Rational site-directed pharmacotherapy for major depressive

Rational site-directed pharmacotherapy formajor depressive disorder

Pierre BlierUniversity of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada

Abstract

It is now accepted that major depressive disorder (MDD) is not a single pathophysiological entity. Itis therefore not surprising that remission rates to a first antidepressant trial are low. In addition, anti-depressants may target various neuronal elements for which there are gene polymorphisms, such as theserotonin (5-HT) reuptake transporter, which may modulate response. Acting on a single monoaminergictarget, such as inhibiting the 5-HT transporter, may confer efficacy in MDD, but other targets may be usedand/or combined in treatment-resistant patients. These include the blockade of norepinephrine trans-porters, monoamine oxidase, 5-HT2A, 5-HT1B and 5-HT7 receptors, and the activation of 5-HT1A and dopa-mine 2 receptors. While antidepressants may have more than one of these properties, so do atypicalantipsychotics. When using the latter medications, however, their regimens should be below those effectivein treating psychosis to avoid dopamine 2 antagonism, which could be counter-productive in MDD. Insome patients, combining medications from treatment initiation may also provide additional therapeuticbenefits.

Received 12 September 2012; Accepted 3 December 2012; First published online 10 June 2013

Key words: Antidepressants, atypical antipsychotic, drug combination, monoamines, polypharmacy.

Introduction

Unipolar depression carries the largest burden of alldiseases in middle to high income countries, as deter-mined by the World Health Organization (2008). Thisburden is estimated using disability adjusted lifeyears and unipolar depression scores immediatelyahead of ischaemic heart disease. The same report pre-dicts that, by the year 2030, unipolar depression willrank first worldwide, again ahead of ischaemic heartdisease. Despite an ‘epidemic’ of obesity, the burdenof unipolar depression will grow more than that ofischaemic heart disease: 50 vs. 30%, respectively.These statistics indicate the severity of major depress-ive disorder (MDD) and a growing trend that needsto be tackled effectively.

Currently, any first-line treatment for MDD yields aremission rate of about 35% (Trivedi et al., 2006a; Lamet al., 2009). This most often consists of a single anti-depressant medication given at an adequate dose for

a sufficient time, anywhere from 6–12 wk. This is avery poor outcome for such a serious illness. Mostguidelines recommend a medication switch after afirst failed trial. This second step commonly requiresanother 6–12 wk and leads to an even smaller successrate than the first trial.

Possible reasons for low remission rates with afirst antidepressant trials

One needs to consider the possible reasons forsuch low success rates. A first possible explanation isthe heterogeneity of the clinical presentations.Indeed, when using the criteria of the Diagnostic andStatistical Manual-IV of the American PsychiatricAssociation (2000), it is possible to have two patientsmeeting the criteria for MDD and not have any signor symptom in common (Fig. 1). With such diametri-cally opposed symptoms for sleep, appetite and psy-chomotor activity and other symptoms, it is evidentthat the pathophysiology of patients with MDDmust be different, implicate different brain structuresand/or anomalies of neurotransmitter functions. Forinstance, elevated levels of cortisol/corticotropin releas-ing factor and substance P have been reported indepressed patients (Holsboer, 2000; McLean, 2005).

Address for correspondence: Dr P. Blier, University of Ottawa Instituteof Mental Health Research, 1145 Carling Avenue, Suite 6405, Ottawa,Ontario, K1Z 7K4, Canada.Tel.: 613 722 6521 ext. 6944 Fax: 613 761 3610Email: [email protected]

International Journal of Neuropsychopharmacology (2014), 17, 997–1008. © CINP 2013doi:10.1017/S1461145713000400

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Altered functions of serotonin (5-HT), norepinephrine(NE) or dopamine (DA) have also been reported insome but not all patients (Delgado, 2000; Dunlop andNemeroff, 2007). It is therefore difficult to imaginethat an antidepressant with a single primary target,such as the 5-HT transporter (5-HTT), could producea therapeutic remission in the majority of patients.

It is now well established that there are functionallyimportant polymorphisms for a variety of receptorsand transporters directly and indirectly targetedby antidepressant medications. This may contributefurther to low remission rates with antidepressantsused in monotherapy. In the case of selective serotoninreuptake inhibitors (SSRIs), for instance, severalstudies have shown that the response rate can belower in patients having one or two short alleles vs.two long alleles in the promoter region of the 5-HTTgene (Porcelli et al., 2012).

Another issue to consider for the low remission rateswith antidepressants is the fact that, upon attemptingto enhance the function of a single monoamine system,there may be an ensuing decrease in the function ofother neurotransmitter systems (see Fig. 2). In thecase of SSRIs, their sustained administration has con-sistently been shown to decrease the firing activity ofNE neurons in the rat locus coeruleus (Szabo et al.,2000; West et al., 2009). Furthermore, such a prolongedregimen of the SSRI citalopram has been reported toproduce a corresponding decrease of extracellularlevels of NE in the rat amygdala (Kawahara et al.,2007). Since an antidepressant response can beobtained with medications that selectively block NEreuptake, such as the non-tricyclic agent reboxetine,

it therefore appears highly likely that, in some patientswho are not responding to a SSRI, the resulting attenu-ation in NE neuronal activity may contribute to thelack of response (Szabo and Blier, 2001a). Such adecreased activity of NE neurons may also contributeto decreased energy and interest in some patientsafter long-term treatment with SSRIs, given that thelatter two symptoms are controlled in part by the NEsystem (Stahl, 2002).

Obviously, patients with MDD may respond fullyto SSRIs and do not present signs or symptoms of low-ered NE activity. It is conceivable that the manifes-tations of such symptoms may be dependent on thefunctional status of the NE system at baseline beforethe treatment was initiated and/or on the polymorph-isms of receptors in the pathway from 5-HT to NEneurons. More specifically, 5-HT neurons project toγ-aminobutyric acid GABA) neurons where they acti-vate an excitatory 5-HT2A receptor, thereby increasingGABA release that inhibits the firing activity of NEneurons (Szabo and Blier, 2001b; Fig. 2). For instance,a polymorphism for the 5-HT2A receptor was linkedto the antidepressant response to citalopram in theinitial phase of the STAR*D project (McMahon et al.,2006). That a dampened NE activity can lead tolower energy is supported by the same problem thatoften arose during the treatment of hypertensionwith the α2-adrenergic agonist clonidine. This anti-hypertensive decreases NE availability by activatingthe inhibitory α2-adrenergic autoreceptors located onthe cell body and terminals of NE neurons (Fig. 2).Clonidine may lower mood in certain individuals,possibly because it decreases the NE activation of

Male aged 70 yr Female aged 35 yr

DSM-IV criteria

+ Depressed mood+ Hypersomnia+ Increased appetite/weight+ Psychomotor retardation+ No energy+ Suicidal ideation

– Marked loss of interest/pleasure– Insomnia– Decreased appetite/weight– Psychomotor agitation– Impaired concentration/decision – Inappropriate guilt

Fig. 1. Signs and symptoms of two patients each having depressive mood or anhedonia, plus five additional symptoms tomeet the criteria for major depressive disorder according to the DSM-IV. Note that sleep, appetite and psychomotor activityare in opposite directions.

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5-HT neurons and directly decreases 5-HT release fromthe activation of inhibitory α2-adrenergic receptors on5-HT terminals (Lacroix et al., 1991; Mongeau et al.,1993).

A similar inhibitory 5-HT pathway exists between5-HT and the DA neurons of the ventral tegmentalarea (Guiard et al., 2008). These DA neurons areknown to play an important role in drive and reward.Serotonin neurons project to GABA neurons wherethey activate an excitatory 5-HT2C receptor, therebyincreasing GABA release, which inhibits the firingactivity of DA neurons (Fig. 2). A decreased firingrate of DA neurons has not been reported with allSSRIs, but the most potent SSRI, escitalopram,decreases both the firing rate and the burst activity ofDA neurons (Dremencov et al., 2009). Again, the differ-ential susceptibility of some patients to side-effects ofSSRIs potentially mediated by a decreased dopamin-ergic activity may be linked to the multiple forms ofthe 5-HT2C receptor, which undergoes mRNA editing(Drago and Serretti, 2009).

