International Journal of Neuropsychopharmacology (2014), 17, 1009–1037.

© CINP 2013 ARTICLE

doi:10.1017/S1461145712001496

On ‘polypharmacy’ and multi-target agents,

complementary strategies for improving
the treatment of depression:
a comparative appraisal

Mark J. Millan
Unité du Recherche et Découverte en Neurosciences, Institut de Recherches Servier, Croissy sur Seine, Paris, France

Abstract

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Major depression is a heterogeneous disorder, both in terms of symptoms, ranging from anhedonia to
cognitive impairment, and in terms of pathogenesis, with many interacting genetic, epigenetic,
developmental and environmental causes. Accordingly, it seems unlikely that depressive states could be
fully controlled by a drug possessing one discrete mechanism of action and, in the wake of disappointing
results with several classes of highly selective agent, multi-modal treatment concepts are attracting
attention. As concerns pharmacotherapy, there are essentially two core strategies. First, multi-target anti-
depressants that act via two or more complementary mechanisms and, second, polypharmacy, which refers
to co-administration of two distinct drugs, usually in separate pills. Both multi-target agents and poly-
pharmacy ideally couple a therapeutically unexploited action to a clinically established mechanism in
order to enhance efficacy, moderate side-effects, accelerate onset of action and treat a broader range of
symptoms. The melatonin MT1/MT2 agonist and 5-HT2C antagonist, agomelatine, which is effective in
the short- and long-term treatment of depression, exemplifies the former approach, while evidence-
based polypharmacy is illustrated by the adjunctive use of second-generation antipsychotics with serotonin
reuptake inhibitors for treatment of resistant depression. Histone acetylation and methylation, ghrelin
signalling, inflammatory modulators, metabotropic glutamate-7 receptors and trace amine-associated-1
receptors comprise attractive substrates for new multi-target and polypharmaceutical strategies. The
present article outlines the rationale underpinning multi-modal approaches for treating depression, and
critically compares and contrasts the pros and cons of established and potentially novel multi-target vs.
polypharmaceutical treatments. On balance, the former appear the most promising for the elaboration,
development and clinical implementation of innovative concepts for the more effective management of
depression.
Received 2 October 2012; Reviewed 8 November 2012; Revised 9 November 2012; Accepted 13 November 2012;
First published online 30 May 2013
Key words: Depression, epigenetic, histone, multi-functional, trace amine, treatment-resistance.

Introduction In light of their multi-factorial origins and complex

clinical profiles, it seems unlikely that disorders such
Psychiatric disorders are generally characterized by a
as major depression and schizophrenia could be fully
broad range of symptoms and high co-morbidity
controlled in all patients by a drug possessing one
with other conditions, and they can be attributed to a
single mechanism of action. This point is of consider-
diverse palette of neurochemical and structural dys-
able significance since the last decade has been domi-
functions provoked in turn by multifarious genetic,
nated by the search for highly selective agents acting
developmental, environmental and epigenetic factors.
at a single target hypothesized to play a key role in
the induction and/or control of specific disorders. Un-
fortunately, despite often compelling preclinical data,
Address for correspondence: Dr M. J. Millan, Unité du Recherche et
many selective agents have yielded mitigated results
Découverte en Neurosciences, Institut de recherches Servier,
125 chemin du ronde, 78290 Croissy sur Seine, Paris, France.
in clinical trials and not been progressed to authoriz-
Tel: 00 33 1 55 722425 Fax: 00 33 1 55 722082 ation. This is not to say, however, that the target in
Email: mark.millan@fr.netgrs.com question is necessarily irrelevant or inactive and,
1010 M. J. Millan
apart from the use of selective drugs in subpopulations
of patients and/or against certain subsets of symptoms,
many targets might be more effectively exploited in
association with other mechanisms of therapeutic
activity. As outlined in this article, there are essentially
two ways of achieving this goal with pharmacothera-
peutics: polypharmacy (drug combinations); and multi-
target drugs (several actions possessed by one drug).
In fact, the term ‘polypharmacy’ has something of
an unfortunate reputation since it is sometimes prac-
tised in an unstandardized and ad hoc basis without
formal supporting data, particularly in patients suffer-
ing from schizophrenia (Goodwin et al., 2009; Zink
et al., 2010) and bipolar disorder (Lin et al., 2006;
Goldberg et al., 2009). Counterproductively, the con-
comitant prescription of numerous drugs to certain
psychiatrically ill patients – in particular the elderly,
who typically take around six to eight – may com-
promise efficacy and provoke serious adverse drug
reactions (Prudent et al., 2008). This type of poly-
pharmacy is often associated with co-morbidity and
generally encompasses a broad range of medication,
including agents for controlling somatic complaints,
as well as psychiatric and/or neurological problems
(Mojtabai and Olfson, 2010). Major depression is also
characterized by an increasing tendency for multiple
drug use over the past decades, not only in geriatric
populations but also in adults and the young (Glezer
et al., 2009; Goodwin et al., 2009; McIntyre and Jerrell,
2009; Mojtabai and Olfson, 2010; Serna et al., 2010).
Conversely, the present article is concerned with
the more positive dimension of evidence-based poly-
pharmacy. That is, the controlled, validated and
authorized use of drug combinations for improving
antidepressant efficacy without any worsening of toler-
ance, in particular following guidelines in treatment-
resistant patients who fail to respond adequately to
monotherapy (Trivedi et al., 2006; Melander et al.,
2008; Shelton et al., 2010; Connolly and Thase, 2011;
Al-Harbi, 2012; Schlaepfer et al., 2012).
As regards drugs possessing multiple mechanisms
of action, there has been a tendency to disparagingly
consider them as ‘dirty’ and to accentuate the side-
effects triggered by their ‘off-target’ actions. For
example, the antimuscarinic, α1-adrenoceptor (AR)
antagonist and histaminergic H1 antagonist properties
of tricyclics (such as amitriptyline) and antipsychotics
(such as clozapine) compromise cognition and elicit
numerous autonomic and cardiovascular side-effects
(Millan, 2006; Gillman, 2007; Sartorius et al., 2007). On
the other hand, other components of their multi-target
profiles – monoamine reuptake inhibition plus 5-HT2C
antagonist properties for tricyclic antidepressants and
dopamine (DA) D2/D3/5-HT2A antagonism plus
5-HT1A partial agonism for antipsychotics – accounts
for their beneficial effects in treating depression and
schizophrenia, respectively (Millan, 2006; Meltzer
et al., 2012; Quesseveur et al., 2012).
Currently, there is particular interest in novel multi-
modal therapies that act at discrete subsets of targets
mediating desirable actions while side-stepping mech-
anisms evoking undesirable side-effects. In this case,
both polypharmacy (drug combinations) and multi-
target agents are of potential interest and these strat-
egies share a suite of therapeutic objectives, which,
if fully realized, could markedly enhance the treatment
and lives of patients suffering from depression
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(Table 1). The present article discusses the basic prin-
ciples and the pros and cons of polypharmacy as com-
pared to multi-target medication, evoking particular
mechanisms that have been harnessed by both. It
also considers a palette of innovative concepts under
experimental exploration, which may eventually lead
to the availability of more effective multi-modal anti-
depressants. The focus on major depression seems par-
ticularly appropriate in light of the disturbing current
trend to disengage from ‘R and D’ in this therapeutic
domain despite well-recognized problems of treat-
ment-resistance and sub-optimal remission (Miller,
2010; Nutt and Goodwin, 2011).
Major depression, a complex and heterogeneous
clinical profile with multiple risk factors
Major depression is characterized by the cardinal
symptoms of depressed mood and anhedonia, coupled
to a state of despair and hopelessness, severe fatigue
and loss of concentration, suicidal ideation and, in
extreme cases, actual attempts at suicide (Millan,
2006; Sartorius et al., 2007; Uher, 2011). In addition,
it is accompanied by a broad spectrum of other symp-
toms. Some are seen in a majority of depressed individ-
uals, such as cognitive impairment and anxiety,
whereas others are seen in only a minority, such as
psychotic episodes and pain (Fig. 1). Moreover,
depression is commonly co-morbid with: (1) psychia-
tric conditions such as obsessive–compulsive disorder,
generalized anxiety disorder and schizophrenia;
(2) neurological disorders such as Parkinson’s disease,
Alzheimer’s disease and chronic pain; (3) somatic dis-
eases such as diabetes, osteoporosis and cardiovascular
disease (Millan, 2006; Sartorius et al., 2007; McIntyre
et al., 2012). While not every patient will display all
symptoms, depression is clearly a heterogeneous dis-
order with a broad range of symptoms requiring
treatment.
 Complementary strategies for improving the treatment of depression 1011

Table 1. Major therapeutic aims of polypharmacy and multi-target pharmacotherapy in the treatment of major depression

Enhance treatment efficacy in terms both of: (1) the extent and breadth of remission in individual patients; (2) the number of
patients showing clinically significant improvement.
Improve quality of treatment not only in terms of rating scales but also as assessed by self-evaluation, and by concrete measures of
quality of life, real-world function and socio-professional integration.
Reduce the risk of relapse: (1) in the course of treatment (tachyphylaxis); (2) following termination of administration.
Accelerate therapeutic efficacy, both in terms of: (1) initial delay to onset; (2) attainment of full effect.
Broaden the therapeutic range of treatment to control not only depressed mood and anhedonia (cardinal symptoms) but also
symptoms like cognitive impairment and anxiety.
Reduce the incidence of side-effects (especially compared to SSRIs) and increase the ‘therapeutic window’ of doses eliciting
undesirable effects as compared to those eliciting beneficial actions.
Promote patient compliance and decrease the risk of premature discontinuation of treatment.

SSRIs, Selective serotonin reuptake inhibitors.

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A number of related terms are applied (not always consistently) for the use of more than one drug to treat depression and other
central nervous system disorders, like association, combination, add-on, adjunctive, augmentation, etc. Polypharmacy in the pre-
sent context mainly refers to ‘augmentation’ strategies, whereby a second potentiating drug does not possess significant anti-
depressant properties itself. In contrast, a ‘combination’ strategy refers to the co-joint administration of two mechanistically
different antidepressants. However, this distinction is often ambivalent since, even if a drug class is not authorized as a clinically
effective treatment for depression, it may exert a favourable influence on depressed mood, anhedonia and other symptoms of
depression. Examples include antagonists at 5-HT2C and NK1 receptors.

