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doi:10.1111/psyg.12014 PSYCHOGERIATRICS 2013; 13: 189195

REVIEW ARTICLE

Dopamine agonist-responsive depression

Hiroaki HORI and Hiroshi KUNUGI

Department of Mental Disorder Research, National Abstract

Institute of Neuroscience, National Center of
Neurology and Psychiatry, Tokyo, Japan
Correspondence: Dr Hiroshi Kunugi MD, PhD,
Department of Mental Disorder Research, National
Institute of Neuroscience, National Center of
Neurology and Psychiatry, 4-1-1, Ogawahigashi,
Kodaira, Tokyo, 187-8502, Japan.
Email: hkunugi@ncnp.go.jp
Received 4 September 2012; accepted 18 March 2013.
This review article was presented by the authors in
Symposium of the 26th annual meeting of Japanese
Psychogeriatrics Society in Tokyo, June 16, 2011.
Key words: augmentation therapy, depression,
dopamine agonist, nucleus accumbens, pramipexole.
Dopaminergic dysfunction is implicated in the pathophysiology of treatment-
resistant depression. In this review, we describe the putative role of dopam-
ine in depression, summarize the evidence for the efficacy of dopamine
receptor agonists in the treatment of treatment-resistant depression, and
discuss the underlying mechanisms by which these medications work. Both
preclinical and clinical data suggest that adjunctive dopamine agonists
could be a promising option for the treatment of such a condition, indicating
that there is a dopamine agonist-responsive subgroup of depression. Future
clinical studies are warranted to clarify unresolved issues regarding dopam-
ine agonists such as long-term efficacy, efficacy as a monotherapy, and
efficacy for juvenile and senile depression. Further basic research is also
necessary to fully understand how dopamine acts in the brain of depressed
patients.

INTRODUCTION irole and pramipexole. Ergot alkaloids (bromocriptine,

Selective serotonin reuptake inhibitors (SSRI) and
serotonin-norepinephrine reuptake inhibitors (SNRI)
are medications currently used as first-line treatments
for depression. However, large-scale clinical trials in
Western countries, such as the Sequenced Treatment
Alternatives to Relieve Depression,1 have revealed
that a significant proportion of patients fail to respond
to or achieve remission with these medications. In
these patients, symptoms such as avolition, psycho-
motor retardation, poor concentration and anhedonia
are likely to persist even after mood symptoms includ-
ing depressed mood and anxiety have resolved.
Because dopamine, particularly mesolimbic dopam-
ine system, regulates motivation, psychomotor
speed, concentration and emotions like pleasure, it
has been postulated that at least some treatment-
resistant patients are in a hypodopaminergic state in
which medications such as dopamine reuptake inhibi-
tors, monoamine oxidase inhibitors and dopamine
receptor agonists, rather than serotonergic or norad-
renergic agents, could be effective.2
There are six dopamine agonists currently used in
clinical practice, mainly for Parkinsons disease: bro-
mocriptine, cabergoline, pergolide, talipexole, ropin-
cabergoline and pergolide) can cause serious,
albeit rare, adverse events including valvular heart
diseases, whereas non-ergot dopamine agonists
(talipexole, ropinirole and pramipexole) do not have
such an effect on cardiac valves. Although these
dopamine agonists have not been approved for the
treatment of depression, a number of studies have
suggested that augmentation with dopamine ago-
nists can be effective, especially for treatment-
resistant depression.
In this review, we first briefly describe the putative
role of dopamine in depression, then summarize the
evidence for the efficacy of dopamine receptor ago-
nists in the treatment of refractory depression, and
lastly discuss the underlying mechanisms by which
these medications work.
INVOLVEMENT OF DOPAMINE IN THE
PATHOPHYSIOLOGY OF DEPRESSION
The monoamine hypothesis is one of the best-known
aetiological hypotheses for depression. Although
there are different classes of antidepressants with dif-
ferent mechanisms of action, they generally inhibit the