Taken together, these anatomical and functionalobservations indicate that even selective drugs can

have profound repercussions on the function of othertransmitter systems to the detriment, or the benefit,of the clinical response. For instance, the attenuationof the firing rate and reactivity of NE neurons bySSRIs may contribute to dampen the intensity of apanic attack because in such a state there is a hyper-adrenergic drive that would then be under serotoner-gic inhibition. Indeed, the levels of the main metaboliteof NE are decreased following fluoxetine treatment ofpanic disorder patients (Coplan et al., 1997). On theother hand, depressed patients not responding to aSSRI may be attributable in some cases to an attenu-ated noradrenergic and/or dopaminergic function.

Taking into consideration that MDD may be morethan one illness, implying that its manifestation inthe form that we currently define it is multi-factorial,and that some of the current treatments exert effectsother than their primary action because of the func-tional connectivity of neurotransmitter systems, itwould seem logical to use more than one single mech-anism to achieve remission in a larger percentage ofpatients. This is indeed the norm in medicine. Whentreating HIV/AIDS, tritherapy has improved success

DA

5-HT

NE

InterneuronPost-synaptic

neuron5-HT2A for NE neurons5-HT2C for DA neurons

D 2

D 2

D 2

5-HT1B

5-HT1A

α1

α2

α2

α2

Fig. 2. Reciprocal norepinephrine (NE)×serotonin (5-HT)×dopamine (DA) neuron interactions showing their functionalconnectivity. Note that some of these pathways are monosynaptic while others utilize γ-aminobutyric acid interneurons. Thecircles with the arrows represent the reuptake transporters. The dots represent the neurotransmitters. The + and− symbolswithin the circles describe the excitatory or the excitatory effects, respectively, on the firing activity of the neurons depicted bythe zig-zags on the axons.

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rates. Asthma is always tackled with at least aβ2-adrenoceptor agonist and a steroid inhaler andsometimes a leukotriene receptor antagonist as well.Septicaemia is treated with two, sometimes threeantibiotics with different action spectra, until the anti-biogram is available. Unfortunately, we do not have‘antidepressant-grams’ for MDD.

Mechanisms that may contribute to theantidepressant response

First-line treatment for MDD often consists of blockingthe 5-HTT, all the more so as most SSRIs are now gen-eric. Serotonin and NE reuptake inhibitors (SNRIs) arealso widely used, as at least one has become generic.These medications, however, need to be used in theupper range of their approved range to significantlyinhibit NE reuptake. Venlafaxine at its minimal effec-tive dose of 75mg/d acts as a SSRI, whereas at 225mg/d it produces a physiologically significant interfer-ence with the NE reuptake process (Debonnel et al.,2007). Since its active metabolite desvenlafaxine takenat its minimal effective dose of 50mg/d producesplasma levels identical to those produced by venlafax-ine at 75mg/d (Nichols et al., 2011), it is evident thatdesvenlafaxine like venlafaxine needs to be titratedup to significantly inhibit NE reuptake. A similartitration of duloxetine from its minimal needs to beimplemented to obtain optimal NE reuptake inhibition(Turcotte et al., 2001; Vincent et al., 2004). It is never-theless difficult to demonstrate that SNRIs by havingan additional mechanism of action are more effectivethan SSRIs if they are compared from treatmentinitiation. Indeed, analysis of the studies comparingSSRIs and venlafaxine in such a manner only yieldeda 7% superior remission rate (Nemeroff et al., 2008).In contrast, when treatment-resistant patients wererandomized to the SSRI paroxetine or high-dose venla-faxine, the remission rate with venlafaxine was twicethat obtained with paroxetine (i.e. 42 vs. 18%; Poirierand Boyer, 1999). In the STAR*D switch from citalo-pram to sertraline, the remission rate was also 18%but that to venlafaxine was only 25% (Rush et al.,2006). The mean of the daily doses of venlafaxine inthat study was, however, only 190mg/d, whereas inthe former it was 272mg/d, being clearly in the SNRIrange for the majority of patients. Although there isno such double-study supporting the greater effective-ness of duloxetine at 120mg/d, there was significantadditional benefit when 60mg/d initial non-respondersreceived the higher regimen (Sagman et al., 2011). Itis noteworthy that these patients had initially been

treated with a SSRI or venlafaxine prior to studyinclusion.

Another mechanism to achieve an antidepressantresponse is to antagonize α2-adrenergic receptors.Importantly, these receptors are located presynapti-cally on the cell body of NE neurons and inhibitfiring on NE terminals and inhibit NE release and on5-HT terminals, where they also inhibit 5-HT release(Fig. 2; Mongeau et al., 1993). Consequently, blockingthese receptors enhances the synaptic availability ofboth NE and 5-HT. The antidepressant mirtazapineantagonizes these three types of presynapticα2-adrenergic receptors while leaving unaffected theresponsiveness of post-synaptic α2-adrenergic recep-tors, at least in the hippocampus (Haddjeri et al.,1997). Several atypical antipsychotics, which can beused in treatment-resistant MDD, also block to someextent α2-adrenoceptors; these include asenapine, clo-zapine, paliperidone, quetiapine, risperidone (Fig. 3;Schotte et al., 1996). Officially, however, only quetia-pine and aripiprazole have an indication for treatment-resistant MDD, although there are controlled studiesfor risperidone (Nelson and Papakostas, 2009). Thedegree of α2-adrenergic antagonism at the four above-mentioned adrenoceptors can vary among these medi-cations. For instance, asenapine partially blocks post-synaptic α2-adrenergic receptors in the hippocampuswhile quetiapine does not (Chernoloz et al., 2012a, b;Osterhoff et al., 2012). The heterogeneity of responseof these receptors, as well as other monoaminergicproperties, may explain whether some atypical anti-psychotics may act as antidepressants when usedalone. For instance, quetiapine has been shown to beeffective in monotherapy for MDD (Maneeton et al.,2012); however, an important metabolite, desalkyl-quetiapine, blocks NE reuptake to a significant extent(Jensen et al., 2008; Chernoloz et al., 2012a, b). Thereis a synergistic action on synaptic NE availabilitywhen the NE transporter and the α2-adrenergic auto-receptors are blocked simultaneously (L’Heureuxet al., 1986). This potentiation is presumably at playwith the combination of high doses of venlafaxineand therapeutic doses of mirtazapine (Blier et al.,2010).

When an atypical antipsychotic is used alone or incombination with an antidepressant medication forMDD, the regimen is almost invariably below thatused to treat psychosis (Nelson and Papakostas,2009). This signifies that such doses do not block to amarked extent DA D2 receptors and they are used fortheir other properties on monoaminergic receptors.Using higher doses may not be effective or lead to aloss of response it diminishes D2 transmission

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(Blier and Blondeau, 2011). The term atypical antipsy-chotic is thus a misnomer. When used in mood andanxiety disorders, these drugs maybe better denotedas anxiothymic modulators.

Agonism of 5-HT1A receptors has been shown to bean effective strategy in MDD (Blier and Ward, 2003).Although most 5-HT1A agonists are partial agonists,this annotation does not hold true for all brain regionsas most are full agonists on the cell body 5-HT1A auto-receptor. Even on post-synaptic 5-HT1A receptors, thepartial agonism of ipsapirone, for example, is not pre-sent when the drug is administered systemically (i.e.it does not attenuate the inhibitory effect of 5-HT;Dong et al., 1997). Consequently, 5-HT1A agonists actby enhancing and not decreasing 5-HT transmission(Haddjeri et al., 1998). The 5-HT1A receptor agonistbuspirone was shown to have antidepressant activityat high doses (Robinson et al., 1990). This medicationis, however, rapidly absorbed and eliminated, givingrise to marked side-effects, thereby often preventingits use at high doses that are antidepressive. Buspironeis better tolerated in patients already on SSRIs sincethey would have already developed a certain toleranceto serotonergic side-effects. In STAR*D, buspironeaddition produced a similar remission rate as bupro-pion in citalopram-resistant patients (Trivedi et al.,2006b). The buspirone analogue gepirone in anextended release formulation was shown to be signifi-cantly superior to placebo in three studies, thusdemonstrating the usefulness of this strategy in MDD(Feiger, 1996; Feiger et al., 2003; Bielski et al., 2008).

Several atypical antipsychotics can also activate5-HT1A receptors; these include aripiprazole, asena-pine, clozapine, iloperidone, lurasidone and ziprasi-done. The affinity of aripiprazole and ziprasidone ismarkedly greater than that of buspirone (Pou et al.,1997; Wood et al., 2006). It is thus likely that this prop-erty can contribute to their beneficial action inSSRI-resistant patients. Similarly, the potent 5-HT1A

receptor agonism of the SSRI vilazodone may notonly contribute to its antidepressant effect, but alsoto its side-effect profile (Heinrich et al., 2004).

Agonism of DA D2 receptors on its own is an effec-tive strategy for MDD. This was first reported withbromocriptine and subsequently with pramipexole ina placebo and fluoxetine controlled study (Waehrensand Gerlach, 1981; Corrigan et al., 2000). Sustainedadministration of pramipexole enhances D2 trans-mission in a time-dependent fashion. Initially, thefiring rate of DA neurons is decreased because of D2

autoreceptor activation on DA neurons (Chernolozet al., 2009). These autoreceptors desensitize with treat-ment prolongation and allow a recovery of the firingrate of DA neurons, at which time there is an increasedactivation of post-synaptic D2 receptors in the frontalcortex (Chernoloz et al., 2012a, b). D2 transmission isalso enhanced at excitatory D2 receptors on 5-HTneurons in the dorsal raphe after long-term pramip-exole administration (Chernoloz et al., 2009). Thiselevates the firing rate of 5-HT neurons and leads toenhanced 5-HT transmission in the hippocampus(Chernoloz et al., 2012a, b). Among the atypical

Detailed receptor pharmacologyof atypical antipsychotics

Atypical antipsychotic

5-HT2A/Cantagonism

α2antagonism

5-HT1Apartial agonism

5-HT7antagonism

5-HT1B/Dantagonism

Clozapine + + + + O

Risperidone + + O + +

Olanzapine + O O + O

Quetiapine + + + O O

Paliperidone + + O + +

Ziprasidone + O + + +

Aripiprazole + O + + O

Asenapine + + + + +

Lurasidone +/O + + + O

Iloperidone + O + O O

Amisulpiride O O O + O

O indicates no activity; + indicates significant activity

D2partialagonismO

O

OO

OO

O

O

O

O

+

Fig. 3. Pharmacological properties of atypical antipsychotics that may contribute to their potential antidepressant activitywhen used in combination with antidepressant medications. Not all of these medications have been reported to be effective intreatment-resistant depression.


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antipsychotics, only aripiprazole is endowed with D2

receptor agonism. It is a partial agonist, but sincethere is likely a decreased availability of DA in MDD(Dunlop and Nemeroff, 2007), the exogenous agonistmay work cooperatively with endogenous DA toenhance the tonic activation of post-synaptic D2

receptors.There are other mechanisms that may contribute

to an antidepressant response and receptors whenused in combination with antidepressants. Theseinclude monoamine oxidase (MAO) inhibition, mono-amine releasers, the terminal 5-HT autoreceptor and5-HT7 receptors.

MAO inhibitors (MAOIs) enhance the availabilityof 5-HT, NE and DA and are sometimes useful afterseveral failed trials with a variety of agents. The effectsof their sustained administration on the firing activityof these three types of neurons in the rat brain overtime have been reported (Blier and de Montigny,1985; Chenu et al., 2009). They will not be reviewedherein, but a variety of augmentation strategies canbe used, as in the case of reuptake inhibitors.

Lithium addition was one of the first documentedaugmentation strategies. While lithium does have avariety of actions, it is believed to act relatively rapidlyin treatment-resistant MDD by enhancing 5-HTrelease. While on its own, lithium is not sufficient toincrease the tonic activation of post-synaptic 5-HTreceptors in the hippocampus, it potentiates the effectsof antidepressants, namely, the MAOI tranylcypro-mine, the tricyclic imipramine and the SSRI paroxetine(Haddjeri et al., 2000).

Bupropion is a catecholamine releaser. This is notsurprising as it is a derivative of the appetite suppres-sant diethylpropion. Initially, bupropion was thoughtto be a DA and NE reuptake inhibitor, despite havingvery low affinity for these transporters (520 and52 000 nM, respectively; Tatsumi et al., 1997). Indeed,four positron emission tomographies have shownthat clinically effective doses of bupropion occupyabout 20% of DA transporters, at times with a variancebarely above the control situation (see Meyer et al.,2002; Argyelán et al., 2005). In acute microdialysisstudies in rodents, bupropion enhances extracellularDA, but not in all brain regions as would be expectedfrom a reuptake inhibitor (Li et al., 2002). In the stria-tum, bupropion is without effects (Egerton et al.,2010). In contrast, bupropion enhances NE availabilityin the vicinity of the cell body of NE neurons anddecreases their firing rate through α2-adrenergicautoreceptor activation. With treatment prolongation,these autoreceptors desensitize, as well as those onNE terminals in the forebrain, and enhance NE

transmission in the hippocampus (El Mansari et al.,2008; Ghanbari et al., 2011). In contrast, bupropionpromptly enhances the firing of 5-HT neurons throughenhanced NE release on excitatory α1-adrenergic recep-tors on 5-HT neurons. This constitutes indirect evi-dence that bupropion does not block NE reuptakebecause NE reuptake inhibitors, such as reboxetine,do not alter the firing rate of 5-HT neurons (Szaboand Blier, 2000a). Prolonged bupropion increases5-HT transmission to a small extent after subacuteadministration, likely as a result of the increase infiring of 5-HT neurons. After prolonged adminis-tration, 5-HT transmission is enhanced to a markedextent in the presence of sustained elevation of 5-HTfiring and the desensitization of the α2-adrenergicreceptors on 5-HT terminals (Ghanbari et al., 2011).

The terminal 5-HT autoreceptor exerts an inhibitoryinfluence on 5-HT release. When it is antagonized,5-HT release is enhanced and when it is blocked inthe presence of a SSRI, 5-HT levels are increasedfurther (Sharp et al., 1997). In parallel with these obser-vations, the terminal 5-HT autoreceptor gets desensi-tized with long-term administration of SSRIs (Piñeyroand Blier, 1999). There is no clinically available selec-tive antagonist of the terminal 5-HT autoreceptor, butseveral atypical antipsychotics can block this auto-receptor; these include risperidone, paliperidone,ziprasidone and asenapine.

The 5-HT7 receptor has been identified as potentialtarget for an antidepressant response. A selective5-HT7 receptor antagonist is active in behaviouraland animal models of antidepressant action. The fol-lowing atypical antipsychotics are antagonists of thisreceptor: clozapine; risperidone; amisulpiride (Rauly-Lestienne et al., 2007; Abbas et al., 2009). Furthermore,in mice lacking the 5-HT7 receptor, amisulpiride doesnot exert its usual antidepressant-like action in twoanimal models. In Europe, low doses of amisulpirideare used in treatment-resistant MDD. This clinicalbenefit may result from a preferential blockade of pre-synaptic D2 receptors (Schoemaker et al., 1997), butpossibly as well from the antagonism 5-HT7 receptorssince amisulpiride has a 10 nM affinity for these recep-tors (Abbas et al., 2009).

All the above-mentioned strategies have beenreported to be effective in treatment-resistantdepression with various level of clinical evidence, ran-ging from double-blind randomized to case series(Fig. 4). It is sometimes difficult for some strategies toattribute a clinical success to a single mechanismbecause drugs can have more than one action knownto contribute to an antidepressant response. The multi-plicity of actions of some old antidepressants indirectly

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supports the notion that more mechanisms may leadto superior effectiveness. Nevertheless, it is importantto follow what can be termed a neurobiologicalalgorithm, that is, to avoid sequential steps that solicitthe same mechanism(s) (Zigman and Blier, 2012).There follows some examples of such irrational poly-pharmacy: (1) switching from venlafaxine to duloxe-tine, or vice versa, when the first drug is welltolerated but there is no response at an adequatedose; (2) adding a SSRI to a SNRI, knowing thatSNRI at doses that inhibit NE reuptake have an opti-mal effect on 5-HT reuptake; (3) using mirtazapineeither alone or in combination following a failed trialof extended release quetiapine, as both drugs areα2-adrenergic, 5-HT2A/2C and histamine type 1 receptorantagonists, as well as 5-HT1A agonists; (4) using pra-mipexole or buspirone addition after a failed trialwith the D2 and 5-HT1A agonist aripiprazole.

How to choose logically an augmentation strategy

1 Primum non nocere. Medications that would be rela-tively contraindicated should be avoided. Combin-ing a SSRI/SNRI with a MAOI is an absolutecontraindication because it would block the onlytwo inactivating pathways for 5-HT, thus triggeringa potentially lethal 5-HT syndrome. In contrast,using a selective NE reuptake inhibitor with aMAOI would not create such a catastrophe becauseNE can also be inactivated by catecholamine-O-methyl transferase. In fact, it would protect thepatient from a hypertensive crisis following the inges-tion of tyramine as it needs to penetrate NE terminalsthrough the NE reuptake pump to release NE(Debonnel et al., 2007). Lithium addition should notbe a first-line augmentation strategy in patientswith hypothyroidism because of its potential todiminish thyroid function; thyroid stimulating

hormone levels would have to be closely monitoredfor an eventual adjustment of thyroidsupplementation.

2 Choosing a medication that would target a cumber-some symptom could produce rapid relief beforea full antidepressant response is achieved. Forinstance, in patients with insomnia and/or highanxiety levels, mirtazapine or quetiapine XR couldresolve insomnia from day 1. A patient with lowenergy could potentially benefit more from an acti-vating drug such as bupropion rather than asedative one such olanzapine.

3 Choosing a strategy thatwould treat amedical or psy-chiatric co-morbidity could minimize the number ofmedications prescribed. For instance, a patient withrestless leg syndrome could benefit from pramip-exole on two fronts, as it is indicated for that patho-logy and can be effective in treatment-resistantMDD (Hori and Kunugi, 2012). Risperidone augmen-tation could help patients with urinary flowproblemsdue to prostate hypertrophy, due to its highα1-adrenergic antagonism (Schotte et al., 1996),which is a treatment for that condition. This strategywould be a first choice if a patient also hastreatment-resistant obsessive–compulsive disordersince there are several positive augmentation studieswith risperidone in this disorder (Dold et al., 2012).

4 Considering properties of medications that wouldfavour compliance is also desirable. These includeundesired side-effects for individual patients, onceper day regimens and cost of the drug.

5 Finally, the weight of the clinical evidence forthe effectiveness of a given strategy should helpthe clinician to make a final decision about theorder of the preferred strategies being used.

When a monotherapy is implemented, if there is nota 20% improvement after 2 wk, the likelihood ofachieving remission by the end of the trial is about4% (Szegedi et al., 2009). In a drug addition to an

• Lithium• Tricyclic antidepressants• Reboxetine/Atomoxetine• T3• Bupropion• Buspirone• Mirtazapine• Pramipexole• Atypical antipsychotics• Electroconvulsive shocks

600–900 mg50–300 mg4–8 mg/18–80 mg25–50 µg150–450 mg30–60 mg30–60 mg1–5 mg/dlower doses than for psychosis2–3/wk × 3–5 wk

Fig. 4. Range of options for add-on therapy to standard antidepressants. The regimens mentioned are those generallyreported to be effective. Most, but not all, of these strategies have been shown to be effective in double-blind studies.


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ongoing treatment, the same 2-wk rule should alsoapply. Indeed, it is not because a medication has notproduced a clinical change that it did not induce a bio-logical change, it is just that a threshold may not havebeen reached to produce an improvement. It may thusbe wise to maintain the first drug, first, to avoid dis-continuation, second, to maintain a possible smallimprovement and, third, to try to potentiate it. Thispotentiation was readily observed when lithium aug-mentation was first used, that is, if patients were torespond to lithium addition even in the absenceof any response, an improvement generally occurredwithin the first 2 or 3 wk if it were to work. As an illus-tration of this, if the non-responders are removed fromthe usual gradual improvement curves on the ratingscales, the curves obviously become much steeper.The sequential combinations thus appear much moretime-efficient (Fig. 5).

As emphasized in the Introduction, there should beno hesitation in using a combination of two effectivemedications early in the treatment of MDD becauseof the low success rate of single agents (Blier et al.,2009, 2010). Physicians often do not hesitate to pre-scribe from treatment initiation an antidepressantand a benzodiazepine to help with insomnia and/oranxiety. The problem with this approach is that benzo-diazepine is not an antidepressant and may cause cog-nitive dysfunctions, especially in elderly patients, canbe problematic if alcohol is consumed and producerebound anxiety and/or insomnia when it is time to

discontinue it. One combination has been reported tobe efficacious both from treatment initiation and asan augmentation strategy in more than one case series:venlafaxine and mirtazapine (see Hannan et al., 2007;Blier et al., 2010). In contrast, there have also beenreports, both double-blind and single-blind, not show-ing a superior effectiveness of this combination(McGrath et al., 2006; Rush et al., 2011). In the latterstudies, the doses of venlafaxine were not in the nor-adrenergic range for venlafaxine in all patients and,with regard to mirtazapine, most patients did notreceive its therapeutic dose of 30mg/d throughoutthe study.

In addition, in the CO-MED study by Rush et al.(2011), there was no difference in the clinical effective-ness of escitalopram monotherapy vs. escitalopramplus bupropion. It is noteworthy that the CO-MEDwas not a double-blind trial with clinicians titratingdrug regimens openly throughout the study. Thismay help understand why more patients on escitalo-pram alone ended up on the 20mg/d dose than inthe combination arm. When using drug combinationsfor depression, the full potential of each medicationshould be exploited in much the same way, forinstance, when using two antibiotics at full doseswhen treating septicaemia in the emergency room ora β2-agonist plus a steroid for asthma.

Subsequent analyses of the CO-MED data revealedthat melancholia, chronic depression, co-morbidanxiety, medical co-morbidity, race and ethnicity andthe level of anxiety symptoms did not affect theresponse to combination treatments (Bobo et al., 2011;Lesser et al., 2011; Chan et al., 2012; Davis et al., 2012;Morris et al., 2012; Sung et al., 2012). In contrast, combi-nationsweremore effective in reducing suicidal ideation(Zisook et al., 2011).

In conclusion, it is important to proceed methodi-cally when treating MDD; using medications withcomplementary mechanisms of action at adequatedoses, attempting to minimize side-effects or usingthem judiciously and implementing such strategies ina time-efficient fashion. When such a rational approachis utilized, it provides clinicians with a structuredframework allowing them to proceed efficiently withconfidence that will also minimize hopelessness forthe treatment-resistant patient.

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Fig. 5. Time-course of possible interventions to tackle majordepressive disorder after a first failed trial. This figure ismeant to show that within the time it generally takes toattempt two consecutive trials, with or without a washoutperiod, it is possible to carry out at least two, if not three,consecutive combinations. In most cases, a substitution ofthe first added medication for the next one should be doneto avoid giving three or more medications concomitantly.

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Rational site-directed pharmacotherapy for major depressive