Clinical evidence and potential neurobiological underpinnings of unresolved symptoms of depression.
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.


METHODS
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.


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


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


RESULTS
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.
Trivedi
Madhukar H
MH
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, TX 75235, USA. madhukar.trivedi@utsouthwestern.edu
Hollander
Eric
E
Nutt
David
D
Blier
Pierre
P
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000465:Algorithms; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism; D003663:Decision Trees; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012893:Sleep Wake Disorders / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors