pramipexole
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Pramipexole augmentation intreatment-resistant majordepressive disorderExpert Rev. Neurother. 14(1), 5–8 (2014)
Chi-Un PaeDepartment 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.
Mary’s 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
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), e636–e641 (2013).
To overcome limited efficacy in antidepressants, clinicians may choose augmentation, switchingto a different antidepressant, or a combination of different antidepressant drugs based on theindividual patient’s clinical circumstances. Among such options for difficult-to-treat majordepressive disorder (MDD) patients, augmentation therapy with atypical antipsychotics,psychostimulants, dopamine agonists, serotonin 1A partial agonists, lithium, and thyroidhormones are commonly used in clinical practice. In fact, augmentation therapy has someclinical merits and is more convenient than switching medications and combination approachesfor treating MDD. One such augmentation agent, pramipexole has been proposed, and hasbeen implicated in the development and treatment of MDD. Recently, randomized controlledtrials with pramipexole augmentation have been conducted and have demonstrated thatpramipexole is a safe and potentially efficacious augmentation strategy. This article will discusscurrently 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) isa relatively new dopamine receptor agonistand has been approved for the treatment ofidiopathic Parkinson’s disease and restless legssyndrome as a monotherapy or augmentationtherapy by US FDA [101]. It has a preferencefor D3, as compared to D2 and D4 receptors,and it is a full agonist with higher affinity forD3 than for D2 and D4 receptor subtypes [1].
The antidepressant potential of pramipexolehas been consistently shown in animal modelsusing the forced swimming test, which is con-sidered critical in proving a drug’s antidepres-sant effects. In such forced swimming tests,pramipexole augmentation (PA) significantlyreduced the immobility time than older (imipr-amine and amitriptyline) [1] and newer (citalo-pram and fluoxetine) [1–3] generationantidepressant monotherapies. In addition,small-scale, open-label studies [4,5], chartreviews/case series [6–8] and case reports [9] have
also shown its potential effects in the treatmentof 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 theparallel comparison design [10]. Corrigan et al.showed that patients in the pramipexole 1.0 and5.0 mg monotherapy groups had betterimprovement in depression symptoms by theend of treatment, while the pramipexole 1.0 mggroup had better tolerability than the 5.0 mggroup [10]. Fluoxetine showed similar efficacy toboth pramipexole groups, without group differ-ences. There have been no randomized con-trolled trials (RCTs) with PA for MDD patientsyet. However, Cusin and colleagues have con-ducted the first RCT of PA for treatment-resistant MDD (TRD), and they found that PAmay be another viable treatment option forTRD [11]. This article discusses currently
www.expert-reviews.com 10.1586/14737175.2014.864556 � 2014 Informa UK Ltd ISSN 1473-7175 5
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available clinical trial data and the potential role of pramipexolein MDD treatment, including consideration of clinical signifi-cance, limitations and future research directions.
Methods & resultsThis study investigated the antidepressant efficacy of a flexible doseof the dopamine agonist pramipexole as an adjunct to standardantidepressant treatment (selective serotonin reuptake inhibitors:paroxetine, fluoxetine, sertraline, escitalopran and citalopram; orserotonin-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 18–75 years) withtreatment-resistant nonpsychotic MDD (diagnosed according toDSM-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 for6-weeks treatment after screening phase), despite treatment with atleast 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 amodest but statistically significant benefit for pramipexole(p = 0.038). The last-observation-carried-forward analyses indicatedthat 40 and 33% of patients randomized to augmentation with pra-mipexole achieved response (defined as 50% improvement inMADRS score, as compared to baseline, c2 = 1.2, p = 0.27) andremission (defined as a MADRS score <10 at study endpoint,c2 = 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 & significanceCusin and colleagues suggest that PA could be potentially effica-cious for patients with TRD in their first, small RCT (mean dailyand target doses of pramipexole = 1.35 and 3 mg/day, respec-tively) [11]. This study clearly distinguishes the first RCT of PA forthe 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 relativelyrigorous 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 repeatedmeasures for mixed-effects analysis. However, absolute sample sizewas not sufficient for generalization to clinical practise. In fact, theonly 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 selectiveserotonin reuptake inhibitors (83.3%) and serotonin-norepinephrine reuptake inhibitors (16.7%), which is a crucialshortcoming, 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. Inaddition, the definition of TRD was a history of one or more pre-vious antidepressants failing, which is a more flexible criterion, ascompared to previous studies. However, only one patient had