Cognition as a Target in Depression: New Developments

European Neuropsychopharmacology (]]]]) ], ]]]]]]
www.elsevier.com/locate/euroneuro
Cognition as a target in major depression:

New developments
Brisa Sol, Esther Jimnez, Anabel Martinez-Aran, Eduard Vietan
Barcelona Bipolar Disorders Program, Institute of Neurosciences, University of Barcelona, IDIBAPS,
CIBERSAM, Barcelona, Catalonia, Spain
Received 29 July 2014; received in revised form 3 December 2014; accepted 23 December 2014
1.
KEYWORDS
Abstract
Cognition;
Major depression;
Monotherapy;
Adjunctive treatment
Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric illness often
accompanied of cognitive dysfunction which may persist even when patients achieve clinical
remission. Currently, cognitive decits emerge as a potential target because they compromise
the functional outcome of depressed patients. The aim of this study was to review data for
several potential pharmacological treatments targeting cognition in MDD, resulting from
monotherapy or adjunctive treatment. An extensive and systematic Pubmed/Medline search
of the published literature until March 2014 was conducted using a variety of search term to
nd relevant articles. Bibliographies of retrieved papers were further examined for publications
of interest. Searches were limited to articles available in English language. We describe studies
using modanil, lisdexamfetamine, ketamine, lanicemine, memantine, galantamine, donepezil, vortioxetine, intranasal oxytocin, omega-3, s-adenosyl-methionine, scopolamine and
erythropoietin. From these articles, we determined that there are a number of promising
new therapies, pharmacological agents or complementary medicines, but data are just
emerging. Drugs and therapies targeting cognitive dysfunction in MDD should prove effective
in improving specic cognitive domains and functioning, while ruling out pseudospecicity.
& 2015 Elsevier B.V. and ECNP. All rights reserved.
Introduction
Major depressive disorder (MDD) is a highly prevalent and

disabling psychiatric disorder ranked as the rst leading
n
Correspondence to: Bipolar Disorder Program, Clinical Institute

of Neuroscience, Hospital Clinic of Barcelona, Villarroel, 170, 08036
Barcelona, Spain. Tel.: +34 93 227 54 01; fax: +34 93 227 5795.
E-mail address: evieta@clinic.ub.es (E. Vieta).
cause of years lost due to disability (WHO, 2012; CatalaLopez et al., 2013). This psychiatric condition is associated
with higher rates of morbidity and mortality. In addition,
the public health cost of this condition is quite high, in part
due to both the limited effectiveness and the long delay (up
to 12 weeks) of conventionally antidepressant treatments
(Kessler et al., 2003; Jick et al., 2004). Different studies
conclude that only 3040% of patients that are optimally
treated with rst line antidepressants achieve remission
(Trivedi et al., 2006; Rush et al., 2011) and more than one
http://dx.doi.org/10.1016/j.euroneuro.2014.12.004
0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: Sol, B., et al., Cognition as a target in major depression: New developments. European
Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2014.12.004
B. Sol et al.
third of patients with depression are classied as treatmentresistant depression (TRD) (Souery et al., 2006), although
the rates may vary depending on the criteria used to dene
TRD (Vieta and Colom, 2011; Posternak et al., 2004).
In this regard, most patients, including those considered
as good responders to antidepressant treatment, continue
suffering from residual subsyndromal symptomatology as
well as presenting persistent functional impairment, being
unable to achieving remission criteria. Some authors point
out that sleepiness, fatigue as well as executive dysfunctions constitute some of the most common residual symptoms presented in this group of patients (Stahl and Grady,
2003). Hence, the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) included some
cognitive symptoms, such as a diminished ability to think
or concentrate, or indecisiveness, in the diagnostic criteria
for major depression, recognizing that cognitive impairment
is a core feature associated to this condition. Nonetheless,
it should be remarked that cognitive difculties may persist
in patients even when depressive symptoms have abated or
disappeared, with small to medium effect sizes for memory
and medium to severe effect sizes for attention and
executive function (Bora et al., 2013; Rock et al., 2013).
Despite the main cognitive dysfunctions in MDD are related
to executive functions, attention, processing speed and memory domains are also signicantly impaired (Bora et al., 2013;
Rock et al., 2013; McIntyre, 2013). These cognitive problems
compromise the individual's coping abilities and the likelihood
of successfully returning to work, which in turn exert a huge
impact on functional recovery (Jaeger et al., 2006). In this
sense, it is well known that cognitive function represents one of
the best predictors of functional outcome in psychiatric
patients (Baune et al., 2010; Bonnin et al., 2014). For this
reason cognitive impairment emerges as a potential target for
both pharmacological and psychosocial treatments, with the
nal goal of improving functioning.
In order to deal with the aforementioned limitations
shown by current antidepressant drugs, the American
Psychiatric Association (APA) treatment guidelines recommend augmentation strategies added to antidepressant
treatment in those patients showing an inadequate response, since most of the proposed antidepressant monotherapy treatment strategies may not be effective enough to
achieve full remission in a substantial group of patients.
So far, most of the widely prescribed antidepressants
agents target the aminergic system, however, evidence
suggests that depression is also associated with alterations
in other neurotransmitter systems (such as glutamatergic
transmission), as well as to a loss of synaptic plasticity in
circuits involved in regulating mood and emotions (Sanacora
et al., 2008; Kavalali and Monteggia, 2012). Therefore, it
seems that the complexity of MDD entails more than the
monoaminergic dysregulation. Currently, there is an increasing interest in the role of glutamatergic neurotransmitter
system in the pathophysiology of mood disorders and the
development of novel and rapid-acting antidepressant
drugs. Additionally, there is an urgent clinical need for
new treatments that target cognitive enhancement since
most current antidepressant medications have no direct
pro-cognitive effects only indirect effects mediated
by mood improvement. In this line, the conventional antidepressants available so far seem not to have enough robust
procognitive effects (McIntyre, 2013). The serotoninergic-noradrenergic reuptake inhibitors (SNRIs) seem to
have a better cognitive prole than serotonin reuptake
inhibitors (SSRIs) (Herrera-Guzman et al., 2009). Nonetheless,
Baune and Renger, in a preliminary study, found that cognitive
effects of SSRIs and selective serotonin reuptake enhancers
(SSREs) were similar. They also reported that SSRIs cognitive
effects were superior to those observed in the group of
patients treated with tricylic antidepressants (Baune and
Renger, 2014).
This systematic review focuses on those studies aimed to
assess the cognitive effects resulting from both the combination
of different pharmacological agents and current antidepressants, as well as monotherapy, in MDD. Although our main focus
of interest are objective cognitive measures, we have included
some studies using subjective cognitive measures if the study
was considered of clinical relevance for testing new compounds
that may inuence cognitive variables. Even so, it is necessary
to keep in mind the distinction between self-reported/objective cognitive measures given that the relationship between
them in patients with affective disorders is controversial and
several studies have found that these variables are not
associated to a great extent (Svendsen et al., 2012). As Rosa
and colleagues pointed out, probably, cognitive complaints are
referred to subjective experience of general cognitive problems
that are not well characterized when reported by patients
(Rosa et al., 2013).
2.
Experimental procedures
To identify relevant studies, we performed a PubMed search of new

treatments for cognitive dysfunction in human studies with major
depressive disorder until March 2014, using the following keywords:
depression or major depression cross-referenced with cognition or cognn. The same keywords were cross-referenced with
different pharmacological agents which were considered that could
inuence cognitive function as well as new agents that were found
in articles reviewed, such as: aniracetam, bitopertin, DHEA,
D-cycloserine, donepezil, D-serine, dextromethorphan,
encelicline, erythropoietin, galantamine, GLYX-13, intranasal oxytocin, ketamine, lixdexamfetamine, lanicemine,
lurasidone, memantine, metyrapone, mifepristone, MK0657, modanil, n-acetyl-cysteine, NRX-1047, omega-3,
pramipexole, propofol, riluzole, rivastigmine, s-adenosyl
methionine, ropinirole, sarcosine, scopolamine, tamoxifen, traxoprodil, vilazodone, vortioxetine. Complementing
the database search, pertinent review articles and reference lists
from identied articles were hand-searched for additional studies
eligible for inclusion in this review not previously identied.
The inclusion criteria for studies were the following:
1. Studies conducted on humans where participants were adults

with diagnoses of MDD.
2. Exploring changes in cognitive functions as primary or secondary

outcome.
3. A randomized, or quasi-randomized controlled trial or an open

study assessing any cognitive measure or social cognition.
4. English language original articles.

The exclusion criteria were:
1. Preclinical studies (such as animal studies).

2. Studies with participants with a diagnosis of depression
Cognition in major depression

secondary to other illness (i.e. post-stroke depression, schizophrenia, bipolar disorder, or any neurological disease such as
multiple sclerosis, dementia or Parkinson disease).
3. Case-report studies.
Following the inclusion and exclusion criteria, 26 studies providing data from pharmacological trials on cognitive function in
depressed patients were found and were included in this review.
We group the compounds into one section with compounds that
might have a potential procognitive effect based on their neurobiological mechanism and other section with compounds that exert
an antidepressant effect with different prole of cognitive effects.
The main ndings of these original studies are reviewed below and
data extracted from them are illustrated in a table (see Table 1),
gathering the following information: (a) pharmacological agent;
(b) name of the rst author and year of publication; (c) core sample
characteristics (sample size, distribution); (d) cognitive measures as
primary or secondary outcome; (e) randomized or not randomized
study; (f) double-blind or not; (g) main neurocognitive ndings; and
(h) neurocognitive tests employed.
3.
Results
3.1. Compounds with potential procognitive

effect
3.1.1. Modanil
Modanil is an agent with stimulant-like properties, without
the abuse and dependence potential of stimulants. This
drug obtained the Food and Drug Administration approval
for treating excessive sleepiness in narcolepsy as a wakepromoting agent. Modanil exerts a multimodal action
targeting several neurotransmitter systems (such as, catecholaminergic, serotonergic glutamatergic, gamma aminobutyric acid, orexin and histaminergic systems) (Minzenberg
and Carter, 2008). Regarding the orexinergic and histaminergic effects, they seem to be related with the alertness
improvement in sleep disturbances, whilst the noradrenergic action may be more associated with the cognitiveenhancing effects (Muller et al., 2004). Modanil has
demonstrated potential procognitive effects in healthy
voluntaries and it has been investigated in some clinical
populations (Minzenberg and Carter, 2008). Nowadays,
modanil is considered as an effective augmentation strategy for both acute unipolar or bipolar depressive episodes
(Goss et al., 2013). However, with regard to its procognitive
effects in patients with major depression, only an 4-week
open-label study has been published some years ago
(DeBattista et al., 2004). The study enrolled 35 patients,
with a history of major depression with partial response on a
stable therapeutic dose of an antidepressant treatment,
who received modanil as an augmentation strategy. Concerning neuropsychological assessment a battery was administered assessing attention, visuomotor processing speed,
working memory and executive functions, where only the
Stroop Interference test scores showed a signicant improvement from baseline to endpoint. Authors concluded that
modanil administration did not appear to adversely affect
neurocognition, in fact, it may even improve some cognitive
functions.
3
Hence, further research focusing on analyze the procognitive effects of this pharmacological treatment in unipolar
depression may be useful.
3.1.2. Memantine
Memantine is a noncompetitive, voltage-dependent NMDAreceptor antagonist approved for the treatment of moderate to severe Alzheimer disease. The modulation of glutamate neurotransmission seems to be associated with
antidepressant response and some studies have demonstrated that memantine may exert a positive impact on
mood regulation (Sani et al., 2012). Memantine have also
been reported to have effects on the monoamine system,
specically on the serotonergic system (Johnson and
Kotermanski, 2006). Overall, despite interesting preclinical
data, results concerning the use of memantine for the
treatment of major depression are not encouraging due to
discrepancies from the different studies (Ferguson and
Shingleton, 2007; Zarate et al., 2006a, 2006b). A randomized double-blind trial, which failed to demonstrate a
benet of memantine as augmentation antidepressant
strategy, gathered cognitive variables as secondary outcomes, although, as far as we know, the results have not
been published yet (Smith et al., 2013).
The co-occurrence of alcohol dependence with MDD is
common and the pharmacological approach to this comorbid
condition is still difcult and controversial (Kessler et al.,
1997; Nunes and Levin, 2004). It is well known that alcohol
acts on NMDA glutamate receptors and memantine may
have neuroprotective properties that may be benecial
against the neurotoxic effects of alcohol use (Krystal
et al., 2003b). Muhonen and co-workers compared escitalopram versus memantine in a group of comorbid patients in
a randomized double-blind trial in order to examine the
efcacy of these compounds with regard to depression and
cognitive functioning among other variables (Muhonen
et al., 2008). Both treatments reduced depressive symptomatology suggesting a potential efcacy of escitalopram
and memantine for alcohol dependent depressed patients,
however, with regard to neurocognitive functions, neither
signicant changes during the study period nor differences
between groups were observed.
3.1.3. Galantamine
Galantamine is a cholinergic agent, a relatively weak
acetylcholinesterase inhibitor and potent nicotinic receptor
modulator. Due to its additional allosteric potentiating
effects at nicotinic receptors, it has been suggested that
this drug also affects other neurotransmitter systems such
as monoamines, glutamate, and -aminobutyric acid
(GABA). Additionally, some animal models of psychiatric
disorders (not tested in behavioral models of depression)
have shown that muscarinic receptor activation through
increased brain acetylcholine levels appears to mediate, at
least in some extent, anti-psychotic effects and the
improvement of cognitive dysfunction (Ago et al., 2011).
With regard to this drug, only two randomized, doubleblind placebo-controlled trials have been conducted and
both studies failed to demonstrate a signicant benet of
galantamine augmentation of antidepressants in cognitive
functioning when compared to placebo (Holtzheimer et al.,
Main characteristics of studies.
Pharmacological
compounds
Subjects
Primary/
Secondary
outcome
measure
Randomized Double- Main nding

blind
MDD with partial

response =31
Secondary
Memantine =29
Escitalopram =29
(MDD +Alcohol
dependence)
GLTM =12
Placebo =18
(MDD; BD
depressed type;
SZA depressed
type)
Primary
Primary
Coprimary
Elgamal and MacQueen (2008)

(pilot study)
Coprimary
GLTM =10
Placebo =10 MDD
(not in an acute
episode)
Matthews et al. (2008) (pilot

study-ECT)
GLTM =9 No
GLTM =8
(consecutive ECT
Author
Compound with potential procognitive effect

Modanil
DeBattista et al. (2004)
Memantine
Muhonen et al. (2008)
Galantamine
(GLTM)
Matthews et al. (2013)
Holtzheimer et al. (2008)

GLTM =19
(pilot, proof-of-concept study) Placebo =19
(older adults)
Coprimary
Cognitive measures
Signicant improvement in the CWST; WAIS-III Letter Number,

