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. 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.