it tends to get worse over time. Get some help, talk to a professional.

I’m off to take my Obecalp pills now, as it’s been raining here in Northern California for more than a week, and I need a boost in my mood. (Hint: what does Obecalp spell backwards?)

Copyright © 2010 Andrew Gottlieb, Ph.D. /The Psychology Lounge/TPL Productions

Which Anti-depressant Should You Take? Now We Know

Accepted wisdom for a number of years has been that all modern anti-depressants work equally well, and that drug selection depends more on the side effect profile desired. Thus a lethargic patient might benefit from an activating antidepressant like Prozac, and an anxious patient would be better off with Paxil. Often prescribing practices are based on individual doctors’ preferences and biases. But a newly published study suggests that this may be wrong. There may be antidepressants that not only work better, but are easier for patients to tolerate.

A terrific new study was recently published in the Lancet medical journal. A team of international researchers, led by Andrea Cipriani at the University of Verona in Italy, reviewed 117 studies of antidepressants which included 25928 patients, two-thirds of whom were women. These studies, done all around the world, compared various antidepressants to either placebo or other antidepressants.

The researcher compared the results of 12 new generation antidepressants in terms of efficacy and acceptabiltiy. They defined efficacy as the proportion of patients who improved at least 50% on a depression rating scale by 8 weeks of treatment. They defined acceptability as the proportion of patients who did not drop out of the study. They made an attempt to adjust for dosages, and did very sophisticated statistical analyses to compare all of the drugs. They used fluoxetine (Prozac) as the common comparison drug, since it has been on the market for the longest time.

What were the results? The winners in terms of short term effectiveness were: (drum roll) mirtazapine (Remeron), escitalopram (Lexapro), venlafaxine (Effexor), and sertraline (Zoloft). The winners in terms of acceptability were: escitalopram (Lexapro), sertraline (Zoloft), citalopram (Celexa), and bupropion (Wellbutrin) were better tolerated than other new-generation antidepressants. Note that the overall winners for effectiveness combined with tolerability were escitalopram (Lexapro) and sertraline (Zoloft). Two of the best drugs in terms of effectiveness (mirtazapine (Remeron) and venlafaxine (Effexor)) were not among the best tolerated medicines.

The losers in terms of both effectiveness and tolerability were reboxetine (Edronax), fluvoxamine (Luvox), paroxetine (Paxil), and duloxetine (Cymbalta). The worst drug of all was reboxetine (Edronax).

So what about cost? I’ve developed a spreadsheet of all of the drugs’ costs based on a 30 day supply, paying full retail price at Costco pharmacy, and using generic equivalents when available. Of the winners in terms of effectiveness and tolerability, the clear cost winner was sertraline (Zoloft), at $12 a month. The other winner, escitalopram (Lexapro), was a loser in terms of cost at $88 a month! The other winners in terms of effectiveness were quite cost effective too, with mirtazapine (Remeron) at $14 a month, and venlafaxine (Effexor) at $28 a month.

So what should doctors and patients do? For patients, the two best drugs appear to be escitalopram (Lexapro) and sertraline (Zoloft), with sertraline the clear winner if you pay much for prescription drugs. Doctors might want to consider costs as well, as this can help with overall health care inflation. If you can tolerate the side effects, consider trying mirtazapine (Remeron), or venlafaxine (Effexor).

Now there are of course a few caveats about this study. It is possible that another meta-analysis could find different results. One criticism was that the study only looked at effectiveness over 8 weeks of treatment. It is possible that some drugs work more slowly, and at 12 or 16 weeks might have different results. But most patients want results in two months or less, so this is not a major criticism.

Another issue is funding bias. Although none of the authors of this study were paid by drug companies, many of the studies they analyzed were funded by drug companies, and may have reflected some bias. But for now, this is the best information we have in terms of effectiveness and toleration of antidepressant medications.

So who’s the winner? Sertraline (Zoloft) was the clear winner by effectiveness, tolerability, and cost!

Should you change medications if you are not on one of the winners? No, of course not. If your medication is working, don’t change it. But if it’s not working, then talk with your doctor about switching.

And no, I don’t receive any funding or sponsorship from any drug companies…


Here’s the table of drug price comparisons.
Comparison of Antidepressant Costs for 30 Day Supply (Costco Pharmacy, Generic Equivalents if possible)
Bolded Drugs were most effective

Drug            Generic Name         Cost          Dose(mg)

Celexa             citalopram                   $3                 40
Prozac             fluoxetine                    $6                  20
Zoloft             sertraline                       $12             100
Remeron     mirtazapine                    $14               30
Luvox              fluvoxamine               $24             100
Effexor         venlafaxine                    $28                75
Welbutrin      bupropion                   $74             200
Lexapro       escitalopram                 $88                10
Paxil                paroxetine                   $91             37.5
Cymbalta       duloxetine                   $128              60


Copyright © 2009 Andrew Gottlieb, Ph.D. /The Psychology Lounge/TPL Productions