Pramipexole augmentation in

treatment-resistant major
depressive disorder
Expert Rev. Neurother. 14(1), 58 (2014)
Chi-Un Pae
Department of Psychiatry, The Catholic
University of Korea College of
Medicine, Seoul, South Korea
and
Department of Psychiatry and Behavio-
ral Medicines, Duke University Medical
Center, Durham, NC, USA
and
Department of Psychiatry, Bucheon St.
Marys Hospital, The Catholic University
of Korea College of Medicine, 2 Sosa-
Dong, Wonmi-Gu, Bucheon, Kyeonggi-
Do 420-717, Republic of Korea
Tel.: +82 323 407 067
Fax: +82 323 402 255
pae@catholic.ac.kr
Evaluation of: Cusin C, Iovieno N, Iosifescu DV et al. A randomized, double-blind, placebo-
controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder.
J. Clin. Psychiatry 74(7), e636e641 (2013).
To overcome limited efficacy in antidepressants, clinicians may choose augmentation, switching
to a different antidepressant, or a combination of different antidepressant drugs based on the
individual patients clinical circumstances. Among such options for difficult-to-treat major
depressive disorder (MDD) patients, augmentation therapy with atypical antipsychotics,
psychostimulants, dopamine agonists, serotonin 1A partial agonists, lithium, and thyroid
hormones are commonly used in clinical practice. In fact, augmentation therapy has some
clinical merits and is more convenient than switching medications and combination approaches
for treating MDD. One such augmentation agent, pramipexole has been proposed, and has
been implicated in the development and treatment of MDD. Recently, randomized controlled
trials with pramipexole augmentation have been conducted and have demonstrated that
pramipexole is a safe and potentially efficacious augmentation strategy. This article will discuss
currently available clinical trial data and the potential role of pramipexole in MDD treatment,
including clinical significance, limitations, and future research directions.
KEYWORDS: augmentation clinical trial depression efficacy pramipexole
Pramipexole (2-amino-4,5,6,7-tetrahydro-6-
propyl-amino-benzthiazole-dihydrochloride) is
a relatively new dopamine receptor agonist
and has been approved for the treatment of
idiopathic Parkinsons disease and restless legs
syndrome as a monotherapy or augmentation
therapy by US FDA [101]. It has a preference
for D3, as compared to D2 and D4 receptors,
and it is a full agonist with higher affinity for
D3 than for D2 and D4 receptor subtypes [1].
The antidepressant potential of pramipexole
has been consistently shown in animal models
using the forced swimming test, which is con-
sidered critical in proving a drugs antidepres-
sant effects. In such forced swimming tests,
pramipexole augmentation (PA) significantly
reduced the immobility time than older (imipr-
amine and amitriptyline) [1] and newer (citalo-
pram and fluoxetine) [13] generation
antidepressant monotherapies. In addition,
small-scale, open-label studies [4,5], chart
reviews/case series [68] and case reports [9] have
also shown its potential effects in the treatment
of major depressive disorder (MDD). More-
over, in a previous randomized, placebo-
controlled clinical trial with 174 MDD patients,
three monotherapy dose strengths of pramipex-
ole (0.375 mg, 1.0 mg and 5.0 mg) were com-
pared to fluoxetine (20 mg) and placebo in the
parallel comparison design [10]. Corrigan et al.
showed that patients in the pramipexole 1.0 and
5.0 mg monotherapy groups had better
improvement in depression symptoms by the
end of treatment, while the pramipexole 1.0 mg
group had better tolerability than the 5.0 mg
group [10]. Fluoxetine showed similar efficacy to
both pramipexole groups, without group differ-
ences. There have been no randomized con-
trolled trials (RCTs) with PA for MDD patients
yet. However, Cusin and colleagues have con-
ducted the first RCT of PA for treatment-
resistant MDD (TRD), and they found that PA
may be another viable treatment option for
TRD [11]. This article discusses currently
www.expert-reviews.com 10.1586/14737175.2014.864556 2014 Informa UK Ltd ISSN 1473-7175 5
Key Paper Evaluation
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available clinical trial data and the potential role of pramipexole
in MDD treatment, including consideration of clinical signifi-
cance, limitations and future research directions.
Methods & results
This study investigated the antidepressant efficacy of a flexible dose
of the dopamine agonist pramipexole as an adjunct to standard
antidepressant treatment (selective serotonin reuptake inhibitors:
paroxetine, fluoxetine, sertraline, escitalopran and citalopram; or
serotonin-norepinephrine reuptake inhibitors: duloxetine and ven-
lafaxine) in an 8-week, randomized, double-blind, placebo-
controlled trial, conducted in a tertiary-level depression center.
They randomized 60 outpatients (aged 1875 years) with
treatment-resistant nonpsychotic MDD (diagnosed according to
DSM-IV) to either pramipexole (n = 30) or placebo (n = 30).
Treatment resistance was defined as continued depression (Mont-
gomery-Asberg Depression Rating Scale [MADRS] score 18 for
6-weeks treatment after screening phase), despite treatment with at
least one prior antidepressant in the current depressive episode.
Patients were recruited between September 2005 and April 2008.
The primary outcome measure was the MADRS score. The analy-
ses that used a mixed-effects linear regression model indicated a
modest but statistically significant benefit for pramipexole
(p = 0.038). The last-observation-carried-forward analyses indicated
that 40 and 33% of patients randomized to augmentation with pra-
mipexole achieved response (defined as 50% improvement in
MADRS score, as compared to baseline, c
2
= 1.2, p = 0.27) and
remission (defined as a MADRS score <10 at study endpoint,
c
2
= 0.74, p = 0.61), respectively, as compared to 27 and 23%
with placebo. However, these differences were not statistically sig-
nificant. Interestingly, loss of sexual desire was significantly lower
(p = 0.03) in PA (n = 1/30) than placebo augmentation (n = 6/30)
during the study. Augmentation with pramipexole was well-
tolerated with no serious adverse events (AEs) identified.
Discussion & significance
Cusin and colleagues suggest that PA could be potentially effica-
cious for patients with TRD in their first, small RCT (mean daily
and target doses of pramipexole = 1.35 and 3 mg/day, respec-
tively) [11]. This study clearly distinguishes the first RCT of PA for
the treatment of TRD and also found that PA would be more ben-
eficial in the treatment of TRD than antidepressant monotherapy.
In addition, the study participant selection criteria were relatively
rigorous for the definition of TRD. The limitations are also defi-
nite. The sample size was only 60 for PA and placebo groups,
although the actual power was >80% since they applied repeated
measures for mixed-effects analysis. However, absolute sample size
was not sufficient for generalization to clinical practise. In fact, the
only prominent result of Cusin et al.s study was the greater reduc-
tion in MADRS total score in PA than in placebo augmentation,
possibly indicating a weak sample power (type II error). The anti-
depressants inclusion was not balanced, especially between selective
serotonin reuptake inhibitors (83.3%) and serotonin-
norepinephrine reuptake inhibitors (16.7%), which is a crucial
shortcoming, as these antidepressants were found to have
differential side effects and potential differences in efficacy. Hence,
patient stratification bias could not be controlled in the study. In
addition, the definition of TRD was a history of one or more pre-
vious antidepressants failing, which is a more flexible criterion, as
compared to previous studies. However, only one patient had one
antidepressant failure history, while all others had a history of two
or more previous antidepressant failures. Finally the discontinua-
tion rate was relatively high (30%). As for early dropout rates in PA
(n = 8/30, 4, 2, 1 and 1 were due to AEs, pregnancy, symptom
worsening and mis-diagnosis) and placebo (n = 10/30, 4, 3, 2 and
1 were due to AEs, withdrawal consent, lost to follow-up and no
improvement) augmentation, all AEs were assessed as mild to mod-
erate but no serious AEs were reported.
There has been a paucity of adequately powered RCTs of prami-
pexole for MDD. Although small RCTs and open-label studies
have tentatively demonstrated the beneficial effect of pramipexole
for the treatment of depression; subsequent larger RCTs are still
needed to confirm the effectiveness and tolerability of pramipexole
for the treatment of MDD. A pooled-analysis may allow critical
comparisons between studies and comparator drugs as well as pro-
viding greater statistical power than individual trials [12]. Hence, we
have examined the literature to determine the efficacy of pramipex-
ole for MDD and have gathered these clinical trial data for pooled-
analysis through a PubMed database search. The searches were lim-
ited to either RCTs or randomized clinical trials of both PA (com-
bination) therapy for the treatment of unipolar (UD) or bipolar
(BD) depression. The search retrieved 129 studies, and then
125 studies were excluded in the pooled-analysis. Open trials,
reviews, monotherapy, case reports, retrospective chart review and
preclinical studies were excluded. A pooled-analysis with a random-
effect model was eventually done for two UD [11,13] (n = 86) and
two BD [14,15] (n = 43) studies (CMA v2, Englewood, NJ, USA).
For the two UD trials for 8-week [11] and 6-week [13] periods,
(PA, [n = 43, 30 [11] and 13 [13] patients in respective study]; escita-
lopram monotherapy [n = 43, 30 [11] and 13 [13] patients in respec-
tive study]), the standardized mean difference (SMD) for mean
changes of primary efficacy measures (MADRS total score) from
baseline between PA and escitalopram monotherapy did not differ
between the two groups (SMD: 0.244; 95% CI: -0.913, 1.402;
p = 0.679). These trends were similar with responder and remitters
analyses (responder odds ratio [OR] for pramipexole monotherapy
[PM]: 1.477; p = 0.445; remitter OR for PM: 0.864; p = 0.886).
These seem to contradict the results of Cusin et al. [11]. However,
one should also consider that PA was more effective for patients
with more than two antidepressant failures than for those with one
antidepressant failure in the Cusin et al. study, indicating the possi-
bility of a differential role of PA for such patients.
Meanwhile, when conducting a pooled-analysis for PA with
mood stabilizers (PA: 10; placebo: 11 [14] and PA: 12; placebo:
10 [15]) in two BD trials for 6 weeks (PA total n = 22; placebo total
n = 21), the SMD for mean changes of primary efficacy measures
(HAMD total score) from baseline was significantly different when
compared with placebo augmentation (SMD: -1.864; 95%
CI: -2.581, -1.146; p < 0.0001). This robust significance was simi-
lar to responder analysis (OR for PM: 10.27; p = 0.003) but not to
Key Paper Evaluation Pae
6 Expert Rev. Neurother. 14(1), (2014)
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remitter analysis (OR for PM: 3.603; p = 0.153). This may indicate
a better potential role for PA in treating BD than UD, reflecting
the results from pooled-analysis of two UD trials [11,13]. This result
preliminarily indicates that we need to further investigate the differ-
ential role of PA in the treatment of UD and BD for the establish-
ment of more effective treatment guidelines in clinical practise.
Although Cusin and colleagues have clearly demonstrated
that PA should be a potential next viable treatment option for
TRD patients, showing 40% response and 33.3% remission
rates, while the placebo group shows 26.7% response and
23.3% remission rates, existing PA clinical data are not suffi-
cient to fully support PA efficacy in treating MDD. In fact,
atypical antipsychotics, including olanzapine, quetiapine XR
and aripiprazole, have clearly demonstrated efficacy as augmen-
tation agents for MDD through a number of RCTs. They
have been approved by the FDA and are widely prescribed by
clinicians across the world. Hence, to consider PA as a reliable
treatment option for the future, more clinical trial data from
adequately-powered and well-controlled RCTs are necessary.
Expert commentary & five-year view
PA was more effective for patients with two or more antidepressant
failures than for those with one antidepressant failure, according to
Cusin et al. indicating the possibility of different roles for PA in a
subset of TRD patients. Since the severity differences in depression
are critically influential for treating such patients [11], this issue
should be further explored in subsequent studies.
In fact, a recent probabilistic approach using operational cri-
teria for diagnostic guidelines for BD was proposed by
Mitchell et al. with an extensive literature review on the clinical
characteristics of UD and BD [16]. This study included some
specific symptoms such as atypical features, psychomotor
retardation and increased prior episodes of depression as a
greater indicator of BD than UD, which may partly explain
the different results from UD and BD pooled-analyses.
Based on the findings from Cusin et al. sexual dysfunction
was substantially lower with PA, indicating a potential PA util-
ity for patients suffering from sexual dysfunction after antide-
pressant treatment. The short trial duration, inadequate dose
titration, patients different characteristics and small sample size
in currently available PA clinical trial data [11,13], should be
reflected in future clinical trials. The question is whether PA
may have clinical utility in the treatment of patients either
experiencing their first depressive episode (comorbid medical
conditions and atypical features) or are candidates for long-
term treatment, supports the need for subsequent clinical trials.
In conclusion, currently available findings describing the role
of PA for patients with MDD appears to be preliminary and
not definitive. In fact, testing the therapeutic efficacy of various
new chemicals or agents with naturalistic origins like anticholi-
nergics, curcumin and creatine has been increasing. The studies
focus on whether these agents can augment ongoing antidepres-
sant therapy or not, producing diverse clinical results [1720].
Hence, more adequately powered and advanced RCTs, includ-
ing an appropriate subpopulation, may provide a foundation
for the clinical usefulness of PA in routine practise.
Financial & competing interests disclosure
This study was supported by a grant of the Korean Health Technology R&D
Project, Ministry of Health & Welfare, Republic of Korea (A120004). The
author has no other relevant affiliations or financial involvement with any organ-
ization or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Cusin and colleagues have found that the use of pramipexole augmentation (PA) was significantly associated with improvement of
depressive symptoms, compared with placebo augmentation.
In addition, PA was beneficial for controlling sexual dysfunction caused by antidepressant treatment.
Currently available pooled-data suggest that pramipexole should be more beneficial in treatment of bipolar depression than unipolar
depression, although available data was quite limited, which should be better determined with more clinical trial data.
Advanced clinical trials in methodological aspects will be needed to achieve better understanding about the exact role of PA in the treat-
ment of major depressive disorder due to relative lack of clinical trial data till today.
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