Getting the balance right: Established and emerging therapies for major depressive disorders

Figures & data

Figure 1 The monoamine deficiency hypothesis.

Abbreviations: MAO-A, monoamine oxidase A; PLC, phospholipase-C; AC, adenylate cyclase; 1P₃, ionsitol trisphosphate; PKC, protein kinase c; DAG, diacylglycerol; cAMP, cyclic AMP; CREB, cAMP response element binding.

Table 1 Efficacy and adverse effects of triciclyc antidepressants, serotonin reuptake inhibitors and newer antidepressants

Drug and treatment dose	Efficacy	Common adverse effects
TCA^a	More efficient than placebo, comparable efficacy to SSRI ^b	Dry mouth, blurry vision, constipation, urine retention, tachycardia, sedation and memory impairment progressing to delirium, seizures and death.^Citation40
SSRI^b	More efficient than placebo, comparable efficacy to TCA ^a	Nausea, diarrhea, insomnia, headache, tremor, nervousness and sexual dysfunction.^Citation47,Citation50,Citation51
Escitalopram 10–20 mg/day	Reponse after 8 weeks 56% in severe depression (MADRS^c ≥ 30).^Citation69 Response after 8 weeks 82.6% and remission 66% after 6 months in severe MDD^d (MADRS^c)^Citation72 Response and remission of escitalopram 62.1%–68.3% and 51.6%–57.8%, respectively after 8 weeks (MADRS^c)^Citation73,Citation75 Possibly more effective than duloxetine, fluoxetine, reboxetine fluvoxamine, paroxetine, and ^Citation77 Escitalopram may be suitable in moderate to severe major depression and in adolescents.	Nausea (15%), insomnia (9%), sexual dysfunction (9%), diarrhea (8%), dry mouth (6%) agitation/restlessness, daytime sedation.^Citation45 Possibly better tolerated than duloxetine, paroxetine, raboxetine, sertraline, fluvoxamine and venlafaxine. ^Citation77 Adverse event withdrawal rate 3%–7%.^Citation67,Citation72
Mirtazapine 15–60 mg/day	Responder rate 50%–73% according to HAM-D^e within 6 months.^Citation102,Citation109^–^Citation111. Possibly better efficacy than duloxetine, fluoxetine, . fluvoxamine, paroxetineandreboxetine^Citation77 Mirtazapine may be superior to SSRI and venlafaxine in the acute phase.^Citation113	Drowsiness, sedation, insomnia, agitation, restlessness, headache, vertigo, appetite disturbances, changes in body weight, dry mouth, constipation, fatigue.^Citation103 Possibly better tolerated than reboxetine, fluvoxamine, duloxetine amitriptyline possibly less well tolerated than bupropion, citalopram, escitalopram, sertraline, venlafaxine.^Citation77,Citation114 Discontinuation due to adverse effects 4%–5%.^Citation108,Citation109
Bupropion IR 200–450 mg/day	Similar efficacy as TCA ^a and fluoxetine. ^Citation134^–^Citation136,Citation140	Bupropion IR: tremor (22%), menstrual complaints (5%), hypertension and impaired sleep (4%).^Citation150
Bupropion XR 150–450 mg/day	Higher remission rates of bupropion (46%) vs venlafaxine (33%) and similar responder rates (HAM-D^e, MADRS^c) after 6–8 weeks treatment.^Citation143,Citation144	Bupropion SR, XR: headache (22%–24%), dry mouth (13%–16%), sweating (4%–11%), constipation (5%–10%), nausea (9%–10%).^Citation132,Citation143
Bupropion SR 150–400 mg/ day	Bupropion may be suitable to augment citalopram and in major depressions.^Citation146,Citation150	Discontinuation rates due to adverse events 5%–11%.^Citation118 Seizures, allergic reactions
Venlafaxine IR 75–375 mg/day	At least as effective as TCA^a and probably more effective than SSRI^b.^Citation168	Nausea, diarrhea, nervousness, sweating, dry mouth, muscle jerks, sexual dysfunction, blood pressure increase.^Citation45,Citation177
Venlafaxine ER 75–225 mg/day	Similar efficacy as sertraline and escitalopram. ^Citation73,Citation75,Citation169 Response odds ratio (1.15) and remission odds ratio (1.19) greater in venlafaxine compared to pooled data from fluoxetine, paroxetine, sertraline, citalopram, escitalopram and fluvoxamine. ^Citation168 Remission rates of venlafaxine 45%, after 6–8 weeks.^Citation170 Possibly more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine and reboxetine. ^Citation77	Withdrawal rate due to adverse effects 9%.^Citation75 Discontinuation syndrome: nausea insomnia, chills, irritability and paresthesias. Possibly better tolerated than reboxetine, fluvoxamine, duloxetine, TCA.^Citation77 Poorer tolerability than bupropion, citalopram, escitalopram, sertraline.^Citation77
