Second-generation Antipsychotics in the Treatment of Major Depressive Disorder

Current Evidence

Changsu Han; Sheng-Min Wang; Masaki Kato; Soo-Jung Lee; Ashwin A Patkar; Prakash S Masand; Chi-Un Pae

Expert Rev Neurother. 2013;13(7):851-870.

Abstract and Introduction

Abstract

Major depressive disorder (MDD) is a chronic and recurrent mental condition leading to huge impacts on direct and indirect personal and public medical costs. To overcome such a serious mental disorder, we currently have a number of different classes of antidepressants, such as selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, noradrenergic and specific serotonin receptor antagonists, dopamine and norepinephrine reuptake inhibitors, along with newly introduced antidepressants (e.g., vilazodone and agomelatine). However, a number of well-controlled clinical trials, meta-analyses and practical clinical studies have found that only a third of such MDD patients remit following adequate antidepressant treatment, while most MDD patients suffer from significant core depressive or residual symptoms during their clinical course. There have been some treatment approaches to overcome such a shortage of antidepressant efficacy, such as augmentation of psychotropics other than antidepressants, switching to a different antidepressant and combinations of different antidepressants. Among these different second treatment options, augmentation treatment has some favorable points compared with the combination and switching option (e.g., maintaining previous antidepressant partial response, synergistic effect between different pharmacological profile and no need to wash out previous antidepressants). Recently, second-generation antipsychotics (SGAs), olanzapine plus fluoxetine, quetiapine extended release and aripiprazole have clearly demonstrated efficacy in the treatment of MDD patients through a number of small-scale, open-label studies or randomized, placebo-controlled clinical trials. Eventually, in November 2007, aripiprazole was the first approved by the US FDA as an adjunctive treatment to antidepressants for treating MDD, followed by the approval of quetiapine and olanzapine plus fluoxetine at 2009. This comprehensive review provides an overview of the clinical trial data of SGAs for treating MDD and clinical issues raised in the use of SGA therapy in patients with MDD in clinical practice.

Introduction

Major depressive disorder (MDD) is a common, chronic, recurrent and debilitating psychiatric condition, leading to significant impairments in personal functional capacities, which also eventually impact directly and indirectly on public medical costs.^[1]

After the advent of the older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants for the treatment of MDD, newer antidepressants with improved tolerability such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors, dopamine and norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressant medications have been introduced and flourished as the first-line treatments options for patients with MDD in clinical practice. However, despite sufficient availability of different classes of antidepressants to date, most patients with MDD do not achieve an adequate response or remission with such antidepressant treatment. The lack of satisfactory clinical efficacy of first-line antidepressant treatment is clearly evidenced in a number of case studies, randomized, double-blind, placebo-controlled clinical trials (RCTs), meta-analyses and practical clinical trials. For instance, a 12-week treatment with SSRI monotherapy (citalopram) showed only a 30% remission rate in MDD patients in the STAR*D trial.^[2] In addition, in a recent meta-analysis including 182 antidepressant RCTs (n = 36,385), the response and remission rates were approximately 54 and 37%, respectively.^[3] Such inadequate antidepressant efficacy results in significant residual symptoms, functional incapacity, increased utilization of medical services, and frequent recurrence and relapse.^[4–6]

According to the cumulative evidence in the last decade, augmentation strategies including second-generation antipsychotic (SGA) augmentation, switching to different antidepressants, or a combination of different antidepressant strategies are recommended in most guidelines for partial or non responders in clinical practice.^[7–10] Among such second-treatment steps, the augmentation strategy has proven its usefulness for enhancing the antidepressant effect, showing increased remission rates and early treatment effects on core depressive symptoms and comorbid symptoms without losing previous antidepressant response as well as minimizing antidepressant-mediated side effects (e.g., sexual dysfunction).^[7–10] Although classical augmentation agents including lithium and thyroid hormones have been commonly used for patients with inadequate response from antidepressant first-line therapy, they were supported by limited data and none of those augmentation agents has been officially approved by the national authority such as the US FDA.

Recently, SGAs including olanzapine, quetiapine extended release (XR) and aripiprazole have clearly demonstrated efficacy as an augmentation agent for MDD patients through a number of small-scale, open-label studies or randomized, placebo-controlled clinical trials (RPCTs). In November 2007, aripiprazole was the first approved by the US FDA as an augmentation therapy to antidepressants for treating MDD, followed by approval of quetiapine XR and olanzapine in 2009.

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[[T1]Table 1. The US FDA indication approval status of atypical antipsychotic use for major depressive disorder.
Drug	Indication	Dose range	Evidence
Olanzapine	TRD in combination with fluoxetine	Olanzapine: 5–20 mg/day; mean dose: 8–14 mg/day Fluoxetine: 20–50 mg/day	Placebo-controlled studies
Risperidone	Not approved for MDD	0.5–3.0 mg/day; mean dose: 1.2–1.6 mg/day	Placebo-controlled studies
Quetiapine XR	Augmentation to antidepressants for MDD	50–300 mg/day in flexible and fixed-dose trials; mean dose: 180 mg/day	Placebo-controlled studies
Aripiprazole	Augmentation to antidepressants for MDD	5–15 mg/day; mean dose: 11–12 mg/day	Placebo-controlled studies
Paliperidone	Not approved for MDD	3 mg/day	Case report
Ziprasidone	Not approved for MDD	80–160 mg/day	Open-label study
Amisulpride	Not approved for MDD	50 mg/day in MDD and dysthymia	Open-label and randomized, (placebo)-controlled studies
Asenapine, iloperidone, setindole and lurasidone	Not approved for MDD	Not available	No clinical data with MDD

MDD: Major depressive disorder; TRD: Treatment-resistant depression; XR: Extended release.

[[T2]Table 2. The potential action mechanisms of second-generation antipsychotics.
Drug	Potential mechanism for antidepressant-like effects
Olanzapine	5-HT2A/2C receptor antagonism, 5-HT7 receptor antagonism
Risperidone	5-HT2A receptor antagonism, α-2 receptor antagonism, 5-HT7 receptor antagonism
Quetiapine	α-2 receptor antagonism, norepinephrine transporter inhibition (metabolite), 5-HT7 receptor antagonism
Aripiprazole	5-HT1A/2C receptor partial agonism, 5-HT2A/2B receptor antagonism, 5-HT6 receptor antagonism, weak 5-HT7 receptor antagonism, D2/3 receptor partial agonism, neuroprotective effects
Paliperidone	5-HT2A receptor antagonism, α-2 receptor antagonism, 5-HT7 receptor antagonism
Ziprasidone	5-HT2A/2C receptor antagonism, 5-HT1A receptor agonism, serotonin/norepinephrine/dopamine transporter inhibition
Amisulpride	5-HT7 antagonism, presynaptic D2/3 autoreceptors antagonism at low dose (50 mg)
Lurasidone	Strong 5-HT7 receptor antagonism, 5-HT1A receptor partial agonism, weak 5-HT2C receptor antagonism, weak α-2 receptor antagonism
Iloperidone	5-HT2A receptor antagonism, 5-HT6/7 receptor antagonism
Asenapine	5-HT2C/2A receptor antagonism, 5-HT6/7 receptor antagonism, 5-HT2B receptor antagonism, α-2 receptor antagonism, partial agonism at 5-HT1A receptor
Sertindole	5-HT2A receptor antagonism, 5-HT6/7 receptor antagonism

Data taken from [13,17,105,106,126,133–137].

[[T3]Table 3. Randomized, double-blind, placebo-controlled clinical trials of aripiprazole in major depressive disorder.
Study (year)	Duration	Patients (n)	Primary end point	Response and remission rates	Ref.
Berman et al. (2007)	6 weeks	ARP: 181; PBO: 172	Change in MADRS total score PBO: -5.8; ARP: -8.8	Response: 33.7 vs 23.8%* Remission: 26 vs 15.7%*	[42]
Marcus et al. (2008)	6 weeks	ARP: 185; PBO: 184 PBO: -5.7; ARP: -8.5	Change in MADRS total score	Response: 32.4 vs 17.4%* Remission: 25.4 vs 15.2%*	[43]
Berman et al. (2009)	6 weeks	ARP: 174; PBO: 169	Change in MADRS total score PBO: -6.4; ARP: -10.1	Response: 46.6 vs 26.6%* Remission: 36.8 vs 18.9%*	[44]
Fava et al. (2012)^†	60 days, two phases	ARP: 56; PBO: 169	Difference in response rate by MADRS total score Pooled, weighted ARP–PBO difference: 5.6%	ARP: 7.4% in phase 1 and 13.1% in phase 2 PBO: 9.58% in phase 1 and 6.4% in phase 2 Pooled, weighted ARP–PBO difference: 2.3%	[45]
Mischoulon et al. (2012)^†	60 days, two phases		Mean change in MADRS total score (mean) in ARP: -9.5	Responder rates: ARP 2 mg: 18.5%; ARP 5 mg: 12.8% PBO: 17.4% in phase 1 and 7.9% in phase 2	[46]

^†Identical placebo-controlled, randomized clinical trial and analyzed differently on primary objective.
*p < 0.05, otherwise not significant.
ARP: Aripiprazole; MADRS: Montgomery-Asberg Depression Rating Scale; PBO: Placebo.

[[T4]Table 4. Randomized, double-blind, (placebo)-controlled clinical trials of quetiapine in major depressive disorder.
Study (year)	Duration (weeks)	Patients (n)	Primary end point	Response and remission rates	Ref.
*Monotherapy*
Katila et al. (2012)	11	QTP XR (n: 166; flexible-dosing 50–300 mg/day); PBO (n: 172)	MADRS total score change: -16 vs -9*	Response: 64.0 vs 30.4% Remission: 45.1 vs 17%	[60]
Bortnick et al. (2011)	10	QTP XR (n: 154; 50–300 mg/day); PBO (n: 156)	MADRS total score change: -16.5 vs -13.1*	Response: 61.9 vs 48% Remission: 49.7 vs 33.6%	[61]
Liebowitz et al. (2010)	52	QTP XR (n: 391; 50–300 mg/day); PBO (n: 385)	Recurrence of depressive event from randomization: risk of recurrence of depressive event was significantly reduced by 66% in QTP continuing group (HR: 0.3, 14.2% in QTP XR group vs 34.4% in PBO group)	NA	[62]
Weisler et al. (2009)	8	QTP XR (n: 182, 178 and 179 for 50, 150 and 300 mg/day, respectively); PBO (n: 184)	MADRS total score change: QTP XR 50 mg/day (-13.6), 150 mg/day (-14.5) and 300 mg/day (-14.2) vs -11.1*	Response: 42.7, 51.2, 44.9% in QTP XR 50, 150, 300 mg/day vs 30.3% in PBO *Remission: 25.8, 20.8, 26.1 vs 18.5%, respectively	[63]
Cutler et al. (2009)	8	QTP XR (n: 152; 150 mg/day) or (n: 152; 300 mg/day), duloxetine (n: 151; 60 mg/day), or PBO (n: 157)	MADRS total score change	Response: 54.4 vs 55.1 vs 49.6 vs 36.2%, for 150, 300 mg/day, duloxetine and PBO, respectively Remission: 26.5 vs 32% vs 31.9% vs 20.4%, respectively	[64]
Earley et al. (2008)	8	QTP XR (n: 157, 50–300 mg/day), escitalopram (n: 157; 10–20 mg/day), PBO (n: 157)	MADRS total score change	Response: 60.4 vs 59.9 vs 51%, for QTP XR, escitalopram and PBO, respectively Remission: 35.7 vs 40.8 vs 35.3%, respectively	[65]
*Augmentation therapy*
El-Khalili et al. (2010)	8	QTP XR (n: 148, 150 mg/day; n: 150, 300 mg/day); PBO (n: 148)	MADRS total score change	Response: 51.7, 58.9, 46.2, for QTP XR 150 mg/day, 300 mg/day and PBO, respectively Remission: 35, 42.5, 24.5, respectively	[66]
Bauer et al. (2009)	6	QTP XR (n: 167, 150 mg/day; n: 163, 300 mg/day); PBO (n: 163)	MADRS total score change	Response: 55.4, 57.8, 46.3%, for QTP XR 150, 300 mg/day and PBO, respectively Remission: 36.1, 31.1, 23.8%, respectively	[67]
Garakani et al. (2008)	8	QTP (n: 57, 25–100 mg/day); PBO (n: 57)	Responders and remitters rates at the end point	Not significantly different with PBO	[68]
Chaput et al. (2008)	12	QTP/CBT (n: 11); PBO plus CBT (n: 11)	*MADRS and HAMD-17 total score change: -8.5 (MADRS) and -7.5 (HAMD) vs NR (PBO)	NA	[69]
McIntyre et al. (2007)	8	QTP (n: 29); PBO (n: 29)	*HAMD-17 total score change: -11.2 vs -5.5	Response: 48 vs 28% Remission: 31 vs 17%	[70]
Wijkstra et al. (2010)	7	Venlafaxine/quetiapine (n: 41); venlafaxine (n: 39); imipramine (n: 42)	HAMD-17 total score change: -18.4 vs -13.9 vs -17.1, respectively	Response: 65.9% (vs venlafaxine) vs 33.3% vs 52.4%, respectively Remission: 41.5% (vs imipramine) vs 28.2% vs 21.4%, respectively	[71]

*p < 0.05, otherwise not significant.
CBT: Cognitive behavioral therapy; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale; MDD: Major depressive disorder; NA: Not available; NR: Not reported; PBO: Placebo; QTP: Quetiapine.

[[T5]Table 5. Randomized, double-blind, placebo-controlled clinical trials of olanzapine in major depressive disorder.
Study (year)	Duration (weeks)	Patients (n)	Primary end point	Response and remission rates	Ref.
*TRD*
Shelton et al. (2001)	8	FOX/PBO (n: 10), OLZ/PBO (n: 8), OLZ/FOX (n: 10)	*MADRS total score change: -1.2 vs -2.8 vs -13.6	Response: 10 vs 0 vs *60% (vs OLZ), respectively Remission: NA	[75]
Shelton et al. (2005)	8	OLZ (6–12 mg/day)/FOX (25–50 mg/day; n: 146), OLZ (6–12 mg/day, n: 144), FOX (25–50 mg/day; n: 142) or NTP (25–175 mg/day; n: 68)	MADRS total score change: -8.7 vs -7 vs -8.5 vs -7.5	Response: 27.5 vs 19.3 vs 28.9 vs 30.3%, respectively Remission: 16.9 vs 12.9 vs 13.3 vs 18.2%, respectively	[76]
Corya et al. (2006)	12	OLZ/FOX (n: 243), OLZ (n: 62), FOX (n: 60) or VFX (n: 59)	MADRS total score change: -14.1* (vs OLZ and FOX but VFX) vs -7.7 vs -11.7 vs -13.7	Response: 43.3 (vs OLZ) vs 25.4 vs 33.9 vs 50%, respectively Remission: 29.9 (vs OLZ) vs 13.6 vs 17.9 vs 22.4%, respectively	[77]
Thase et al. (2007)^†	8	OLZ/FOX (n: 200), OLZ (n: 199) or FOX (n: 206)	*MADRS total score change: -12.7 vs -8.8 vs -9, respectively	*Response: 40.4 vs 25.9 vs 29.6%, respectively Remission: 27.3 vs 14.7 vs 16.7%, respectively	[78]
*Psychotic MDD*
Rothschild et al. (2004)^†	8	OLZ (5–20 mg/day; n: 90), OLZ (5–20 mg/day)/FOX (20–80 mg/day; n: 45) or PBO (n: 94)	HAMD-24 total score change Trial 1: -14.9 vs -20.9* (vs PBO) vs -10.4, respectively Trial 2: -13.9 vs -15.8 vs -12.5, respectively	Response: Trial 1: 34.9 vs 63.6%* (vs PBO) vs 28%, respectively Trial 2: 36.2 vs 47.8 vs 31.8%, respectively Remission: Trial 1: 12 vs 23; vs 8%, respectively Trial 2: 15 vs 17; vs 14%, respectively	[79]
Meyer et al. (2009)	12	OLZ/SERT (n = 129) and OLZ/PBO (n = 130)	Remission: HAMD score of ≤10 at two consecutive assessments	*Remission: 41.9 vs 23.9%	[80]

^†Two studies published together.
*p < 0.05, otherwise not significant.
FOX: Fluoxetine; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale; MDD: Major depressive disorder; NTP: Nortriptyline; OLZ: Olanzapine; PBO: Placebo; SERT: Sertraline; TRD: Treatment-resistant depression; VFX: Venlafaxine.

[[T6]Table 6. Randomized, double-blind, placebo-controlled clinical trials of risperidone in major depressive disorder.
Study (year)	Duration (weeks)	Patients (n)	Primary end point	Response and remission rates	Ref.
Mahmoud et al. (2007)	6	RPR (1 mg/day; n: 141), PBO (n: 133)	HAMD-17 total score change: -10.8 vs -8.2, respectively*	Response: 35.6 vs 18.8%* Remission: 24.5 vs 10.7%*	[86]
Reeves et al. (2008)	8	RPR (0.25–2 mg/day; n: 12), PBO (n: 11)	Reduction in suicidality based on BSSI: -13.9 vs -5.7, respectively*	NA	[87]
Keitner et al. (2009)	4	RPR (0.25–3 mg/day; n: 64), PBO (n: 30)	Remission: MADRS score of ≤10 at two consecutive assessments	Response: 54.8 vs 33.3%* Remission: 51.6 vs 24.2%*	[88]
Rapaport et al. (2006)	24	RPR (0.25–2 mg/day; n: 123), PBO (n: 120)	Relapse prevention: relapse rates were 53.3 and 54.6%, respectively	Median time to relapse was 102 days with RPR and 85 days with PBO	[89]
Alexopoulos et al. (2008)		RPR (0.25–1 mg/day; n:32), PBO (n: 31)	Time to relapse	105 days and 57 days in the RPR and PBO groups, respectively	[90]

* p < 0.05, otherwise not significant.
BSSI: Beck Scale for Suicidal Ideation; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale; NA: Not available; PBO: Placebo; RPR: Risperidone.

[[T7]Table 7. Randomized, double-blind, placebo-controlled clinical trials of amisulpride in major depressive disorder and dysthymia.
Study (year)	Duration (weeks)	Patients (n)	Primary end point	Response and remission rates	Ref.
Zanardi and Smeraldi (2006)	12	AMSP (50 mg/day; n: 94), ALCAR (1000 mg/day; n: 99)	HAMD-21 total score change: -10.8 vs -10	Response based on proportion of patients showing CGI-I scores on 1 or 2: 64.4 vs 65.5% Remission: NR	[97]
Cassano and Jori. (2002)	8	AMSP (50 mg/day; n: 137), paroxetine (20 mg/day; n: 138)	Responder rate (50% decrease in HAMD-17 total score) at end point, with a maximal allowable difference of 15%	Response: 76 vs 84% Remission based on HAMD-17 (≤8): 60 vs 64%	[98]
Ravizza (1999)	24	AMSP (50 mg/day; n: 93), amitriptyline (25–75 mg/day; n: 46)	Incidence of treatment-emergent adverse events: 64 vs 73%	Response based on MADRS: 60 vs 62% Remission: NR	[99]
Boyer et al. (1999)	12	AMSP (50 mg/day; n: 104), amineptine (200 mg/day; n: 111), PBO (n: 108)	Response based on proportion of patients showing CGI-I scores of 1 or 2	Response: 69 vs 74 vs 38% Remission based on MADRS (≤10): 50.5 vs 49.5 vs 21.9%	[100]
Smeraldi (1998)	12	AMSP (50 mg/day; n: 139), fluoxetine (20 mg/day; n: 129)	Responder rate (50% decrease in MADRS total score)	Response: 74 vs 87% Remission: NR	[101]
Lecrubier et al. (1997)	24	AMSP (50 mg/day; n: 73), imipramine (50–100 mg/day; n: 73), PBO (n: 73)	HAMD-21 total score change and responder rate based on proportion of patients showing CGI-I scores on 1 or 2: -12.7* vs -12.2* vs -7.6	Response: 72.2* vs 68.6* vs 33.3% Remission based on MADRS (≤7): 35.6 vs 32.9 vs 21.9%	[102]
Amore and Jori (2001)	12	AMSP (50 mg/day; n: 157), sertraline (50–100 mg/day; n: 156)	Time to onset of initial improvement in baseline HAMD-21 (≥25%): *AMSP (11 days) < sertraline (15 days)	Response based on HAMD-21: 84 vs 79% Remission (≤6 in HAMD-21): 74 vs 68%	[104]

*p < 0.05, otherwise not significant.
ALCAR: Acetyl-L-carnitine; AMSP: Amisulpride; CGI-I: Clinical Global Impression-Improvement; HAMD: Hamilton Depression Rating Scale; MADRS: Montgomery Åsberg Depression Rating Scale; NR: Not reported; PBO: Placebo.