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ultiple sources of evidence support a role for diminished dopaminergic neurotrans-
mission in major depression. The physiological alterations underlying reduced dopa-
mine (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 mecha-
nisms, although interpretation of previous research is confounded by issues around study population,
medication status, and technological limitations. In some patients with depression, DA-related dis-
turbances improve by treatment with antidepressants, presumably by acting on serotonergic or nor-
adrenergic circuits, which then affect DA function. However, most antidepressant treatments do not
directly enhance DA neurotransmission, which may contribute to residual symptoms, including im-
paired motivation, concentration, and pleasure. Animal models of major depression show consider-
able responsiveness to manipulations of DA neurotransmission. Several studies, including postmor-
tem 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 sup-
port the hypothesis that major depression is associated with a state of reduced DA transmission, pos-
sibly 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 sub-
jects. 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 depres-
sion is justified to improve outcomes for patients with treatment-resistant and nonremitting depression.
Caudate/Putamen
Nucleus Accumbens
Entorhinal Cortex
Amygdala/Hippocampus
Hypothalamus
Periaqueductal Grey Area Medial Forebrain Bundle
Substantia Nigra
Figure 1. 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.
served effects on mood of reserpine, which depletes ve- nigra pars compacta (A9), and the ventral tegmental area
sicular monoamine stores and reduces mood; of amphet- (VTA) (A10). Projection pathways of the axons arising
amine, which briefly increases synaptic concentrations from these cell bodies follow 1 of 3 specific paths (with
of monoamines, and raises mood; and of monoamine oxi- some overlap) via the medial forebrain bundle to inner-
dase inhibitors (MAOIs), which increase the central ner- vate specific cortical and subcortical structures, unlike
vous system concentrations of monoamines and are, of the more diffuse innervation patterns of serotonergic and
course, effective antidepressants.2,3 Although these agents noradrenergic cells (Figure 1). The nigrostriatal path-
all affect DA similarly to NE and 5HT, it wasn’t until the way projects from the substantia nigra pars compacta to
mid 1970s that a role for DA in depression was postu- the dorsal striatum (caudate and putamen) and has a
lated.4 The primary reason for the limited focus on DA prominent role in the motor planning and execution of
was the finding that the efficacy of tricyclic antidepres- movement, although it clearly also plays an important
sants (TCAs) stemmed from their ability to inhibit the role in nonmotor functions, such as cognition.7 The me-
reuptake of NE and/or 5HT. However, a long-standing socortical pathway arises from the VTA and projects to
conundrum associated with the original monoamine hy- the frontal and temporal cortices, particularly the ante-
pothesis is that the reuptake inhibiting effects of TCAs rior cingulate, entorhinal, and prefrontal cortices. This
(and SSRIs and SNRIs) occur within hours of drug in- pathway is believed to be important for concentration and
gestion, but their antidepressant effects take longer to oc- executive functions such as working memory. The me-
cur. This temporal discrepancy implies that other mecha- solimbic pathway also arises in the VTA but projects to
nisms must be involved in recovery from a depressive the ventral striatum (including the nucleus accum-
episode. bens), bed nucleus of the stria terminalis, hippocam-
There is now a convergence of data from animal mod- pus, amygdala, and septum. It is particularly important
els, genetics, neuroimaging, and human clinical trials that for motivation, the experience of pleasure, and reward.
strengthen the case for DA dysfunction in the patho- Aspects of anterior pituitary function are also under
physiology of major depression, at least in a significant dopaminergic control. The tuberoinfundibular pathway
subgroup of patients. This monograph comprehen- arises from the arcuate nucleus of the hypothalamus (A12)
sively reviews the current evidence with subsequent rec- and projects to the median eminence of the hypothala-
ommendations for future studies of dopaminergic sig- mus, where DA released into the portal vessels acts to
naling in depression and its treatment. inhibit the secretion of prolactin from the anterior pitu-
itary.8 This pathway is also involved in dopaminergic regu-
DOPAMINERGIC PATHWAYS lation of growth hormone release from the anterior pi-
IN THE CENTRAL NERVOUS SYSTEM tuitary.9 The incertohypothalamic pathway originates from
cell bodies in the medial portion of the zona incerta (A13)
Most DA-producing neurons in the brain are located in and innervates amygdaloid and hypothalamic nuclei in-
brainstem nuclei: the retro-rubro field (A8), substantia volved in sexual behavior.
D1 Family D2 Family
Characteristic D1 D5 D2 D3 D4
Homology with D1 100 82 45 42 42
Homology with D2 45 50 100 75 54
Second messenger effect Increase AC Increase AC Decrease AC Decrease AC Decrease AC
Localization Dorsal striatum Hippocampus Dorsal striatum Ventral striatum Frontal cortex
Ventral striatum Thalamus Ventral striatum Islands of Calleja Midbrain
Thalamus Striatum Pituitary Amygdala
Prefrontal cortex Hippocampus
Hypothalamus
Agonists* SKF 38393 Chloro-PB Bromocriptine, pergolide, piribedil, PD 168077
Pergolide pramipexole, quinpirole Quinpirole
Chloro-PB
Antagonists SCH 23390 SCH 23390 Sulpiride, typical antipsychotics raclopride Clozapine
PD 101387
Medication Status of
Source Year Subjects Patients Technique Primary Findings
D2 Binding in Depressed vs Controls
D’Haenen and 1994 21 inpatients; 11 controls ⱖ7 d antidepressant SPECT 10% greater basal ganglia/cerebellum D2
Bossuyt92 washout 123
IZBM binding ratio in depressed patients
(P=.03).
