Art No.4

Psychiatry Research 219 (2014) 25–50
Contents lists available at ScienceDirect
Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres
Review article
Pharmacological and non-pharmacological interventions to improve

cognitive dysfunction and functional ability in clinical depression – A
systematic review
Bernhard T. Baune n, Lisa Renger
Discipline of Psychiatry, University of Adelaide, Adelaide, Australia
art ic l e i nf o a b s t r a c t
Article history: Cognitive dysfunction is of clinical significance and exerts longstanding implication on patients' function.
Received 16 September 2013 Pharmacological and non-pharmacological treatments of cognitive dysfunction are emerging. This review
Received in revised form evaluates pharmacological and non-pharmacological treatments of cognitive impairment primarily in the
12 April 2014
domains of memory, attention, processing speed and executive function in clinical depression. A total of 35
Accepted 5 May 2014
Available online 14 May 2014
studies were retrieved from Pubmed, PsycInfo and Scopus after applying inclusion and exclusion criteria.
Results show that various classes of antidepressants exert improving effects on cognitive function across
Keywords: several cognitive domains. Specifically, studies suggest that SSRIs, the SSRE tianeptine, the SNRI duloxetine,
Cognitive dysfunction vortioxetine and other antidepressants such as bupropion and moclobemide may exert certain improving
Cognitive impairment
effects on cognitive function in depression, such as in learning and memory and executive function. Class-
Depression
specific cognitive domains or specific dose–response relationships were not identified yet. The few non-
Mood disorder
Antidepressant treatment pharmacological studies conducted employing cognitive orientated treatments and cognitive remediation
Remediation therapy therapy show promising results for the improvement of cognitive impairment in depression. However, several
Cognitive therapy methodological constraints of studies limit generalizability of the results and caution the interpretation. Future
direction should consider the development of a neuropsychological consensus cognitive battery to support the
discovery, clinical assessment, comparison of studies and registration of new agents in clinical depression.
& 2014 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1. The effects of antidepressant therapy on neuropsychological performance and functional ability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.1.1. Studies investigating effects of selective serotonin reuptake inhibitors (SSRIs), selective serotonin reuptake enhancers (SSREs),
and selective norepinephrine reuptake inhibitors (SNRIs) on cognitive function and functional ability in depression . . . . . . . . 27
3.1.2. Other pharmacological agents affecting cognitive function in depression: antidepressant therapy, bupropion,
S-Adenosyl methionine (SAMe), galantamine and donepezil augmentation, and acute tryptophan depletion (ACT). . . . . . . . . . 27
3.1.3. Comparative studies exploring effects of antidepressant treatment on cognitive performance in depression: SSRIs vs TCAs; SSREs vs
TCAs; SSREs vs SSRIs; SSRIs vs SNRIs; SSRIs vs NRIs; moclobemide vs viloxazine vs maprotiline; Lu AA21004 vs duloxetine . . . . . . . 27
4. Differential effects of antidepressants on emotion processes and cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.1. Neuropsychological approaches for the improvement of neuropsychological functioning and functional ability in depression . . . . . . . . 34
5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
6. Effects of pharmacological treatment on cognitive function and functional ability in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
7. Effects of non-pharmacological treatment on cognitive function and functional ability in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
8. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
n
Corresponding author. Tel.: þ 61 8 8222 5141; fax: þ61 8 8222 2774.
E-mail address: [email protected] (B.T. Baune).
http://dx.doi.org/10.1016/j.psychres.2014.05.013
0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
26 B.T. Baune, L. Renger / Psychiatry Research 219 (2014) 25–50
1. Introduction contrast, SSRI antidepressants such as citalopram have been sug-

gested to diminish neural processing of aversive and rewarding
According to the World Health Organization (WHO, 2012), stimuli in healthy individuals (McCabe et al., 2010), suggesting the
depression is estimated to affect around 350 million people across possibility that antidepressants may exert negative effects on
the world, marking the leading cause of disability worldwide neuropsychological function during antidepressant treatment of
regarding the total years lost due to disability. It is well-known that depressed patients. Other antidepressants that have been examined
depression is often accompanied by cognitive deficits that are and seem to have improving effects on neuropsychological func-
regarded as consistent, replicable, nonspecific, clinically significant, tioning in depression include selective serotonin reuptake enhan-
and of small to medium effect size (McIntyre et al., 2013). Cognitive cers (SSREs), tricyclic antidepressants (TCAs), and other specific
impairments in clinical depression have most often been identified drugs (Allain et al., 1992; Nickel et al., 2003; Gallassi et al., 2006;
in the domains of attention, learning and memory, and executive Holtzheimer et al., 2008; Katona et al., 2012; Levkovitz et al., 2012);
functioning (Beblo and Lautenbacher, 2006; Lee et al., 2012). however, their mechanisms of action on cognitive processes remain
Research has shown that some cognitive deficits such as to be fully understood.
immediate memory and attention (Baune et al., 2010) last even In addition to pharmacological antidepressant treatment, cog-
when depressive severity decreases and/or depression is remitted nitive approaches for the treatment of cognitive deficits in depres-
in both medicated and un-medicated patients with major depression have been employed. These approaches in depression
sive disorder (MDD) (Baune et al., 2012). Cognitive dysfunction primarily include cognitive remediation therapy. In brief, cognitive
might therefore be regarded as both, a state- and a trait-marker of remediation involves the application of systematic instruction and
depression. Conversely, since it has been suggested that SSRI and structured experience to alter the functioning of cognitive systems,
SNRI treatments can decrease the resting-state functional con- with the aim of improving the quality or quantity of cognitive
nectivity independent of mood change and in areas known to processing in the targeted domain(s) (Robertson and Murre, 1999).
mediate reward and emotional processing in the brain (McCabe Although the mechanisms underlying functional change are poorly
and Mishor, 2011), antidepressant treatment may also decrease understood, repeated stimulation of impaired cognitive functions
cognitive function. For this reason, the importance of dissociating through targeted, repetitive exercises has been shown to improve
the cognitive consequences of MDD from those of SSRI treatment, cognitive performance in patients with psychiatric illness, most
and from cognitive evaluation of MDD subjects in a medication- prominently schizophrenia (Bell et al., 2001, 2003; Fiszdon et al.,
naïve state before the administration of antidepressants has been 2004). Despite cognitive remediation therapy has been less exten-
recently highlighted in a study by Herzallah et al. (2013a). More- sively studied in depression as compared to schizophrenia, few
over, additional factors such as demographic, psychological, and studies suggest this to be an effective method to improve at least
biological factors have been suggested to influence the profile and some areas of cognitive functioning, such as attention, verbal
severity of neuropsychological deficits, but overall, etiological learning and memory and executive function (Elgamal et al.,
mechanisms are not fully understood yet (Beblo et al., 2011). 2007; Naismith et al., 2010). In addition, a study using cognitive
In addition to the cognitive deficits, it is known that a remediation in bipolar patients with residual (subsyndromal)
depressive episode is also characterized by deficits in psychosocial depressive symptoms showed improvements in executive func-
and overall functioning. A prospective study found that patients tioning, occupational and overall psychosocial functioning as well
with MDD or bipolar depressive episodes had moderate to severe as a reduction in residual depressive symptoms (Deckersbach et
impairments in work and home functioning as well as mildly to al., 2010). Other neuropsychological approaches such as psycho-
moderately impaired relational functioning (Godard et al., 2012). dynamic psychotherapy have also been examined to improve
Even if the relationship between cognitive dysfunctions and cognitive function in depression. In a recent study examining a
general functioning is controversial, there is evidence that the sample size of 60 subjects with a current moderate depressive
persistent cognitive deficits in depression play an important role in episode, it was reported that psychodynamic psychotherapy
some patients' ability to functionally recover (Jaeger et al., 2006; increases the improving effect of antidepressant treatment on
Baune et al., 2013). Also, cognitive function in depression is short-term memory and attention (Klasik et al., 2011). Similar
significantly related to employment status although the causal synergistic treatment effects between antidepressants and psy-
relationship remains to be clarified (Baune et al., 2010). A pre- chological treatments have been suggested in a neuropsychologi-
liminary study suggests that deficits in executive functioning have cal model of antidepressant drug action by Harmer et al. (2009a).
a mediating effect on the relationship between depression and It is argued that some antidepressants have the ability to change
impaired activities of daily living (Kiosses and Alexopoulos, 2005). the relative balance of positive to negative emotional processing,
Moreover, mood disorder patients with neuropsychological defi- which provides a platform for subsequent cognitive and psycho-
cits tend to be less compliant with antidepressant treatment logical reconsolidation (Harmer et al., 2009a; Harmer, 2010).