oneantidepressant failure history, while all others had a history of twoor 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, symptomworsening and mis-diagnosis) and placebo (n = 10/30, 4, 3, 2 and1 were due to AEs, withdrawal consent, lost to follow-up and noimprovement) 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 studieshave tentatively demonstrated the beneficial effect of pramipexolefor the treatment of depression; subsequent larger RCTs are stillneeded to confirm the effectiveness and tolerability of pramipexolefor the treatment of MDD. A pooled-analysis may allow criticalcomparisons between studies and comparator drugs as well as pro-viding greater statistical power than individual trials [12]. Hence, wehave 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 then125 studies were excluded in the pooled-analysis. Open trials,reviews, monotherapy, case reports, retrospective chart review andpreclinical studies were excluded. A pooled-analysis with a random-effect model was eventually done for two UD [11,13] (n = 86) andtwo 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 meanchanges of primary efficacy measures (MADRS total score) frombaseline between PA and escitalopram monotherapy did not differbetween the two groups (SMD: 0.244; 95% CI: -0.913, 1.402;p = 0.679). These trends were similar with responder and remittersanalyses (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 patientswith more than two antidepressant failures than for those with oneantidepressant 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 withmood stabilizers (PA: 10; placebo: 11 [14] and PA: 12; placebo:10 [15]) in two BD trials for 6 weeks (PA total n = 22; placebo totaln = 21), the SMD for mean changes of primary efficacy measures(HAMD total score) from baseline was significantly different whencompared 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
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remitter analysis (OR for PM: 3.603; p = 0.153). This may indicatea better potential role for PA in treating BD than UD, reflectingthe results from pooled-analysis of two UD trials [11,13]. This resultpreliminarily 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 demonstratedthat PA should be a potential next viable treatment option forTRD patients, showing 40% response and 33.3% remissionrates, while the placebo group shows 26.7% response and23.3% 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 XRand aripiprazole, have clearly demonstrated efficacy as augmen-tation agents for MDD through a number of RCTs. Theyhave been approved by the FDA and are widely prescribed byclinicians across the world. Hence, to consider PA as a reliabletreatment option for the future, more clinical trial data fromadequately-powered and well-controlled RCTs are necessary.
Expert commentary & five-year viewPA was more effective for patients with two or more antidepressantfailures than for those with one antidepressant failure, according toCusin et al. indicating the possibility of different roles for PA in asubset of TRD patients. Since the severity differences in depressionare critically influential for treating such patients [11], this issueshould be further explored in subsequent studies.
In fact, a recent probabilistic approach using operational cri-teria for diagnostic guidelines for BD was proposed byMitchell et al. with an extensive literature review on the clinicalcharacteristics of UD and BD [16]. This study included somespecific symptoms such as atypical features, psychomotor
retardation and increased prior episodes of depression as agreater indicator of BD than UD, which may partly explainthe different results from UD and BD pooled-analyses.
Based on the findings from Cusin et al. sexual dysfunctionwas 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 dosetitration, patients’ different characteristics and small sample sizein currently available PA clinical trial data [11,13], should bereflected in future clinical trials. The question is whether PAmay have clinical utility in the treatment of patients eitherexperiencing their first depressive episode (comorbid medicalconditions and atypical features) or are candidates for long-term treatment, supports the need for subsequent clinical trials.
In conclusion, currently available findings describing the roleof PA for patients with MDD appears to be preliminary andnot definitive. In fact, testing the therapeutic efficacy of variousnew chemicals or agents with naturalistic origins like anticholi-nergics, curcumin and creatine has been increasing. The studiesfocus on whether these agents can augment ongoing antidepres-sant therapy or not, producing diverse clinical results [17–20].Hence, more adequately powered and advanced RCTs, includ-ing an appropriate subpopulation, may provide a foundationfor 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.
References
Papers of special note have been highlighted as:
• of interest
1 Maj J, Rogoz Z, Skuza G, Kolodziejczyk K.
Antidepressant effects of pramipexole, a
novel dopamine receptor agonist. J. Neural.Transm. 104(4–5), 525–533 (1997).
2 Maj J, Rogoz Z. Synergistic effect of
pramipexole and sertraline in the forced
swimming test. Polish J. Pharmacol. 51(6),471–475 (1999).
3 Rogoz Z, Skuza G. Mechanism of
synergistic action following co-treatment
with pramipexole and fluoxetine or
sertraline in the forced swimming test in
rats. Pharmacol. Rep. 58(4), 493–500(2006).
