Key Paper Evaluation
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
Pramipexole augmentation in treatment-resistant major depressive disorder Expert Rev. Neurother. 14(1), 5–8 (2014)
Chi-Un Pae Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, South Korea and Department of Psychiatry and Behavioral 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 SosaDong, Wonmi-Gu, Bucheon, KyeonggiDo 420-717, Republic of Korea Tel.: +82 323 407 067 Fax: +82 323 402 255 [email protected]
Evaluation of: Cusin C, Iovieno N, Iosifescu DV et al. A randomized, double-blind, placebocontrolled 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, switching to a different antidepressant, or a combination of different antidepressant drugs based on the individual patient’s 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-6propyl-amino-benzthiazole-dihydrochloride) is a relatively new dopamine receptor agonist and has been approved for the treatment of idiopathic Parkinson’s 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 considered critical in proving a drug’s antidepressant effects. In such forced swimming tests, pramipexole augmentation (PA) significantly reduced the immobility time than older (imipramine and amitriptyline) [1] and newer (citalopram and fluoxetine) [1–3] generation antidepressant monotherapies. In addition, small-scale, open-label studies [4,5], chart reviews/case series [6–8] and case reports [9] have
www.expert-reviews.com
10.1586/14737175.2014.864556
also shown its potential effects in the treatment of major depressive disorder (MDD). Moreover, in a previous randomized, placebocontrolled clinical trial with 174 MDD patients, three monotherapy dose strengths of pramipexole (0.375 mg, 1.0 mg and 5.0 mg) were compared 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 differences. There have been no randomized controlled trials (RCTs) with PA for MDD patients yet. However, Cusin and colleagues have conducted the first RCT of PA for treatmentresistant MDD (TRD), and they found that PA may be another viable treatment option for TRD [11]. This article discusses currently
2014 Informa UK Ltd
ISSN 1473-7175
5
Key Paper Evaluation
Pae
available clinical trial data and the potential role of pramipexole in MDD treatment, including consideration of clinical significance, limitations and future research directions.
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
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 venlafaxine) in an 8-week, randomized, double-blind, placebocontrolled trial, conducted in a tertiary-level depression center. They randomized 60 outpatients (aged 18–75 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 (Montgomery-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 analyses 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 pramipexole achieved response (defined as 50% improvement in MADRS score, as compared to baseline, c2 = 1.2, p = 0.27) and remission (defined as a MADRS score 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 reduction in MADRS total score in PA than in placebo augmentation, possibly indicating a weak sample power (type II error). The antidepressants inclusion was not balanced, especially between selective serotonin reuptake inhibitors (83.3%) and serotoninnorepinephrine reuptake inhibitors (16.7%), which is a crucial shortcoming, as these antidepressants were found to have 6
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 previous 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 discontinuation 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 moderate but no serious AEs were reported. There has been a paucity of adequately powered RCTs of pramipexole 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 providing greater statistical power than individual trials [12]. Hence, we have examined the literature to determine the efficacy of pramipexole for MDD and have gathered these clinical trial data for pooledanalysis through a PubMed database search. The searches were limited to either RCTs or randomized clinical trials of both PA (combination) 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 randomeffect 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]; escitalopram monotherapy [n = 43, 30 [11] and 13 [13] patients in respective 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 possibility 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 similar to responder analysis (OR for PM: 10.27; p = 0.003) but not to Expert Rev. Neurother. 14(1), (2014)
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
Pramipexole augmentation in treatment-resistant MDD
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 differential role of PA in the treatment of UD and BD for the establishment 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 sufficient to fully support PA efficacy in treating MDD. In fact, atypical antipsychotics, including olanzapine, quetiapine XR and aripiprazole, have clearly demonstrated efficacy as augmentation 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 criteria 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
Key Paper Evaluation
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 utility for patients suffering from sexual dysfunction after antidepressant 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 longterm 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 anticholinergics, curcumin and creatine has been increasing. The studies focus on whether these agents can augment ongoing antidepressant therapy or not, producing diverse clinical results [17–20]. Hence, more adequately powered and advanced RCTs, including 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 organization 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 treatment of major depressive disorder due to relative lack of clinical trial data till today.
References
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).
Papers of special note have been highlighted as: • of interest 1
2
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). Maj J, Rogoz Z. Synergistic effect of pramipexole and sertraline in the forced swimming test. Polish J. Pharmacol. 51(6), 471–475 (1999).
www.expert-reviews.com
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).