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H. Hori and H. Kunugi

reuptake of neurotransmitters (released into the syn-
aptic cleft), including serotonin, noradrenaline and
dopamine, into the neurons via transporters. They
also inhibit the breakdown of these neurotransmitters
with monoamine oxidase, thereby increasing these
monoamines in the synaptic cleft. Given the findings
from in vitro studies that SSRI and SNRI inhibit the
reuptake of serotonin, the simple conclusion seems to
be that serotonin is the most important monoamine in
the treatment of depression.
Nonetheless, evidence on the reduction of brain
extracellular serotonin levels in depressed patients
is not conclusive. For example, post-mortem brain
studies have not consistently observed a reduction
in serotonin (or its metabolites). The finding that
5-hydroxyindoleacetic acid, a serotonin metabolite
in cerebrospinal fluid (CSF), is reduced in de-
pressed patients is also controversial.3 Indeed, a
number of studies have reported reduced CSF
5-hydroxyindoleacetic acid in individuals who have a
history of impulsive behaviours, such as suicidal
attempts and violent acts,4,5 irrespective of their diag-
nosis (i.e. schizophrenia, personality disorder). There-
fore, it is conceivable that reduced serotonin is
associated with impulsivity in general rather than
depression per se. This idea corresponds well to the
fact that SSRI are effective at reducing anxiety,
agitation and depressed mood but not necessarily
at ameliorating other symptoms such as avolition,
psychomotor retardation, poor concentration and
anhedonia.
With regard to other catecholamines such as nora-
drenaline and dopamine, findings from post-mortem
brain studies and CSF studies in depressed patients
have not been uniform. However, there has been one
relatively consistent finding: reduced homovanillic
acid (a primary dopamine metabolite) in CSF,6 which
suggests an important role of dopamine in the patho-
physiology of depression.
Although in vitro studies show that SSRI do not
inhibit the reuptake of dopamine, in vivo animal
studies using microdialysis have demonstrated that
many SSRI increase extracellular dopamine in the
prefrontal cortex. Because tricyclic antidepressants
also increase prefrontal dopamine (Fig. 1), some
investigators argue that this process could be central
to the effects of antidepressants.7 It should be
noted, however, that tricyclic antidepressants do not
increase dopamine in the nucleus accumbens, a brain
region known as the pleasure centre, according to
the study of Tanda et al. (Fig. 1).7
One of the potential mechanisms by which SSRI
and SNRI increase prefrontal dopamine is by stimu-
lating dopamine release via 5-hydroxytryptamine
(5-HT)1A receptors as a result of elevated serotonin
levels. Another one is that the inhibition of dopamine
reuptake via the noradrenaline transporter by SNRI
leads to an increase in extracellular dopamine levels
because the noradrenaline transporter, but not the
dopamine transporter, is mainly responsible for the
dopamine reuptake in the prefrontal cortex.
DOPAMINE AGONISTS: EVIDENCE
FOR THEIR EFFICACY IN
TREATMENT-RESISTANT DEPRESSION
Table 1 summarizes the receptor binding affinity
and pharmacokinetics of dopamine agonists that are
approved for the treatment of Parkinsons disease
and/or hyperprolactinemia.8 Dopamine receptors
comprise five subtypes, D1, D2, D3, D4 and D5 recep-
tors, which are classified into D1-like (D1 and D5) and
D2-like (D2, D3 and D4) receptors.9 All the dopamine
agonists used to treat Parkinsons disease have high
affinity for the D2-like receptors and low affinity for

Table 1 Receptor binding affinity and pharmacokinetics of dopamine agonists (adapted from Kvernmo et al.8)
Bromocriptine Cabergoline Pergolide Pramipexole Ropinirole
Receptor affinity (inhibitor D1 1659 182 172 >50 000 36 600
constants: nM) D2 12.2 2.1 0.5 2.2 4.4
D3 2.5 0.7 0.2 3.9 3.7
D4 59.7 9 1.3 5.1 7.8
D5 1691 165 164 >10 000 41 211
5-HT2B 56.2 <partial agonist> 1.2 <agonist> 7.1 <agonist> >10 000 >10 000
Oral bioavailability (%) 6 5080 2060 >90 50
Half-life (hour) 37 63110 27 812 6

5-HT,5-hydroxytryptamine.