It is possible that a single anomaly, such as a genetic
mutation, could ultimately trigger a broad range of
symptoms, in particular if it occurred early in develop-
ment – and perinatal trauma is indeed a risk factor
for depression (Uher, 2011; Heim and Binder, 2012).
However, although certain monogenic neurodevelop-
mental conditions are associated with a broad range
of dysfunction affecting both the brain and other
organs (Kramer and van Bokhoven, 2009; Millan,
2013; Sanchez-Mut et al., 2012), depression is a poly-
genic disorder (cumulative impact of many genes
with minor effects) that can be triggered or aggravated
by adverse environmental events occurring at essen-
tially any time of life from conception and foetal devel-
opment via infancy and puberty to adulthood and
senescence (Fig. 2) (Millan, 2006; Lohoff, 2010; Uher,
2011). Interestingly, both genetic and environmental
factors converge onto epigenetic mechanisms control-
ling gene expression, which include DNA methylation
and post-transcriptional histone marking as well as the
control of mRNA processing and translation by non-
coding RNAs (Covington et al., 2010; Lohoff, 2010;
Uher, 2011; Millan, 2013; Mouillet-Richard et al.,
2012; Sun et al., 2012). This interplay of mechanisms
favouring (and countering) depressed states leads to
a complex pattern of neuroplastic signalling and struc-
tural anomalies, both within and between neurones,
and impacting a diversity of neural networks in the
frontal hippocampus, amygdala and other corticolim-
bic structures (Fig. 1; Millan 2006; Covington et al.,
2010; Autry and Monteggia, 2012; Dumas and Voleti,
2012; Heim and Binder, 2012; Schloesser et al., 2012).
Thus, the multifaceted symptomology of depression
is mirrored by a complex hierarchy of cellular (neuro-
nal and glial) anomalies manifested across overarch-
ing cerebral regions. It is also important to note that
certain pathological changes anticipate the appearance
of unambiguous clinical symptoms and diagnosis
(Millan, 2006; Heim and Binder, 2012; Duman and
Voleti 2012).
The above observations have several important
implications for treatment. First, since network shifts
are not always reversible, treatment should be initiated
as soon as possible – ideally preventatively, once
robust biomarkers become available (Millan 2008;
Schmidt et al., 2011; Uher, 2011). Second, as discussed
herein, it is likely that multiple mechanisms will need
to be harnessed for the broad-based control of de-
pressed states across substantial populations of
patients, questioning the wisdom of highly selective
agents. Third, multi-modal therapies concern both
agents designed to normalize a pathological process
causing depression, as well as symptomatic inter-
ventions for relief of symptoms by the manipulation
of ‘intact’, compensatory substrates not affected by
depression per se.
Genome-driven, rational drug discovery: a decade
of selective antidepressants in perspective
There is a multitude of (interrelated and non-exclusive)
explanations for the limited progress seen over the last
1012 M. J. Millan

Agents with complementary mechanisms of action

Circadian
dysruption
Poor Sexual
sleep dysfunction

Somatic Depressed
Psychotic
symptoms, mood,
episodes
pain anhedonia

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Motor
retardation, Cognitive
excitation deficits
Anxiety,
nervousness

Improved efficacy, ↑ rapidity of action, control of other symptoms

Fig. 1. Symptoms other than depressed mood commonly associated with major depression. In addition to depressed mood
and anhedonia, which are cardinal symptoms of major depression, it is often accompanied by a broad palette of other
symptoms contributing to functional impairment. As outlined in the text, depression is also frequently co-morbid with a
wide range of other central nervous system and somatic diseases, such generalized anxiety disorder and schizophrenia,
Parkinson’s and Alzheimer’s disease, diabetes and cardiovascular disease. The complex pattern of symptoms and
co-morbidity implies the involvement of numerous pathological processes and supports arguments in favour of treatments
acting via several, complementary mechanisms of action.

few decades in the pharmacotherapy of depression.
They relate to all dimensions of the ‘R and D’ process
as well as to authorization of new medication, embrac-
ing preclinical, clinical, regulatory, intellectual prop-
erty and commercial issues. Several important points
may be highlighted: persistent question-marks over
the pertinence of animal models of depression; poor
experimental validation of novel targets; the relevance
of tests for evaluating potential antidepressant activity;
their translational dimension, whether comparable pro-
cedures can be undertaken in humans; lack of rigorous
patient recruitment for clinical investigations, use of
antiquated rating scales and a strikingly high response
to placebo (the most common cause of failed trials); the
need to show superiority of a new drug if not over pla-
cebo, then over another antidepressant; increasingly
stringent safety concerns; limited patent life for new
drugs, generic competition and the difficulty in rapidly
negotiating a realistic level of reimbursement for novel
drugs from national institutions post-launch, in par-
ticular bearing in mind the comparatively low rate of
success, yet high cost of development for central ner-
vous system (CNS) drugs vs. other therapeutic areas
(Brady et al., 2009; Miller, 2010; Nutt and Goodwin,
2011).
Three additional and interlinked issues that have
dominated the agenda over the last decade should be
briefly discussed since they are highly relevant to
the development and use (or non-use) of multi-target
drugs and polypharmacy. First, the impact of geno-
mics and ‘rational’ drug discovery (Fig. 3); second,
the above-mentioned preoccupation with highly-
selective agents; third, the prioritization of novel, non-
monoaminergic targets – with a particular focus on
intracellular substrates of plasticity (Millan, 2006,
2008; Covington et al., 2010; Duman and Voleti, 2012;
Autry and Monteggia, 2012; Connolly and Thase,
2012; Schloesser et al., 2012). It was originally thought
 Complementary strategies for improving the treatment of depression 1013

Vast array of potential causes – diverse pathologies

Lifelong: Developmental:
Stress
environmental/internal childhood/adolescent
adverse events trauma

aNumerous
Diverse bComplex

depressed changes in DNA/

interacting
histone
risk genes, states and ‘marking’ by
CNVs, inherited
and de novo
symptoms methylation,
acetylation,
mutations

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phosphorylation

Genetica risk factors: Epigeneticb control

Non -coding of gene expression
epistatic networks
RNAs

(Control of mRNA processing and translation)

No single trigger - no single solution

(Causal factors NOT synonymous with treatment targets)

Fig. 2. Multiple and interacting causes of major depression throughout life. Mirroring the heterogeneity of major
depression in terms of its clinical profile, no single factor has been identified as causal. Dependent on the individual
(and probably symptom) it reflects a deleterious interplay of both genetic and environmental (early and late life) factors,
which in many cases converge upon epigenetic mechanisms that modify gene expression without any change in gene
sequence. As regards genetic factors, multiple genes of small effect appear to be incriminated, as well as more extensive
copy number variants (CNVs) and both inherited and de novo mutations. As for epigenetic mechanism, anomalous
histone (and probably DNA) marking, a dysfunction of non-coding RNAs (such as microRNAs) and aberrant control
of mRNA translation are likely involved. While uncontrolled, severe and chronic stress is a threat throughout life,
stress during early childhood is an important risk factor, both immediately and for later life even when stress has
dissipated.

that cloning the human genome would yield a sig-
nificant number of new genes with novel functions,
permitting a clarification of the causes of CNS dysfunc-
tion in psychiatric disorders and offering innovative
targets for improved therapy. With hindsight, this
proved naive. The number of protein-coding genes
(about 21 000, or 3% of the genome) in humans scar-
cely differs from many ‘simpler species’ and complex-
ity is derived more from epigenetic and other modes of
transcriptional control, including regulatory and struc-
tural roles of many classes of protein non-coding RNA,
and the operation of genes in networks (Millan, 2006;
Cardon et al., 2009; Manolio et al., 2009; Penrod
et al., 2011). Moreover, studies of the human genome
have not yet led to any radically new insights
into the causes of depression nor unveiled a palette
of new sites for its treatment. Further, although it
was anticipated that combinatorial chemistry and
high-throughput screening would ‘revolutionize’ the
detection of innovative drugs at established and
novel targets (the ‘magic of high numbers’), this did
not materialize, not least since the procedures used
were rather simplistic and mainly aimed at identifi-
cation of highly selective ligands (Brady et al., 2009;
Campbell, 2010). In addition, despite impressive con-
ceptual foundations and extensive experimental data,
many selective antidepressants advanced into patients
failed to demonstrate efficacy sufficient for registration
(Millan, 2006, 2009; Miller, 2010). Finally, reflecting an
understandable desire to explore novel therapeutic
mechanisms, monoaminergic substrates were largely
neglected (‘from monoamines to genomics’) despite
the fact that there remained (and still remains)
scope for their potentially more effective exploitation
when coupled to other, non-monoaminergic sites
(see below).
1014 M. J. Millan

a Gene-rush: patents taken on many genes

REALITY
b Genetic,
developmental
(difficult, long, costly)
and environmental factors
b Many interacting genes implicated
c Low success rate
Functiond

Human ‘Druggable Depressionb Selective

Development
genome genea’ related protein Antidep.

SNP, man/KO, mice

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Combinatorial chemistry/HTSc:
Hit → Lead
d Many (pleiotropy)
d Beneficial and deleterious
d Challenging to establish
‘RATIONAL’
Fig. 3. The rational and reality of drug discovery for improved antidepressant (antidep) agents. Upon sequencing of the
human genome, it was hoped that its ‘mining’ would rapidly identify many new potential targets for treating depression and
other poorly controlled disorders. Unfortunately, as outlined in Figs. 1 and 2, depression is complex both as regards its causes
and its characteristics, so the simplistic idea of finding a dysfunctional gene [by, for example, single nucleotide polymorphism
(SNP) studies in man and gene knock-out (KO) techniques in mice] has proven elusive. Moreover, much of the genomic
signal can be overwritten by epigenetic processes, many genes reciprocally interact with others to modify their mutual effects
(epistasis), many have several functions – both favourable and detrimental – and gene functions are in general hard to
establish. In addition, many genes were locked up in patents at the time of cloning the genome so ironically lost to
research. Finally, ‘rational’ drug discovery based on high throughput screening (HTS) techniques coupled to combinatorial
chemistry did not prove very effective in the search for leads for clinically effective antideps. The ‘reality’ is that
genome-driven rational drug discovery remains very challenging, time-consuming and expensive, just like other modes of
drug discovery.

From highly selective to multi-modal strategies for
the improved treatment of depression
Ironically, then, the disavowal of monoaminergic mech-
anisms as obsolete in the search for improved treat-
ment was not followed by the anticipated emergence
of novel drugs aimed at hitherto unknown ‘genomic’
targets, but rather by a frustrating succession of incon-
clusive clinical trials with selective ligands acting at
non-monoaminergic sites, such as neurokinin1 (NK1)
and corticotrophin releasing factor (CRF1) receptors
(Quartara et al., 2009; Kehne and Cain, 2010). This
led to the inference that these mechanisms might actu-
ally be red herrings generated by misleading pre-
clinical observations. However, these therapeutic
trials were performed in far more challenging circum-
stances (not least, a high response to placebo) than pre-
decessor substances such as selective inhibitors of 5-HT
reuptake (SSRIs) and the assumption of a lack of
clinical relevance may be an over-interpretation. The
conviction remains that NK1 receptors, CRF1 receptors
and certain other targets unsuccessfully evaluated in
the clinic, as well as targets where clinical data are
awaited, such as metabotropic glutamate (mGluR) 2
receptors (Bespalov et al., 2008; Campo et al., 2011),
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptors (Farley et al., 2010; Nations et al.,
2012) and 5-HT7 receptors (Mnie-Filali et al., 2011),
may well be of therapeutic relevance. However, they
will best be exploited in a more effective multi-modal
manner for the treatment of depression; that is, either
in association with ‘alternative’ (non-medication) treat-
ments or integrated with complementary mechanisms
in polypharmacy and multi-target drugs (Fig. 4).
In addition to negative findings with highly selec-
tive agents in clinical trials, several arguments support
the assertion that multi-modal pharmacotherapy may
be more effective. First, despite their improved toler-
ance, SSRIs are no more effective than tricyclic agents.
While 5-HT/noradrenaline (NA) reuptake inhibitors
 Complementary strategies for improving the treatment of depression 1015

Co-administration: ‘true’ polypharmacy

a e.g. Citalopram, SSRI a

+ NK 1 Ant b 2 drugs in 2
Fluoxetine separate pills
b e.g. GR205,171,
‘Hybrid’
MK869

NK 1 Ant 2 drugs in one and

SSRI NK 1 Ant the same pill
SSRI

SSRI: ↑Synaptic
levels of 5-HT Multi-target

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1 drug possessing
NK 1 Ant/ both properties
NK1 antagonist: blockade
SSRI – in one pill
of Substance P overdrive

Selectively Multi- S41744 Dual- Designed Synonyms

Non-selective functional acting bipotent

Fig. 4. Basic principles of polypharmacy as compared to multi-target drugs as illustrated by inhibition of 5-HT reuptake and
blockade of neurokinin 1 (NK1) receptors. 5-HT reuptake inhibitors (SSRIs) are designed to elevate extracellular levels of
5-HT, while NK1 antagonists (Ant) are thought to counter the deleterious effects of Substance P and also to potentiate the
actions of SSRIs. These complementary and synergistic mechanisms of action can be united either by genuine ‘polypharmacy’
(co-administration of two selective drugs), multi-target pharmacotherapy, whereby the two pharmacological actions are
united in one chemical structure, or a ‘hybrid’ solution, whereby two separate drugs are mixed into one pill. The choice of
solution will be influenced by many factors, including drug availability for polypharmacy and whether structure–activity
relationships actually allow the two actions to be incorporated into one single, developable structure.

appear to globally be more effective than SSRIs (with
the possible exception of escitalopram – see below),
tricyclics are still recognized as the most effective of
antidepressants, likely reflecting their interaction not
only with 5-HT and/or NA transporters, but also
other sites such as 5-HT2A, 5-HT2C, 5-HT3, 5-HT7 and
α2-ARs. Furthermore, they exert a broad pattern of
effects across various cerebral loci (Millan, 2006;
Gillman, 2007; Sartorius et al., 2007; Cipriani et al.,
2009). Second, antidepressant augmentation strategies
are not simply a case of more of the same, but rather
of something else on top; that is, the incorporation of
additional, mechanistically distinct actions. For tri-
cyclics themselves, efficacy can be reinforced by
adjunctive treatment with lithium or (although seldom
employed) the thyroid hormones, triiodothyronine and
thyroxine, while second generation antipsychotics such
as aripiprazole, quetiapine and olanzapine amplify
the efficacy of SSRIs, reflecting their interaction with
a variety of other cellular substrates (McIntyre and
Moral, 2006; Crossley and Bauer, 2007; Connolly and
Thase, 2011; Al-Harbi, 2012). Other mechanisms of
SSRI potentiation likewise act at sites very different
from 5-HT transporters – see below. Third, both precli-
nical and clinical evidence suggests that electroconvul-
sive therapy as well as deep-brain and transcranial
stimulation techniques for treatment of medication-
refractory depression act via recruitment of broad-
based neural circuits and multiple cellular and
neurochemical substrates. Although fewer mechanistic
data are available, the same seems to hold for sleep
deprivation, which is rapidly effective in the relief of
depressed states (Eitan and Lerer, 2006; Millan, 2006;
Hemmeter et al., 2010; Bunney and Bunney, 2012;
Del’Osso et al., 2012; Lee et al., 2012; Minichino
et al., 2012).
While multi-target strategies are primarily con-
ceived for promoting efficacy and accelerating onset
of efficacy, they may even be better tolerated
(Table 1). In this regard, older tricyclics display inter-
actions at sites other than those mediating positive
actions (see above), but the goal is to build what has
1016 M. J. Millan
been termed ‘selectively non-selective’ agents directed
against a chosen palette of targets transducing ben-
eficial properties while eliminating interactions with
sites eliciting side-effects (Hopkins et al., 2006; Millan,
2006; Morphy and Rankovic, 2006, 2007; Zimmermann
et al., 2007; Wong et al., 2010; Peters et al., 2012).
Thus, although the risk of additional side-effects
should not be ignored, judiciously designed multi-
modal strategies may even possess improved toler-
ance. This is illustrated by antipsychotics possessing
α2-AR and/or 5-HT2A antagonist properties to blunt
induction of extrapyramidal actions and by the intro-
duction of 5-HT2C antagonist properties into anti-
depressants to oppose side-effects of excessive 5-HT,
such as sexual dysfunction and nervousness at the
onset of treatment (Dekeyne et al., 2000, 2012; Millan,
2006; Meltzer et al., 2012).
Finally, as summarized in Table 1 and exhaustively
discussed elsewhere (Millan, 2006), multi-modal treat-
ments with complementary mechanisms of action
should afford additional scope for the control of a
greater range of symptoms accompanying depression
(Fig. 1) and for the more effective alleviation of de-
pression co-morbid with other conditions, such as
anxiety disorders or Parkinson’s disease.
Complementary mechanisms of antidepressant
action: polypharmacy and multi-target exploitation
It remains unclear to what extent the combination
of established antidepressants at effective doses
will guarantee a better patient response and, in certain
cases, a lack of further improvement may reflect redun-
dancy in the neuronal substrates mediating their
actions (Millan, 2006; Blier et al., 2010; Bobo et al.,
2011; Connolly and Thase, 2011; Rush et al., 2011;
Al-Harbi, 2012; Rocha et al., 2012). Although there
are examples where remission is indeed augmented,
the most appealing feature of multi-modal strategies
is the generation of novel antidepressant mechanisms
that cannot otherwise be reproduced by the use of
existing agents.
Melatonin MT1/MT2 receptors have attracted much
interest in recent years in view of their role in control-
ling sleep and circadian rhythms, which are often per-
turbed in depression (Bunney and Potkin, 2008). The
most compelling example of an innovative multi-target
agent is currently agomelatine, a melatonin MT1/MT2
agonist and 5-HT2C antagonist, which has been clini-
cally shown to relieve depressed states upon both
short and long-term administration, and which also
possesses anxiolytic properties (De Bodinat et al.,
2010; Kasper et al., 2010; Srinivasan et al., 2011;
Catena-Dell’Osso et al., 2012; Stein et al., 2012).
Inasmuch as melatonin is ineffective alone in the relief
of depression and selective 5-HT2C antagonists are
unavailable for therapeutic exploration, this profile is
unique and cannot be mimicked by polypharmacy.
Nonetheless, motivated by studies of enhanced neuro-
genesis in rodents, a mixture of melatonin and buspir-
one (a 5-HT1A partial agonist) is in development and it
recently yielded positive findings in a controlled trial
(Fava et al., 2012).
In contrast to agomelatine, as depicted in Table 2,
the majority of multi-modal concepts for improving
treatment of depression have been articulated around
inhibition of 5-HT reuptake. That is, in the case of poly-
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pharmacy, adjunctive administration with SSRIs of a
second agent with a contrasting mechanism of action
and, as regards multi-target agents, the coupling to
5-HT reuptake inhibition of a further and different
pharmacological action. While the diversity of ideas
under experimental and/or clinical exploration cannot
be comprehensively discussed herein (Millan, 2006,
2009; Butler and Meegan, 2008; Carvalho et al., 2008;
Shelton et al., 2010; Wong et al., 2010; Schlaepfer
et al., 2012; Al-Harbi, 2012; Connolly and Thase,
2012), the following observations are of particular
interest within the framework of comparisons between
multi-target and polypharmaceutical strategies.
Several monoaminergic (‘SSRI-plus’) strategies have
been based around suppressing reuptake of NA and/or
DA as well as 5-HT, blocking the negative feedback of
monoamines at presynaptic sites inhibitory to release
and/or blocking 5-HT2C receptors which, via recruit-
ment of GABAergic interneurons, restrain monoami-
nergic transmission (Millan et al., 2000a, b, 2009;
Millan, 2006; Sartorius et al., 2007). In principle, these
goals can be attained by either drug association or by
the use of equivalent multi-target drugs. Currently,
5-HT/NA reuptake inhibitors (SNRIs) such as venlafax-
ine and duloxetine are generally considered somewhat
more effective than SSRIs (Montgomery et al., 2007;
Cipriani et al., 2009; Papakostas, 2010). One exception
may be the ‘SSRI’, escitalopram, possibly reflecting
its distinctive actions at allosteric sites on 5-HT trans-
porters as well as its binding to a high affinity site on
NA transporters (Nguyen et al., 2013; Plenge et al.,
2012; Zhong et al., 2012). Not surprisingly, SNRIs are
prescribed in preference to the association of a NA
reuptake inhibitor with a SSRI. The DA reuptake inhi-
bitor, buspirone, appears to be beneficial on top of
SSRIs (Trivedi et al., 2006; Connolly and Thase, 2011)
but, rather than dual-acting drugs recognizing 5-HT
and DA transporters, there has been considerable inter-
est in triple monoamine reuptake inhibitors – although
Table 2. Strategies for enhancement of SSRI efficacy based upon augmentation with a complementary mechanism of action, either as pharmacotherapy or as an
equivalent multi-target agent

Primary neuronal Clinically tested Multi-target

Mechanism of action substrates Potential advantages Potential disadvantages agents equivalent References

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NA reuptake inhibition
NA ext Delay CV side-effects Reboxetine VenlafaxineL Millan et al., 2001a, b;

DA ext (FCX) Motor retardation Desipramine DuloxetineL Lopez-Munoz et al., 2007;
(
efficacy) DesvenlafaxineL Sartorius et al., 2007
MilnacipranL
DA/NA reuptake
NA ext Delay CV tolerance Bupropion Amitifadine II Trivedi et al., 2006;
inhibition
DA ext Motor retardation Abuse potential (
efficacy) Tesofensine, II(D) Aluisio et al., 2008; Calderone
Sexual dysfunction Psychosis risk JNJ-7925476PC et al., 2010;
(Parkinson’s disease, Stimulation-sensitization JZAD-IV-22PC Tran et al., 2012
obesity)
5-HT1A antagonist
5-HT ext Delay Interference with (-)-Pindolol SB649,915PC Starr et al., 2007; Watson

ACh ext (FCX, hipp)
Cognition (variable
WAY-211,612PC

Complementary strategies for improving the treatment of depression

(autoreceptor) post-synaptic and Dawson, 2007;
5-HT1A/1B antagonist
Sleep antidepressant properties. efficacy/delay) Beyer et al., 2012
(autoreceptor) (Alzheimer’s disease)
5-HT1A partial agonist
NA ext Anxiety Poor tolerance Buspirone VilazodoneL Dawson and Bromidge, 2007;

DA ext (FCX)
Cognition Nausea (little
efficacy) OPC14523PC De Paulis, 2007; Frampton,

ACh (FCX, hipp) Sexual dysfunction Nervousness 2011
(GAD)
5-HT2C antagonist
NA/DA ext (FCX, hipp). Anxiety Weight gain Ritanserin TrazodoneL Millan, 2005; Cremers et al.,
Control of stress responsive Sexual dysfunction Motor stimulation Mirtazapine Lu-AA24530 2007; Blier et al., 2010
limbic circuits
Sleep (
efficacy)
α2-AR antagonist
NA ext
Cognition, CV tolerance Yohimbine S35966PC Cordi et al., 2001; Sanacora et al.,
(autoreceptor)
DA/ACh (FCX) Sexual dysfunction Endocrine side-effects (
efficacy/delay) R226,161PC 2004; Andres et al., 2007

ACh (FCX, hipp) Parkinson’s disease.
Dopamine Recruitment of mesolimbic Anhedonia Nausea Pramipexole WS-50030 Rogoz and Skuza, 2006;
D2 agonist reward systems
Reward Abuse potential OPC34712 Brennan et al., 2010
(Parkinson’s disease) CV side-effects (
efficacy?)
Psychosis
Histamine
Hist/ACh ext
Cognition
Wakefulness Not described JNJ-28583847PC Barbier et al., 2007;
H3 antagonist (FCX, hipp)
Attention Stocking et al., 2010

NA/DA ext (FCX) (Parkinson’s,
Alzheimer’s disease,
EDSD, narcolepsy)
Acetylcholinesterase
ACh ext
Cognition Poor tolerance Not described RS-1259PC Abe et al., 2003
inhibitor (degradation) (Alzheimer’s disease)

1017
Table 2 (cont.)

1018 M. J. Millan
Primary neuronal Clinically tested Multi-target

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Mechanism of action substrates Potential advantages Potential disadvantages agents equivalent References

Nicotinic Limbic actions: precise Delay Unclear (S)-Mecamylamine Not described George et al., 2008; Bacher et al.,
(α4/β2 and α3β4>α7) neuronal substrates (TC-5224), IIID 2009; Philip et al., 2012
antagonist unclear (variable
efficacy)
AMPA
BDNF
Cognition Overstimulation in Not described LY392,098PC Li et al., 2003; Farley et al., 2010;
positive allosteric
Neurogenesis
Attention presence of high LY404,187PC Nations et al., 2012
modulator
Neural plasticity Circadian glutamate levels?
synchronization
(ADHD)
NMDA
5-HT/DA ext Neurotoxic damage Psychosis AZD6765 Not described Aan het Rot et al., 2012; Bunney
channel blocker
BDNF and Delay Motor disruption (Efficacy study and Bunney, 2012; Ibrahim

mTOR/GSK-3β (Parkinson’s disease) Cognitive deficits underway) et al., 2012; Zarate et al., 2013

AMPA signalling
Neurokinin1
5-HT ext (FCX, hipp) Delay Unclear Vestipitant, IID GSK424,887PC Gobert et al., 2008; Millan et al.,
antagonist
NA/DA (FCX) Anxiety Results not disclosed S41744PC 2010; Quartara et al. 2009; Ratti

BDNF Pain and nausea et al., 2011
(GAD, OCD)
CRF1 HPA overdrive and Anxiety Basal corticosterone (R121,919, IID, Several patents Millan, 2009; Kehne and Cain,
antagonist limbic over-activation Stress release GR561,679,IID) 2010
in response to stress Inflammation Interaction studies
(GAD, inflammatory probably not done?
bowel disorder)
Glucocorticoid Neurotoxic and ‘amnesic’ Neuroprotective Baseline HPA activity. Mifepristone, IID? Not described? Shatzberg and Lindley, 2006;
antagonist/synthesis actions of excess stress Psychosis Not desirable for atypical/ Metapyrone, IID? Gallagher et al., 2008
inhibitor corticosterone.
Cognition seasonal depression (variable
efficacy)

AMPA expression
COX 2 inhibition*
NA/5-HT ext. Anti-inflammatory Gastrointestinal side-effects. Celecoxib Not described Müller et al., 2006, 2010; Abbasi
Pro-inflammatory Analgesic.
Risk heart attacks and Naproxen et al., 2012; Johansson et al.,
mediators like IL6 Adjunctive treatment stroke (?). 2012
of schizophrenia?
Melanocortin Stress-induced activation Anxiety Metabolic, CV and Not evaluated MCL-0042PC Chaki et al., 2005; Chaki and
4 agonist of HPA, limbic actions HPA overdrive endocrine side-effects Okubo, 2007
Oestrogen receptor
NA/5-HT ext.
Cognition Endocrine and oncological 17 β-oestradiol Not described Hughes et al., 2008;
β agonist Modulation GABA Neuroprotection side-effects (
efficacy) Molinda-Hernandez and
transmission. Tellez-Alcantara 2011
P21-kinase and ERK
recruitment.
 Complementary strategies for improving the treatment of depression 1019

none has as yet reached the market and any decisive

are depicted, as well as use for treatment of co-morbid disorders such as generalized anxiety (GAD), attention-deficit hyperactivity (ADHD) and obsessive–compulsive (OCD)
inhibition alone. In certain cases, no comparable multi-target agent has been described. Further, in most cases – although experimentally characterized – clinical data for multi-target

example, essentially all antidepressant mechanisms favour limbic brain-derived neurotrophic factor (BDNF) expression and neurogenesis and induce structural changes in dendritic
depression. Rather, for polypharmacy, it focuses on association with selective serotonin reuptake inhibitors (SSRIs) since this accords with current guidelines, clinical trials and real-
This is not an exhaustive inventory of all drugs to date tested in association with antidepressants, nor a compendium of every multi-target evaluated in experimental models of

world practice. By analogy, the table depicts comparable SRI-based multi-target concepts where experimental data suggest that the mechanism presents benefits vs. 5-HT reuptake

agents are lacking. Certain augmenting agents have multiple mechanisms of action, such as second-generation antipsychotics but also, for example, mirtazapine. Neuronal substrates
indicated are not exhaustive, with a focus on primary drug actions and how they influence extracellular (ext) monoamines in frontal cortex (FCX) and hippocampus (hipp). For
DA, Dopamine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; PC, preclinical; L, launched (approved); D, discontinued (note, actual drug status not always

plasticity, so this is not generally indicated (Duman and Voleti, 2011; Autry and Monteggia, 2012). Potential advantages in terms of control of symptoms other than depressed mood
* Celecoxib also tested in association with the noradrenaline (NA) reuptake inhibitor, reboxetine. Olanzapine has only been tested in association with fluoxetine (Symbax®).
Goodwin et al., 2007; Carvalho
et al., 2008; Connolly and gains in efficacy over SSRIs (or SNRIs) remains to be
demonstrated (Skolnick and Basile, 2006; Aluisio
et al., 2008; Millan, 2009; Tran et al., 2012).
In an effort to mimic the 5-HT1A (dendritic)
and 5-HT1B (terminal) autoreceptor desensitization
Thase, 2011

thought to underlie the progressive onset of anti-

depressant efficacy for SSRIs, both polypharmaceutical
obvious); CV, cardiovascular; EDSD, excessive daytime sleep disorder; HPA, hypothalamo-pituitary axis; COX 2, cyclooxygenase-2; PAG, partial agonist.

and multi-drug pistes have been pursued. However,

despite a plethora of preclinical findings and promis-

For further information see Carvalho et al., 2006; Millan, 2006, 2009; Shelton et al., 2010; Connolly and Thase, 2011, 2012; Schlaepfer et al., 2012).
ing clinical evidence for an accelerated onset of action,
Not described

gains in efficacy have proven inconsistent upon co-

administration of the 5-HT1A antagonist, (−)-pindolol,
with SSRIs (Artigas et al., 2006; Dawson and

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Bromidge, 2008; Connolly and Thase, 2012). This
may reflect its residual intrinsic efficacy at autorecep-
tors and, by analogy, it has proven difficult to link
pure antagonist properties at 5-HT1A and/or autorecep-
AripiprazoleL
OlanzapineL

tors to suppression of 5-HT reuptake, although several

QuetiapineL

(
efficacy)

mixed ligands have now been documented (Millan,

2006, 2009; Starr et al., 2007; Watson and Dawson,
2007; Beyer et al., 2009). Rather paradoxically, then,
notwithstanding: (1) studies in rats indicating that
5-HT1A partial agonists blunt SSRI-induced increases
(akathesia) side-effects
CV, metabolic, motor

in 5-HT levels (Gobert et al., 1999); (2) less than scintil-

lating findings with adjunctive use of the 5-HT1A par-
tial agonist, buspirone, in depression (Millan, 2006;
Weight gain

Connolly and Thase, 2011), it is the mixed 5-HT1A par-

tial agonist/SSRI, vilazodone, that has been granted
approval for treatment of depression (De Paulis,
disorders. Some mechanisms are especially promising for accelerating onset.

2007; Dawson and Bromidge, 2008; Frampton, 2011;

Reed et al., 2012). Rather than 5-HT, alterations in
levels of other transmitters such as acetylcholine, NA
(schizophrenia,

and DA may account for any potential advantages of

OCD, GAD)

vilazodone over SSRIs (Millan et al., 1994; Millan,

Anxiety

2006; Watson and Dawson, 2007).

While partial agonism at 5-HT1A receptors favours
NA and DA release in the frontal cortex (Millan et al.,
possibly glutamate (FCX)

2000a, b), their elevation can be more robustly and

NA/DA/Ach ext and

reproducibly achieved by blockade of 5-HT2C receptors.

The induction of NA and DA release marries well with
Lu-AA24530 is also a 5-HT3 antagonist.

inhibition of 5-HT reuptake and 5-HT2C antagonism

affords additional anxiolytic and sleep-enhancing
GSK-3β

properties while opposing the sexual dysfunction pro-

voked by excessive levels of 5-HT (Dekeyne et al., 2000,
2008; Millan, 2005; Quesseveur et al., 2012). 5-HT2C
antagonism is inherent to many tricyclic agents as
(5-HT2A/2C antagonist,

well as to trazodone (of which a new long-release

5-HT1A PAG, etc)
Second generation

form is becoming available), but these drugs all have

antipsychotics

other undesirable actions like histamine H1 receptor

and α1-AR blockade (Millan, 2006; Gillman, 2007;
Stahl, 2009). Hence, dual 5-HT2C antagonists/SSRIs
shorn of detrimental actions still appear attractive;
1020 M. J. Millan
in particular, since selective 5-HT2C antagonists for
association with SSRIs are not clinically available and
since mirtazapine, which potentiates the actions of
SSRIs, shares the potent H1 and α1-AR antagonist
actions of tricyclics (Blier et al., 2010; Connolly and
Thase, 2011; Watanabe et al., 2011). More favourably,
mirtazapine antagonizes α2-ARs inhibitory to mono-
aminergic transmission and, mirroring preclinical
work, clinical data suggest that α2-AR blockade has-
tens and intensifies antidepressant properties elicited
by monoamine reuptake inhibition (Sanacora et al.,
2004). Correspondingly, mixed α2-AR/SSRIs and
α2-AR/SNRIs, in which negative feedback at α2-ARs
autoreceptors is interrupted, display powerful anti-
depressant profiles in rodents (Cordi et al., 2001;
Andres et al., 2007; Millan, 2009; Serres et al., 2012).
It is frustrating that these agents have not been author-
ized for the control of treatment-resistant depression,
primarily due to concerns of untoward cardiovascular
side-effects. Inasmuch as the above lines evoked the
interest of associating 5-HT2C and α-AR antagonism
with SSRI properties, it is of note that dual 5-HT2C/
α2-AR antagonists lacking the potential side-effects of
mirtazapine were recently described, although their
clinical effects await characterization (Dekeyne et al.,
2012; Millan et al., 2012).
All the above-evoked monoaminergic strategies
would be expected to reinforce dopaminergic trans-
mission in the frontal cortex and hence to counter
depressed mood and impairment of cognitive domains
such as executive function and working memory, but
only triple reuptake inhibitors should elevate extra-
cellular levels of DA in limbic structures (Millan et al.,
2000a, b, 2012; Skolnick and Basile, 2006; Aluisio et al.,
2008; Millan, 2009; Tran et al., 2012). Mesolimbic
actions counter both motor retardation and defective
mechanisms of reward, of particular relevance to mel-
ancholic depression and depression co-morbid with
Parkinson’s disease. An alternative approach would
be to directly recruit post-synaptic D2 receptors by
use of drugs possessing agonist properties and both
polypharmaceutical and multi-target approaches
have been described in this regard but, perhaps in
view of numerous issues of tolerance, little real pro-
gress has been made and this line of research does
not appear particularly inspiring (Rogoz and Skuza,
2006; Brennan et al., 2010; Al-Harbi, 2012).
Positive phase II efficacy studies associating the
nicotinic antagonist, (S)-mecamylamine, with SSRIs
led to much excitement, but more recent phase III
investigations were something of an anti-climax, lead-
ing to termination of its development in depression.
The precise reasons underlying inadequate and/or
inconsistent clinical efficacy remain to be elucidated,
but it is worth noting evidence that both blockade
and/or stimulation of α4β2 nicotinic sites in rodents
positively influences depressed mood in rodents,
while the molecular substrates for putative anti-
depressant actions of (S)-mecamylamine warrant fur-
ther investigation (Millan, 2006; George et al., 2008;
Bacher et al., 2009; Andreasen et al., 2011; Philip
et al., 2012). Regrettably, although there is considerable
cross-talk amongst nicotinic ligands (certain of which
interact with 5-HT transporters) and SSRIs (several of
which recognize nicotinic receptor subtypes, Millan,
2006), these structure-activity insights do not appear
to been systematically exploited for generation of
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multi-target nicotinic agents of potentially more robust
antidepressant efficacy than either class of agent
alone – or, indeed, their combination.
Another mechanism worth highlighting is
N-methyl-D-aspartate (NMDA) receptor blockade in-
asmuch as a suite of recent studies has shown that
the NMDA receptor channel blocker, ketamine, at sub-
anaesthetic doses, elicits robust and rapid antidepress-
ant properties (Aan Het Rot et al., 2012; Bunney and
Bunney, 2012). NMDA receptor antagonists are
known to recruit frontocortical and subcortical mono-
aminergic pathways in rodents. In addition, AMPA
receptors and the modulator of mRNA translation
and neuroplasticity, mammalian target of rapamycin
(mTOR) – which is deficient in depression (Jernigan
et al., 2011) – are implicated in the actions of ketamine
(Maeng et al., 2008; Li et al., 2010; Aan Het Rot et al.,
2012). To date, the combined administration of keta-
mine with SSRIs has not been documented, but a clini-
cal evaluation of this question is currently underway
with a further, low affinity non-competitive antagonist
at NMDA receptors, AZD6765 (Connolly and Thase,
2012). The integration of 5-HT transporter and NMDA
channel blocking activity into a single drug seems unli-
kely but an alternative approach may be to combine
SSRI activity with selective blockade of the NR2B
receptor subunit in a single drug since: (1) NMDA re-
ceptors containing this subunit seem to be the major
class involved in the control of mood and depressed
states; (2) selective legends at NR2B subunits are
under evaluation for potential antidepressant proper-
ties in animals and man (Aan Het Rot et al., 2012;
Ibrahim et al., 2012). The major concerns for the
broader use of this concept, whether as drug combi-
nations or multi-target agents, is the induction of psy-
chosis and blunting of efficacy upon prolonged
administration (Aan Het Rot et al., 2012; Mathew,
2012). In any event, the actions of ketamine may pro-
vide insights into molecular substrates permitting
 Complementary strategies for improving the treatment of depression
more rapid control of depression by other, more tract-
able strategies. Interestingly, mGluR2 antagonists,
which likewise possess potential antidepressant prop-
erties, mimic ketamine in recruiting mTOR in the fron-
tal cortex (Dwyer et al., 2012). Note, however, the
caveat that: (1) NMDA receptor blockade is
pro-psychotic; (2) mGluR2 receptors are deficient in
schizophrenia and antagonists possess potential pro-
psychotic properties (Nicoletti et al., 2011); while (3)
over-expression of mTOR in the frontal cortex accounts
for certain cognitive deficits of both schizophrenia and
neurodevelopmental disorders like Fragile X (Meffre
et al., 2012; Millan, 2013).
In view of the impressive pedigree of data sup-
porting their roles in the response to stress, the control
of mood and the induction of depressed states, two
of the most conspicuous failures to achieve authoriz-
ation (so far) are CRF1 and NK1 receptor antagonists
(Quartara et al., 2009; Kehne and Cain, 2010; Ratti
et al., 2011). As pointed out above, the core problem
may be that these mechanisms are not sufficient for
robust efficacy alone and require integration with
other actions. While compounds inhibiting 5-HT trans-
port and blocking CRF1 receptors are feasible and
active in vivo (M.J. Millan, unpublished observations),
appropriate pharmacokinetic parameters remain elu-
sive. Rather oddly, the effects of co-administration of
CRF1 antagonists and SSRIs in humans do not appear
to have been investigated despite the inherent logic
underpinning such studies, especially in psychotic de-
pression and mixed depression/anxiety. Today, CRF1
antagonists are mainly being pursued for anxiety dis-
orders and irritable bowel syndrome (Millan, 2009;
Kehne and Cain, 2010). As for NK1 receptors, a high-
profile report of antidepressant actions of the selective
NK1 antagonist, aprepitant, had considerable re-
sonance but these actions could not be consistently
confirmed by succeeding studies, even at doses
shown to saturate NK1 receptors – possibly due to an
intervening amplification of the response to placebo
in the course of clinical trials, rather than any ostensi-
ble loss of efficacy (Millan, 2009; Quartara et al.,
2009; Ratti et al., 2011). Although this remains to be
clarified, other selective NK1 antagonists have hardly
fared better so they are now employed mainly for con-
trol of chemotherapy-evoked nausea and vomiting
arising in the treatment of cancer – as part of a multi-
drug treatment package designed to enhance efficacy
(Ratti et al., 2011; Dos Santos et al., 2012). Mixed
NK1 antagonists/SSRIs have been documented in pre-
clinical studies, where they manifest the positive attri-
butes of each of these class of compounds, and their
profiles resemble those of combined injection of
1021
selective NK1 antagonists and SSRIs, although data
from humans are awaited (Brocco et al., 2008; Gobert
et al., 2009; Millan et al., 2010). Further, mirroring
findings with concomitant administration of selective
NK1 antagonists and SSRIs in rodents, vestipitant
has been under development as polypharmacy with
SSRIs for the treatment of major depression (Millan,
2009). To date, clinical data have not been disclosed,
the status of this project is uncertain and it may have
been abandoned for strategic reasons related to factors
other than clinical efficacy. The theoretical and exper-
imental arguments supporting co-joint blockade of
NK1 receptors and 5-HT reuptake for treatment of
depression are compelling. Both classes of drug are
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safe and well studied, so this still remains an ideal plat-
form for a structured comparison of multi-target drugs
vs. polypharmacy for the ameliorated treatment of
depression.
Contrasting with NK1 antagonists, there is abundant
support for the use of second-generation antipsycho-
tics as adjuncts to SSRIs in the control of treatment-
resistant depression and data are particularly solid
for aripiprazole and olanzapine (both authorized),
although the latter was evaluated only with fluoxetine
(Connolly and Thase, 2011). The precise mechanisms
involved in the potentiation of SSRI efficacy remain
to be defined, but a role for partial agonist properties
at 5-HT1A receptors, as well as blockade of 5-HT2A/2C
receptors and α2-ARs seems probable. These mechan-
isms were evoked above and blockade of 5-HT7 sites
may likewise be implicated inasmuch as their inacti-
vation is associated with antidepressant properties in
rodents – although clinical data for 5-HT7 antagonists
alone and together with SSRIs are not yet available
(Mnie-Filali et al., 2011). Partly in view of the complex
pharmacological profiles of second-generation antipsy-
chotics, but also in light of the robust results attained
upon their association with SSRIs, there have been no
real attempts to reproduce this profile with a multi-
target strategy. Note that the major metabolite of que-
tiapine possesses affinity for NA transporters and
ziprasidone for 5-HT transporters, suggesting that
such multi-target compounds would be feasible from
a chemical perspective (McIntyre et al., 2007; Millan,
2009).
Depressive states in humans and experimental
models of depression in rodents are associated
with inflammation and elevations in levels of inter-
leukins. These observations have prompted studies
of the potential adjunctive use of inhibitors of
cyclooxygenase-2 like Celecoxib, both with SSRIs and
with the NA reuptake inhibitor, reboxetine (Müller
et al., 2006; Guo et al., 2009, 2009; Muller, 2010;
1022 M. J. Millan
Capuron and Miller, 2011; Abbasi et al., 2012; Leonard
and Maes, 2012). Despite promising data, and preclini-
cal studies suggesting that Celecoxib acts both by anti-
inflammatory mechanisms and via an influence on
monoaminergic transmission (Muller, 2010;
Johansson et al., 2012; Krause et al., 2012; Leonard
and Maes, 2012), clinical observations remain limited.
Further, not all data support benefits of associating
anti-inflammatory agents with SSRIs (Warner-
Schmidt et al., 2011). Accordingly, there is a need for
further evaluation of this intriguing concept in
patients, yet studies have – not unexpectedly – been
restrained by questions concerning the cardiovascular
safety of this class of drugs.
To date, no mixed SSRI/cyclooxygenase 2 inhibitors
are known and, despite the above indications that
many other classes of multi-target drug incorporating
5-HT reuptake can be designed, a number of augmen-
tation mechanisms would be challenging to incor-
porate into a single chemical structure. For example,
as regards the actions of thyroid hormones (tri-
iodothyronine and thyroxine), inhibitors of corticoster-
one synthesis, glucocorticoid 2 receptor antagonists
and agonists at oestrogen β receptors (Millan, 2006;
Carvalho et al., 2008; Dhir and Kulkarni, 2008;
Gallagher et al., 2008; Hughes et al., 2008; Schatzberg
and Lindley, 2008; Molina-Hernandez and Tellez-
Alcantara, 2011; Connolly and Thase, 2012). Note,
however, that thyroid hormones are little used today
and that data for oestrogen agonists (mostly tested
in peri-menopausal women) remain preliminary.
Moreover, despite considerable efforts and a strong
rationale, clinical studies with mefepristone (a gluco-
corticoid antagonist) and metyrapone (an inhibitor of
glucocorticoid synthesis) – which should protect cells
from detrimental effects of excessive stress-induced
corticosterone release and favour cognitive perform-
ance – have not been brought to fruition, even in
patients showing psychotic depression, where the
hypothalamic-pituitary axis activity is disinhibited
(Millan, 2006; Gallagher et al., 2008; Schatzberg and
Lindley, 2008).
Other examples (not depicted in Table 2) of absent
multi-target lookalikes for a clinically tested SSRI
augmentation strategy include instances where the
drug added on: (1) has a poorly defined mechanism;
(2) acts itself in a multi-target fashion; (3) the associ-
ation has yielded ambivalent experimental and clinical
data providing only a modest incentive to launch a dis-
covery programme for an equivalent multi-target
agent. Anticonvulsants such as riluzole and lamotri-
gine illustrate this point, as does the ‘stimulant’
methylphenidate (Carvalho et al., 2008; Connolly and
Thase, 2011, 2012). Another prominent example is
modafinil (and its active isomer, armodafanil) which
exerts a complex pattern of actions via monoaminergic,
glutamatergic and orexinergic mechanisms. Modafinil
revealed modest and possibly non-sustained im-
provements in mood upon addition to SSRIs and, not
surprisingly in view of its wake-promoting character-
istics, reduced fatigue (Minzenberg and Carter, 2008;
Shelton et al., 2010; Connolly and Thase, 2012;
Millan, 2013).
Finally, the most striking feature of Table 2 is just
how few drug combinations and/or comparable multi-
target agents have been formally authorized and
become available to patients despite an abundance of
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auspicious preclinical data, compelling hypotheses
and at least small-scale clinical testing. Clearly, there
is considerable scope for further work to clinically vali-
date these and other (see below) multi-modal concepts
for the improved treatment of depression.
Polypharmacy and multi-target agents: similarities
and differences, advantages and disadvantages
As outlined above, theoretical considerations, exper-
imental studies and, in several instances, clinical feed-
back underscores the interest of multi-modal treatment
strategies for the improved treatment of depression,
although much remains to be learned. While polyphar-
maceutical strategies and multi-target agents share
certain features, they also reveal differences and both
have their merits and their disadvantages, as summar-
ized in Table 3.
The principal challenge with multi-target agents is
the integration of two or more (preferably overlapping)
pharmacophores into a small structure (molecular
weight not more than 500 if possible) in order to recon-
cile chosen promiscuity with favourable pharmaco-
kinetic properties of CNS penetration and biostability
(Hopkins et al., 2006; Millan, 2006; Morphy and
Rankovic, 2006, 2007; Zimmermann et al., 2007;
Wong et al., 2010). Ironically, more than a decade of
focus on highly selective ligands has enhanced the abil-
ity of chemists to eliminate (unwanted) activities rather
than favour their integration when desired. Nonethe-
less, while structure–activity relationships for multi-
target ligands can be challenging, it is not usually
necessary to generate compounds with high affinities
for two sites. As a rule, more modest affinities than
for selective agents suffice and the real issue is acquir-
ing an appropriate balance as defined less in vitro than
by use of in vivo experimental models of depression
(see above citations). This can be arduous and it is
hard to be certain that the ratio of activities is optimal,
 Complementary strategies for improving the treatment of depression
Table 3. General features, advantages and drawbacks, of polypharmacy as compared to multi-target agents
Factor Polypharmacy (drug combinations)
General acceptance Non-evidence-based polypharmacy is discouraged
for CNS disorders and especially problematic in
the elderly. However, when mechanisms are
supported by clinical data, administration is
carefully monitored and drugs are prescribed in
accordance with guidelines to poorly responsive
patients, it is an important option.
Generation and design If individual drugs exist, they can be combined,
of drugs although there may be issues of intellectual
property and availability. If drugs with desired
pharmacological activities are inexistent, then
combination is impossible. A mixture of more
than three compounds is rarely a realistic
proposition.
Hypothesis validation, Characterization of drug combinations requires
experimental evaluation testing of components alone and in association,
time-consuming for determination of optimal
ratios, which may be test-symptom dependent.
However, drug ratios can still be titrated in the
clinic.
Therapeutic range and Additional activities should expand therapeutic
properties range, although they may also introduce
constraints, e.g. dopamine D2 agonist properties
are fine for Parkinson’s disease but unacceptable
for psychotic depression.
Tolerance, therapeutic Additional activities may bring other side-effects,
window yet tolerance can be improved. Thus, a second
mechanism of additive or synergistic
antidepressant activity allows for reduced doses
of each at equivalent efficacy, hence enhancing
the therapeutic window. Certain actions may
directly counter side-effects, e.g. 5-HT2C
antagonism to counter sexual dysfunction and
nervousness.
Safety/toxicity testing Toxicological and safety pharmacology profiles
need to be available for both drugs separately as
well as together.
Drug pharmacokinetics Pharmacokinetic profiles (time to max. effect,
half-life, etc.) of component drugs need to be
comparable for co-administration to make sense.
Drug interactions Drug interactions among component ligands need
careful monitoring, such as those related to
cytochrome 450 isoform inhibition. Interactions
with other drug classes especially complicated.
Clinical testing Designs complex, both vs. placebo and vs.
comparative agents. Large scale, long-term trials
not easy, especially if other than add-on to SSRIs.
Industry primarily interested in testing novel
monotherapy*.
Compliance Major issue for antidepressants: may be even more
problematic for multiple pills although improved
efficacy should favour adherence.
1023
Multi-target agents
No inherent difference in attitude to
multi-target vs. selective agents for patients or
prescribers, although the potential advantages
of multi-target over highly selective agents are
still insufficiently recognized.
In principle, any hypothetical association
of two or more actions can be built
into one chemical structure. However,
structure–activity relationships are more
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challenging and onerous than for selective
agents and some may be chemically
unrealizable.
Once the hypothesis is validated, multi-target
drugs can be characterized similarly to
selective agents. However, the ratio of
respective activities is invariant and cannot be
adjusted in the clinic.
Same potential advantages and
limitations as for polypharmacy.
Same potential advantages and
limitations as for polypharmacy.
Spared the drawback of polypharmacy, no
disadvantage vs. selective agents.
Spared the drawback of polypharmacy, no
disadvantage vs. selective agents.
Spared the drawback of polypharmacy, no
disadvantage vs. selective agents.
Spared the drawback of polypharmacy, no
disadvantage vs. selective agents.
Spared the drawback of polypharmacy, no
disadvantage vs. selective agents.
1024 M. J. Millan

Table 3 (cont.)

