Intermediate phenotypes and biomarkers of treatment outcome in major depressive disorder.
Major depressive disorder (MDD) is a pleomorphic illness originating from gene x environment interactions. Patients with differing symptom phenotypes receive the same diagnosis and similar treatment recommendations without regard to genomics, brain structure or function, or other physiologic or psychosocial factors. Using this present approach, only one third of patients enter remission with the first medication prescribed, and patients may take longer than 1 year to enter remission with repeated trials. Research to improve treatment effectiveness recently has focused on identification of intermediate phenotypes (IPs) that could parse the heterogeneous population of patients with MDD into subgroups with more homogeneous responses to treatment. Such IPs could be used to develop biomarkers that could be applied clinically to match patients with the treatment that would be most likely to lead to remission. Putative biomarkers include genetic polymorphisms, RNA and protein expression (transcriptome and proteome), neurotransmitter levels (metabolome), additional measures of signaling cascades, oscillatory synchrony, neuronal circuits and neural pathways (connectome), along with other possible physiologic measures. All of these measures represent components of a continuum that extends from proximity to the genome to proximity to the clinical phenotype of depression, and there are many levels along this continuum at which useful IPs may be defined. Because of the highly integrative nature of brain systems and the complex neurobiology of depression, the most useful biomarkers are likely to be those with intermediate proximity both to the genome and the clinical phenotype of MDD. Translation of findings across the spectrum from genotype to phenotype promises to better characterize the complex disruptions in signaling and neuroplasticity that accompany MDD, and ultimately to lead to greater understanding of the causes of depressive illness.
Laboratory of Brain, Behavior, and Pharmacology, and the Depression Research and Clinical Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Andrew F
AF
Leuchter
Laboratory of Brain, Behavior, and Pharmacology, and the Depression Research and Clinical Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Aimee M
AM
Hunter
Laboratory of Brain, Behavior, and Pharmacology, and the Depression Research and Clinical Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
David E
DE
Krantz
Laboratory of Brain, Behavior, and Pharmacology, and the Depression Research and Clinical Program, Semel Institute for Neuroscience and Human Behavior, UCLA; the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA; the Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, UCLA, Los Angeles, California, USA.
Ian A
IA
Cook
D000928:Antidepressive Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D010641:Phenotype; D016896:Treatment Outcome
D000928:Antidepressive Agents; D015415:Biomarkers
Huntington's disease (HD); Major Depressive Disorder (MDD); RDoC; biomarker; biosignature; cognitive and motivational domain; cordance; genotype; intermediate phenotype; oscillation; oscillatory synchrony; prediction; qEEG; thalamocortical dysrhythmia; treatment outcome