Deshauer, 2008 Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials.

[Altostrata]

This is an analysis of study design in research on antidepressant efficacy. It allows that withdrawal syndrome may be a confounding factor in these studies: "Discontinuation trials are believed to minimize the number of participants with depression who must be exposed to placebo. This advantage comes at a cost, since the results apply only to patients with a response to the medication, not to those who experience spontaneous recovery; furthermore, withdrawal symptoms may lead to an overestimate of the true effect of the medication. When this design is used to test long-term therapy with selective serotonin reuptake inhibitors for the treatment of depression, the results are difficult to interpret with confidence because rates of spontaneous recovery in depression are potentially high and because withdrawal effects can mimic depression."

 

CMAJ. 2008 May 6;178(10):1293-301.

Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials.

Deshauer D, Moher D, Fergusson D, Moher E, Sampson M, Grimshaw J.

 

Source

Department of Psychiatry, University of Ottawa, Ottawa, Ont. deshauer1@sympatico.ca

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/18458261 Full text here.

 

BACKGROUND:

 

Selective serotonin reuptake inhibitors are increasingly used in the long-term treatment of depression. Much of the supporting evidence about the effects of these drugs comes from discontinuation trials, a variant of randomized controlled trials whose design is problematic to interpret. We conducted a systematic review to examine the efficacy and acceptability of long-term therapy with selective serotonin reuptake inhibitors relative to placebo in the treatment of unipolar depression.

 

METHODS:

 

We identified placebo-controlled randomized trials with a treatment duration of at least 6 months by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to update a recently published systematic review. Efficacy was defined in terms of response to treatment (50% improvement in depression score relative to baseline) and remission (score of 7 or below on the Hamilton rating scale for depression). Key secondary outcomes included quality of life, return to work, need for additional treatment and self-harm. Overall acceptability was defined in terms of dropouts for any reason over a course of treatment.

 

RESULTS:

 

Of the 2693 records identified initially, we included 6 randomized controlled trials that met our eligibility criteria. These studies had a moderate risk of bias, had assigned a total of 1299 participants with depression to either treatment or placebo and had followed both groups for 6-8 months. We observed statistically significant improvements in response to treatment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.12-2.48), but not in remission (OR 1.46, 95% CI 0.92-2.32) or acceptability (OR 0.87, 95% CI 0.67-1.14). The effects appeared greater among patients without comorbidities.

 

INTERPRETATION:

 

There is a lack of classic randomized controlled trials of serotonin reuptake inhibitors lasting more than 1 year for the treatment of depression. The results of our systematic review support current recommendations for 6-8 months of antidepressant treatment following initial recovery but provide no guidance for longer treatment.

[Altostrata]

I had quite a bit of correspondence with Dr. Deshauer in 2008:

 

From: [altostrata]

Subject: Your recent paper in CMAJ

Date: May 11, 2008 11:50:48 AM PDT

To: deshauer1 (at) sympatico.ca

 

Dr. Deshauer:

 

I read with interest your recent paper Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials. CMAJ. 2008 May 6;178(10):1293-301.

 

I highly commend your team for making the point that antidepressant withdrawal symptoms contaminate many studies of antidepressant effectiveness. Indeed, clinicians and patients often take these symptoms to indicate the emergence of serious psychiatric disorder, confirming the necessity of continuing the same or even more strenuous medication. Misdiagnosis and mistreatment of antidepressant withdrawal syndrome can cause further harm to the patient's nervous system.

 

The faulty studies showing antidepressant effectiveness tend to further reinforce the almost total misdiagnosis of withdrawal syndrome as they emphasize rate of relapse without taking into account withdrawal syndrome. It is highly likely that some number of patients identified as "relapsed" after discontinuation of medication were in fact suffering from antidepressant withdrawal reactions.

 

This flaw, along with the subjective judgment of experimenters who are funded by a drug company to find "response" or efficacy, also contaminates those classic randomized controlled trials that look at rate of relapse or "recurrent depression" after discontinuation. One also wonders about the unreported frequency of adverse effects -- surely a reflection of a lack of efficacy -- among the very large number of dropouts in these trials and whether they suffered withdrawal symptoms.

 

Indeed, any study that discusses a rate of relapse or "recurrence of depression" but does not provide statistics for antidepressant withdrawal reactions is suspect as the withdrawal reactions probably were counted as relapse or "recurrence of depression."

 

The short duration of almost all antidepressant efficacy studies probably vastly underestimates the prevalence of antidepressant withdrawal syndrome in actual practice, as doctors are encouraged to persuade patients to take antidepressants for much longer periods of time, likely enhancing the frequency and severity of withdrawal syndrome. (You may read many patient reports of withdrawal syndrome on the Web....)

 

Personally, I am in my fourth year of recovery from Paxil withdrawal syndrome, which has been repeatedly misdiagnosed and mistreated. After searching for treatment for 38 months and becoming completely disabled by autonomic dysfunction, I finally found a knowledgeable doctor, one of the very few in the world, who can identify and treat damage from psychiatric drugs.

 

That doctors are misinformed about antidepressant withdrawal syndrome by the pharmaceutical companies and psychiatric researchers, who unrelentingly churn out flawed studies of antidepressant effectiveness, is a profound disgrace to all of medicine.

 

Thank you for making this paper widely available to the public.

 

Sincerely,

 

[altostrata]

San Francisco, California, USA

----------

 

Dr. Deshauer very graciously responded:

 

Thank you for your comments. We agree that too little is known about the

long term effects of this class of drugs. Others may find your comments

helpful and you may want to consider posting this letter on the CMAJ website

as a response to this paper.

 

Best regards

 

Dorian Deshauer

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This is the comment published on the Web site of the Canadian Medical Association Journal:

 

As a patient advocate, I read with interest the recent paper Selective serotonin reuptake inhibitors for unipolar depression: a systematic review of classic long-term randomized controlled trials, Deshauer et al, CMAJ. 2008 May 6;178(10):1293-301.

 

I highly commend Deshauer et al for making the point that withdrawal symptoms contaminate many studies of antidepressant effectiveness. Indeed, clinicians and patients often take these symptoms to indicate the emergence of serious psychiatric disorder, confirming the necessity of continuing the same or even more strenuous medication. Misdiagnosis and mistreatment of antidepressant withdrawal syndrome can cause further harm to the patient's destabilized nervous system.

 

The faulty studies showing antidepressant effectiveness tend to further reinforce the almost total clinical misdiagnosis of withdrawal syndrome as they emphasize rate of relapse without mentioning withdrawal syndrome. It is highly likely that some number of patients identified as "relapsed" after discontinuation of medication were in fact suffering from antidepressant withdrawal reactions.

 

This flaw also contaminates those classic randomized controlled trials that look at rate of relapse or "recurrent depression" after discontinuation. One also wonders about the unreported frequency of adverse effects -- surely a reflection of a lack of efficacy -- among the very large number of dropouts in these trials and whether they suffered withdrawal symptoms.

 

Indeed, any study that discusses a rate of relapse or "recurrence of depression" but does not provide statistics for antidepressant withdrawal reactions is suspect as withdrawal reactions probably were counted as relapse, "recurrence of depression," or even emergence of a new mood disorder.

 

Still, the short duration of almost all antidepressant efficacy studies probably would continue to vastly underestimate the prevalence of antidepressant withdrawal syndrome in actual practice, as doctors are encouraged to persuade patients to take antidepressants for much longer periods of time than any studied, likely enhancing the frequency and severity of withdrawal syndrome. (You may read many real-world patient reports of withdrawal syndrome on the Web site ******.)

 

That psychiatric research continues to misinform doctors about antidepressant withdrawal syndrome damages the medical profession as well as patients.

 

Thank you for making this paper widely available to the public.