Shah et al93 1997 15 inpatients; 15 controls 8 receiving antidepressant; SPECT Depressed subjects demonstrated
123
7 unmedicated (duration IZBM significantly greater D2 binding in right
of treatment not striatum. Binding correlated with
reported) reaction time and verbal fluency.
Ebert et al94 1996 20 male inpatients; 10 male 10 unmedicated ⱖ6 mo; 10 SPECT No difference among the 3 groups at
123
controls receiving AMI for 2 wk IZBM baseline. Psychomotor retarded patients
had 6% increase in striatal D2 binding vs
all others (P⬍.05).
Klimke et al95* 1999 15 inpatients (3 BP); ⱖ7 d antidepressant SPECT No difference in striatal D2 binding for
123
17 controls with washout IZBM whole group. At baseline, responders to
melanoma SSRI treatment had significantly
decreased D2 binding vs nonresponders
and controls.
Parsey et al96 2001 9 patients; 10 controls ⱖ2 wk antidepressant SPECT No difference in striatal D2 binding at
123
washout IZBM baseline. No difference in striatal D2
binding after amphetamine
administration.
Depressed Before and After Treatment
Ebert et al94 1996 10 inpatients Treatment with 150 mg AMI SPECT Nonresponders to 3 wk of AMI showed
123
per day for 3 wk IZBM increased or no change in striatal D2
binding. Responders to AMI significantly
decreased D2 binding (P⬍.05).
Klimke et al95 1999 15 inpatients (3 BP) Treatment with fluoxetine or SPECT After 3-7 wk of SSRI treatment:
123
paroxetine for 6 wk IZBM nonresponders had decreased D2
binding in striatum;responders had
increased D2 binding in striatum and
increased D2 binding correlated with
reduction in HAMD score.
DAT Expression and Function
Martinot et al97 2001 6 inpatients with PMR and 3 patients in each group PET Patients with PMR and AF had lower
AF; 6 inpatients with receiving an SSRI; 3 in [18F]DOPA [18F]DOPA uptake Ki values in left
impulsivity/anxiety; each group unmedicated caudate than impulsive/anxious
10 controls depressed or controls.
Meyer et al98 2001 9 patients; 23 controls ⱖ3 mo unmedicated with PET Striatal DAT levels lower bilaterally in
psychotropics [11C]RTI-32 patients than controls. Patients with
lower DAT levels performed better on
finger tapping test and Stroop test.
Brunswick et al99 2003 15 patients (5 BP); ⱖ7 d antidepressant SPECT DAT levels higher in bilateral putamen and
46 controls washout [99mTc]- TRODAT-1 left caudate in patients vs controls.
Abbreviations: ACC, anterior cingulate cortex; AF, affective flattening; AMI, amitriptyline; BP, bipolar depressed; DAT, dopamine transporter; [18F]DOPA,
[18F]fluorodopa; D2, dopamine receptor; HAMD, Hamilton Depression Scale; 123IBZM, 123I-iodobenzamide; Ki, inhibition constant; PET, positron emission
tomography; PMR, psychomotor retardation; [11C]RTI-32, [11C]methyl (1R-2-exo-3-exo)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate;
SPECT, single-photon emission computed tomography; SSRI, selective serotonin reuptake inhibitor; [99mTc]TRODAT-1, technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-
methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3-)-oxo-[1R-(exo-exo)].
*Klimke et al (1999) report updated results of their group’s original publication (Larisch et al100).
inhibitor102; amineptine, a DAT antagonist; sertraline, an hibit 80% or more of serotonin transporter binding sites
SSRI that also blocks DA reuptake at high doses; bupro- at minimally effective doses.105 The greater efficacy of MAOIs
pion, although this remains controversial; and MAOIs, over TCAs in atypical depression and anergic bipolar de-
which prevent degradation of DA, NE, and 5HT. More- pression suggests that alterations in DA metabolism may
over, the absence of DAT in the prefrontal cortex and the be particularly important for these conditions.106
role of the norepinephrine transporter in inactivating the In addition, several drugs acting on the DA system have
DA signal in this critical brain region, taken together, have been evaluated for their efficacy in major depression. The
revealed an effect of NE reuptake inhibitors to increase first agents used to treat depression that directly altered
DA availability in this area. dopaminergic signaling were the psychostimulants, act-
Although bupropion is often considered to produce ing through increases in DA release and blockade of the
its antidepressant effects via DAT blockade, at clinically DAT, although these agents also act on 5HT and NE neu-
significant doses the drug occupies less than 22% to 26% rons. In double-blind, placebo-controlled studies of un-
of DAT binding sites.103,104 In contrast, SSRIs typically in- selected depressed patients, psychostimulants are infe-