(Martinez-Aran et al., 2009) and show an increased risk for suicide Lastly, alternative approaches such as meditation suggest addi-
(Westheide et al., 2008), both of which highlight the clinical tional improving effects on cognitive function in depressed
importance of neuropsychological deficits. patients treated with antidepressants (Sharma et al., 2006).
Taken together, the clinical findings on the relevance of neu- The above literature suggests that the cognitive dysfunction is a
ropsychological deficits in clinical depression suggest that these clinical feature of clinical depression and that cognitive dysfunction
symptoms deserve clinical attention and possible treatment. So far has been identified as a target of pharmacological and non-
however, research has rather focused on pharmacological interven- pharmacological treatment approaches in depression. However, this
tions that address mood-related symptoms in depression and field has not been comprehensively reviewed and evaluated yet.
currently, very little is known about interventions that might Since this area is emergent in the literature and appears to have
improve cognitive, psychosocial and general functioning. Some clinical relevance, a comprehensive review is timely and necessary.
antidepressants have been reported to improve not only mood- The purpose of this review is to provide a comprehensive overview
related symptoms, but also cognitive performance in depressive of the studies that have examined effects of pharmacological and
patients. Research has primarily examined serotonin reuptake non-pharmacological interventions on cognitive, psychosocial or
inhibitors (SSRIs) and serotonergic–noradrenergic reuptake inhibi- overall functioning in patients with clinical depression considering
tors (SNRIs) indicating that SNRIs are superior to SSRIs at improving a wide range of pharmacological antidepressant drug classes and
certain cognitive functions (Herrara-Guzman et al., 2009). In comparative studies. On this basis, we evaluate the current evidence
B.T. Baune, L. Renger / Psychiatry Research 219 (2014) 25–50 27
and discuss which further research is needed to eventually imple- and cognitive symptoms (Saiz-Ruiz et al., 1998). In support of these
ment effective interventions to improve neuropsychological func- findings, another 3-month observation showed that tianeptine led
tioning in the treatment of depression. to significant improvement on short-term memory, reaction time
and attention (UBS, SBS, SDT, RTI) after 1 month, which increased
even more after 3 months (Klasik et al., 2011).
2. Methodology
To assess functional ability after treatment with duloxetine two
double-blind, randomized, placebo-controlled trials were con-
Studies until December 2013 were identified by searching PubMed and PsycInfo
databases, using the following search terms: “depression”, “cognitive deficits”, “cognitive ducted under the same protocol (Oakes et al., 2012). The two
functions”, “treatment”, “cognitive remediation”, “compensatory strategies”, “integrated trials did not yield consistent findings on all measures but both the
psychological therapy”, “functional skills training”, “remediation therapy”, “cognitive trials demonstrated significant improvements with duloxetine
behavioral therapy”, “effectiveness”, “memory”, “cognitive”, “cognition”, “cognitive
treatment in depressive symptoms and in social functioning in
functioning”, “cognitive effects”, “cognitive symptoms”, “antidepressants”, “bupropion”,
“tianeptine”, “SSRI”, “serotonin”, “duloxetine”, “sertraline”, and “tricyclics”.
the beginning as early as week 4 and continuing to the end of 12
Studies that examined effects of pharmacological or cognitive interventions on weeks. In one study among elderly patients it was shown that
cognitive, psychosocial or overall functioning in the participants were included. duloxetine did not exceed placebo on any cognitive measure
Participants that were at least 18 years old with a primary diagnose of clinical (VLRT, DSST, TDCT, TT B) (Robinson et al., 2014), and in another
depression as well as healthy controls were considered. Participants with post-
study duloxetine was superior to placebo on the VLRT but on no
stroke depression, schizophrenia, non-depressive bipolar disorder, substance
abuse, suicidality or any neurological disease like multiple sclerosis, dementia or other cognitive tests (MMSE, DSST, TDCT, LNST) (Raskin et al.,
Parkinson's disease were excluded. Studies were not included, if their full text was 2007; Tables 1 and 2).
