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Clinical Evidence and Potential Neurobiological Underpinnings of Unresolved Symptoms of Depression

Madhukar H. Trivedi, M.D.; Eric Hollander, M.D.; David Nutt, M.D.; and Pierre Blier, M.D., Ph.D.

Objective: Recent data indicate that more than 65% of patients with major depressive disorder (MDD) fail to achieve remission. This article reviews research on the current understanding and management of residual symptoms, i.e., subthreshold depressive symptoms present after recovery from a major depressive episode.

Data Sources: MEDLINE (1966 to June 2006) was searched using combinations of the following search terms: major depressive disorder, residual symptoms, remission, response, tachyphylaxis, antidepressant, algorithm, treatment, responsiveness, serotonin, norepinephrine, and dopamine.

Study Selection: All relevant articles that were published in English and reported original study data related to residual symptoms in MDD were included.

Data Extraction: Studies were examined for data related to the prevalence, presentation, consequences, treatment, and neurobiological underpinnings of residual symptoms associated with MDD.

Data Synthesis: Residual symptoms are common among patients treated for MDD who do not achieve full remission. Incomplete remission is associated with increased risk of relapse, suicide, functional impairment, and higher use of health care resources. Several factors, including "downstream" neurochemical mechanisms and clinical factors such as lack of adherence, contribute to the high prevalence of residual symptoms. Various clinical strategies, including switching and substitution antidepressant therapies, are used to address unresolved depressive symptoms. Individual differences in therapeutic response contribute to inadequate treatment and are linked to numerous clinical and neurobiological factors, including noncompliance, underdosing, intolerance, disturbances in neural circuitry, and genetic variability in neurotransmitters.

Conclusions: Future research is needed to more precisely characterize residual symptoms and their underlying biochemical and molecular mechanisms in order to develop more effective treatment methods.

(J Clin Psychiatry 2008;69:246-258; online ahead of print January 9, 2008)

Received April 20, 2007; accepted Aug. 28, 2007. From the Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas (Dr. Trivedi); Department of Psychiatry, Mount Sinai School of Medicine, New York, N.Y. (Dr. Hollander); Psychopharmacology Unit, School of Medical Sciences, University of Bristol, United Kingdom (Dr. Nutt); and the Mood Disorders Research Unit, University of Ottawa Institute of Mental Health Research, Ontario, Canada (Dr. Blier).

This article was developed from a clinical roundtable discussion funded by Wyeth Research and held on Dec. 11, 2005.

The authors wish to thank Trish Bakos, M.S., R.D.; Kristin Carlin, R.Ph., M.B.A.; and Jennifer B. Hutcheson for their writing and editorial assistance. Mss. Bakos, Carlin, and Hutcheson are employees of Advogent, a scientific communications company located in Wayne, N.J., which was paid by Wyeth Research for help in preparing this manuscript.

Financial disclosure appears at the end of this article.

Correspondence author and reprints: Madhukar H. Trivedi, M.D., University of Texas Southwestern Medical Center at Dallas, 6363 Forest Park Road, Suite 13.354, Dallas, TX 75235(e-mail: