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Review

Combined treatment with atypical antipsychoticsand antidepressants in treatment-resistantdepression: preclinical and clinical efficacy

Zofia Rogó¿

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12,PL 31-343 Kraków, Poland

Correspondence: Zofia Rogó¿, e-mail: rogoz@if-pan.krakow.pl

Abstract:

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with anti-depressants,particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. Theaim of this paper wasto summarizesome preclinical evidence describingthe mechanism responsible for the therapeuticaction of combined treatment withantidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strat-egy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis

studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extra-cellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-inducedeffects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatment-resistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics(olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the ex-tracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olan-zapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypicalantipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mecha-nisms) the serotonin 5-HT1A, 5-HT2A and adrenergic a2 receptors likely playingan important role in their action. The results supportthe conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.

Key words:

atypical antipsychotics, antidepressants, preclinical and clinical studies, depression, augmentation

Introduction

Major depressive disorder (MDD) is a chronic mentalillness with a lifetime prevalence of 5 to 12% of adultmen and 9 to 26% of adult women [e.g., 48]. Al-

though initial antidepressant (AD) therapy signifi-cantly reduces symptoms of depression in many pa-

tients, only 50 to 60% of patients with a MDD re-spond to the treatment. Moreover, ca. 30 to 40% of 

 patients suffering from MDD never achieve symptomresolution via standard AD therapy [2, 40]. The prob-lem of AD-resistant depression has been the subjectof a number of thorough studies, with no apparent

therapeutic advances. Hence, there is a pressing needfor alternative AD treatments. Atypical antipsychotics

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(e.g., aripiprazole, olanzapine, quetiapine, risperidoneand ziprasidone) are agents expected to potentiate theefficacy of ADs [41, 48]. These drugs more potently

 bind to 5-HT     serotonin receptors than to dopamineD

 

  receptors, and they also bind to    

  -adrenergic,

 

 -adrenergic and histamine H 

 receptors, with aripi- prazole and ziprasidone each exhibiting potent partialagonist activity at 5-HT

 

  receptors [16, 21, 33, 39,49]. Moreover, disturbances in dopamine (DA), sero-tonin (5-HT) and noradrenaline (NA) neurotransmit-ter systems have been suggested to be involved in the

 pathogenesis of mood disorders, including depressionand schizophrenia [22, 37, 47]. This review summa-rizes pre-clinical data describing the mechanism un-derlying the therapeutic actions of combined AD andatypical antipsychotic treatments and clinical datasupporting the efficacy and safety of the augmenta-tion strategy of resolving treatment-resistant depres-sion (TRD) using atypical antipsychotics.

Neurochemical effects

To elucidate the mechanism underlying the clinical ef-

ficacy combined atypical antipsychotics and ADs inameliorating TRD, Zhang et al. [50] studied the effectof olanzapine and other antipsychotics in combinationwith the selective serotonin reuptake inhibitors(SSRI) fluoxetine and sertraline on neurotransmitter release in the rat prefrontal cortex (PFC) using micro-dialysis and HPLC with electrochemical detection.The results showed that atypical antipsychotic drugs,including olanzapine (3 mg/kg,   sc), risperidone(1 mg/kg, sc) and clozapine (3 mg/kg,  sc), alone in-creased extracellular levels of both DA and NA tovarying degrees in rat PFC. Olanzapine, risperidone

and clozapine did not produce appreciable changes in5-HT levels, although risperidone had been reportedto increase 5-HT in the rat medial prefrontal cortex(mPFC) [15]. Haloperidol (1 mg/kg, sc), a typical an-tipsychotic, and MDL 100907 (1 mg/kg, sc), a selec-tive 5-HT

 

  antagonist, did not significantly changethe level of any of the monoamines. Fluoxetine andsertraline (10 mg/kg, sc) robustly increased the con-centration of 5-HT. Moreover, fluoxetine elevated NAand DA in the PFC. The levels of NA and DA in thePFC were not significantly affected by sertraline

treatment. Co-treatment with olanzapine and fluoxet-ine produced increases in DA and NA levels in the

PFC, which were statistically compared with the re-sponses to either drug alone. Combined treatmentwith the above drugs did not significantly alter 5-HT

levels compared to fluoxetine alone. Co-treatmentwith olanzapine and sertraline did not further increase

 NA and 5-HT levels than did olanzapine alone. Olan-zapine and sertraline in combination produced a sub-stantial increase in DA levels, but to a lesser extentthan the olanzapine and fluoxetine combination did.Risperidone in combination with fluoxetine produceda robust and significant increase in extracellular DAlevels; however, the effects of the combined treatmenton NA and 5-HT levels were not significantly differ-ent from those of fluoxetine alone. Clozapine plus

fluoxetine produced a significant increase in DA lev-els, but the combination did not increase either NA or 5-HT levels compared to fluoxetine alone. Neither thetypical antipsychotic haloperidol (1 mg/kg, sc) nor the5-HT

 

  -selective antagonist MDL 100907 (1 mg/kg, sc) in combination with fluoxetine increased extracel-lular levels of DA, NA and 5-HT more than fluoxetinealone [50].

We also studied the effect of risperidone at doses of 0.1 or 1 mg/kg ip and fluoxetine (10 mg/kg, ip), givenseparately or jointly, on the extracellular levels of DA,

5-HT and NAin the frontal cortex using microdialysisin freely moving rats [18]. Our data showed thatrisperidone at either dose (0.1 and 1 mg/kg) andfluoxetine increased the extracellular levels of corticalDA, 5-HT and NA. Co-treatment of both drugs wasmore effective at increasing DA release than was ei-ther drug alone at doses of 1 mg/kg risperidone and10 mg/kg fluoxetine. Co-treatment with fluoxetineand risperidone (0.1 mg/kg) was more potent thanfluoxetine alone, while the effect of joint injection of fluoxetine and risperidone (1 mg/kg) on 5-HT releasewas greater than that of risperidone (1 mg/kg) alone.

The combination of fluoxetine with both doses of risperidone was not effective at increasing NA releasecompared with each drug alone [18]. Our data are alsoin line with those from a previous study [50], whichshowed that risperidone at a higher dose (1 mg/kg)and fluoxetine (10 mg/kg) increased the extracellular levels of cortical DA, 5-HT and NA and that the com-

 bination of risperidone (1 mg/kg) and fluoxetine(10 mg/kg) increased the extracellular levels of DAand of 5-HT slightly less (but not of NA). In contrast,co-treatment with olanzapine (3 mg/kg,   sc) and

fluoxetine (10 mg/kg, sc) produced a robust, substan-tial increase in the levels of DA and NA in the PFC

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[50]. Because pharmacokinetic data showed that after co-treatment, neither the levels of olanzapine andfluoxetine nor those of the active fluoxetine metabo-

lite norfluoxetine were higher in the combinationtreatment group than after either drug alone treatment,the increase in DA and NA levels was more likely dueto neurochemical mechanisms than to a pharmacoki-netic interaction [50].

Huang et al. studied the effect of combined treat-ment with risperidone (1 mg/kg,  sc) and citalopram(10 mg/kg, sc) on the extracellular levels of DA, 5-HTand NA in the rat mPFC using microdialysis [14].Risperidone alone significantly increased the concen-trations of DA, 5-HT and NA in the mPFC. Citalo-

 pram only produced a significant increase in 5-HTlevels. Moreover, the combination of risperidone andcitalopram produced significant increases in the levelsof both DA and NA, which were greater than after risperidone alone. However, the effect of this combi-nation on extracellular 5-HT concentration was notsignificantly different than that of citalopram alone.The elevation of DA and NA levels induced byrisperidone plus citalopram was partially blocked bythe selective 5-HT

 

  antagonist, WAY 100635(0.2 mg/kg, sc) [14].

It is known that olanzapine, risperidone and

fluoxetine or citalopram have relatively low affinitiesfor the 5-HT

 

  receptor, indicating that increases incatecholamines are not likely mediated by an interac-tion with that receptor. Neither haloperidol, a typicalantipsychotic with mainly D

 

 /D 

 /D 

  antagonistic properties, nor the selective 5-HT

 

  antagonist MDL100907 enhanced the effect of fluoxetine on mono-

amine release, suggesting that the observed augmen-tation was not likely mediated by either D

 

 or 5-HT  

receptors alone [50].

Atypical antipsychotics (e.g., olanzapine, risperi-done and clozapine) have similarly high affinities for a number of receptor subtypes [33]. For example,

 both olanzapine and clozapine, but not risperidone,have relatively high affinities for 5-HT

 

  receptors.On the other hand, olanzapine has a higher affinity for 

 

 - than for    

 -adrenergic receptors, whereas cloza- pine and risperidone showed high affinity for both

 

 -and  

 

  -adrenergic receptors (Tab. 1). It may be thatthe augmentation resulting from olanzapine plusfluoxetine is mediated by either 5-HT

 

  or  

 -adrener-gic receptors. In addition, some data suggest that5-HT

 

  receptors exert a tonic, inhibitory influence onfrontocortical dopaminergic and adrenergic transmis-sion, possibly by their excitatory effects on GABAer-gic interneurons [28, 30]. Thus, in combination withfluoxetine, the 5-HT

 

  antagonistic property of olan-zapine could facilitate the persistent and robust effecton extracellular levels of DA and NA in the PFC. It isalso possible that receptors other than 5-HT

 

  or    

 -adrenergic receptors are involved in the augmenta-tion, as olanzapine has such a promiscuous receptor 

 binding profile.

The effect of the atypical antipsychotic quetiapine(10 mg/kg, ip) combined with fluvoxamine (10 mg/kg, ip) on extracellular levels of DA and 5-HT wasmeasured in microdialysates from the rat PFC, dorsalstriatum, nucleus accumbens (core and shell) andthalamus [11]. Quetiapine did not significantlychange the extracellular levels of DA and 5-HT in the

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Atypical antipsychotics and antidepressants treatment  

Tab. 1. The binding of atypical antipsychotic drugs and haloperidol to human brain receptors

Compound D2

  5-HT2A

  D2 /5-HT

2A ratio 5-HT

2C  5-HT

1A 

1-ADR  

2-ADR H

1

Olanzapine K d 

Risperidone K d 

Quetiapine K d 

Clozapine K d 

Ziprasidone K d 

Aripiprazole Ki *

20

3.77

770

210

2.6

0.8

1.48

0.15

31

2.59

0.12

21

13.5

25.1

24.8

81.1

21.7

4.1

32

3500

4.8

0.9

2200

190

300

160

1.9

5.6

44

2.7

8.1

6.8

2.6

25.7

280

8

80

15

154

0.087

5.2

19

3.1

4.6

Haloperidol K d 

  2.6 61 0.04 4700 1800 17 600 260

Values of the equilibrium dissociation constants (K  

 ) are expressed asthe mean(in nM) atthe dopamineD 

  receptor (D 

 ), theserotonin 5-HT  

receptor (5-HT  

  ), the  

 -adrenergic receptor (

 -ADR), the   

 -adrenergic receptor ( 

 -ADR), and the histamine H

 receptor (H

 ). The data

were obtained from [33]. The binding of the quinoline- and isoquinoline-sulfonamides for D 

  and 5-HT  

  , 5-HT  

  or  

 -ADR receptors(Ki , in nM) of aripiprazole* was obtained from [49]

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PFC and thalamus but increased DA and 5-HT levelsin the dorsal striatum. In the nucleus accumbens,quetiapine increased DA levels and decreased 5-HT

levels. Fluvoxamine increased 5-HT levels in all brainareas and also increased DA levels in the striatum. Al-though neither quetiapine nor fluvoxamine givenalone affected DA levels in the PFC and thalamus, thecombination of the two drugs caused a synergistic DAincrease in the PFC and the thalamus. Moreover, thecombination of quetiapine and fluvoxamine increasedDA and 5-HT levels in all brain areas compared with

 baseline measurements [11].The inability of quetiapine to increase extracellular 

DA levels in the PFC is surprising, as data haveshown that atypical antipsychotics (risperidone, olan-zapine and clozapine), but not typical antipsychotic(haloperidol), produced greater increases in DA in therat PFC than in the nucleus accumbens or the stria-tum. In vitro receptor binding studies in normal hu-man brain tissue showed that quetiapine had a similar 

 profile to other atypical antipsychotics. However, thisdrug, in contrast to other atypical antipsychotics andsimilarly to haloperidol, showed an affinity for 5-HT

 

  receptors [33]. Moreover, the increase in DAlevels in the accumbens and striatum may result from

 blockade of presynaptic dopamine D 

  auto-receptors.

Because the density of D    auto-receptors is higher in the nucleus accumbens than in the PFC, the actionof auto-receptors in the nucleus accumbens may bemore efficient than in the PFC. In addition, the in-crease in DA levels in the nucleus accumbens andstriatum may result from the ability of quetiapine to

 block 5-HT  

  /D 

 receptors or  

 -adrenergic receptors.The above data suggest that the 5-HT

 

  receptor playsan important role in the control of cortical DA func-tion and may underlie the unique clinical properties of atypical antipsychotics [11].

Monoamine levels were measured in the rat PFCafter co-treatment with risperidone and mirtazapine by Kamiñska et al. [in preparation]. Risperidone (0.1and 1 mg/kg/kg, ip) and mirtazapine (10 and 20 mg/kg, ip) increased the extracellular level of DA. Acom-

 bination of mirtazapine and the higher dose of risperi-done (1 mg/kg) produced a greater effect on the extra-cellular levels of DA than did either of those drugsgiven separately. Both drugs elevated the extracellular level of NA, and the effect of co-treatment withrisperidone and mirtazapine was greater than that ob-served after their separate administration. Risperidone

increased the extracellular level of 5-HT, and mir-

tazapine did not alter this effect. The above data are inline with the previous study [29] showing that mir -tazapine (4 to 16 mg/kg, ip) did not change the level

of 5-HT, but did produce a dose-dependent increase inextracellular levels of DA in the mPFC of freely mov-ing rats, and the 5-HT

 

  receptor-selective antagonist(WAY 100,635, 0.3 mg/kg,   ip) markedly attenuatedthe effect.

The mechanism of action of the classic antipsy-chotic drugs such as haloperidol seems to result fromantagonism of the dopamine D

 

 receptor. In contrast,atypical antipsychotics weakly block the dopamine D

 

receptor but also affect presynaptic DA release [27].A weak dopamine D

 

  blockade coupled with in-creased synaptic DA results in increased competitionfor the binding of an atypical antipsychotic to dopa-mine D

 

  receptors. This effect may reduce the propen-sity of atypical antipsychotics to induce Parkinsonianside effects. In addition, blockade of both 5-HT

 

  and5-HT

 

  receptors (in the case of olanzapine), together with a weak D

 

  receptor blockade, enhance DA re-lease to a greater extent than would be observed by

 blockade of either receptor alone. Furthermore, re-lease of both NA and DA is increased by both 5-HT

 

 blockade and 5-HT  

  activation (as observed with zi- prasidone and aripiprazole [49, 50]). The enhanced

DA and NA release in the frontal cortex and nucleusaccumbens would be expected to improve attentionand motivation, deficits in which are common symp-toms of depression. In addition, as SSRIs suppress theactivity of the locus coeruleus (the principal source of 

 brain NA) and the ventral tegmental area (the regionof extrastriatal DA), the effect of atypical antipsychot-ics on catecholamines could counterbalance this ten-dency [see 50].

It is known that the PFC plays a pivotal role inmood arousal and working memory, integrating sen-

sory input. Moreover, there are cognitive and emo-tional defects accompanying affective psychiatric dis-orders, such as depression and schizophrenia [see 50].

 Neuroanatomically, the PFC receives innervationfrom 5-HT-, DA-, and NA-releasing projections origi-nating in the dorsal nucleus, ventral tegmental areas,and locus coeruleus, respectively. By complex and re-ciprocal modulations   via  auto- or hetero-receptors,such as dopamine DA

 

  , 5-HT  

  , and    

  -adrenergic receptors, the PFC could also modulate thefunction of the temporolimbic cortex and subcortical

 brain regions involved in mood control [22, 37, 47].

Therefore, the robust increase in extracellular levels

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of DA and NA, as well as similar increases in 5-HTlevels, produced in the PFC by combined treatmentwith atypical antipsychotics and ADs provides com-

 pelling evidence for the mechanism underlying theclinical efficacy of these combinations in human TRDtrials. In addition, TRD therapy may require a robustincrease in two or more of the monoamines and, thus,combination therapy may have an additive and more

 powerful therapeutic effect than therapy involving anincrease in only one neurotransmitter alone [see 50].

Behavioral effects

The effect of addition of risperidone to an AD(fluoxetine or venlafaxine) on performance in Por-solt’s forced swimming test (an animal test of depres-sion) was studied in mice by Dhir and Kulkarni [12].Fluoxetine (10 and 20 mg/kg,   ip) and venlafaxine(4 and 8 mg/kg, ip) induced an antidepressant-like ef-fect, shortening the immobility time of mice in thistest. The addition of an inactive dose of risperidone(0.1 mg/kg, ip) potentiated the antidepressant-like ef-fect of either fluoxetine or venlafaxine. Moreover, the

antidepressant-like effect of combined treatment withthe studied drugs was potentiated by an  

 -adrenocep-tor antagonist, yohimbine (2 mg/kg, ip). It was sug-gested that yohimbine, a modulator of the NA system,also modulates the 5-HT system in the brain.The acti-vation of  

 

  -adrenergic auto- and heteroreceptors isknown to decrease 5-HT transmission. Moreover, in-hibitory  

 

 -autoreceptors located on NA neurons inthe locus coeruleus decrease the firing of these neu-rons and, thus, decrease 5-HT transmission by reduc-ing activation of stimulatory  

 

  receptors located onthe 5-HT cell bodies in the raphe nucleus. Systemic

administration of      antagonists has been shown toenhance 5-HT neurotransmission via direct inhibitionof the  

 

 heteroreceptors located on 5-HT nerve ter-minals and indirect stimulation of  

 

 receptors by in-hibition of  

 

 autoreceptors [see 12]. Thus, the en-hancement of the antidepressant-like effects observedafter co-treatment with fluoxetine or venlafaxine withrisperidone by the addition of yohimbine suggests animportant interaction of  

 

 -adrenergic and 5-HT  

  re-ceptors in this action [12].

We also showed an enhancement of the antidepres-

sant-like effect of ADs belonging to different pharma-cological groups (citalopram, fluoxetine, fluvoxa-

mine, sertraline milnacipran, mirtazapine and re- boxetine, 5 or 10 mg/kg,   ip) by risperidone at lowdoses (0.05 or 0.1 mg/kg, ip) in the forced swimming

test in mice. WAY 100635 (a 5-HT    receptor antago-nist) at a dose of 0.1 mg/kg sc inhibited the effects in-duced by co-administration of ADs and risperidone.Active behavior in the forced swimming test was nota consequence of increased general activity, as thecombined treatment with ADs and risperidone failedto enhance the locomotor activity of mice. The ob-tained results indicated that a low dose of risperidoneenhanced the activity of ADs in an animal test of de-

 pression and that, among other mechanisms, 5-HT  

receptors may play a role in these effects [34, 35].

Potentiation of the antidepressant-like effect of fluoxetine by aripiprazole in the mouse tail suspen-sion test was described by Kamei et al. [17]. Com-

 bined treatment with ineffective doses of aripiprazole(0.1 or 0.3 mg/kg, ip) and fluoxetine (10 mg/kg, ip)induced an antidepressant-like effect, decreased theimmobility time of mice in the tail suspension test.Aripiprazole showed partial agonist activity at 5-HT

 

receptors [21] and antagonist activity at 5-HT  

  re-ceptors [16]. It was recently suggested that theantidepressant-like effect of fluoxetine in the tail sus-

 pension test was mediated by activation of 5-HT  

  re-ceptors, while the effect of imipramine was elicited byactivation of dopamine D

 

  and a 

 -adrenergic recep-tors. These results suggest that the activities of thesereceptors are essential for an antidepressant-like ef-fect of fluoxetine and imipramine in the mouse tailsuspension test. It has been reported that blockade of dopamine D

 

  receptor augments the antidepressant-like effect of SSRI in the tail suspension test. Thus,the augmentation of the antidepressant-like effect of fluoxetine by aripiprazole is associated with the com-

 bined effect of stabilizing the action of DA and acti-

vating 5-HT    receptors [see 17].Aripiprazole (0.03 and 0.06 mg/kg,   ip) also en-

hanced the antidepressant-like effect of ADs of theSSRI class (sertraline, paroxetine and citalopram at4 and 8 mg/kg,   ip) and of the selective serotonin-noradrenaline reuptake inhibitor (SNRI) class (venla-faxine and milnacipran at 4 and 8 mg/kg,  ip), but notof the selective NA reuptake inhibitor class (desi-

 pramine at 2 and 4 mg/kg, ip) and dual DA and NA re-uptake inhibitor class (bupropion at 4 and 8 mg/kg,ip) in the forced swimming test in mice. These results

suggest that the augmentation effect of aripiprazoleonly appears when the 5-HT system is activated and

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may involve a complex regulation of DA and 5-HT  

and 5-HT  

  receptors [7].In rats, it has been shown that a higher dose of 

aripiprazole (6 mg/kg,  ip) given acutely, but not re- peatedly (for 7 or 14 days), induced antidepressant-like effects in the forced swimming test. Moreover,aripiprazole improved the spatial memory of rats inthe Morris water maze test [8].

Our study in rats also showed that co-treatmentwith fluoxetine (10 mg/kg,   ip) and risperidone(0.1 mg/kg, ip) induced an antidepressant-like effectin the forced swimming test by significantly increas-ing the time spent swimming and decreasing the im-mobility, while combined treatment with mirtazapine

(5 and 10 mg/kg,   ip) and risperidone (0.05 and0.1 mg/kg,   ip) evoked a significant increase in thetime spent swimming and climbing and also decreasedthe immobility time. WAY 100635 (a 5-HT

 

  receptor antagonist) at a dose of 0.1 mg/kg,  sc   inhibited theantidepressant-like effect induced by co-administra-tion of fluoxetine or mirtazapine and risperidone. Theactive behavior in that test did not reflect an increasein general activity, as combined treatment withfluoxetine or mirtazapine and risperidone failed to en-hance the exploratory activity of rats. Co-treatment

with fluoxetine or mirtazapine and risperidone did notreduce the stress-induced increase in plasma corticos-terone concentration in animals subjected to theforced swimming test. The obtained results indicatethat risperidone administered at a low dose enhancesthe antidepressant-like activity of fluoxetine or mir-tazapine in the forced swimming test (but does notnormalize the stress-induced increase in corticoster-one level in these rats) and that 5-HT

 

  receptors may play some role in these effects [36].

ADs are frequently used to treat the affectivesymptoms of schizophrenia. It was recently shownthat escitalopram (40–640 µg/kg,  iv), but not citalo-

 pram (80–1280 µg/kg,   iv) or R-citalopram (40–640µg/kg, iv), increased the firing rate and burst firing of midbrain DA neurons. At a low concentration (5 nM),escitalopram potentiated NMDA-induced currents in

 pyramidal neurons. The effect of escitalopram wasantagonized by R-citalopram and blocked by the do-

 pamine D 

  antagonist SCH2339 (0.1 µM). Escitalo- pram also improved recognition memory. Together,the data suggest that the excitatory effect of escitalo-

 pram on DA and NMDA receptor-mediated neuro-

transmission may bear upon its cognition-enhancing

effects and its superior efficacy compared with other SSRIs in major depression [38].

Moreover, another study from the same group

showed that escitalopram (5 mg/kg, sc), but not cita-lopram (10 mg/kg,   sc) or R-citalopram (10 mg/kg,

 sc), dramatically enhanced the antipsychotic-like ef-fect of a low dose of risperidone (0.25 mg/kg,  ip) inthe conditioned avoidance response test, without in-creasing catalepsy. Given alone, escitalopram, but notcitalopram or R-citalopram, markedly enhanced bothcortical DA output and NMDA receptor-mediatedtransmission. In addition, escitalopram and R-citalo-

 pram, but not citalopram, significantly enhanced bothcortical DA output and cortical NMDA receptor-mediated transmission induced by a suboptimaldose/concentration of risperidone. These results sug-gest that adjunct treatment with escitalopram, but notcitalopram, may enhance the effect of a sub-thera-

 peutic dose of risperidone on positive, negative, anddepressive symptoms in schizophrenia, without an in-crease in extrapyramidal side effect liability [24].

The evidence summarized above shows that atypi-cal antipsychotics administered in low doses enhancethe antidepressant-like activity of ADs in behavioraltests and that, among other mechanisms, 5-HT

 

  ,5-HT

 

  and a 

 -adrenergic receptors may play impor-

tant roles in their actions.

Clinical evidence for augmentation of AD

treatment with atypical antipsychotics

The evidence for the efficacy and safety of the aug-mentation strategy for ameliorating TRD using atypi-cal antipsychotics was summarized by Kato and

Chang [19]. Fourteen studies using atypical antipsy-chotics for augmenting AD treatment were includedin this analysis: three randomized control trials(RCTs) for aripiprazole, five RCTs for olanzapine,three RCTs for quetiapine, and three RCTs for risperi-done.

Aripiprazole

In three RCTs, patients were given aripiprazole 2 to20 mg/day as an add-on to standard AD (citalopram,venlafaxine) therapy [5, 6, 25]. All trials had the same

design, with a 7 to 28 day washout phase, an 8-week 

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 prospective treatment phase with a standard AD, anda 6-week, randomized, double-blind augmentation

 phase. The mean dose of aripiprazole was approxi-

mately 11 mg daily at the end of the study. In all threetrials, a benefit of aripiprazole augmentation on treat-ment efficacy was observed in the response rate, re-mission rate and mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) totalscore. When the three trials were pooled, a subpopula-tion analysis of older patients (50 to 67 years of age)showed a greater benefit of aripiprazole augmentation[44]. Aripiprazole augmentation in conjunction withADs was generally well tolerated in TRD patients inshort-term trials. The most common adverse eventsthat occurred in more than 10% (of the 737 patients)were akathisia (24.8%) and restlessness (12.1%). Themean weight change was significantly greater in thearipiprazole group compared with the placebo group(1.73 kg vs. 0.38 kg, respectively). One longer-termstudy reported the tolerability of adjunctive aripipra-zole treatment in an open-label 52-week trial involv-ing 994 patients. Common adverse events were as fol-lows: akathisia (26.2%), fatigue (18%) and weightgain (17.1%). No clinically relevant changes in other metabolic parameters were observed [19].

Olanzapine

Five trials were performed to evaluate the efficacy of olanzapine plus fluoxetine compared with fluoxetinemonotherapy in patients with TRD [10, 42, 43, 45, 46].Olanzapine was initiated at either 5 or 6 mg/day, anddoses were titrated up to a maximum of 12, 18, or 20mg/day, with a modal dose of 8 to 13 mg/day at the endof those studies. Two of those trials demonstrated a sig-nificant benefit of olanzapine plus fluoxetine comparedwith fluoxetine only for the primary outcome of the

mean MADSR score change as the endpoint [42, 45].However, three trials found no significant difference between co-treatment and treatment with either drugalone [10, 43, 45]. Significantly better remission andresponse rates for olanzapine plus fluoxetine therapywere observed in only one trial [45]. Regarding toler-ability, the most common adverse events were as fol-lows: metabolic abnormalities including weight gain (+4.42 kg change from baseline), altered glucose levels(+ 7.92 mg/dl), altered cholesterol levels (+12.4 mg/dl)and increased appetite (+ 24%) compared with thefluoxetine group. The other adverse events occurring in

more than 10% of the cases were dry mouth (18.6%),

somnolence (15.6%), fatigue (14%) and peripheraledema (11.2%) [46].

Quetiapine

In two six-week large, double-blind RCTs [4, 13] andin one eight-week small RC [26], researchers investi-gated quetiapine augmentation of ADs (citalopram,venlafaxine) compared with adjunctive placebo plusAD for TRD. In those trials, quetiapine was initiatedat 5 mg/day, and the dose was titrated up to a maxi-mum of 150, 300, or 600 mg/day, with a mean dose of 182 mg/day (in the small eight-week study) and 150or 300 mg/day (in the two large six-week studies) at

the end of the trials. A benefit of quetiapine augmen-tation, as assessed by the MADRS total score as theendpoint, was observed in all studies except for that

 published by El-Khalili et al. [13], in which theauthors found no significant difference between queti-apine augmentation (150 mg/day) and placebo aug-mentation in response rate or remission rate end-

 points. The pooled analysis of the two largest studies(n = 936) found a significant benefit of quetiapineaugmentation compared with placebo augmentationon the MADRS total score, the response rate and theremission rate at week 6 as endpoints. The most com-

mon adverse events in this pooled analysis were asfollows: somnolence, sedation, and weight gain (ap-

 proximately 7%). Extrapyramidal symptom measuresand adverse events were generally low and equal be-tween the quetiapine and placebo groups [3].

Risperidone

Three double-blind RCTs [20, 23, 32] investigated theeffects of risperidone augmentation in conjunction withvarious AD (citalopram, fluoxetine, fluvoxamine, par-

oxetine, sertraline, escitalopram, mirtazapine, venla-faxine) therapies in groups of TRD patients. In thosetrials, risperidone was initiated at 0.25 to 1 mg/day, andthe dose was titrated to a maximum of either 2 or 3mg/day, with a mean dose of 1 to 2 mg/day at the endof the studies. The primary endpoints and durationsvaried among the three studies. One of those studies[23] found that total endpoint scores on the 17-itemHAM-D were significantly lower for the risperidoneaugmentation group in a six-week study (n = 274). Thesecond study [32] demonstrated no significant differ -ence between risperidone and placebo augmentation

(n = 23). Another study [20] investigated the remission

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rate, assessed by MADRS, and found a significantlyhigher rate for the risperidone group after 4 weeks in

 patients with TRD (n = 95). Two studies (n = 241 and

n = 63) [1, 31] evaluated the sustained effect of risperi-done over a six-month period. In both studies, no sig-nificant benefit of risperidone was found, and relapserates were similar. Regarding tolerability, the mostcommon symptoms were as follows: somnolence, drymouth, fatigue, weight gain and insomnia. In the largestudy, the rate of extrapyramidal symptoms was notsignificantly different for risperidone augmentation [9].

rate, assessed by MADRS, and found a significantlyhigher rate for the risperidone group after 4 weeks in

 patients with TRD (n = 95). Two studies (n = 241 and

n = 63) [1, 31] evaluated the sustained effect of risperi-done over a six-month period. In both studies, no sig-nificant benefit of risperidone was found, and relapserates were similar. Regarding tolerability, the mostcommon symptoms were as follows: somnolence, drymouth, fatigue, weight gain and insomnia. In the largestudy, the rate of extrapyramidal symptoms was notsignificantly different for risperidone augmentation [9].

In conclusion, based on clinical evidence, atypicalantipsychotics may be successful adjunctive medicalagents for patients who fail to respond to pharmacol-ogical monotherapy with ADs. The amelioration of TRD may require a robust increase in two or more of the monoamines, and thus, a combination therapymay have an additive and more powerful therapeuticeffect compared to therapy involving an increase of only one neurotransmitter alone. The atypical antipsy-chotics analyzed in this review by Kato and Chang[19], including aripiprazole, olanzapine, quetiapineand risperidone, have varying degrees of efficacy inTRD patients and account for approximately a three-

 point difference on the rating scale for depression andan approximately 10% improvement in remission rate

compared with placebo augmentation, although thereis no clear evidence to recommend one over the other.Each atypical antipsychotic has particular adverse

 properties that range from severe, leading patients todiscontinue the treatment, to mild, with fewer risks of discontinuation. Clinicians should carefully weigh the

 benefits against the risks when planning to implementadjunctive pharmacotherapy following a failed treat-ment with an AD alone.

Acknowledgment:This study was supported by the grant POIG.01.01.02-12-004/09-00 “Depression-Mechanisms-Therapy”financed by the European Regional Development Fund.

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Received: July 31, 2013; in the revised form: September 5, 2013;accepted: September 10, 2013.

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