The objective of this meta-analysis is to assess the efficacy and safety of partial and complete dopamine agonists in the treatment of acute mood disorder episodes. Randomized, double-blind and placebo-controlled trials of dopamine agonists in the treatment of acute mood disorder episodes were identified in the MEDLINE and PsycINFO databases and included in the meta-analysis. In monotherapy of mania, improved remission rates were found for cariprazine (odds ratio (OR): 2.08, P < 0.01) and for high-dose aripiprazole (OR: 3.00; P = 0.05), but not for low-dose aripiprazole. In bipolar depression, no improvement of remission and response rates was found for aripiprazole in monotherapy, whereas improved response rate (OR: 10.27, P < 0.01) was found for pramipexole only as an add-on to another mood stabilizer. In major depressive disorder, relatively similar improvements of remission rates were found for high-dose (OR: 1.96, p < 0.01) and low-dose aripiprazole (OR: 1.68, P = 0.01), as well as brexpiprazole (OR: 1.52, P = 0.05) as an add-on to antidepressant medication. Our meta-analysis shows that partial dopamine agonists at high doses are effective in treating acute mania. In major depressive disorder, which is resistant to classical antidepressants, low doses of partial dopamine agonists as adjunct therapy may represent a relatively safe and effective alternative.
AshokAHMarquesTRJauharSet al. (2017) The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry22: 666–679.
2.
BelmakerRHWaldD (1977) Haloperidol in normals. Br J Psychiatry J Ment Sci131: 222–223.
3.
BermanRMFavaMThaseMEet al. (2009) Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr14: 197–206.
4.
BermanRMMarcusRNSwaninkRet al. (2007) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry68: 843–853.
5.
BlackKJHersheyTKollerJMet al. (2002) A possible substrate for dopamine-related changes in mood and behavior: prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc Natl Acad Sci U S A99: 17113–17118.
6.
BrownASGershonS (1993) Dopamine and depression. J Neural Transm Gen Sect91: 75–109.
7.
BrownRTaylorMJGeddesJ (2013) Aripiprazole alone or in combination for acute mania. Cochrane Database Syst Rev12: CD005000.
8.
CalabreseJRKeckPEMacfaddenWet al. (2005) A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry162: 1351–1360.
9.
CalabreseJRKeckPEStaraceAet al. (2015) Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry76: 284–292.
10.
CiprianiADieterichMBarbuiC (2008) Review: atypical antipsychotics are effective adjuncts for treatment resistant depression but increase discontinuation due to adverse effects. Evid Based Ment Health11: 14.
11.
CitromeL (2015) The ABC’s of dopamine receptor partial agonists - aripiprazole, brexpiprazole and cariprazine: the 15-min challenge to sort these agents out. Int J Clin Pract69: 1211–1220.
12.
CorriganMHDenahanAQWrightCEet al. (2000) Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety11: 58–65.
13.
CusinCIovienoNIosifescuDVet al. (2013) A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder. J Clin Psychiatry74: 636–641.
14.
DerSimonianRLairdN (1986) Meta-analysis in clinical trials. Clin Trials7: 177–188.
15.
DomecqJPPrutskyGLeppinAet al. (2015) Clinical review: drugs commonly associated with weight change: a systematic review and meta-analysis. J Clin Endocrinol Metab100: 363–370.
16.
DurgamSEarleyWGuoHet al. (2016a) Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry77: 371–378.
17.
DurgamSEarleyWLipschitzAet al. (2016b) An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry173: 271–281.
18.
DurgamSStaraceALiDet al. (2015) The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord17: 63–75.
19.
El MallakhRSVietaERollinLet al. (2010) A comparison of two fixed doses of aripiprazole with placebo in acutely relapsed, hospitalized patients with bipolar disorder I (manic or mixed) in subpopulations (CN138–007). Eur Neuropsychopharmacol20: 776–783.
20.
FavaMMischoulonDIosifescuDet al. (2012) A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A Study). Psychother Psychosom81: 87–97.
21.
FibigerHC (1995) Neurobiology of depression: focus on dopamine. Adv Biochem Psychopharmacol49: 1–17.
22.
FindlingRLNyilasMForbesRAet al. (2009) Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry70: 1441–1451.
23.
Franco-ChavesJAMateusCFLuckenbaughDAet al. (2013) Combining a dopamine agonist and selective serotonin reuptake inhibitor for the treatment of depression: a double-blind, randomized pilot study. J Affect Disord149: 319–325.
GoldbergJFBurdickKEEndickCJ (2004) Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry161: 564–566.
26.
GoodwinGMHaddadPMFerrierINet al. (2016) Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol30: 495–553.
27.
GreenSHigginsJ (2006) Cochrane Handbook for Systematic Reviews of Interventions 4.2.6. Chichester: Wiley.
28.
HanCWangS-MKwakK-Pet al. (2015) Aripiprazole augmentation versus antidepressant switching for patients with major depressive disorder: a 6-week, randomized, rater-blinded, prospective study. J Psychiatr Res66–67: 84–94.
29.
HigginsJPTAltmanDGGøtzschePCet al. (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ343: d5928.
30.
KamijimaKHiguchiTIshigookaJet al. (2013) Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: a randomized, double-blind, placebo-controlled study (ADMIRE study). J Affect Disord151: 899–905.
31.
KanbaSKawasakiHIshigookaJet al. (2014) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole for the treatment of acute manic or mixed episodes in Asian patients with bipolar I disorder (the AMAZE study). World J Biol Psychiatry15: 113–121.
32.
KapurSMannJJ (1992) Role of the dopaminergic system in depression. Biol Psychiatry32: 1–17.
33.
KeckPEJrMarcusRTourkodimitrisSet al. (2003) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry160: 1651–1658.
34.
KeckPEOrsulakPJCutlerAJet al. (2009) Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord112: 36–49.
35.
KesslerRCBerglundPDemlerOet al. (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry62: 593–602.
36.
LammersCHDiazJSchwartzJCet al. (2000) Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments. Mol Psychiatry5: 378–388.
37.
LaoKSJHeYWongICKet al. (2016) Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: a systematic review with meta-analysis of randomized controlled trials. CNS Drugs30: 1043–1054.
38.
LenzeEJMulsantBHBlumbergerDMet al. (2015) Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet386: 2404–2412.
39.
LinC-HLinS-HJangF-L (2011) Adjunctive low-dose aripiprazole with standard-dose sertraline in treating fresh major depressive disorder: a randomized, double-blind, controlled study. J Clin Psychopharmacol31: 563–568.
40.
LoebelACucchiaroJSilvaRet al. (2014) Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry171: 160–168.
41.
MarcusRNMcQuadeRDCarsonWHet al. (2008) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol28: 156–165.
42.
MarkouAKoobGF (1991) Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacol4: 17–26.
43.
MierauJSchneiderFJEnsingerHAet al. (1995) Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors. Eur J Pharmacol290: 29–36.
44.
MischoulonDWitteJLevyMet al. (2012) Efficacy of dose increase among nonresponders to low-dose aripiprazole augmentation in patients with inadequate response to antidepressant treatment: a randomized, double-blind, placebo-controlled, efficacy trial. J Clin Psychiatry73: 353–357.
45.
PierceyMF (1998) Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson’s disease. Clin Neuropharmacol21: 141–151.
46.
PierceyMFWalkerELFeldpauschDLet al. (1996) High affinity binding for pramipexole, a dopamine D3 receptor ligand, in rat striatum. Neurosci Lett219: 138–140.
47.
QuanteAZeugmannSLuborzewskiAet al. (2010) Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study. Hum Psychopharmacol Clin Exp25: 126–132.
48.
SachsGSanchezRMarcusRet al. (2006) Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol20: 536–546.
49.
SachsGSGreenbergWMStaraceAet al. (2015) Cariprazine in the treatment of acute mania in bipolar I disorder: A double-blind, placebo-controlled, Phase III trial. J Affect Disord174: 296–302.
50.
SchneiderCSMierauJ (1987) Dopamine autoreceptor agonists: resolution and pharmacological activity of 2, 6-diaminotetrahydrobenzothiazole and an aminothiazole analog of apomorphine. J Med Chem30: 494–498.
51.
SilverstoneT (1985) Dopamine in manic depressive illness. A pharmacological synthesis. J Affect Disord8: 225–231.
52.
SmithAHChambersCNaylorGJ (1980) Bromocriptine in mania–a placebo-controlled double-blind trial. Br Med J280: 86.
53.
StahlSM (2016) Mechanism of action of cariprazine. CNS Spectr21: 123–127.
54.
ThaseMEJonasAKhanAet al. (2008) Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol28: 13–20.
55.
ThaseMEYouakimJMSkubanAet al. (2015a) Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry76: 1224–1231.
56.
ThaseMEYouakimJMSkubanAet al. (2015b) Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry76: 1232–1240.
57.
TohenMMcDonnellDPCaseMet al. (2012) Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. Br J Psychiatry J Ment Sci201: 376–382.
58.
TrivediMHRushAJWisniewskiSRet al. (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry163: 28–40.
59.
VietaEBourinMSanchezRet al. (2005) Effectiveness of aripiprazole v. haloperidol in acute bipolar mania. Br J Psychiatry187: 235–242.
60.
VietaET’joenCMcQuadeRDet al. (2008) Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry165: 1316–1325.
61.
WillnerP (1997) The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol12: S7–14.
62.
YildizAVietaELeuchtSet al. (2011) Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacol36: 375–389.
63.
YoshimuraRHoriHUmene-NakanoWet al. (2013) Comparison of lithium, aripiprazole, and olanzapine as augmentation to paroxetine for inpatients with major depressive disorder. Ther Adv Psychopharmacol4: 123–129.
64.
YoungAHOrenDALowyAet al. (2009) Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry194: 40–48.
65.
ZarateCAPayneJLSinghJet al. (2004) Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry56: 54–60.
66.
ZhouXKeitnerGIQinBet al. (2015) Atypical antipsychotic augmentation for treatment-resistant depression: a systematic review and network meta-analysis. Int J Neuropsychopharmacol18: pyv060.
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