4 Lattanzi L, Dell’Osso L, Cassano P et al.Pramipexole in treatment-resistant
depression: a 16-week naturalistic study.
Bipolar Disord. 4(5), 307–314 (2002).
5 Inoue T, Kitaichi Y, Masui T et al.Pramipexole for stage 2 treatment-resistant
major depression: an open study. Prog.Neuropsychopharmacol. Biol. Psychiatry 34(8),1446–1449 (2010).
6 Sporn J, Ghaemi SN, Sambur MR et al.Pramipexole augmentation in the treatment
of unipolar and bipolar depression:
a retrospective chart review. Ann. Clin.Psychiatry 12(3), 137–140 (2000).
Pramipexole augmentation in treatment-resistant MDD Key Paper Evaluation
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ert R
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f N
euro
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Dow
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info
rmah
ealth
care
.com
by
Yas
er Y
acoo
b on
06/
25/1
4Fo
r pe
rson
al u
se o
nly.
7 Gupta S, Vincent JL, Frank B. Pramipexole:
augmentation in the treatment of depressive
symptoms. CNS spectr. 11(3), 172–175(2006).
8 Ostow M. Pramipexole for depression. Am.J. Psychiatry 159(2), 320–321 (2002).
9 DeBattista C, Solvason HB, Breen JA,
Schatzberg AF. Pramipexole augmentation
of a selective serotonin reuptake inhibitor in
the treatment of depression. J. Clin.Psychopharmacol. 20(2), 274–275 (2000).
10 Corrigan MH, Denahan AQ, Wright CE,
Ragual RJ, Evans DL. Comparison of
pramipexole, fluoxetine, and placebo in
patients with major depression. DepressAnxiety 11(2), 58–65 (2000).
11 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),e636–e641 (2013).
• The original randomized controlled study.
12 Pae CU, Lim HK, Peindl K et al. Theatypical antipsychotics olanzapine and
risperidone in the treatment of
posttraumatic stress disorder: a meta-analysis
of randomized, double-blind,
placebo-controlled clinical trials. Int. Clin.Psychopharmacol. 23(1), 1–8 (2008).
13 Franco-Chaves JA, Mateus CF,
Luckenbaugh DA, Martinez PE,
Mallinger AG, Zarate CA Jr. Combining a
dopamine agonist and selective serotonin
reuptake inhibitor for the treatment of
depression: a double-blind, randomized
pilot study. J. Affect. Disord. 149(1–3),319–325 (2013).
14 Zarate CA Jr, Payne JL, Singh J et al.Pramipexole for bipolar II depression:
a placebo-controlled proof of concept study.
Biol. Psychiatry 56(1), 54–60 (2004).
15 Goldberg JF, Burdick KE, Endick CJ.
Preliminary randomized, double-blind,
placebo-controlled trial of pramipexole
added to mood stabilizers for
treatment-resistant bipolar depression. Am.J. Psychiatry 161(3), 564–566 (2004).
16 Mitchell PB, Goodwin GM, Johnson GF,
Hirschfeld RM. Diagnostic guidelines for
bipolar depression: a probabilistic approach.
Bipolar Disord. 10(1 Pt 2), 144–152 (2008).
17 Lyoo IK, Yoon S, Kim TS et al.A randomized, double-blind placebo-
controlled trial of oral creatine monohydrate
augmentation for enhanced response to a
selective serotonin reuptake inhibitor in
women with major depressive disorder. Am.J. Psychiatry 169(9), 937–945 (2012).
18 Khajavi D, Farokhnia M, Modabbernia A
et al. Oral scopolamine augmentation in
moderate to severe major depressive
disorder: a randomized, double-blind,
placebo-controlled study. J. Clin. Psychiatry73(11), 1428–1433 (2012).
19 Pae CU, Forbes A, Patkar AA. Aripiprazole
as adjunctive therapy for patients with
major depressive disorder: overview and
implications of clinical trial data. CNS drugs25(2), 109–127 (2011).
20 Bergman J, Miodownik C, Bersudsky Y
et al. Curcumin as an add-on to
antidepressive treatment: a randomized,
double-blind, placebo-controlled, pilot
clinical study. Clin. Neuropharmacol. 36(3),73–77 (2013).
Website
101 US FDA. Pramipexole Dihydrochloride.
www.accessdata.fda.gov/scripts/cder/
drugsatfda/
(Accessed 10 September 2013)
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25/1
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