Stroop Interference Test
Digit Span; TMT-A, TMT-B.
(executive function) was seen
at 4 weeks, as an adjunctive
treatment of depressed
patients.
No cognitive changes in both
CERAD; MMSE
groups.
GLMT may be protective

against impairment in
retention of new learning
during ECT. The GLTM group
scored signicantly higher at
discharge than did the control
group for the Delayed Memory
Index.
Authors failed to demonstrate
a benet of GLTM
augmentation of
antidepressant medication in
older adults. Both groups
showed improvement in
cognitive functioning over
time, but there was no
statistically signicant group
by time interaction.
Patients had a numeric
improvement on cognitive
measures although there were
no statistically signicant
differences.
GLTM may reduce cognitive
impairment during ECT,
especially with regards to new
learning.
RBANS; 3MS; WASI (vocabulary,

matrix reasoning)
RBANS; MMSE
CVLT; TMT-A, TMT-B; Ruff 2 and

7 Selective Attention Test;
Digit Span Test; DSST; COWAT
3MS
B. Sol et al.
Table 1
Primary
Donepezil =12
Placebo =9
(elderly
depressed,
cognitive
impaired)
Reynolds et al. (2011) (Open AD Donepezil =67
Primary
treatment with supportive
Placebo =63
depression care management (Cognitively
to establish eligibility for
normal =73/
(b) the randomized, placebo- MCI =57) (elderly)
controlled maintenance phase
of treatment (2 years))
Patients with donepezil showed BSRT; digit symbol WAIS-III;

improvement in memory.
TMT-A, TMT-B; CFL
Whether donepezil should be

used as augmentation in the
maintenance treatment of
late-life depression depends
upon a careful weighing of risks
and benets in those with MCI.
Donepezil appears to have no
clear benet in cognitively
intact patients, for preventing
progression to MCI/dementia or
recurrence of depression.
McIntyre et al. (2014)
VRTX 10 mg =195 Primary

VRTX 20 mg =207
Placebo =196
Katona et al. (2012)
VRTX =156
Duloxetine =151
Placebo =145
(elderly MDD)
Secondary
Vortioxetine signicantly
DSST; RAVLT; TMT-A,TMT-B;
improved objective and
Stroop; SRT; CRT; PDQ
subjective measures of
cognition. Their effects were
largely independent of its
effect on improving depressive
symptoms.
MMSE; RAVLT;DSST
Patients showed a positive
effect compared to placebo in
processing speed and verbal
learning and memory.
Miskowiak et al. (2010)
EPO=10
Placebo =9
Secondary
Miskowiak et al. (2014)
EPO=18
Placebo =21
(TRD)
Secondary
Compounds with antidepressant effect and different prole of cognitive effects

Lisdexamfetamine Madhoo et al. (2014)
LXD=60
Primary
(LXD)
Placebo =59 (MDD
Donepezil
Vortioxetine
Erytrophoietin
(EPO)
Pelton et al. (2008) (pilot study

Phase A: Open AD treatment/
Phase B: Donepezil vs placebo/
Phase C: Extended open
donepezil)
TMT-A, TMT-B; Digit Symbol,

Block Design; Grooved
Pegboard; Modied ROFC;
Simple Drawings; BNT; Spotthe-Word; Letter Fluency;
Animal Fluency; Logical
Memory; CVLT; Stroop NST;
Executive Interview; WCST
patients: MDD,
BD, SZA)
EPO modulates the neural and fMRI paradigm of facial

cognitive processing of
expression recognition
emotional facial expression in
depressed patients.
Sustained enhancement in
RAVLT
memory recall and in
recognition task after EPO
repeated administrations as
adjunctive treatment.
LDX augmentation signicantly BRIEF-A

improved executive function
Pharmacological
compounds
Ketamine
Author
Subjects
Shiroma et al. (2014)
+executive
dysfunction)
TRD=13
Diamond et al. (2014)
Murrough et al. (2014)
Rasmussen et al. (2014)
Yoose et al. (2014)
Loo et al. (2012)
TRD=28 (3
infusions = 15;
6 infusions =13)
(unipolar or
bipolar patients)
TRD=25
Primary/
Secondary
outcome
measure
Randomized Double- Main nding

blind
Coprimary
Secondary
Post-hoc
subanalysis
Primary
Coprimary
Ketamine =21
Methohexital =17
Non-psychotic
MDE (unipolar or
bipolar)
Ketamine =15
Secondary
Thiopental =14
Ketamine =22
Placebo =24
Primary
Cognitive measures
and depressive symptoms in

patients with mild MDD.
Signicant improvements in
CogState battery
visual memory, simple and
working memory after six
ketamine infusions. However,
neurocognitive changes were
accounted for by improvement
in the severity of depressive
symptoms. Performance in
attention at baseline was a
signicant predictor of change
in severity of depressive
symptoms.
Ketamine was not associated
AMI-SF; AFT; Story Recall test;
with memory impairment after ECT-MQ
3 or 6 ketamine infusions
Potential baseline
neurocognitive predictor of
ketamine response. An inverse
relationship between cognitive
effects of ketamine and
antidepressant efcacy.
No signicant differences in
cognitive outcomes between
the two groups. Ketamine did
not diminish the cognitive side
effects.
Ketamine during ECT was well
tolerated. Patients may
experience better cognitive
performance when compared
with thiopental. Persistency of
the benecial effects.
The addition of ketamine to
thiopentone during anesthesia
Estimated premorbid IQ;

current IQ; MATRICS (MCCB).
MMSE
MMSE (before rst ECT, 48

afterbefore second session-,
3 to 7 days after the 6th ECT,
1 month after the 6th)
B. Sol et al.
Table 1 (continued )
Intranasal oxytocin Macdonald et al. (2013)

(OT)
(crossover study)
17 depressed
Secondary
male (OT or
placebo)
Pincus et al. (2010) (crossover Unmedicated
Secondary
study)
depressed =8
Healthy
controls =9 (OT or
placebo)
Omega-3
Rogers et al. (2008)
Antypa et al. (2012)
for ECT did not decrease

cognitive impairment.
CFT; HVLT; COWAT; SDMT; Wood

cock Johnson Cross-Out Test;
AMI-SF; NART
RMET
OT improved performance on
the RMET (social cognition).
OT has a differential effect

RMET; fMRI
upon the brain of depressed or
healthy subjects in a mental
attribution task and enhances
cognitive and emotional
appraisal.
EPA+DHA =96
Placebo =94
(individuals with
depressed mood)
Omega-3 =36
Placebo =35
(recovered
depressed
individuals)
Secondary
No evidence effects of
Simple RT; lexical decision;
supplementation on any
digit-symbol substitution WAISmeasure of cognitive function. III; impulsivity; N-Back
Coprimary
Only small effects of omega-3

supplementation on aspects of
emotional decision-making, not
on other cognitive functions.
Adjunctive SAME may be

CPFQ
effective in improving memoryrelated symptoms in TRD
patients.
The effect of scopolamine in
Computerized selective
selective attention task was
attention task
relatively small.
S-adenosyl
methionine
(SAME)
Levkovitz et al. (2012)
SAME =27
Placebo =19
Post-hoc
subanalysis
primary
Scopolamine
Furey and Drevets (2006)

(crossover study)
Placebo/
scopolamine = 10
Scopolamine/
placebo =9 (MDD
or BD)
Not
specied
(unipolar or
Bipolar patients)
Affective Go/No-Go task;

Attentional Go/No-Go task; 15
Word test; Facial Expression
recognition task; Decisionmaking (gambling) task
MDD=Major Depressive Disorder; MDE =Major Depressive Episode; TRD =Treatment Resistant Depression; IQ =Intelligence Quotient; BD=bipolar disorder; SZA=schizoaffective; MCI =Mild
Cognitive Impairment; CWST=Color Word Stroop Test; WAIS =Wechsler Adult Intelligence Test; TMT=Trail Making Test; MATRICS (MCCB)=Matrics Consensus Cognitive Battery; MMSE=Mini
Mental State Examination; CFT=Medical College of Georgia Complex Figure; HVLT=Hopkins Verbal Learning Test; COWAT=Controlled Oral Word Association Test; SDMT=Symbol Digit
Modalities Test; AMI-SF=Autobiographical Memory Interview-shortform; AFT=Autobiographical Fluency Task; ECT-MQ=ECT Memory Questionnaire; NART=National Adult Reading Test;
DSST=Digit Symbol Substitution Test; RAVLT =Rey Auditory Verbal Learning Test; SRT=simple reaction time task; CRT=choice reaction time task; PDQ=Perceived Decits Questionnaire;
RBANS=Repeatable Battery for the Assessment of Neuropsychological Status; 3MS=Modied Mental Status Examination; WASI=Wechsler Abbreviated Scale of Intelligence;
CVLT =California Verbal Learning Test; CERAD=consortium to Establish a Registry for Alzheimer's Disease cognitive test battery; BRIEF-A =Behavior Rating Inventory of Executive
Function-Adult Version; BSRT=Buschke Selective Reminding Test; CFL=verbal uency; Modied ROFC =Rey-Osterreith Figure Copy; BNT=Boston Naming Test; Stroop NST=Stroop
Neuropsychological Screening Test;WCST =Wisconsin Card Sorting Test, WMS=Wechsler Memory Scale; BVMT-R=Brief Visual Memory Test-Revised; SST=Syndrome Short Test; STGI=Short
Test For General Intelligence; NCT=Zahlen-Verbindungs-Test; REP=nonvalidated Reproduction List with Concept Clusters; VL=nonvalidated Vocabulary List; RMET =Reading the mind in
the eyes test; CPFQ =self-rated cognitive and physical symptoms questionnaire.
B. Sol et al.
2008; Elgamal and MacQueen, 2008). Some considerations

need to be mentioned concerning these studies. First, both
studies used small samples. In addition, the rst study only
enrolled older adults, whilst the latter included patients
ranging from 40 to 80 years. Another limitation is related to
the high discontinuation rate observed in the galantamine
group from the study carried out by Hotzheimer. Hence, it
may be useful to test galantamine in a homogeneous sample
of young adult patients in order to test the efcacy of this
drug enhancing, since late-life depression could imply
specic pathophysiological characteristics that would be
often related to prodromal symptoms of dementia.
Besides, it should be mentioned that Galantamine has also
been evaluated as a pharmacological strategy to mitigate
cognitive side effects derived from ECT (Matthews et al.,
2013). This study which included MDD, bipolar and schizoaffective patients, reported that patients who received galantamine were protected against impairment in retention of
new learning during ECT. Replications with larger and more
homogeneous samples are needed to reinforce these ndings.
As far as we know, no more clinical trials of galantamine are
currently being carried out.
3.1.4. Donepezil
Donepezil is a longer acting, orally available, reversible
cholinesterase inhibitor, indicated for treating mild to
moderate Alzheimer disease.
Regarding this pharmacological agent, only two randomized, double-blind, placebo-controlled studies have been
published with neurocognition as a primary outcome. Both
studies enrolled patients with late-life depression and some
of them presenting with Mild Cognitive Impairment (MCI). It
is worth to mention that there is an increased likelihood of
conversion to dementia in patients with co-occurrence,
which is highly prevalent.
In the rst pilot study, where all the depressed older adults
were cognitive impaired, a short-term improvement in the
verbal memory domain was found in patients treated with
adjunctive donepezil to antidepressant treatment (Pelton
et al., 2008). These results raise the possibility that combined
treatment may be considered in patients when cognitive
impairment and depression co-occurs, since cholinergic neurotransmission may be involved in cognitive dysfunction associated with depression. The second one was conducted with
elderly outpatients. In this study authors included, on one hand,
a group of non-cognitively affected patients to test whether
donepezil protects against MCI and, on the other hand, patients
with MCI in order to test for cognitive improvement on
donepezil (Reynolds III et al., 2011). Authors found a temporary
positive effect of donepezil on global cognition, executive
functions and memory. Nonetheless, some issues should be
taken into account: (1) donepezil as an augmentation treatment also led to higher rates of recurrent depressive episodes
and (2) do not appear to clear benet for preventing progression to dementia or recurrence of depression in cognitively
intact remitted patients and, nally, (3) in the case of MCI
patients, the addition of donepezil seems to prevent dementia
but it could also increase the risk of depressive relapse.
According to these observations, authors suggested that it
may be necessary to weigh up risks and benets for the
combined treatment with donepezil in patients with MCI.
Therefore, the available evidence does not suggest a

clear benet for donepezil as an adjunctive therapy to
antidepressants for cognitive enhancement for depressed
older patients. Currently, a clinical trial (NCT01658228) is
being carried out aiming at assessing a large sample of
cognitively impaired depressed patients with combined
treatment of antidepressant and donepezil as cognitive
enhancer treatment.
Therefore, it would be interesting to test donepezil in
young adult depressed patients without MCI.
3.1.5. Vortioxetine
Vortioxetine (Lu AA21004) is a new multimodal antidepressant, acting via the combination of a direct effect on
receptor activity and serotonin (5-HT) reuptake inhibition.
It is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5HT1B receptor partial agonist, 5-HT1A receptor agonist, and
a 5-HT transporter inhibitor. First, Katona and colleagues
demonstrated the efcacy of vortioxetine on both depressive symptoms and cognitive function in elderly depressed
patients (Katona et al., 2012). In this study, where cognition
was considered as a secondary efcacy outcome, patients
on vortioxetine showed a positive effect compared to
placebo group in processing speed, verbal learning and
memory. Recently, another group of authors has extended
the investigation in adult MDD patients with cognition as a
primary outcome (McIntyre et al., 2014). Patients were
randomized to two different doses of vortioxetine or
placebo. The improvement of vortioxetine was evident on
the both primary outcomes measures of attention and
processing speed (DSST, Digit Symbol Substitution Test) as
well as verbal learning and memory (RAVLT, Rey Auditory
Verbal Learning Test). The improvement was also noted on
other secondary measures of cognition. The authors suggested that both vortioxetine doses signicantly improved
objective and subjective measures of cognition independently of its effects on improving depressive symptoms,
based on the results of a path and subgroup analyses where
the mood improvement that patients showed simultaneously was controlled for. Therefore, it seemed reasonable
to assume that these antidepressant and procognitive
effects work via distinct mechanisms. However, it is worth
to mention that a path analysis has its own limitations.
Probably, some recently completed clinical trials, or
other ongoing studies, will provide new data about the
truly direct procognitive effects of vortioxetine in the near
future (NCT01564862, NCT01607125, NCT02279953, NCT022
72517, NCT02279966). Some of these studies, which recruit
subjects remitted from depression and healthy controls, will
help to explore if vortioxetine will lead to improved
cognitive function in the absence of depression, that is,
with a direct procognitive effect.
3.1.6. Erythropoietin
Erythropoietin (EPO), also known for its effects on blood
cells and as a treatment of anemia, is also produced in the
brain. Results from both animal models and neuropsychiatric patients, suggested that this compound presents neurotrophic and neuroprotective effects and would improve
cognitive functioning (Siren et al., 2009). Indeed, it has
been reported that EPO would present antiapoptotic,

antioxidant and anti-inammatory properties and preclinical studies have shown that these actions contribute to an
antidepressant-like effects and improvement of cognitive
function together with enhanced hippocampal plasticity and
long-term potentiation.
Miskowiak and colleagues demonstrated that a single high
dose of EPO enhances memory and executive functions
(Miskowiak et al., 2012). They also found that EPO modulates the neural and cognitive processing of emotional
facial expression in depressed patients (Miskowiak et al.,
2010). Later, in a randomized double-blind placebo-controlled study with TRD patients, authors found a sustained
improvement in verbal learning and memory after repeated
EPO administrations as adjunctive treatment (8 weekly
infusions of 1 ml recombinant EPOdoses of 40,000 UI)
versus saline infusions (Miskowiak et al., 2014). Although
EPO did not demonstrate superiority over placebo regarding
depressive symptoms in the Hamilton Depression Rating
Scale (HDRS), which was the primary outcome, patients
treated with EPO showed a reduction in other related
measures such as the Beck Depression Inventory (BDI).
Moreover, when some patients who showed unexpected
symptom improvement before trial start were excluded
from exploratory analyses, a higher clear effect on primary
outcome was found. Concerning cognitive function, authors
suggested that EPO has direct, mood-independent effects
on verbal memory. Interestingly, there were no correlations
between the changes in red blood cells and memory and the
memory-effect persisted after normalization of red blood
cells. This suggests that the cognitive effects were at least
partially independent of hematological actions.
Further studies with larger samples of TRD to analyze the
antidepressant effects of EPO are needed, since the latter
study was not enough empowered to detect a clinically
relevant difference in the primary outcome variable (HDRS).
The clinical application of EPO is limited by its hematopoietic actions, which increase the risk of hypertension and
blood clotting, so a careful safety monitoring would be
necessary (Miskowiak et al., 2014). Other disadvantages of
EPO are related with its unclear potential risk of promoting
malignant tumor growth as well as the intravenously or
subcutaneously delivery. However, research focused on
developing derivates of EPO without hematopoietic activity
and other alternative administration (i.e. the intranasal
EPO) routes are being carried out (Miskowiak et al., 2012).
3.2. Other compounds with antidepressant effect

and different proles of cognitive effects
3.2.1. Lisdexamfetamine
Lisdexamfetamine Dimesylate (LDX) is a pharmacologically
inactive prodrug of D-amphetamine which has been
approved for treating attention-decit/hyperactivity disorder (ADHD). It modulates dopamine and norepinephrine
systems, which in turn are critical to maintain executive
functions mediated by the prefrontal cortex (Arnsten and
Li, 2005). In addition, this drug administered as an augmentation therapy to antidepressants has demonstrated to
effectively reduce depressive symptomatology in poor
responders to escitalopram (Trivedi et al., 2013).
9
Recently, Madhoo and colleagues evaluated the efcacy
of LDX augmentation of selective serotonin reuptake inhibitor (SSRI) monotherapy in a randomized, double-blind,
placebo-controlled, parallel-group study for treating executive dysfunction in partially or fully remitted MDD patients
with self-reported executive dysfunction (Madhoo et al.,
2014). In this study, the primary outcome was the change in
the Self-report BRIEF-A from baseline to endpoint. Secondarily, changes in the Informant Report BRIEF-A and neuropsychological test performance were also analyzed. In
addition to an improvement of residual depressive symptomatology, patients treated with LDX displayed a greater
executive improvement in the two BRIEF-A reports when
compared to placebo, however the improvement in the
neuropsychological tests did not achieve statistical signicant levels. Although these results should be interpreted
cautiously since these derived from subjective cognitive
measures, these are of clinical relevance to be mentioned
since is the only one study that assesses cognitive effects of
LDX in depression. Future studies analyzing the potential
procognitive prole of LDX augmentation treatment using
objective cognitive measures are needed.
3.2.2. Ketamine
Ketamine is a high-afnity, noncompetitive N-methyl-Daspartate (NMDA) glutamate receptor antagonist that has
demonstrated a rapid antidepressant effect even within
hours in patients with TRD. In addition, ketamine exerts a
robust impact on reducing suicidal ideation which might
occur independently of its antidepressant effect (Blier,
2013). This drug, usually used as an anesthetic agent, has
the disadvantage of inducing negative neurocognitive
effects as well as transient dissociative and psychotomimetic effects at subanesthetic doses. However, it should be
remarked that, at the doses usually used in depressed
patients, most of them generally resolved within minutes
or rst hours following drug cessation. Some studies have
assessed the clinical utility of ketamine as an anesthetic
agent for electroconvulsive therapy (ECT) with the interest
that it could improve the antidepressant efcacy of ECT and
some of them have analyzed if ketamine could exert a
protective role against the neurocognitive side effects of
ECT, with inconsistent ndings. The rationale for these
studies is based on that one postulated mechanism for
cognitive impairment is excitotoxic damage related to
excessive glutamatergic transmission through the NMDA
receptor during ECT. In this regard, several lines of evidence
suggests that ketamine, an NMDA antagonist, may have
neuroprotective effects, including in a ECT treatment
context (Hudetz and Pagel, 2010; MacPherson and Loo,
2008), supported at the same time by indirect and brief
preliminary clinical reports (Krystal et al., 2003a; McDaniel
et al., 2006).
On one hand, in a randomized double-blind clinical trial,
Yossemi and co-authors found a better cognitive performance in patients receiving ECT with ketamine when
compared to patients from the thiopental group, which
remains stable even one month later (Yoose et al., 2014).
In contrast, Rasmussen and colleagues suggested that
ketamine did not diminish the cognitive impairment since
no signicant differences between depressive patients
10
receiving ketamine or methohexital were found (Rasmussen
et al., 2014). Similarly, Loo and colleagues also reported
that adding ketamine or placebo to thiopentone did not
reduce cognitive side effects (Loo et al., 2012). Nevertheless, it is difcult to draw conclusions regarding the use
of ketamine in ECT since conicting results may be related
to methodological differences (e.g. ketamine doses, anesthetic combinations, type of ECT administrationbilateral/
unilateral, time of assessment as well as sample characteristicsbipolar/unipolar depression). Furthermore, ketamine
is also associated with difculty to treat patients in a
clinical setting, not in a hospital (Sanacora et al., 2014).
Moreover, recently Murrough et al. (2014) assessed
neurocognitive functioning in a group of 25 TRD patients
before and after a 40 min intravenous infusion of ketamine
in an open-label fashion. The authors found that the
baseline neurocognitive performance may be a predictor
of ketamine response (lower levels of neurocognitive
performance were associated with an increased antidepressant response). They also reported an inverse correlation between the altered cognitive effects of ketamine and
its antidepressant efcacy, that is, when negative cognitive side effects occur following ketamine, it carried lower
response rate. In this study, ketamine was not associated
with an overall signicant neurocognitive decline; only a
minimal impairment in memory recall was observed after
administration of the drug. Afterwards, when patients
were categorized based on presence/absence of diminished cognitive performance following the ketamine administration, patients who had negative cognitive effects
were more associated with nonresponse to the antidepressant effects of ketamine. Similarly, two studies did not nd
a cognitive decline in TRD patients after several serial
infusions (three or six) of ketamine (Shiroma et al., 2014;
Diamond et al., 2014), neither in a 4-week follow-up.
Moreover, Shiroma and colleagues found an association
between a baseline attention performance and an antidepressant improvement after a series of ketamine infusions (Shiroma et al., 2014). It would be necessary to assess
more long-term neurocognitve effects of ketamine administered at low doses to evaluate the safety of ketamine on
neurocognition to be considered as a potential treatment
for TRD (Murrough et al., 2014).
Moreover, some of the aforementioned studies assessed
cognition using a simple cognitive measure (the MMSE) and
only a few studies have analyzed the neurocognitive effects
of Ketamine as primary outcome by means of a comprehensive neuropsychological battery.
We expect that some of the ongoing clinical trials
(NCT01700829, NCT01881763, NCT01260649, NCT02012335,
NCT01441505) would give further evidence of the role of
ketamine in the treatment of depression and its potential
neuroprotective effects.
3.2.3. Lanicemine
Lanicemine, also known as AZD6765, is a low-trapping
N-methyl-D-aspartate (NMDA) channel blocker which might
be a potential novel glutamatergic-based therapeutics for
the treatment of refractory affective disorders without
presenting the acute psychotomimetic, dissociative side
effects attributed to ketamine.
B. Sol et al.
Results from different studies conrm the antidepressant
effect of this pharmacological agent as an adjunctive
treatment (single or repeated doses) in both patients
experiencing a moderate-to-severe MDD and TRD. In this
sense, Zarate and colleagues found a rapid antidepressant
effect of lanicemine in TRD patients with a single intravenous dose of 150 mg of lanicemine but with a shortprolonged action (Zarate et al., 2013). In contrast, they
found a more robust and sustained effect of ketamine in
TRD patients in a previous study (Zarate et al., 2006a).
So far, no clinical meaningful effects on cognitive variables have been reported concerning the use of lanicemine.
A phase IIA, double-blind, randomized study conducted in
TRD patients with single doses of 100 mg of lanicemine
where cognitive variables were assessed as secondary outcomes did not found differences between the two arms
(lanicemine versus placebo) (Sanacora et al., 2014). Further
studies with this compound will be necessary to conrm the
supposed antidepressant efcacy of lanicemine as well as its
lower cognitive side effects when compared to ketamine.
Unfortunately, lanicemine's clinical development has been
recently stopped after a failed phase III study.
3.2.4. Intranasal oxytocin

It has been observed that oxytocin, a neuropeptide, is
involved in socialemotional functioning, such as emotion
recognition, memory for faces, interpersonal trust, etc. and
in promoting prosocial behaviors (Ellenbogen et al., 2013).
Despite many questions still remains to be answered about
how intranasal oxytocin (OT) acts, in recent years an
increased interest on OT and its impact on the treatment
of several clinical populations has emerged (e.g. autism,
social anxiety, postnatal depression, obsessive-compulsive
problems, schizophrenia, borderline personality disorder
and post-traumatic stress). The doses of OT administered
in studies assessing OT could range from 15 IU to more than
7000 IU, and also included a great variety of outcomes (for
example, related with social cognition, emotional recognition, social behaviour, etc.). However, some authors have
pointed out that, at the moment, the pharmacotherapeutic
use of OT seems less effective in several psychiatric
disorders, being the individuals diagnosed with autism or
related disorders who might prot most from the adjunct
application of OT (Bakermans-Kranenburg and van, 2013).
In a pilot study assessing the OT effects in male depressed
patients in a psychotherapeutic setting, authors found that
OT improved social cognition through the performance on
the Reading the Mind in the Eyes Test (RMET), a test
developed to assess emotional mental attribution (Macdonald
et al., 2013). To the contrary to what was expected, patients on
OT, experienced increased levels of anxiety, but interpreted
more accurately the states of mind from visual facial cues than
placebo group. Other authors studied the inuence of a single
dose of OT on functional brain activity using an fMRI paradigm,
with a randomized double-blind crossover design, comparing
unmedicated depressed females with matched healthy control
subjects (Pincus et al., 2010). Obtained results suggest that OT
acts in a different way in depressed patients and healthy
controls. The former showed an increased activation in primary
emotional circuits such as the cingulated and insula when
compared to healthy subjects. Moreover, depressed subjects

showed a slower speed of response when received OT whereas
the healthy subjects presented faster reaction times. It should
be mentioned that oxytocin did not affect the accuracy of
responses in either group.
Apart from that, in a study carried out with a sample of
university students with high levels of depressive symptoms
which did not meet MDD criteria, the authors found that,
those patients on OT presented more difculties to inhibit
the processing of sad faces in a negative affective priming
(NAP) task (Ellenbogen et al., 2013). This was an unexpected nding for the authors since no global effect on
inhibition has been proved concerning OT administration.
However, other studies has demonstrated that OT effects
may vary due to individual differences and on the context
(Guastella and MacLeod, 2012; Bartz et al., 2011). One
possible explanation to their results could be related to an
increasing empathy toward others.
The effect of OT has also been explored in other clinical
populations, such as mothers with postnatal depression and
assessing sensitive parenting, with an improvement in the
relationship between mothers and their infants (Mah et al.,
2013).
3.2.5. Omega-3
During the last few years, there has been a growing interest
about the benets and practical use of long chain omega-3
fatty acids since benecial effects for mood disorders has
been described. In this sense, it has been suggested that a
low dietary intake of them may be related with an increased
risk for some psychiatric disorders, particularly for depression. Levels of omega-3 polyunsaturated fatty acids (PUFAs)
have been found to be depleted in MDD patients in an acute
episode. For instance, DHA is associated with neural membrane stability and with serotonin and dopamine transmission, which in turn has been traditionally linked to
depression pathophysiology (Chalon, 2006).
A double-blind randomized controlled trial assessed the
effects of n-3 LCPUFA supplementation on mood and cognition, as primary and secondary outcomes, respectively
(Rogers et al., 2008). This study failed to provide any
evidence of positive effects on depressed mood or on
cognitive domains (visual probe task, speed of information
processing, reasoning, impulsivity and working memory)
among people with mild to moderate depression. It is
necessary to mention that this trial recruited patients from
general population presenting depressed mood, although
none of them met criteria for major depression in a clinical
setting neither followed any antidepressant treatment.
These data comport with a meta-analysis carried out by
Appleton and co-authors which showed a limited effect of n3 long-chain polyunsaturated fatty acids on depressed mood
(Appleton et al., 2006). However, a recent update metaanalysis by Appleton and colleagues supports the efcacy of
omega-3 on depressed mood but heterogeneity is still an
issue to draw rm conclusions, as other authors also pointed
out (Lin and Su, 2007). It seems that a distinguishing effect
of PUFAs between patients diagnosed of depression and
individuals with depressed mood (without diagnosis) may
exist: there is some evidence suggesting a positive effect of
n-3 PUFA supplementation for the rst group whereas there
is no evidence for the latter (Appleton et al., 2010).
11
Therefore, currently there is a growing debate about the
role of PUFAs on depression.
Moreover, Antypa and colleagues have tested the effects
of n-3 PUFA supplementation on emotional information
processing and mood in remitted depressed patients in a
double-blind randomized design (Antypa et al., 2012). They
found a small effect of omega-3 supplementation on aspects
of emotional decision-making, however, they did not nd
any inuence in other neutral cognitive domains such as
attention and memory.
3.2.6. S-adenosyl-methionine
S-adenosyl-methionine (SAME) is a naturally occurring molecule in all living human cells with an important role in
cellular metabolism which serves as methyl donor in cellular
metabolism (Mischoulon and Fava, 2002). Currently, it is
also considered as a dietary supplement. Clinical trials have
demonstrated that parenteral SAME monotherapy is superior
to placebo and comparable to tricyclic antidepressants in
treating depressed patients (Papakostas, 2009). In a preliminary study, it has been also demonstrated to be effective as an oral adjunctive treatment for depressed patients
with low response to antidepressant (Papakostas et al.,
2010). Nevertheless, similarly to what happens to other
aforementioned agents, one of the main clinical limitations
stems from the route of administration, since there is little
evidence concerning oral administration.
Despite different potential mechanisms of action have been
proposed, it remains unclear how SAME exerts its antidepressant action. It has been hypothesized that when SAME may alter
the uidity of neural membrane trough methylation of plasma
phospholipids, it would affect the activity of proteins that
transverse the membrane, among them the monoamine receptors and transporters (Mischoulon and Fava, 2002).
Regarding cognitive function, the group of Papakostas
provided preliminary evidence on the ability to improve
recall information and a trend toward a greater enhancement in word-nding in depressed patients treated with oral
adjunctive SAME based on subjective self-reports measures
(Levkovitz et al., 2012). The authors administered the CPFQ
(Massachusetts General Hospital Cognitive and Physical
Functioning Questionnaire), validated as a reliable measure
of cognitive and physical symptoms of MDD, however, it
relays on patients' self-report. As far as we know, no more
studies have evaluated the cognitive effects of SAME in
MDD, therefore, it would be necessary to conrm these
ndings by using a comprehensive neuropsychological battery in studies specically designed to assess the effects of
SAME on cognitive function.
3.2.7. Scopolamine
As mentioned earlier, it is well known that hypersensivity of
the cholinergic system play a role in the pathophysiology of
depression. In this regard, scopolamine, which is a muscarinic cholinergic receptor antagonist, produces a rapid and
long-lasting antidepressant effect (Drevets et al., 2013). In
addition to the antagonist effects at muscarinic receptors,
it modulates other neurotransmitter systems such as the
dopaminergic, serotonergic and the neuropetide Y, as well
as it seems to involve modulation of NMDA receptor
function.
12
B. Sol et al.
Furey and Drevets assessed the role of the cholinergic

system in selective attention in a pilot study with an
intravenous administration of scopolamine hydrobromide.
They hypothesized that selective attention would
improve under antimuscarinic agents treatment (Furey
and Drevets, 2006). However, no signicant overall
changes in the attention task were found when patients
on scopolamine were compared with those on placebo.
Hence, scopolamine seems to have a small impact on
attention.
To the best of our knowledge, no more studies have
assessed the effects of scopolamine in depressed patients.
4.
Discussion
We provide a descriptive overview about the available

research on different pharmacological agents that might
inuence cognitive functions in patients with a MDD, either
as monotherapy or as an adjunctive treatment. Despite the
high number of promising new therapies, current evidence
is insufcient to support any augmentation strategy as a
treatment recommendation for cognitive symptoms in
major depressive disorder. Most of the reviewed agents
require further investigation.
Modanil is currently considered an effective augmentation treatment for major depressive disorder, but their
cognitive effects in MDD have still been understudied,
whereas there is some evidence suggesting that modanil
improves cognition in other psychiatric conditions (i.e.
ADHD children and schizophrenia). The same occurs with
lixdexamfetamine, which seems to be effective not only
reducing depressive symptomatology in some populations
of depressed patients, but also improving self-reported
cognitive measures of patients. However, more studies
focused on objective cognitive measures are needed in
order to conrm the potential procognitive effects of
lixdexamfetamine.
At the moment, agents targeting the glutamatergic system
emerge as a promising intervention for mood symptoms, since a
growing body of evidence implicates this system in the
pathophysiology of depression. In addition, it should be
remarked that NMDA receptors are also involved in executive
processing and learning/memory, among other cognitive functions. With regard to ketamine, several studies have studied
their cognitive side effects, for example, when administered as
an anesthetic agent in ECT. Nevertheless, data indicating a
better cognitive prole of ketamine when compared to other
anesthetic agents is still limited and inconclusive. In the future,
some ongoing clinical trials could help to elucidate the
potential cognitive effects of ketamine in ECT. Moreover, other
routes of ketamine administration, as oral and intranasal, are
currently being tested in TRD patients. Future randomized
placebo-controlled studies with larger samples will be needed
in order to determine the cognitive effects in a short or
medium-term of glutamatergic antagonist and, as some authors
pointed out, it is necessary to examine if longer duration of
infusions as well as higher doses could induce cognitive decline
(Diamond et al., 2014). In fact, concerning safety, whereas
lower doses of ketamine have been associated with neuroprotection and neutotrophic effects, on the other side higher doses
of ketamine and longer duration of exposure have been
associated to neurotoxic effects and cognitive impairments.

Therefore, more research is necessary before this can be
recommended as a treatment.
Lanicemine might appear as an alternative pharmacological
option but the future of this drug is unclear given the
discontinuation of its clinical development in TRD. In view of
the rapid antidepressant effect of ketamine, several new
agents affecting the glutamate pathway are under investigation, such as modulators of AMPA receptors, NMDA receptor
subunit GluN2B and metabotropic glutamate receptors
(mGluRs). For instance, traxoprodil and MK-0657 are GluN2B
antagonists which have demonstrated efcacy in TRD
(Preskorn et al., 2008; Ibrahim et al., 2012), although further
studies with larger samples are needed to support these
ndings. Moreover, as far as we know, no studies focused on
cognitive effects of this group of agents in MDD have been
reported yet. Other compounds related to the glycine modulatory site on the NMDA receptors, such as D-cycloserine and
GLYX-13, have also led to a signicant improvement in
depressive symptomatology (Heresco-Levy et al., 2013;
Burgdorf et al., 2013) and have great potential. In addition,
due to the fact that mGluR seem to play a signicant role in
depression, some agents acting on them have been developed
(i.e. MGS0039, LY341495, among others). In fact, one of them,
the RO4432717, has shown positive effects on cognition in
some preclinical models (Goeldner et al., 2013). Hopefully,
the development of novel potential antidepressant treatments
targeting this neural system in a near future provide us with
effective therapeutic tools not only for treating depression,
but also with the cognitive impairment usually associated to
this clinical condition.
Data concerning potential cognitive benets of memantine, galantamine and donepezil (all of them approved for
treating cognitive dysfunction in Alzheimer's disease) lack
substantial efcacy as an augmentation treatment for MDD.
Probably this fact has led few studies assessing cognition in
depressed patients. Memantine, which also targets glutamatergic system, has not demonstrated a clear efcacy in
depression in RCT. On the other hand, the few existing
studies examining the cognitive performance of patients
treated with galantamine and donepezil were conducted
with older depressed adult patients and failed to demonstrate a clear cognitive benet. While decits in cholinergic
function are related to the cognitive symptoms of depression, several authors hypothesized that depressive patients
may show a cholinergic hypersensitivity to depressogenic
effects of cholinoceptive agents (Dilsaver, 1986). To the best
of our knowledge, the effects of rivastigmine on the
cognitive functioning of unipolar depressed patients have
not been evaluated.
Data derived from some clinical trials on scopolamine,
another agent which acts on cholinergic system, suggest
that it could be considered as an effective adjunctive
treatment for patients with MDD. Only one study has so
far assessed the cognitive effects of scopolamine showing a
minor impact on selective attention.
Vortioxetine is a promising new multimodal antidepressant which may improve cognitive function in depressed
adults independently of its antidepressant effects (McIntyre
et al., 2014). Several trials are currently ongoing to test
the precognitive effects of this compound in depressed
patients.

Antiglucocorticoid treatments are thought to attenuate
depressive symptoms in some diagnostic subtypes since the
hypothalamicpituitaryadrenocortical (HPA) axis dysregulation
seems to play an important role on the pathophysiology of
depression. Despite one might argue that these compounds
could improve cognitive functioning, no studies have evaluated
their cognitive effects, specically in MDD patients. While the
efcacy of mifepristone in depressed patients has been demonstrated in some small, double-blind, placebo-controlled studies,
other studies failed to signicantly separate mifepristone from
placebo in depression (Schule et al., 2009). Furthermore,
mifepristone seems to be more effective to treat psychosis in
psychotic depression than to have a consistent effect on core
depressive features. In a bipolar sample treated with the
aforementioned drug, a spatial working memory improvement
was detected and this result was sustained at six weeks after
cessation of treatment (Watson et al., 2012). Whereas in
bipolar disorder there are studies with positive results (Young
et al., 2004; Watson et al., 2012; Dias et al., 2012), no
published studies have assessed the cognitive properties of
mifepristone in major depressive samples. However, it should
be mentioned that, currently, there are some ongoing clinical
trials with depressed patients which have been completed with
not yet published results. Other antiglucocorticoids have been
reviewed here (i.e. ketoconazole, metyrapone) but, as far as
we know, no studies have evaluated their cognitive effects on
depressed patients.
Apart from that, other augmentation strategies related to
dietary supplements, such as omega-3 and s-adenosyl
methionine, are now being studied regarding their potential
effects on cognition. Nevertheless, further studies will be
required to clarify their utility. Omega-3 seems to present
an effect improving emotional information processing
(Antypa et al., 2012).
Similarly, intranasal oxytocin also could be implicated in
emotional/social cognition. The inhibition of information with
an emotional component may be related to the regulation of
negative emotion, particularly, in depressed patients. A small
number of studies have addressed the effects of OT in clinically
depressed patients. It is necessary to better understand how
oxytocin inuences cognition since it seems to be mediated by
different factors and contexts (Ebner et al., 2013). Further
studies in clinically depressed patients or remitted patients are
warranted.
Lastly, other pharmacological candidate for the management
of memory impairment in unipolar depression is erythropoietin
(EPO). Although evidence is still scarce, EPO could represent a
novel add-on strategy for patients with persistent cognitive
decits. It should be remarked that there are some limitations
regarding its route of administration and its potential hematological side effects lending to a necessary monitoring. That is
why some other routes of administration are currently being
investigated.
As recommendations, one consideration derived from this
review is that further clinical trials will be required in order
to assess cognitive function as a primary outcome. Cognitive
function has been traditionally considered as a secondary
outcome (Keefe et al., 2014) and most studies were not
specically designed nor powered to assess the cognitive
effects of the different pharmacological drugs covered in
this review. In the same line, longer follow-up studies of
cognitive changes in response to different pharmacological
13
treatments are required to better characterize the potential procognitive proles of each of them. In addition,
studies with larger samples of depressed patients also are
necessary. Besides, some of the included studies (i.e.
galantamine, donepezil) were conducted only with elderly
depressed samples. For this reason, it will be necessary to
analyze these drugs in depressed young populations since
the former group presents with specic characteristics due
the risk of developing cognitive impairment associated to
dementia. Moreover, as other authors have previously
proposed, it would be necessary to develop and employ an
standardized neuropsychological battery to assess cognitive
functioning in unipolar depression in order to allow comparisons between studies (Anaya et al., 2012; Baune and
Renger, 2014). A critical issue, once a drug with clear
procognitive effects is identied or developed, will be to
proof that improvements in cognition translate into better
psychosocial functioning, and that those pro-functional
effects are not pseudospecic (meaning that they are
independent from the improvement of mood). Tools such
as the FAST or the UPSA-B may be useful in that regard (Rosa
et al., 2007; Mausbach et al., 2007).
It is worth to mention that despite non-pharmacological
strategies have not been included in the current review,
psychosocial interventions, such as cognitive remediation
(CR), might ameliorate cognitive dysfunction associated to
depressive symptoms. Recent studies have shown that functional remediation, based on cognitive enhancement, may be
helpful in patients with bipolar disorder (Torrent et al., 2013;
Sole et al., 2014). However, very few studies have specically
addressed the efcacy of CR in depressed patients with MDD.
Anaya and colleagues as well as, more recently, Baune and
Renger, covered this topic (Anaya et al., 2012; Baune and
Renger, 2014). Both reviews pointed out that, despite results
are encouraging, additional studies are needed to properly
assess the effects of CR in depression. Furthermore, CR
programs specically addressed to patients with MDD should
be developed. Exercise as a procognitive intervention is also
worth studying. Lastly, studies on combination of pharmacological treatments and CR should be considered to enhance
cognition in MDD.
One of the main limitations of our review is the use of
only Pubmed database, which may have restricted the
search to published, publicly available information. Since
this is an extremely hot topic nowadays, there may be
emerging data which has not been published yet that might
be relevant to this topic.
In conclusion, currently there is an increased interest to nd
new treatments targeting the cognitive impairment associated
to depression due to the clinical signicance on functional
outcome. A few agents in monotherapy or augmentation
strategies seem to reduce some cognitive impairment, but it
is difcult to draw clear conclusions due the large variability of
studies and some negative ndings, so, further studies are
warranted.
Role of funding source

Supported by a grant from the Spanish Ministry of Economy and
Competitiveness (PI11/00637, PI12/00912) integrated into the Plan
Nacional de I +D +I y conanciado por el ISCIII-Subdireccin General
de Evaluacin y el Fondo Europeo de Desarrollo Regional (FEDER);
14
CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUE
de la Generalitat de Catalunya (2014 SGR 398 to the Bipolar
Disorders Group) and with the support of the Esther Koplowitz
Centre (CEK). Anabel Martinez-Aran's project is supported, in part,
by a 2013 NARSAD, Independent Investigator Grant from the Brain &
Behavior Research Foundation.
Contributors
All the authors have been sufciently involved in the submitted
study and have approved the nal paper.
Conict of interest
Dr. Martinez-Aran has served as speaker or advisor for the following
companies: Bristol-Myers Squibb, Otsuka, Lundbeck and Pzer.
Dr. Vieta has received grants, CME-related honoraria, or consulting fees from Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb,
Cephalon, Eli Lilly, Ferrer, Forest Research Institute, Gedeon
Richter, GlaxoSmith-Kline, Janssen, Janssen-Cilag, Jazz, Johnson
& Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pzer,
Pierre-Fabre, Qualigen, Roche, Sano-Aventis, Schering-Plough,
Servier, Shire, Solvay, Takeda, Teva, CIBERSAM, the Seventh European Framework Programme (ENBREC), the Stanley Medical
Research Institute, United Biosource Corporation, and Wyeth. The
other authors report no nancial relationships with commercial
interests.
Acknowledgments
The authors thank the support of the Esther Koplowitz Centre (CEK)
and of the Spanish Ministry of Economy and Competitiveness,
Instituto de Salud Carlos III, CIBERSAM, the Spanish Ministry of
Education and the Comissionat per a Universitats i Recerca del DIUE
de la Generalitat de Catalunya to the Bipolar Disorders Group (2014
SGR 398)and the 2013 NARSAD, Independent Investigator Grant
from the Brain & Behavior Research Foundation (Grant no. 20288).
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Cognition as a Target in Depression: New Developments

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European Neuropsychopharmacology (]]]]) ], ]]]]]]

Cognition as a target in major depression:

Major depressive disorder (MDD) is a highly prevalent and

Correspondence to: Bipolar Disorder Program, Clinical Institute

To identify relevant studies, we performed a PubMed search of new

1. Studies conducted on humans where participants were adults

2. Exploring changes in cognitive functions as primary or secondary

3. A randomized, or quasi-randomized controlled trial or an open

4. English language original articles.

1. Preclinical studies (such as animal studies).

Cognition in major depression

3.1. Compounds with potential procognitive

Main characteristics of studies.

Randomized Double- Main nding

MDD with partial

Elgamal and MacQueen (2008)

Matthews et al. (2008) (pilot

Compound with potential procognitive effect

Muhonen et al. (2008)

Matthews et al. (2013)

Holtzheimer et al. (2008)

Signicant improvement in the CWST; WAIS-III Letter Number,

GLMT may be protective

RBANS; 3MS; WASI (vocabulary,

CVLT; TMT-A, TMT-B; Ruff 2 and

Patients with donepezil showed BSRT; digit symbol WAIS-III;

Whether donepezil should be

McIntyre et al. (2014)

VRTX 10 mg =195 Primary

Katona et al. (2012)

Miskowiak et al. (2010)

Miskowiak et al. (2014)

Compounds with antidepressant effect and different prole of cognitive effects

Pelton et al. (2008) (pilot study

TMT-A, TMT-B; Digit Symbol,

Cognition in major depression

EPO modulates the neural and fMRI paradigm of facial

LDX augmentation signicantly BRIEF-A

Shiroma et al. (2014)

Diamond et al. (2014)

Murrough et al. (2014)

Rasmussen et al. (2014)

Yoose et al. (2014)

Loo et al. (2012)

Randomized Double- Main nding

and depressive symptoms in

Estimated premorbid IQ;

MMSE (before rst ECT, 48

Intranasal oxytocin Macdonald et al. (2013)

Rogers et al. (2008)

Antypa et al. (2012)

for ECT did not decrease

CFT; HVLT; COWAT; SDMT; Wood

OT has a differential effect

Only small effects of omega-3

Adjunctive SAME may be

Levkovitz et al. (2012)

Furey and Drevets (2006)

Cognition in major depression

Affective Go/No-Go task;

2008; Elgamal and MacQueen, 2008). Some considerations

Therefore, the available evidence does not suggest a