7
Key Paper Evaluation
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
7
Pae
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
11
Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11(2), 58–65 (2000). 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. The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind,
8
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 placebocontrolled 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. Psychiatry 73(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 drugs 25(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)
Expert Rev. Neurother. 14(1), (2014)
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
Pramipexole augmentation in treatment-resistant major depressive disorder Expert Rev. Neurother. 14(1), 5–8 (2014)
Chi-Un Pae Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, South Korea and Department of Psychiatry and Behavioral 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 SosaDong, Wonmi-Gu, Bucheon, KyeonggiDo 420-717, Republic of Korea Tel.: +82 323 407 067 Fax: +82 323 402 255 [email protected]
Evaluation of: Cusin C, Iovieno N, Iosifescu DV et al. A randomized, double-blind, placebocontrolled 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, switching to a different antidepressant, or a combination of different antidepressant drugs based on the individual patient’s 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-6propyl-amino-benzthiazole-dihydrochloride) is a relatively new dopamine receptor agonist and has been approved for the treatment of idiopathic Parkinson’s 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 considered critical in proving a drug’s antidepressant effects. In such forced swimming tests, pramipexole augmentation (PA) significantly reduced the immobility time than older (imipramine and amitriptyline) [1] and newer (citalopram and fluoxetine) [1–3] generation antidepressant monotherapies. In addition, small-scale, open-label studies [4,5], chart reviews/case series [6–8] and case reports [9] have
www.expert-reviews.com
10.1586/14737175.2014.864556
also shown its potential effects in the treatment of major depressive disorder (MDD). Moreover, in a previous randomized, placebocontrolled clinical trial with 174 MDD patients, three monotherapy dose strengths of pramipexole (0.375 mg, 1.0 mg and 5.0 mg) were compared 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 differences. There have been no randomized controlled trials (RCTs) with PA for MDD patients yet. However, Cusin and colleagues have conducted the first RCT of PA for treatmentresistant MDD (TRD), and they found that PA may be another viable treatment option for TRD [11]. This article discusses currently
2014 Informa UK Ltd
ISSN 1473-7175
5
Key Paper Evaluation
Pae
available clinical trial data and the potential role of pramipexole in MDD treatment, including consideration of clinical significance, limitations and future research directions.
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
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 venlafaxine) in an 8-week, randomized, double-blind, placebocontrolled trial, conducted in a tertiary-level depression center. They randomized 60 outpatients (aged 18–75 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 (Montgomery-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 analyses 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 pramipexole achieved response (defined as 50% improvement in MADRS score, as compared to baseline, c2 = 1.2, p = 0.27) and remission (defined as a MADRS score 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 reduction in MADRS total score in PA than in placebo augmentation, possibly indicating a weak sample power (type II error). The antidepressants inclusion was not balanced, especially between selective serotonin reuptake inhibitors (83.3%) and serotoninnorepinephrine reuptake inhibitors (16.7%), which is a crucial shortcoming, as these antidepressants were found to have 6
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 previous 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 discontinuation 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 moderate but no serious AEs were reported. There has been a paucity of adequately powered RCTs of pramipexole 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 providing greater statistical power than individual trials [12]. Hence, we have examined the literature to determine the efficacy of pramipexole for MDD and have gathered these clinical trial data for pooledanalysis through a PubMed database search. The searches were limited to either RCTs or randomized clinical trials of both PA (combination) 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 randomeffect 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]; escitalopram monotherapy [n = 43, 30 [11] and 13 [13] patients in respective 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 possibility 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 similar to responder analysis (OR for PM: 10.27; p = 0.003) but not to Expert Rev. Neurother. 14(1), (2014)
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
Pramipexole augmentation in treatment-resistant MDD
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 differential role of PA in the treatment of UD and BD for the establishment 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 sufficient to fully support PA efficacy in treating MDD. In fact, atypical antipsychotics, including olanzapine, quetiapine XR and aripiprazole, have clearly demonstrated efficacy as augmentation 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 criteria 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
Key Paper Evaluation
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 utility for patients suffering from sexual dysfunction after antidepressant 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 longterm 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 anticholinergics, curcumin and creatine has been increasing. The studies focus on whether these agents can augment ongoing antidepressant therapy or not, producing diverse clinical results [17–20]. Hence, more adequately powered and advanced RCTs, including 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 organization 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 treatment of major depressive disorder due to relative lack of clinical trial data till today.
References
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).
Papers of special note have been highlighted as: • of interest 1
2
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). Maj J, Rogoz Z. Synergistic effect of pramipexole and sertraline in the forced swimming test. Polish J. Pharmacol. 51(6), 471–475 (1999).
www.expert-reviews.com
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).
7
Key Paper Evaluation
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by UB der LMU Muenchen on 06/18/14 For personal use only.
7
Pae
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
11
Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11(2), 58–65 (2000). 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. The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind,
8
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 placebocontrolled 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. Psychiatry 73(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 drugs 25(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)
Expert Rev. Neurother. 14(1), (2014)
