Lateral Thinking In ActionOther Ways to Demonstrate the Effectiveness of Antidepressants

Background: Ask yourself if there is sufficient evidence to conclude that antidepressant medication does what it is supposed to do.  If you want to find the answer, it might seem that the direct approach would be best.  Find the studies that drug companies used in their initial application to the FDA, when they filed an application to have a new drug approved.  The FDA requires that all prescription medication in the USA be proven to be safe and effective. 

The problem is that the FDA is not really a scientific organization.  It is part of the executive branch of the federal government.  Like any part of the government, it does things in strange ways.  They ask for short-term studies, usually 12 weeks or less.  They require only that the drug be more effective than placebo in some of the studies.  So it turns out that reading those studies is not really the best way to assess the effectiveness of the product.  As many of you know, the analysis of these studies is not straightforward, and there appear to be endless controversies about them.  Some of these controversies have been covered in earlier posts here, and by the various comments.  Perhaps we can find some other way to test the effectiveness of the antidepressant medication.

1. For many persons, treatment of depression is a lifelong project.  As a result, what is most important is how well the medication works over months or years.  If antidepressant medication is effective, it should demonstrate a lasting effect in a time frame greater than six months.  So one was to test the hypothesis that antidepressant works is to look at long-term relapse rates.

Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review

Nortriptyline plus lithium increased time to relapse in unipolar depressed patients who responded to electroconvulsive therapy

Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression

Efficacy of mirtazapine for prevention of depressive relapse

Venlafaxine versus placebo in the preventive treatment of recurrent major depression

Relapse prevention by citalopram in SAD patients responding to 1 week of light therapy. A placebo-controlled study

Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression

Randomized, placebo-controlled trial of nefazodone maintenance treatment in preventing recurrence in chronic depression

Five-year outcome for maintenance therapies in recurrent depression


2. One of the problems with demonstrating the effectiveness of medication in a short-term trial is that there is a high placebo response rate.  Doing a long-term study partly circumvents that problem.  There is another way to address the placebo response problem:  Depression probably is a blanket term for several related conditions that differ in some fundamental ways.  The way human bodies work, there is a finite number of symptoms a human body can exhibit.  But there are many different internal problems that can produce the same symptoms.  If it turns out that there are some conditions that share some of the features of depression, but which have a low placebo response rate, testing antidepressant medication in those other conditions could show a greater separation from placebo, and thus provide indirect evidence of the effectiveness of antidepressants for treating depression.  Obsessive-compulsive disorder is such a condition.  The placebo response rate for OCD is very low.  OCD does respond well to treatment with SSRI's (and a couple of related medications).  So looking at the effect of antidepressant medication for the treatment of OCD might help confirm or refute the contention that antidepressants work.

Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder

Venlafaxine in treatment-resistant obsessive-compulsive disorder

Early response with clomipramine in obsessive compulsive disorder--a placebo controlled study

Acute and long-term treatment and prevention of relapse of obsessive-compulsive disorder with paroxetine

Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized, controlled, multicenter trial


3. Depression is known to increase the mortality from various medical conditions.  If antidepressants work, it should be possible to show a decrease in mortality in persons who have a medical condition and depression at the same time.  Thus, studies of mortality in depressed patients with heart disease, for example, may show an effect. 

The SErzone Antidepressant Remedy in Congestive Heart Failure (SEARCH) trial

Mortality and Poststroke Depression: A Placebo-Controlled Trial of Antidepressants

Depression and Social Support Impact Myocardial Outcomes

ENRICHD Study Overview (This is a clinical trial that is underway; we will have to wait for the results)

Myocardial INfarction and Depression - Intervention Trial (MIND-IT study) (This is a clinical trial that is underway; we will have to wait for the results)

Sertraline Antidepressant Heart Attack Randomized Trial (SADHART)

Preventing poststroke depression: a 12-week double-blind randomized treatment trial and 21-month follow-up.


4. In addition to the fact that depression increases the mortality associated with medical illness, there are times that treatment of somatic illness can induce depression.  If antidepressants can be shown to reduce the risk of treatment-induced depression, that would be an indication that antidepressants can be effective.

Paroxetine for the Prevention of Depression Induced by High-Dose Interferon Alfa


5. To examine the question in yet another way, there is evidence that psychotherapy and antidepressant medication together are more effective that either one alone.  The presence of an additive effect, seen in several studies, is evidence that antidepressants can have a beneficial effect.  

Patient's therapeutic skill acquisition and response to psychotherapy, alone or in combination with medication

Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression (This also was cited is section 1; it is included here because it demonstrates an additive effect in addition to a preventative effect)

Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) (This is a clinical trial that is underway; we will have to wait for the results)

Differential symptom reduction by drugs and psychotherapy in acute depression

Cognitive therapy and pharmacotherapy for depression: Singly and in combination

Integration of Care: Integrating Psychotherapy and Pharmacotherapy to Improve Outcomes Among Patients With Mood Disorders


6. The last indirect approach to assessing the effectiveness of antidepressant medication involves either a financial analysis of the cost-effectiveness of the treatment of depression, or an analysis of the effect of treatment on psychosocial function.  Often, the goal of the treatment is to restore the patient to a certain level of function.  If antidepressant medication is effective, it should be possible to demonstrate that the patient's ability to function is improved.

Improvement in subjective work performance after treatment of chronic depression: some preliminary results. Chronic Depression Study Group

The treatment of chronic depression, part 3: psychosocial functioning before and after treatment with sertraline or imipramine

Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: psychosocial outcomes

Improving the Quality and Cost-Effectiveness of Treatment for Depression


Conclusion: although there are endless controversies about the effectiveness of antidepressant medication, there are ways to strengthen the case for the effectiveness of antidepressants that in some ways sidestep the methodological problems inherent in the direct approach.  I think the last article cited above is the most interesting.  It was the result of collaboration between a psychiatry professor (who is a senior scientist at RAND) and a a econometrician at the RAND corporation.  Neither had a direct economic interest in the outcome of the study.  Presumably, the parent organization (RAND) has no vested interest in proving that antidepressants work.  Their interest is in public policy.  Because the primary outcome measurement (functional capacity) was based upon objective measures, there is less reason to quibble about the validity of the outcome. 

I am aware of the fact that the use of indirect lines of evidence will not really settle the question posed at the beginning of this article (is there sufficient evidence to conclude that antidepressant medication does what it is supposed to do?)  However, I am hopeful that the existence of this evidence, together with the fact that the various lines of evidence converge toward the same conclusion, will help some people feel a greater degree of confidence in the conclusion.

As always, I welcome contrasting, enriching, and opposing views.  The authors at INDC Journal, Empty Days, Dean's World, A Small Victory, and Pseudoscience-in-Psych Blog  have expressed interest in this topic. 

If this article has not exhausted your attention span, you may wish to look at the previous CC posts: 1  2  3  4  5  6  7  8