Factor Polypharmacy (drug combinations) Multi-target agents

Intellectual property, Association (and use) patents tend to be weak,
patent issues, financial especially if one or other of the drugs is generic
considerations and/or the property of another firm. Use of
additional drugs will increase health-care costs.
Robust protection. Multiple components of
pharmacological activity offer additional
opportunities for patent strategies compared to
selective agents. Costs of mechanistically novel
drugs superior to existing agents may be high
at launch.

CNS, Central nervous system; SSRIs, selective serotonin reuptake inhibitors.

*Fluoxetine plus olanzapine is an interesting exception, since both drugs belong to Lilly.
The pros and cons of polypharmacy and multi-target drugs are indicated for a broad range of characteristics from discovery and
experimental characterization to clinical development and therapeutic exploitation. Comparisons are made among these two

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families of agents as well as to monotherapy with highly selective agents. Multi-target drugs share most of the benefits of poly-
pharmacy yet lack many of their disadvantages and they also display several distinctive benefits of their own. However, they
reveal a few drawbacks, notably in their design and discovery.

a core consideration since it is obviously invariant and
cannot later be modified in the clinic.
Conversely, drug associations can be titrated in
patients, with one component (like a SSRI) remaining
constant and the other being systematically varied,
although, for pragmatic reasons and in view of time
and cost, a fairly well-defined notion of the desired
drug:dose ratio should be available before com-
mencing clinical studies. Moreover, as outlined in
Table 3, in particular where the two drugs to be com-
bined are not well characterized in humans, there are
many developmental, pharmacokinetic and clinical
issues that are more complex to address for drug com-
binations than for multi-target (or selective) agents.
To date, most polypharmaceutical concepts have
been limited to small-scale trials, where at least one
drug is commercially available, and the concomitant
development from scratch of two novel ligands in
association has not, to the author’s knowledge, been
accomplished. Indeed, while polypharmacy for de-
pression is incarnated by the approval of adjunctive
use of second-generation antipsychotics (such as aripi-
prazole) with SSRIs in treatment-resistant subjects,
both of these drug classes are well known, of proven
clinical utility and inherently ‘safe’. Further, olanza-
pine has been specifically developed in association
with fluoxetine, both drugs emanating from the same
company (Lilly). The development of drug mixtures
containing two or more new chemical entities from
the outset is a far more formidable challenge.
Polypharmacy and multi-target agents both have
their merits as compared to selective agents (some
shared, some distinctive) and both present certain
drawbacks. On balance, although it would be unwise
to neglect polypharmacological opportunities, assum-
ing that the requisite drug can be made, multi-target
strategies appear to be the most promising strategy
for future progress.
Perspectives for future development of multi-target
drugs and polypharmacy
A general strategy for exploiting multi-target
concepts and polypharmacy
As articulated in detail elsewhere (Millan, 2006, 2009),
one pragmatic way of reconciling the competing de-
mands and merits of polypharmacy, multi-target
drugs and selective agents would be to simultaneously
pursue all three of these complementary strategies. For
all new targets, it is imperative to identify highly selec-
tive ligands as exploratory pharmacological tools and
they can be evaluated both alone and in association
with: (1) SSRIs; (2) other classes of clinically available
antidepressant; (3) promising and novel modes of anti-
depressant activity. This would provide a framework
both for the development of drugs alone and in associ-
ation. In parallel, and guided by such data, multi-target
modes of target exploitation can likewise be generated
based on the integration of one or more complementary
pharmacological action into a single drug, either estab-
lished or new. Thus, where feasible and desirable,
multi-target drugs should systematically be designed
and progressed in parallel with selective ligands
(required for polypharmacy) at innovative targets for
the potentially improved treatment of depression.
 Complementary strategies for improving the treatment of depression 1025

Novel targets for multi-target and possesses anxiolytic properties and appears to promote
polypharmaceutical exploitation: sleep (De Bodinat et al., 2010; Kasper et al., 2010;
new vistas for monoaminergic mechanisms Racagni et al., 2011; Catena-Dell’Osso et al., 2012).
Clearly, there remains an urgent need to pursue
Underscoring the notion that novel monoaminergic
other multi-target strategies oriented around a non-
mechanisms may still have something to offer in the
monoaminergic target for further gains in effectiveness
multi-target treatment of depression, 5-HT4 agonists
and control of other symptom clusters. In this regard, it
have attracted interest as rapid onset antidepressants
is worth mentioning some novel avenues of research
(Lucas, 2009) and, as mentioned above, efforts are
(highlighted in Fig. 5), which could profitably be devel-
being made to develop 5-HT7 antagonists (Mnie-Falili
oped along lines evoked above.
et al., 2011). Although for reasons accentuated herein,
First, in light of the above-mentioned use of triio-
it is dubious whether such mechanisms will suffice
dothyronine for augmentation of tricyclics and, less
alone for adequate efficacy, both 5-HT4 agonists and
consistently, SSRIs (Cooper-Kazaz and Lerer, 2008;
5-HT7 receptor blockade may potentiate at least some
Connolly and Thase, 2012), it is intriguing that the

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actions of SSRIs (Lucas, 2009; Shelton et al., 2009)
endogenous (decarboxylated) derivative, 3-iodothyro-
and several multi-target monoaminergic antidepress-
namine behaves like tyramine, phenylethylamine and
ants are currently under investigation. Notably, clinical
other trace amines as an agonist at trace amine associ-
data support the effectiveness of Lu-AA21004, which
ated receptor 1 receptors (Sotnikova et al., 2009;
inhibits 5-HT reuptake, acts as a partial agonist at
Di Cara et al., 2012). Their activation modulates mono-
5-HT1A and 5-HT1B sites and as an antagonist at
amine transport and exerts a variety of other cellular
5-HT3 and 5-HT7 receptors (Alvarez et al., 2012;
effects associated with potential antidepressant proper-
Katona et al., 2012; Mork et al., 2012). However, it is
ties and ligands at these sites may also be useful for
not yet clear which (if any) advantages it offers over
controlling psychosis associated with depression (Xie
currently available antidepressants.
and Miller, 2009; Revel et al., 2012a, b). Trace amine
Another innovative idea would be to couple DA
associated receptor 1 receptors are a novel and promis-
D3 antagonist properties to SSRIs and other antide-
ing site for new classes of multi-modal antidepressant.
pressant mechanisms in view of compelling evidence
Second, as depicted in Fig. 2, there is increasing
for improvements in a broad spectrum of depression-
interest in epigenetic mechanisms in the pathogenesis
compromised cognitive domains, such as social
of depressed states and the broad range of epigenetic
cognition, working memory, attention and executive
processes controlling gene expression independent of
function. Moreover D3 receptor blockade elevates
DNA sequence (from DNA methylation and histone
neurogenesis in the hippocampus (which is defective
marking to non-coding RNA control of mRNA splicing
in depression), counters stress-induced drug-seeking
and translation) provides a broad palette of potential
behaviour (for example, of cocaine) and promotes
targets for new classes of multi-modal antidepressant
motor function in models of Parkinson’s disease
(Millan, 2011; Uher, 2011; Mouillet-Richard et al.,
(Millan et al., 2007; Millan and Brocco, 2008;
2012; Sun et al., 2012). Of particular interest are histone
Heidbreder and Newman, 2010; Loiseau et al., 2009;
deacetylase 2 inhibitors, which possess antidepressant
Egeland et al., 2012; Watson et al., 2012). Selective D3
properties in rodents, as well as complementary
antagonists have not yet reached patients, yet multi-
pro-cognitive actions (Graff and Mansuy, 2009; Cov-
target antidepressants possessing D3 receptor antagon-
ington et al., 2010; Day and Sweatt, 2012; Lin et al.,
ist properties could be of particular use for treatment,
2012; Yamawaki et al., 2012). Interestingly, there is evi-
not only of major depression but also of depressed
dence that folate (folic acid) is lacking in depression
mood co-morbid with substance abuse, schizophrenia
and its deficiency may not only compromise active
and Parkinson’s disease (see above citations).
DNA formation but also methylation of both histones
and DNA (Gilbody et al., 2007). Antidepressant-like
Novel targets for multi-target and
actions of folate have been reported in rodents and
polypharmaceutical exploitation:
studies are being pursued of its administration alone
non-monoaminergic concepts
and together with SSRIs to patients (Taylor et al.,
Agomelatine still holds its position as a uniquely 2004; Stahl, 2007; Molina-Hernandez et al., 2011,
innovative and clinically proven, multi-target anti- 2012). On this basis, and in view of the significance
depressant reflecting its complementary (perhaps of DNA and histone methylation to the mood and cog-
synergistic) agonist and antagonist properties at mela- nitive deficits of neurodevelopmental disorders,
tonin and 5-HT2C receptors, respectively. It also histone methyltransferases and demethylases, as well
1026 M. J. Millan