not available or when they did not examine humans. No language or publication
date restrictions were imposed. Applying both the inclusion and exclusion criteria,
35 studies provided data from pharmacological or non-pharmacological trials on 3.1.2. Other pharmacological agents affecting cognitive function in
cognitive function in depression and were finally included in this review. depression: antidepressant therapy, bupropion, S-Adenosyl
methionine (SAMe), galantamine and donepezil augmentation, and
acute tryptophan depletion (ACT)
3. Results
This section evaluates studies employing various pharmacological
agents to investigate effects on cognitive performance in depression. In
3.1. The effects of antidepressant therapy on neuropsychological
a prospective cohort study with database linkage 281 elderly medical
performance and functional ability
inpatients were diagnosed with major, minor or no depression and
followed up with the MMSE and the HAM-D over 1 year to examine
3.1.1. Studies investigating effects of selective serotonin reuptake
the relationship between antidepressant medication and long-term
inhibitors (SSRIs), selective serotonin reuptake enhancers (SSREs), and
cognitive effects (Han et al., 2011). The authors found an association
selective norepinephrine reuptake inhibitors (SNRIs) on cognitive
between antidepressant medication and cognitive improvement in
function and functional ability in depression
minor depression, but not in major or no depression. A case-control
This section presents studies that found evidence that SSRIs and
study examined the cognitive response to antidepressant treatment
the SSRE tianeptine are able to improve certain cognitive functions
(nortriptyline or paroxetine) for patients with late-life depression and
whereas limited evidence was found for effects of the SNRI duloxetine
compared patients to those without concomitant cognitive impair-
on cognition, but it possibly improves social functioning. A preliminary
ment (Butters et al., 2000). It was found that as a group, the elderly
study tested the effects of four different SSRIs (fluoxetine, sertraline,
depressed patients showed a small improvement in overall cognitive
citalopram, paroxetine) on auditory–verbal declarative and working
and social functioning and that patients with cognitive impairment
memory performance in a case-control design comparing the results
improved in specific domains but they might not necessarily reach
of patients with remission to those without remission (Talarowska et
normal levels of performance.
al., 2010). As a result, patients with and without remission made
In a study among young depressed adults the neuropsycholo-
significantly less errors in the Stroop Test showing no significant
gical effects of the dopamine modulator bupropion and the
difference to the control group anymore but no improvements on the
cognitive predictors of treatment response to the drug were
other assessed measures (Stroop Test time of reading and of color
examined. The overall results suggest that memory and mental
naming, AVLT) were observed. However, another clinical trial among
processing speed performance could be predictors of response to
depressed adults showed that all measured cognitive functions (WAIS-
bupropion, and they are also the functions that are improved after
R RDS, RAVLT, d2 test) improved as well as depressive symptoms and
bupropion treatment (Herrera-Guzman et al., 2008).
cortisol values decreased during treatment with citalopram for 4 weeks
Moreover, three different double-blind, randomized, placebo-
(Zobel et al., 2004). Moreover, there was a significant correlation
controlled trials showed that S-Adenosyl methionine (SAMe)
between the cortisol values (DEX–CRH test) and the working memory
augmentation, as well as galantamine augmentation and donepe-
(Digits Backward Test) whereas the correlation between the DEX–CRH
zil augmentation improved certain cognitive functions in
test and the global severity of depression was not significant. A
antidepressant-treated elderly patients (Holtzheimer et al., 2008;
randomized case-control study among elderly patients also found that
Pelton et al., 2008; Levkovitz et al., 2012). High-dose acute
treatment with escitalopram significantly improved affective and
tryptophan depletion (ACT) however, only seems to improve
cognitive symptoms (GDS, MMSE) as well as facial identity recognition
attention for neutral stimuli (Stroop interference) but to impair
memory for angry faces (Savaskan et al., 2008). Furthermore, in a 1-
the processing of positive information independent of mood
year follow-up among elderly patients with minor or subsyndromal
change (Booij et al., 2005; Table 3).
depressive symptomatology the effects of sertraline and citalopram
were compared suggesting that both antidepressants equally
improved depressive and cognitive symptoms and social functioning 3.1.3. Comparative studies exploring effects of antidepressant
(Rocca et al., 2005). Besides, two studies showed that the effect of the treatment on cognitive performance in depression: SSRIs vs TCAs;
antidepressant treatment with sertraline was accompanied by a SSREs vs TCAs; SSREs vs SSRIs; SSRIs vs SNRIs; SSRIs vs NRIs;
beneficial effect on psychomotor slowing and executive functions moclobemide vs viloxazine vs maprotiline; Lu AA21004 vs duloxetine
(Constant et al., 2005; Schrijvers et al., 2009). Several studies indicate that SSRIs might be superior to TCAs in
A 3-months open multicentre study among elderly depressed terms of improving cognitive impairment (Levkovitz et al., 2002;
patients indicated that tianeptine is able to improve depressive Doraiswamy et al., 2003; Culang-Reinlieb et al., 2012). A 12-week
Table 1
Effects of SSRI-antidepressant therapy on cognitive performance and functional ability in depression.