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 Dopamine and depression

Figure 1 Effect of tricyclic antidepressants on dopamine output (expressed as a percentage of basal) (a) from the prefrontal cortex, (b) from
the nucleus accumbens and (c) on 5-HT output from the prefrontal cortex. Error bars represent standard errors of the mean. (Adapted from
Tanda et al.7) *P < 0.05 compared with basal in post-hoc test. 5-HT, 5-hydroxytryptamine.

the D1-like receptors. Ergot alkaloids (bromocriptine,
cabergoline and pergolide) have high affinity for the
5-HT2B receptor and therefore can cause serious,
albeit rare, adverse events including valvular heart
diseases. In contrast, non-ergot dopamine agonists
(talipexole, ropinirole and pramipexole) do not have
such an effect on cardiac valves because of their low
affinity for the 5-HT2B receptor, although these three
agents can potentially cause sleep attack. Table 2 lists
the studies that have examined the possible effect of
dopamine agonists on treatment-resistant depression
and/or bipolar depression.1028
In the 1990s, several studies, mostly from Japan
(particularly from a research group at Hokkaido Uni-
versity in Sapporo), reported the efficacy of the ergot
alkaloids bromocriptine and pergolide in the treatment
of (treatment-resistant) depression.1016 More recently,
attention has shifted to the efficacy of non-ergot
dopamine agonists pramipexole and ropinirole.1728 In
treatment-resistant bipolar depression, two random-
ized controlled trials demonstrated that the addition of
pramipexole, a D2/D3 receptor agonist approved for
the treatment of Parkinsons disease and restless legs
syndrome, to existing mood stabilizers resulted in a
significant improvement in depressive symptoms.22,23
The Canadian Network for Mood and Anxiety Treat-
ment lists the combination of lithium and pramipexole
as a third-line option for bipolar depression.29

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H. Hori and H. Kunugi

Table 2 Evidence for efficacy of dopamine agonists in treatment-resistant depression

Study Year Design Sample characteristics n Efficacy (%)
Bromocriptine
Kishimoto10 1993 Open-label trial Not specified 9 0
Inoue et al.11 1996 Open-label trial UP patients who did not respond to 6 67
one antidepressant or more
Inoue et al.12 1996 Retrospective chart review UP/BP patients who did not respond to 22 64
two or more antidepressants
Hirayama et al.13 1996 Case report A BP patient who did not respond to 1 (effective)
two antidepressants
Pergolide
Bouckoms and 1993 Open-label trial UP/BP patients 20 55
Mangini14
Izumi et al.15 1996 Case report A UP patient who did not respond to 1 (effective)
two antidepressants
Izumi et al.16 2000 Open-label trial UP patients who did not respond to 20 40
one antidepressant or more
Pramipexole
Sporn et al.17 2000 Retrospective chart review UP/BP patients who did not respond to 32 44
one antidepressant or more
Perugi et al.18 2001 Open case series BPII patients who did not respond to 10 40
mood stabilizers or antidepressants
Lattanzi et al.19 2002 Open-label trial UP/BP patients who did not respond to 37 68
one antidepressant or more
Takahashi et al.20 2003 Case report UP patients who did not respond to 2 (effective)
one antidepressant
Cassano et al.21 2004 Prospective naturalistic UP/BP patients who did not respond to 23 61
study one antidepressant or more
Zarate et al.22 2004 Placebo-controlled RCT BPII patients who did not respond to 10 (placebo: 11) 60 (placebo: 9)
one antidepressant or more
Goldberg et al.23 2004 Placebo-controlled RCT BP patients who did not respond to 12 (placebo: 10) 67 (placebo: 20)
two or more antidepressants
Tanaka et al.24 2006 Retrospective chart review BP patients who did not respond to 8 63
one antidepressant or more
Inoue et al.25 2010 Open-label trial UP/BP patients who did not respond to 10 60
two or more antidepressants
El-Mallakh et al.26 2010 Retrospective chart review BP patients 16 100
Hori and Kunugi27 2012 Open-label trial UP/BP patients who did not respond to 17 71
one antidepressant or more
Ropinirole
Perugi et al.18 2001 Open case series BPII patients who did not respond to 8 50
mood stabilizers or antidepressants
Cassano et al.28 2005 Open-label trial UP/BP patients who did not respond to 10 40
one antidepressant or more

BP, bipolar disorder; RCT, randomized control trial; UP, unipolar major depressive disorder.

