Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine (DA) signaling could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. There are data supporting each of these mechanisms, although interpretation of previous research is confounded by issues around study population, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possibly reflected by a compensatory up-regulation of D2 receptors. These alterations in DA signaling may underlie the findings of increased “liking” or “high” feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depression is justified to improve outcomes for patients with treatment-resistant and nonremitting depression.
Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more
Subscribe for full-text access to content from 1998 forward and a host of useful features
Activate your current subscription (AMA members and current subscribers)
Purchase Online Access to this article for 24 hours
Dopaminergic pathways in the human brain. Reprinted with permission from Szabo et al (2004)5 and Sanchez-Gonzalez et al (2005).6 (Brain drawing used with the permission of Robert Finkbeiner.) Note that this image is a midline sagittal section of the brain. Many of the structures identified are located more laterally than the drawing indicates.
Dopaminergic synaptic signaling. Reprinted with permission from Szabo et al (2004).5 AADC indicates aromatic acid decarboxylase; AMPT, α-methylparatyrosine; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; COMT, catechol-O-methyltransferase; D1-D5, dopamine receptors 1 through 5; DA, dopamine; DAT, dopamine transporter; DOPA, 3,4-dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; Gi, Go, and Gs, protein subunits; HVA, homovanillic acid; MAO, monoamine oxidase; MT, 3-methoxytyramine; TH, tyrosine hydroxylase; and VMAT, vesicular monoamine transporter.
Differing structures of dopamine terminals in the striatum and prefrontal cortex. Reprinted with permission from Sesack et al (1998).14 COMT indicates catechol-O-methyltransferase; DA, dopamine; and NE, norepinephrine.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
Thank you for submitting a comment on this article. It will be reviewed by JAMA Psychiatry editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 189
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
and access these and other features:
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.