Desvenlafaxine 50–100 mg/day	More efficient than placebo at doses of 50 and 100 mg according to HAM-D^e scores after 8 weeks. Response and remission rates of desvenlafaxine were 53% and 32% respectively.^Citation175,Citation182 No signifficant difference in efficacy between 50 and 100mg. ^Citation175	Nausea, diarrhea, constipation, dry mouth, insomnia, decreased appetite, hyperhidrosis and dizziness (≥10%)^Citation175 ; less common: nervousness, tremor, and increased blood pressure (2%).^Citation45,Citation183 Withdrawal rates due to adverse events 4% 8%.^Citation183
Duloxetine 40–120 mg/day	Remission rates in patients with severe MDD^d: 35.9%.^Citation201 Response and remission rates: 58% and 48%, respecitvely, after 8 weeks.^Citation204 Similar efficacy to venlafaxine after 6 weeks treatment.^Citation202 Possibly less efficacious than escitalopram, mirtazapine, sertraline and venlafaxine.^Citation77	Nausea, dry mouth, constipation, insomnia, dizziness, fatigue, diarrhea, somnolence, increased sweating, decreased appetite (>5%).^Citation206 Minimal effect on body weight^Citation208, modest effect on blood pressure and heart rate^Citation209, increased incidence of sexual dysfunction.^Citation210 Better tolerated than reboxetine. Possibly less well tolerated than bupropion, citalopram, escitalopram and sertraline.^Citation77 Withdrawal rates due to adverse events 17%.^Citation204
Milnacipran 100–200 mg/day	Reponse to treatment after 8 weeks 65% at dose 50 mg/day (HDRS).^Citation222 Response rate 58.9% MADRS^c and 59.7% HAM-D^e.^Citation222,^224 Possibly less efficacious than mirtazapine, escitalopram, venlafaxine, sertraline and citalopram. Possibly more efficacious than bupropion, duloxetine, fluvoxamine, paroxetine, fluoxetine and reboxetine. ^Citation77	Nausea, nervousness, constipation, vertigo (5%), anxiety (4%), hot flushes (3%), dysuria (2%), dizziness, sweating (4%).^Citation45,^226 Possibly better tolerated than TCA, reboxetine, fluvoxamine, fluoxetine, mirtazapine, venlafaxine, duloxetine, paroxetine.^Citation77,^225 and possibly less well tolerated than bupropion, citalopram, escitalopram, sertraline.^Citation77
Reboxetine 4–10 mg/day	Response rate in 27 patients with MDD^d, 74% after 6 weeks according to HAM-D^e.^242 In severe MDD^d responder rate with reboxetine were 56%–74% after 4–8 weeks.^243 Relapse rates afte 46 weeks were 22% (HAM-D)^e.^244 Possibly less efficacious than bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, sertraline, venlafaxine.^Citation77	Dry mouth, insomnia, headache, constipation, sweating, nausea, dizziness, anorexia and asthenia (>5%).^240 Male patients: tachycardia, urinary retention or hesitancy, impotence and sexual dysfunction.^240 Frequency of discontinuation was 10%.^245 Possibly less well tolerated than bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, sertraline, venlafaxine.^Citation77
Agomelatine 25–50 mg/day	Response to treatment was 56% 63% and remission 30% after 8 weeks (HAM-D^e.^255 Response rate 49% (HAM-D^e) and improvement in CGI-S^f after 6 weeks was reported, remission rate 21%.^254	Nausea dizzines (9%), dry mouth, diarrhea nasopharyngitis (7%) and influenza (7%). ^250,254 absence of serotonin syndrome, weight gain and low incidence of sexual dysfunction and gastrointestinal side effects.^250
Aripiprazole 2–5 mg/day	Remission rates with adjunctive aripiprazole to standard antidepressant treatment vs placebo 25.4% vs 15.2%, response rates 32.4% vs 17.4% respectively after 6 weeks.^262 Mean change in MADRS^c total score was significantly greater with adjunctive aripiprazole −8.8 than adjunctive placebo −5.8 after 6 weeks.^261	Akhatisia (23%), nausea (3%), insomnia (8%), restlessness (14%), upper respiratory tract infections (8%), weight gain.^261, 262

Abbreviations: TCA, tricyclic antidepressants; SSRI, selective serotonin reuptake inhibitors; MADRS, Montgomery Asberg Depression Rating Scale; MDD, major depressive disorder; HAM-D, Hamilton Rating Scale for Depression; CGI-S, Clinical Global Impressions-Severity of illness scale.

Table 2 Pharmacokinetic properties of newer antidepressants

Drug	Tmax (h)	BA^a (%)	Food	Vd^b	PB^c	Metabolism	Interactions	t1/2^d (h)	Ex-cretion	CL^e (L/h)	SS^f (days)	PK^g
Escitalopram	3–4	80	No influence	1100 L	56%	CYP1A2	MAOI	27–33	Renal	2.7	7	Linear
						CYP2C9	SSRI
						CYP2D6
						CYP3A4
Bupropion IR	1.5	87	No influence	19 L/kg	85%	CYP2B6	desipramine	21			7–10	Linear
Bupropion SR	~3						venlafaxine					300–450 mg
Bupropion XR	~5						carbamazepine
							lopinavir
							ritonavir
Mirtazapine	1–2.1	50		339 L	85%	CYP1A2	carbamazepine	20–40	Renal	31	5	Linear
						CYP2D6	phenytoin					15–75 mg
						CYP3A4	fluvoxamine
							paroxetine
							cimetidine
							diazepam
Venlafaxine	2	92		6–7 L/kg	27%	CYP2D6	imipramine	5	Renal			Linear
Desvenlafaxine	2.8					CYP3A4	risperidon	11				75–450 mg
						CYP2C9
						CYP2C19
Duloxetine	6	91	Delays absorption	1943 L	90%	CYP1A2	desimipramine		Renal	114	3	Linear
						CYP2D6	CYP2D6 and CYP1A2 inhibitors
						CYP2C9
Milnacipran	2–6	85% – 90%	No influence	5.3 L/kg	13%	CYP3A4	MAOI, tramadol, triptanes, linezolid duloxetine adrenaline noradrenaline	6–7	Renal	37.6	2–3	Linear
Reboxetine	2	94	Tmax delayed 2–3h	32 L	96%	CYP3A4		13		2.21	4	Linear 1.5–4.5 mg
Agomelatine	1–2	74%		35 L	95%	CYP1A2		2–3	Renal
						CYP2C9
						CYP2C19
Aripiprazole	3–5		Tmax delayed 3h		99%	CYP3A4 CYP2D6	carbamazepine, ketoconazole	75	Renal, fecal		14

Abbreviations: BA, bioavailability; Vd, volume of distribution; PB, protein binding; t_1/2, elimination half-life; CL, total clearance; SS, steady-state; PK, pharmacokinetics; MAOI, monamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitors.

Table 3 Risk factors which may influence the pharmacokinetics of newer antidepressants

Drug	Factors that may require dose adjustment
Escitalopram	Dose adjustment recommended in patients with impaired hepatic function
Mirtazapine	Age (elderly), hepatic impairment, caution in patients with moderate or severe renal insuficiency
Bupropion	Gender; caution in elderly, and those with renal and hepatic impairment.
Venlafaxine/Desvenlafaxine	Renal and hepatic impairment If creatinine clearance is ≤ 30 mL/min dose adjustment for venlafaxine recommended
Duloxetine	Hepatic impairment, neccessary dose adjustment. Gender, age, nicotine and race – monitor adverse effects, dose adjustment if necessary
Milnacipran	Caution in severe hepatic and moderate to severe renal impairment
Reboxetine	Elderly require lower starting doses Caution in renal and hepatic dysfunction
Agomelatine	Caution in patients with hepatic impairment; lack of data about other effects

BillupsSJDelateTDuganDEvaluation of risk factors for elevated tricyclic antidepressant plasma concentrationsPharmacoepidemiol Drug Saf200918325325719148878

 PubMed Web of Science ®Google Scholar

OwensMJKnightDLNemeroffCBSecond-generation SSRIs: Human monoamine transporter binding profile of escitalopram and R-fluoxetineBiol Psychiatry200150534535011543737

 PubMed Web of Science ®Google Scholar

SidhuJPriskornMPoulsenMSegonzacAGrollierGLarsenFSteady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humansChirality1997976866929366029

 PubMed Web of Science ®Google Scholar

RochatBKoselMBossGTestaBGilletMBaumannPStereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidase in human in human liverBiochem Pharmacol199856115239698084

 PubMed Web of Science ®Google Scholar

BechPAndersenHFWadeAEffective dose of escitalopram in moderate versus severe DSM-IV major depressionPharmacopsychiatry200639412813416871468

 PubMed Web of Science ®Google Scholar

AnttilaSAKLeinonenEVJA review of the pharmacological and clinical profile of mirtazapineCNS Drugs Rev 200173249264

 PubMedGoogle Scholar

VoortmanGPaanakkerJEBioavability of mirtazapine from Remeron® tablets after single and multiple oral dosingHum Psychopharmacol199510Suppl 2S83S96

 Web of Science ®Google Scholar

SpaansEvan den HeuvelMWSchnabelPGConcomitant use of mirtazapine and phenytoin: A drug-drug interaction study in healthy male subjectsEur J Clin Pharmacol200258642342912242602

 PubMed Web of Science ®Google Scholar

AnttilaAKRasanenLLeinonenEVFluvoxamine augmentation increases serum mirtazapine concentrations three- to four-foldAnn Pharmacother200135101221122311675851

 PubMed Web of Science ®Google Scholar

DraperBBermenKTolerability of selective serotonin reuptake inhibitorsDrugs Aging200825650151918540689

 PubMed Web of Science ®Google Scholar

CiprianiAFurukawaATSalantiGComparative efficacy and acceptability of 12 new-generation antidepressants: A multiple-treatments meta-analysisLancet2009373966574675819185342

 PubMed Web of Science ®Google Scholar

TurpeinenMKoivuviitaNTolonenAEffect of renal impairment on the pharmacokinetics of bupropion and its metabolitesBr J Clin Pharmacol200764216517317335546

 PubMed Web of Science ®Google Scholar

WeihsKLSettleEJrBateySRHouserTLDonahueRMAscherJABupropion sustained release versus paroxetine for the treatment of depression in the elderlyJ Clin Psychiatry200061319620210817105

 PubMed Web of Science ®Google Scholar

HewettKChrzanowskiWSchmitzMEight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XRJ Psychopharmacol200923553153818635695

 PubMed Web of Science ®Google Scholar

RushAJTrivediMHWisniewskiSRBupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depressionN Engl J Med2006354121231124216554525

 PubMed Web of Science ®Google Scholar

ReimherrFWCunninghamLABateySRJohnstonJAAscherJAA multicenter evaluation of the efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets versus placebo in depressed outpatientsClin Ther19982035055169663366

 PubMed Web of Science ®Google Scholar

TrivediMHFavaMWisniewskiSRMedication augmentation after the failure of SSRIs for depressionN Eng J Med20063541212431252

 PubMed Web of Science ®Google Scholar

ColemanCCKingBRBolden-WatsonCA placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetineClin Ther20012371040105811519769

 PubMed Web of Science ®Google Scholar

ThaseMEEntsuahRAhmedSSloanDMNemeroffCBMeta-analysis of randomized controlled trials comparing venlafaxine and SSRIs: The evidence revisitedPresented at the 2005 annual meeting of the American Psychiatric AssociationAtlanta, GeorgiaMay 21–26, 2005

 Google Scholar

HansenRAGartlehnerGLohrKNGaynesBNCareyTSEfficacy and safety of second-generation antidepressants in the treatment of major depressive disorderAnn Intern Med2005143641542616172440

 PubMed Web of Science ®Google Scholar

HaddadPMAntidepressant discontinuation syndromesDrug Saf200124318319711347722

 PubMed Web of Science ®Google Scholar

FramptonJEPloskerGLDuloxetine: A review of its use in the treatment of major depressive disorderCNS Drugs200721758160917579500

 PubMed Web of Science ®Google Scholar

PaeCUDesvenlafaxine: A new antidepressant or just another oneExpert Opin Pharmacother200910587588719351235

 PubMed Web of Science ®Google Scholar

ClaytoneAHKornsteinSGRosasGGuico-PabiaTourianKAAn integrated analysis of the safety and tolerability of desvenlafaxine compared with placebo in the treatment of major depressive disorderCNS Spectr200914418319519407730

 PubMed Web of Science ®Google Scholar

SirAD’SouzaRFUguzSRandomized trial of sertraline versus venlafaxine XR in major depression: Efficacy and discontinuation symptomsJ Clin Psychiatry200566101312132016259546

 PubMed Web of Science ®Google Scholar

BymasterFPDreshfield-AhmadLJThrelkeldPGComparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptorsNeuropsychopharmacology200125687188011750180

 PubMed Web of Science ®Google Scholar

EreshefskyLDuganDReview of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: Focus on venlafaxineDepress Anxiety200012Suppl 1S30S44

 PubMed Web of Science ®Google Scholar

NelsonJCLu PritchettYMartynovOYuJYMallinckrodtCHDetkeMJThe safety and tolerability of duloxetine compared with paroxetine and placebo: A pooled analysis of 4 clinical trialsPrim Care Companion J Clin Psychiatry20068421221916964316

 PubMedGoogle Scholar

MacherJPSichelJPSerreCVon FrenckellRHuckJCDemarezJPDouble-blind placebo-controlled study of milnacipran in hospitalized patients with major depressive disordersNeuropsychobiology198922277822701744

 PubMed Web of Science ®Google Scholar

SpencerCMWildeMIMilnacipran: A review of its use in depressionDrugs19985634054279777315

 PubMed Web of Science ®Google Scholar

VaishnaviSNNemeroffCBPlottSJRaoSGKranzlerJOwensMJMilnacipran: A comparative analysis of human monoamine uptake and transporter binding affinityBiol Psychiatry200455332032214744476

 PubMed Web of Science ®Google Scholar

PuozzoCHermannPChassardDLack of pharmacokinetic interaction when switching from fluoxetine to milnacipranInt Clin Psychopharmacol200621315315816528137

 PubMed Web of Science ®Google Scholar

EdwardsDMPellizzioniCBreuelHPPharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein bindingBiopharm Drug Dispos19951664434607579027

 PubMed Web of Science ®Google Scholar

FleishakerJCMucciMPellizzioniCPoggesiIAbsolute bioavailability of reboxetine enantiomers and effects of gender on pharmacokineticsBiopharm Drug Dispos1999201535710086838

 PubMed Web of Science ®Google Scholar

ServierValdoxanSummary of product characteristics Available from: http://www.servier.co.uk/pdfs/Valdoxan_SPC.pdfAccessed on 2010 May 5

 Google Scholar

MontgomerySAKasperSSevere depression and antidepressants: Focus on a pooled analysis of placebo-controlled studies on agomelatineInt Clin Psychopharmacol200722528329117690597

 PubMed Web of Science ®Google Scholar

KennedySHEmsleyRPlacebo-controlled trial of agomelatine in the treatment of major depressive disorderEur Neuropsychopharmacol20061629310016249073

 PubMed Web of Science ®Google Scholar

GuilleminaultCEfficacy of agomelatine versus venlafaxine on subjective sleep of patients with major depressive disorderEur Neuropsychopharmacol200515Suppl 3S419S420 Abstract

 Google Scholar

WeberJLyseng-WilliamsonKAScottLJAripiprazole: In major depressive disorderCNS Drugs2008221080781318788833

 PubMed Web of Science ®Google Scholar

BermanRMMarcusRNSwaninkRThe efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled studyJ Clin Psychiatry200768684385317592907

 PubMed Web of Science ®Google Scholar

MarcusRNMcQuadeRDCarsonWHThe efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A second multicenter, randomized, double-blind, placebo-controlled studyJ Clin Psychopharmacol200828215616518344725

 PubMed Web of Science ®Google Scholar

RooseSPCompliance: The impact of adverse events and tolerability on the physician’s treatment decisionsEur Neuropsychopharm200313Suppl 3S85S92

 PubMed Web of Science ®Google Scholar