However, data on the efficacy of dopamine agonists in
treating treatment-resistant unipolar major depressive
disorder (MDD) is scarce. To our knowledge, six open-
label studies (excluding case reports and naturalistic
studies), including ours, have investigated the
possible effect of adjunctive dopamine agonists
in the treatment of treatment-resistant MDD
(Table 2).11,16,19,25,27,28 These studies overall showed
substantial efficacy of dopamine agonist augmenta-
tion therapy, with the strongest evidence obtained for
pramipexole. Therefore, it has been suggested that
pramipexole augmentation, among various dopamine
agonists, may be a worthwhile option for treatment-
resistant depressed patients. In our open-label trial,27
17 patients with DSM-IV major depressive episode
who failed to respond to previous treatment with a
SSRI were enrolled. Five patients were diagnosed as
having bipolar II disorder and 12 as having unipolar
MDD. Patients were monitored at an ambulatory care
facility every 2 weeks for 12 weeks, and pramipexole
was added to existing medication. Depression sever-
ity was assessed with the Hamilton Depression Rating

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25
Mean HDRS-21 scores
20
15
10
5 and that the time spent in closed arms tended to
0 based on the brain-derived neurotrophic factor
0 2 4 6 8 10 12
Weeks
Figure 2 The samples (n = 17) mean scores over time on the
Hamilton Depression Rating Scale 21-item version (HDRS-21),
based on the intent-to-treat analysis. Error bars represent standard
errors of the mean. (Adapted from Hori and Kunugi.27)
Scale 21-item version (HDRS-21). The mean 1 SD
maximum dosage of pramipexole was 1.6 1 0.9 mg.
As shown in Figure 2, the HDRS-21 total score
decreased from 19.4 1 3.8 at baseline to 7.2 1 5.4
at endpoint (P < 0.000001). Twelve patients (71%)
responded based on a reduction of 50% or more
in the HDRS-21 score. Ten patients (59%) remitted
(HDRS-21 total score at endpoint <8). These results
were almost unchanged when the sample was con-
fined to patients with MDD. No serious adverse events
were observed. Our study confirmed previous findings
and indicated that pramipexole augmentation therapy
might be effective and well tolerated in treatment-
resistant depressed patients.
With respect to cognitive function, a recent ran-
domized placebo-controlled study found greater
improvements on measures of processing speed
and working memory in euthymic bipolar patients
taking pramipexole than those taking placebo.30
Potential cognitive enhancement effects of dopamine
agonists in mood disorder patients deserve further
investigations.
OUR PRECLINICAL STUDY ON
THE EFFICACY OF PRAMIPEXOLE
MONOTHERAPY
While there have been a number of studies in which
dopamine agonists were added on to other medica-
tions such as antidepressants and/or mood stabilizers
(see Table 2), few clinical or preclinical studies have
examined the efficacy of dopamine agonists as a
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Psychogeriatrics 2013 Japanese Psychogeriatric Society
Dopamine and depression
monotherapy in depression. We therefore conducted
a preclinical study to investigate the possible
antidepressant-like effect of cabergoline mono-
therapy.31 In this study we administered cabergoline
repeatedly and found that immobility in the forced
swimming test and latency of feeding in the novelty-
suppressed feeding test were significantly reduced
decrease in the elevated-plus maze test. Furthermore,
(BDNF) hypothesis of depression,32,33 the hippocam-
pus was removed 24 h after the last injection of cab-
ergoline, and Western blotting was used to examine
the protein levels of BDNF and the activation of intra-
cellular signalling molecules, which revealed that the
expression of BDNF and activation of extracellular
signal-regulated kinase 1 were upregulated (Fig. 3).
These results indicated that potentiation of intracellu-
lar signalling of BDNF in the hippocampus may be
involved in the antidepressant- and anxiolytic-like
effects of cabergoline.
POTENTIAL MECHANISM(S) UNDERLYING
THE EFFICACY OF DOPAMINE
AGONISTS FOR THE TREATMENT OF
REFRACTORY DEPRESSION
Although the mechanisms enabling dopamine ago-
nists to exert an antidepressant effect have not been
elucidated, several possibilities have been suggested.
First, as dopamine regulates motivation, psychomotor
speed, concentration and pleasure, these emotional
circuits in the brain can be activated and reinforced
through the stimulation of dopamine receptors.
Activity-dependent BDNF release and its signals may
be involved in the process of the transition from acti-
vation to reinforcement. Second, SSRI and tricyclic
antidepressants also increase dopamine in the pre-
frontal cortex, but they do not increase dopamine in
the nucleus accumbens (Fig. 1). Thus, it is possible
that the stimulation of the dopaminergic system of the
nucleus accumbens could be a mechanism of action
of dopamine agonists.34 Third, the selective stimula-
tion of D2-like receptors by dopamine agonists is
fundamentally different from the indirect increase of
extracellular dopamine caused by SSRI, SNRI and
tricyclic antidepressants and from the dopamine
reuptake inhibition caused by norepinephrine-
dopamine reuptake inhibitors such as bupropion.
193
H. Hori and H. Kunugi

