Antidepressants May Only Be Effective in Treatment of the Severest Depression

Caroline Cassels

January 08, 2010

January 8, 2010 — Antidepressant medications (ADMs) offer significant benefit in the treatment of the severest depressive symptoms, but the current standard of treatment may have little or no therapeutic benefit over and above placebo in patients with mild to moderate depression — a population which accounts for most cases.

An analysis of 6 randomized, placebo-controlled trials conducted by investigators at the University of Pennsylvania, Philadelphia, indicates that compared with placebo, the magnitude of benefit of ADMs varies with the severity of depressive symptoms.

"True drug effects (an advantage of ADM over placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms," the investigators, with first author Jay C. Fournier, MA, write.

"I think the most surprising part of the findings was how severe depression has to be in order to see this clinically meaningful difference emerge between medication and placebo and that the majority of depressed patients presenting for treatment do not fall into that very severe category," Mr. Fournier told Medscape Psychiatry.

According to the investigators the study's findings are supported by 2 previous meta-analyses of placebo-controlled trials (PLoS Med. 2008;5:e45, J Clin Psychopharmacol. 2002;22:40-45), both of which found that greater baseline symptom severity was associated with a greater response to ADMs compared with placebo.

"Our findings should be viewed in the context of these 2 other studies, which essentially demonstrated the same thing," said Mr. Fournier.

The study is published in the January 6 issue of the Journal of the American Medical Association.

Patients With Mild to Moderate Symptoms Often Excluded

According to the authors, although ADMs are the best established treatment for major depression, there is little evidence demonstrating their efficacy in patients with less severe symptoms because most major clinical trials tend to exclude patients in the mild to moderate range.

To estimate the relative benefit of ADMs vs placebo across a wide range of initial symptom severity in patients diagnosed as having depression, the researchers conducted a search of 2 large electronic databases, including PubMed and PsycINFO, as well as the Cochrane Library.

Selection criteria included randomized, placebo-controlled trials of Food and Drug Administration–approved antidepressants for the treatment of major or minor depression. Studies were only included if they did not exclude patients on the basis of a placebo washout period and used the Hamilton Depression Rating Scale (HDRS).

The final analysis included 6 randomized, placebo-controlled studies of either the selective serotonin reuptake inhibitor paroxetine or the tricyclic antidepressant imipramine. There were a total of 718 subjects, and the duration of the studies ranged from 6 to 11 weeks.

Individualized Decision-Making

The study showed that among patients with HDRS scores below 23, effect sizes for the difference between medication and placebo were estimated to be less than 0.20.

Furthermore, the study authors report the magnitude of the superiority of medication over placebo only crossed the threshold for a clinically significant difference (compared with placebo) at a baseline HDRS score of 25.

According to Mr. Fournier, the underlying mechanisms that might explain this effect are not clear. However, he added, the study findings suggest a need for further research to investigate alternative treatment options — including nonpharmacologic approaches — for patients with mild to moderate depression.

In the meantime, he said, it is premature and potentially hazardous to suggest patients with mild to moderate depressive symptoms discontinue use of their ADMs.

"Treatment decisions need to be made on an individual basis between patients and their doctors," said Mr. Fournier.

Mr. Fournier also pointed out that it is important for depressed patients to take an active role in their own care, regardless of the severity of their symptoms.

"One additional point that may be getting overlooked in the broader messages about this paper is that even placebo treatment helps a great many people, and although we don't fully understand why that is, part of it likely comes from patients taking their symptoms seriously, acting on their concerns, and speaking with mental health professionals.

"Rather than walking away with the impression that nothing works for mild or moderate depression, I hope patients understand that treating their illness seriously and actively engaging in treatment can be quite beneficial," he said.

Don't Draw Broad Conclusions

Commenting on the study findings, David J. Hellerstein, MD, a research psychiatrist at New York State Psychiatric Institute and director of Medical Communications, Columbia University Medical Center, New York City, said he is concerned that patients and possibly even clinicians may draw broad conclusions from the paper without recognizing its limitations.

"We have to keep in mind that this analysis is only based on 6 studies that were of relatively short duration and only included 2 medications — imipramine and paroxetine — yet the message seems to be that all antidepressants may not be effective in the mild to moderate patient population," Dr. Hellerstein told Medscape Psychiatry.

Furthermore, he pointed out that of all the selective serotonin reuptake inhibitors, paroxetine, with its high rates of sedation, nausea, and sexual adverse effects, among others, is one of the most poorly tolerated drugs in its class.

Dr. Hellerstein also pointed out that at least 1 of the 3 imipramine studies had a target dose of 100 mg/day, which, he said, is subtherapeutic. He added that the analysis did not include any studies of serotonin norepinephrine reuptake inhibitors, which are generally to be considered "more potent."

Nevertheless, he said, despite these limitations the study's suggestion that ADMs may not be optimal in patients with mild to moderate disease is worth further exploration.

"It raises the question of whether patients with mild to moderate depression should have antidepressant therapy as a first-line approach, and I think that is a valid thing to consider. As a clinician it will certainly prompt me to look more carefully at my own case load and consider whether an individual patient is benefitting from medication or whether their response could be attributed to other treatment factors," said Dr. Hellerstein.

The study was supported by the National Institute of Mental Health. Mr. Fournier has disclosed no relevant financial relationships. Dr. Hellerstein is an employee of New York State and Columbia University and currently receives grant funding from Eli Lilly. Disclosures of the other investigators can be found in the original study.

JAMA. 2010;303:47-53.