> 30 Many potential

monoaminergic non-monoaminergic
targets 5-HT targets

1 Neurotransmitters
2 Neuropeptides
3 Hormones
4 Cellular modulators
DA NA

Modulator Activity Functional properties

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1 Trace amines TAAR1 Ago ↓ Psychosis
Core, clinically 1 Acetylcholine α7Ago/PAM ↑ Cognition +
validated 1 Glutamate mGluR5 Ant, mGluR7 Ago ↓ Anxiety/Psychosis Complementary
monoaminergic 2 Neuropeptide Y mechanism of
Y1 Ago, Y2 or Y5Ant ↓ Anxiety/Obesity
mechanism activity
3 Ghrelin Ago ↑ Cognition
4 Histone deacetylase Inhibitor ↑ Cognition
Multi-target concepts/Polypharmacy combinations

Fig. 5. Novel mechanisms under exploration for multi-target and/or polypharmaceutical exploitation in the improved
treatment of depression. Including receptors, transporters and enzymes for degradation, there are about 30 ways of
manipulating monoaminergic transmission, of which several – but not all – are already clinically exploited. In addition, there
are innumerable, potential non-monoaminergic mechanisms for improving various dimensions of depressed states, although
none has yet become available to patients as selective drugs. It should be possible to harness clinically validated mechanisms
of antidepressant action [such as 5-HT and/or noradrenaline (NA) reuptake suppression or 5-HT2C receptor blockade] and
add on complementary mechanisms (either mono- or non-monoaminergic) to strengthen efficacy, improve tolerance, reduce
delay to action and control a broader range of symptoms. An example of a multi-target agent would be agomelatine
[melatonin agonist (Ago) plus 5-HT2C antagonist (Ant)] and an example of polypharmacy would be fluoxetine plus
olanzapine for treatment-resistant depression. Many more permutations remain to be experimentally and clinically explored
(see text). Dependent upon drug availability and other factors, both polypharmacy (drug combinations) and multi-target
agents are appropriate vehicles for uniting the mechanisms of action indicated. DA, Dopamine; TAAR, trace amine associated
receptor; PAM, positive allosteric modulator; mGluR, metabotropic glutamatergic.

as enzymes controlling DNA methylation, justify
evaluation as potential targets for antidepressants
(Kramer and van Bokhoven, 2009; Gomes and Joca,
2011; Sanchez-Mut et al., 2012; Millan, 2013).
Third, in addition to ionotropic AMPA and NMDA
receptors (vide supra), recent evidence supports a role
for various classes of mGluR receptor in the control
of mood and, specifically, in depressive states. Thus,
blockade of mGluR2 (Bespalov et al., 2008; Campo
et al., 2011; Dwyer et al., 2012) and mGluR5 (Hughes
et al., 2012; Inta et al., 2012) receptor subtypes on the
one hand and activation of the mGluR7 subtype
on the other (Palucha et al., 2007; Bradley et al., 2012)
is associated with antidepressant (and anxiolytic)
properties. Apart from multi-target agents, adjunctive
use of mGluR ligands is an attractive possibility
(Matrisciano et al., 2008).
Fourth, neuropeptide Y has long been implicated
in the response to stress and in the control of mood.
Activation of post-synaptic Y1 sites, or blockade of
their Y2 presynaptic counterparts, has been associated
with antidepressant and anxiolytic properties in
rodents (Ishida et al., 2007; Tasan et al., 2010; Gelfo
et al., 2012). Interestingly, subthreshold doses of
neuropeptide Y and fluoxetine synergistically elicited
antidepressant effects (Molina-Hernandez and Tellez-
Alcantara, 2011). Finally, suggesting a further dimen-
sion to the role of neuropeptide Y, a non-peptidergic
antagonist at Y5 receptors was recently found to elicit
antidepressant effects (Packiarajan et al., 2011).
Fifth, another intriguing peptide for which data are
less extensive is the appetite-stimulating hormone
ghrelin, which is secreted by the gut yet enters the
brain where it facilitates cognition and counters the
 Complementary strategies for improving the treatment of depression
deleterious impact of stress on mood (Lutter et al.,
2008; Atcha et al., 2009; Chuang and Zigman, 2010).
Although its precise role in the control of anxious
and depressed states remains somewhat unclear, ghre-
lin may possess antidepressant properties and further
studies of therapeutic relevance to the control of
depression is warranted (Chuang and Zigman, 2010;
Carlini et al., 2012; Ishitobi et al., 2012).
Sixth, as mentioned above, there is considerable
interest in the influence of nicotinic receptors upon
depressed mood, with most attention to date directed
towards antagonists at α4β2 receptors – despite the
recent disappointment of (S)-mecamylamine as adjunc-
tive therapy for SSRIs (Ledford, 2011; Philip et al.,
2012). α7 receptors are likewise of interest in view of
their positive influence upon cognition (Graef et al.,
2011; Levin, 2012; Millan et al., 2012). Although
affinities of α7 ligands at 5-HT transporters, and reci-
procally of SSRIs at nicotinic receptors, complicates
studies of interactions, there is evidence that α7 recep-
tor blockade potentiates the actions of SSRIs in rodent
models of antidepressant properties (Millan, 2006;
Andreasen et al., 2012). Although rapid antidepressant
actions of the muscarinic antagonist, scopolamine,
have been reported, it would appear more appropriate
to identify and exploit the underlying cellular sub-
strates – perhaps analogous to those harnessed by
ketamine or sleep deprivation (Bunney and Bunney,
2012) – rather than pursue multi-target drugs block-
ing muscarinic receptors in view of gender differences
and their notorious side-effect profile, although
allosteric sites may represent a hitherto unexplored
opportunity for therapeutics (Drevets and Furey,
2010).
Finally, although not illustrated in Fig. 5, a few
words should be devoted to glial mechanisms, long
implicated in the pathogenesis of depression (and
other CNS disorders) but still not harnessed thera-
peutically (Czeh and Di Benedetto, 2012). An interest-
ing link has been made to a further potential substrate
for multi-modal treatment of depression: p38-mitogen
activated kinase, which phosphorylates and increases
the membrane expression of 5-HT leading to reduced
levels of extracellular 5-HT (Bruchas et al., 2011;
Connolly and Thase, 2012). Glycogen synthase
kinase-β inhibition remains under consideration as
well as a potential antidepressant strategy (Millan,
2009; Connolly and Thase, 2012; Duman and Voleti,
2012). Nonetheless, even for multi-target drugs, the
above mechanisms all raise important questions of
specificity and safety if they are to be therapeutically
exploited for treatment of depression or other CNS
disorders.
1027
While mechanistic details of how the above drug
classes affect mood and other functions disrupted in
depression are beyond the scope of this review (see
above citations), they suggest scope for the exploration
of novel multi-modal strategies for the improved treat-
ment of depressed states.
Integration of multi-modal pharmacotherapy with
‘alternative’ treatments
Not surprisingly, in view of persistent difficulties in
identifying improved pharmacotherapy for depression,
there is ever-increasing interest in ‘alternative’ (and,
from a network perspective, ‘multi-target’) strategies
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as diverse as, for example, mindfulness (Marchand,
2012), cognitive behavioural therapy (DeRubeis et al.,
2008), light exposure (Crowley and Youngstedt, 2012)
and transcranial direct stimulation (Del’Osso et al.,
2012). Ultimately, the goal would arguably be to abol-
ish artificial barriers and the knowledge gap between
medication and validated, non-pharmacotherapeutic
strategies and to unite them in a coherent and
evidence-based manner to the profit of individual
(subsets of) patients. Thus, a final issue concerns the
potential use of multi-target antidepressants and poly-
pharmacy in association with alternative treatment
strategies, where medication is not sufficient alone
for satisfactory remission. Cognitive behavioural
therapy acts at the ‘cerebral circuit’ level rather than
homing in on any discrete molecular substrate and it
recruits contrasting cerebral mechanisms vs. pharma-
cotherapy (Kennedy et al., 2007). This supports the
logic of its combination with pharmacotherapy for
improving efficacy, reducing relapse and enhancing
quality of life (Guidi et al., 2011; Ishak et al., 2011;
Köhler et al., 2011). While such dual treatment
strategies would be difficult to integrate into early
development programmes, small-scale pilot trials and
post-authorization studies should prove useful in
more fully exploring the clinical utility of novel classes
of multi-target drug and polypharmacy. Finally, stimu-
lation procedures for alleviating depression might be
combined with antidepressant agents in an attempt
to improve efficacy (Eitan and Lerer, 2006).
Concluding comments
As compared to highly selective agents, multi-modal
therapeutic strategies appear to offer greater promise
for the broad-based and improved treatment of
depressed states. The systematic pursuit of selective
and multi-target agents together with the exploration
of novel drug combinations is a reasonable blueprint
1028 M. J. Millan
for future progress. There is nothing inherently radical
in all this inasmuch as multi-modal strategies are
already a focal point for the improved control of
complex disorders as diverse as cancer, malaria,
Parkinson’s and Alzheimer’s disease (Toda et al.,
2003; Millan, 2006; Van der Schyf et al., 2007; Petrelli
and Giordano, 2008; Piazzi et al., 2008). On the con-
trary, it is surprising that multi-modal thinking is not
more predominant in the field of depression ‘R and
D’ as a potential foundation for future progress.
While combinations of clinically characterized com-
pounds remain feasible and potentially important (as
illustrated by second-generation antipsychotics plus
SSRIs), the development of mixtures of two new
drugs is more challenging and there are several limit-
ations to polypharmaceutical approaches for treating
depression. Conversely, while not ignoring the chemi-
cal difficulty of multi-target drug design and their
invariant ratio of component pharmacological activi-
ties, they share many of the benefits of polypharmacy
while lacking a number of important drawbacks. All
things considered, multi-target agents may be the
most attractive route towards novel and improved
antidepressant agents. Currently, they are exemplified
by the mechanistically innovative agent, agomelatine,
but it is to be hoped that complementary multi-target
agents with other advantages for treating additional
dimensions of depression will eventually become
available. Together with improvements in translational
measures of drug actions between rodents and
humans, more objective biomarkers of incipient and
actual depressed states and innovations in clinical
evaluation of new drugs, a shift in mindset from highly
selective to multi-modal treatment strategies may help
revitalize a domain greatly in need of further progress
in view of the insufficient current treatment of major
depression.
Acknowledgements
The author thanks Carmen Munoz, Elisabeth Mocaer
and Philippe Delagrange for helpful comments on
the paper, Marianne Soubeyran for preparing citations
and tables and Alain Gobert for help with the figures.
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