a with a reduction in regional metabolism in orbitofron-

Cabergoline - + - + - + tal cortex, ventrolateral prefrontal cortex and antero-
medial prefrontal cortex.35 This finding provides
support for a role of the central dopaminergic system
BDNF p75 TrkB
in the pathophysiology of depression, as cerebral
b metabolic activity in these regions has been found to
2.5 Vehicle be elevated in depression.36
(Mean value of vehicle =1)
Relative expressin levels

Cabergoline
2.0
* CONCLUSION
1.5
In this review, we have described the role of dopamine
1.0
in depression and the efficacy of dopamine receptor
agonists in (treatment-resistant) patients with depres-
0.5 sion, with some discussion on the mechanisms. Evi-
dence suggests that there may be a subgroup of
0 depression that is responsive to the dopamine ago-
BDNF p75 TrkB
nists but not to the current first-line antidepressants
c such as SSRI, SNRI, or tricyclics. Further randomized
Cabergoline - + - + controlled trials in a large sample would be needed to
prove the efficacy and safety of dopamine agonists
Phosphorylation for treatment-resistant major depression. In addition,
Total many issues regarding the efficacy of dopamine ago-
nists remain to be resolved, including long-term effi-
ERK1/2 Akt
cacy, efficacy as a monotherapy, and efficacy for
d juvenile and senile depression.
Relative phosphorylation levels

2.5 Vehicle Basic research, including cell biology and animal

(Mean value of vehicle =1)

2.0 * Cabergoline model studies, is also necessary to understand where

# and how dopamine is involved in the brain of
1.5
1.0
0.5
0
pERK1 pERK2
Figure 3 Effects of chronic administration of cabergoline on the
expression and activation of BDNF-related signals. (a) Repre-
sentative blotting of BDNF (left), p75 (centre), and TrkB (right).
(b) Densitometry quantified values of BDNF and its receptors. (c)
Representative blotting of pERK1/2 (left) and pAkt (right). (d) Den-
sitometry quantified values of BDNF-related signals. Columns and
bars represent mean 1 SEM. n = 6 for each group. (Adapted from
Chiba et al.31) *P < 0.05, #P < 0.1 versus vehicle. BDNF, brain-
derived neurotrophic factor; pAkt, phosphorylated protein kinase B;
pERK, phosphorylated extracellular signal-regulated kinase; TrkB,
tyrosine receptor kinase B.
With regard to functional brain systems affected by
dopamine agonists, a recent neuroimaging study
showed that clinical improvement with pramipexole
augmentation in bipolar depression was associated
depressed patients and to determine which receptor
is of more importance than others. Such attempts
may ultimately lead to the elucidation of the patho-
physiology of depression as well as the development
of new drugs with greater efficacy and less side
effects.
pAkt
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