Authors Aim of the study Study design Measures Results
Talarowska Determine the effect of antidepressive therapy on Preliminary study Comparison of test All antidepressants measured
et al. the efficiency of auditory–verbal declarative and scores at onset together:
(2010) WM performance and end of
treatment:
30 patients (16♀,14♂, M ¼ 45.15 years) Stroop Test, AVLT Before therapy correlations
with current MDD, 57 CG (38♀,19♂,
M ¼44.95 years), 8weeks
N ¼16: fluoxetine (M ¼35 mg/day) HAM-D Between the performance of the
cognitive tests and the intensity of
depression symptoms:
N ¼4: sertraline (M ¼ 130 mg/day) Stroop (reading, time) (p ¼ 0.012)
N ¼6: citalopram (M ¼31 mg/day) Stroop (naming color, time) (p ¼0.027)
N ¼4: paroxetine (M ¼ 32 mg/day) Stroop (errors) (p ¼0.029)
Response ¼HAM-D reduction 4 50% to AVLT (first trial) (p ¼ 0.029)
baseline
RemissioN ¼HAM-D score o 8 AVLT (after 30 min) (p¼ 0.043)
After 8-week therapy:
Recovery: 22
Response of treatment: 8
↑Stroop Test (errors) (p ¼ 0.007)
2Stroop Test (time)
2AVLT
↑HAM-D (p o 0.001)
n.s. differences between remitters and
non-remitters
Zobel et al. Explore the relationship between depression, Clinical trial Assessed at day After treatment:
(2004) memory functions and the responsiveness 8 and 36:
of the HPA system
64 Patients (19-65 years) with recurrent DEX–CRH test ↓Cortisol mean (0.01o p o 0.05)
MDD and current MDE, 4 weeks
Citalopram (stepwise increase to 20, 30 or Assessed at day ↓Cortisol AUC (0.001o po 0.01)
40mg from day 1 to 4, then fixed dose) 7 and 35:
N ¼37: adjunctive lorazepam WAIS-R RDS ↑WAIS-R RDS (0.01o po 0.05)
(M¼ 1.4 mg/day)
RAVLT ↑RAVLT (0.001 op o 0.01)
d2 test ↑d2 test (p o 0.001)
Assessed on day 0, ↑HAM-D (p o 0.001)
8 and 36:
HAM-D Significant correlation between
change scores in cortisol AUC and RDS
r¼ 0.475 (po 0.01)
Savaskan Investigate the antidepressive effects of Single-centre, randomized, open-label trial

Assessed 1 day Mean dosage of escitalopram after
et al. escitalopram before and at end 4 weeks: 16.1 mg/day
(2008) of treatment:
18 Patients (14♀,4♂, M ¼76.2 years) with FPRT No severe AEs, 3 patients with mild
MDD, 4 weeks AEs
N ¼18: Escitalopram (5 mg/day, Assessed during FPRT:
increased in 5-mg steps every 1–2 wk, treatment:
max.: 20 mg/day)
CG: 22 healthy controls (16♀,6♂, AEs CG4MDD-patients
M ¼76.9 years)
Assessed only Total (p ¼ 0.038)
before treatment:
GDS, MMSE Happy facial expressions (p ¼ 0.018)
CG: happy faces 4angry faces
(p ¼ 0.046)
MDD-patients: happy faces¼ angry
faces
Escitalopram:
2FPRT happy faces
↑FPRT angry faces (p ¼0.05)
↑MMSE (p ¼0.023)
↑GDS (p o0.0001)
Rocca et al. Compare the effects of sertraline and citalopram A 1-year follow-up clinical trial Assessed at n.s. differences between citalopram
(2005) on CF of non-demented elderly patients with baseline and after and sertraline
minor depressive disorder and subsyndromal 1, 2, 3 and
depressive symptomatology 6 months and
1 year:
138 Patients (39♀, 99♂, M ¼72.14 years) TT A&B, WMS, From 1 month forward:
with minor depressive disorder or MMSE, VFT
subsyndromal depressive
symptomatology
N ¼66: citalopram (20 mg/day) HAM-D, GDS, GAF ↑WMS
Table 1 (continued )
N ¼ 72: sertraline (50 mg/day) ↑HAM-D, GDS, GAF

From 2 months forward:
↑TT A, VFT, MMSE
From 6 months forward:
↑TT B
At end of follow-up:
Scores of TT A&B, VFT and WMS
similar to normal Italian elderly
population
Constant Investigate the changes induced by sertraline in Case-control clinical trial Assessed at After treatment:
et al. potential attentional and executive loss during baseline and after
(2005) subacute period 3 and 7 weeks:
20 Patients (12♀, 8♂, M ¼ 47.65 years) TAP, Stroop Test, ↑BDI (group session interaction
with depression 7 weeks: sertraline supraliminal and p o0.0001)
(50 mg/day) subliminal Stroop
Test
26 matched healthy controls (13♀,13♂, BDI, STAI ↑STAI state (group session
M ¼48.85 years) interaction p o 0.02)
↑STAI trait (group session
interaction p o 0.01)
2TAP errors
↑TAP RTI with Warning Signal (n.s.
group Warning Signal interaction)
↑Stroop, RTI (p o0.00001)
↑Supraliminal Stroop negative words,
RTI (po 0.001)
↑Subliminal Stroop, RTI (po 0.05)
However, patients' scores stayed
worse than controls' scores on all
measures
Schrijvers Examine the psychomotor effects of sertraline Case-control clinical trial Assessed at week At baseline controls4patients:
et al. 0, 1, 2, 3, 4, 5, and
(2009) 6:
19 Patients (11♀, 8♂, M ¼ 39.1 years) with Figure copy task, Copying task, initiation time
a current MDE 6 weeks: sertraline BDI (p o 0.001)
(50 mg/day; if no response between
weeks 2 and 4 100 mg/day)
22 healthy controls (12♀,10♂, M ¼ 39.0 Assessed at weeks Copying task movement time
years) 0, 2, 4, 6: (p o 0.05)
DSST,6: Copying task, errors (po 0.05)
Assessed at weeks After treatment:
0, 3
SRRS DSST
HAM-D ↑Initiation time, errors (n.s. difference
to controls)
2Movement time (controls
improved, patients did not)
Copy lines
↑Initiation time, movement time
(patients more than controls p o 0.05)
Copy simple figures
↑Initiation time (n.s. difference to
controls)
↑Movement time (patients more than
controls p o 0.05)
Copy complex figures
↑Initiation time (patients more than
controls p o 0.05)
2Movement time, reinspection time
↑HAM-D, BDI (p o 0.001)
n.s. correlations between between-
session differences in HAM-D scores
and between-session differences in
psychomotor performance
Abbreviations: ↑ ¼ improved, ↓ ¼decreased, 2¼ no significant change, 4 ¼ superior to, APRT ¼Abstract Pattern Recognition Task, ACT ¼Auditory Consonant Trigrams,
ACTH ¼ adrenocorticotropic hormone, AMI-SF¼ Autobiographical Memory Interview-SF, APRT ¼ Abstract Pattern Recognition Test, ATD ¼acute tryptophan depletion,
AUC ¼area under the curve, AVLT ¼Auditory Verbal Learning Test, BAS¼ Barnes Akathisia Scale, BCRT¼ Buschke cued recall test, BDI ¼ Beck Depression Inventory, BDQ ¼Brief
Disability Questionnaire, BFRT ¼ Benton Facial Recognition Test, BL ¼bilateral, BNT ¼ Boston Naming Test, BPD ¼Bipolar Disorder, BPRS ¼ Brief Psychiatric Rating Scale,
BSRT ¼ Buschke Selective Reminding Test, CDS ¼Calgary Depression Scale, CFF ¼Critical Flicker Fusion, CFT¼ Complex Figure Test, CG¼ control group, CGI ¼Clinical Global
Impression Scale, CHESS-84 ¼Guelfr and Pull Somatic Complaints Inventory, CIRS-G ¼ Cumulative Illness Rating Scale for Geriatrics, COWAT¼ Controlled Oral Word
Association Test, CPFQ ¼ self-rated cognitive and physical symptoms questionnaire, CPT ¼ Continuous Performance Test, C-SSRS ¼Columbia-Suicide Severity Rating Scale,
CVLT¼ California Verbal Learning Test, DART¼ Danish Adult Reading Test, DASS ¼Depression, Anxiety and Stress Scales, D–KEFS ¼Delis–Kaplan Executive Functioning
System, DMS¼ delayed matching to sample, DRI¼ deficient response inhibition, DRS ¼ Dementia Rating Scale, DSST¼Digit Symbol Substitution Test, FDS ¼Forward digit span
test, ECT ¼electroconvulsive therapy, EF¼ Executive Functioning, EM ¼Episodic memory, DEX–CRH ¼dexamethasone–corticotropin-releasing hormone, FPRT ¼ Face Portrait
Recognition Test, FR¼ Faces Recognition, FrSBe ¼Frontal Systems Behavior Rating Scale, FST¼ Functional Skills Training, GDS ¼Geriatric Depression Scale, GAF ¼Global
Assessment of Functioning, HAM-A ¼ Hamilton Anxiety Scale, HAM-D¼ Hamilton Depression Scale, ID/ED ¼ Intra-Extra Dimensional Set Shift, IPT ¼Integrated Psychological
Therapy, iSPOT-D ¼ International Study to Predict Optimized Treatment for Depression, LCT ¼Letter Cancellation Test, LDLPFC ¼left dorsolateral prefrontal cortex, LIFE-
RIFT¼ Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool, LNAA ¼ Large Neutral Amino Acids, LNST¼Letter-Number-Sequencing Test, LTE-
Q¼ List of Threatening Experiences Questionnaire, M ¼ mean value, MADRS ¼ Montgomery Åsberg Depression Rating Scale, MARS ¼ Motor Agitation and Retardation Scale,
MDD¼ Major depressive disorder, MDE ¼Major Depressive Episode, MDRS ¼Mattis Dementia Rating Scale, MINI-Plus ¼ Mini International Neuropsychiatric Interview–Plus,
MLT '88 ¼ Test for historical events, (m)MMSE ¼ (modified) Mini-Mental State Examination, MPI ¼ Memory Performance Index, MTS ¼Match to Sample Visual Search,
NART¼ National Adult Reading Test, NEAR ¼ Neuropsychological Educational Approach to Remediation, NOSIE¼ Nursing Observation Rating Scale for Inpatient Evaluation,
NPT ¼Neuropsychological Test, NRS¼Numeric Rating Scale, n.s. ¼ not significant, PAL¼ paired associates learning, PANSS ¼ Positive and Negative Syndrome Scale,
PD ¼psychodynamic, PGI-I ¼Patient Global Impression of Improvement, POMS ¼Profile of Mood States, PRM¼ pattern recognition memory, PSS ¼ Psychological Software
Service, QIDS ¼Quick Inventory of Depressive Symptomatology, QOL ¼Quality of life, RAVLT ¼Rey Auditory Verbal Learning Test, RBANS¼ Repeatable Battery for the
Assessment of Neuropsychological Status, RBMT ¼ Rivermead Behavioral Memory Test, RCFT¼ Rey Complex Figure Test, RDLPFC ¼ right dorsolateral prefrontal cortex,
RDS ¼Reverse digit span test , RFFT¼ Ruff figural fluency test, RSAT ¼Ruff's Selective Attention Test, R-O CFC ¼Rey-Osterreith Complex Figure Copy, RSPM ¼Raven Standard
Progressive Matrices , RTI ¼reaction time, rTMS¼ repetitive transcranial magnetic stimulation, RUL ¼ right unilateral RVP ¼ Rapid Visual Information Processing, SAMe¼S-
adenosylmethionine, SAS¼ Simpson-Angus Scale, SASS¼ Social Adaptation Self-evaluation Scale, SBS ¼Supra Block Span, SCID ¼Structured Clinical Interview for DSM-IV,
SCL-90 ¼ Symptom Checklist 90, SCT ¼ Stem Completion Test, SDMT ¼Symbol Digits Modalities Test, SDS ¼ Sheehan Disability Scale, SDT ¼Signal Detection Test, SLE ¼stressful
life event, SLT ¼ Shopping List Task, SMQ¼ Subjective Memory Questionnaire, SNRIs ¼ serotonergic–noradrenergic reuptake inhibitors, SOC¼ Stockings of Cambridge,
s-r¼ self-reported, SRM¼ spatial recognition memory, SS ¼Similarities Subtest, SSRIs ¼selective serotonin reuptake inhibitors, STAI¼ State-Trait Anxiety Inventory,
SWM¼ spatial working memory, SY¼ Sahaj Yoga, TAP¼ test for attentional performance, TCA ¼tricyclic antidepressant, TDCT¼ Two-Digit Cancellation Test, TESS¼ Treatment
Emergent Symptom Scale, TOL ¼Tower of London, Trp¼ Tryptophan, TT¼ Trail making test, UBS¼ Immediate Block Span, UKUSES ¼ Udvalg for Kliniske Unders Lgelser side
effect Scale, VASP¼ Visual Analogue Scale for Pain, VFT ¼Verbal Fluency Test, VLRT ¼ Verbal Learning and Recall Test, VRM ¼verbal recognition memory, WAIS(-R) ¼ Wechsler
Adult Intelligence Scale(-Revised), WCST¼ Wisconsin Card Sorting Test, WHO HPQ ¼World Health Organization's Health and Work Performance Questionnaire,
WM¼ Working memory, WMS(-R) ¼Wechsler Memory Scale(-Revised), WTAR¼ Wechsler Test of Adult Reading, YMRS¼ Young Mania Rating Scale.
part-randomized study showed that escitalopram was superior to MMSE, the WMS total score and some memory tests (Familial FR,
nortriptyline regarding the observed mood and cognition symp- autobiographical memory, MLT '88), but the patients still differed
toms but nortriptyline was more effective in improving neurove- from the healthy controls in the more complex tasks (Gallassi et
getative symptoms (Uher et al., 2009). Additionally, one study al., 2006). Besides, the results of a double-blind, randomized trial
indicated that sertraline treatment was also associated with a among young depressed outpatients indicated that the MAOI
significantly greater improvement in almost all quality of life moclobemide had a rapid and stable improving effect on vigilance,
measures (Bondareff et al., 2000). Moreover, a case-control study attention and some crucial components of memory, being superior
that focused on the long-term effects of TCAs and SSRIs evaluated to treatment with viloxazine and maprotiline (Allain et al., 1992).
the memory and psychomotor performance of 56 outpatients with Recently, a randomized, double-blind, placebo-controlled,
MDD who had been treated with imipramine, clomipramine, duloxetine-referenced study among elderly depressed patients
fluoxetine or sertraline for at least 6 months (Gorenstein et al., examined the efficacy and safety of Lu AA21004 and revealed that
2006). Patients taking fluoxetine and clomipramine did not show it was well tolerated and improved speed of processing, verbal
impairment in memory tests but these findings varied according learning and memory (Katona et al., 2012). Moreover, path analysis
to dose/weight. Patients treated with imipramine showed worse showed that Lu AA21004 had an 83% direct effect on the DSST
psychomotor performance in inserting pins and a visual reaction (duloxetine 26%), a 71% direct effect on RAVLT acquisition (dulox-
time task. On a tapping task the difference from controls varied etine 65%), and a 72% direct effect on RAVLT delayed recall
according to dose/weight for patients taking clomipramine and (duloxetine 66%).
fluoxetine. A randomized, double-blind study examining the
effects of the SSRE tianeptine and nortriptyline in elderly patients
did not find any significant differences on cognitive tests between
antidepressant-treated patients and controls (Nebes et al., 2003). 4. Differential effects of antidepressants on emotion processes
One double-blind, randomized study among patients with either and cognitive function
MDD or depressed bipolar disorder I or II found that the treatment
with flexible dosages of the SSRE tianeptine or the SSRI paroxetine The above reviewed literature suggests that antidepressant
equally improved alertness, selective attention and visual problem- may exert direct pro-cognitive effects on cognitive function as
solving and depressive symptoms after 42 days, with a trend opposed or in addition to indirect effects via mood regulation first
towards better response to SSRI in women (Nickel et al., 2003) and subsequent positive effects on cognitive function. In addition,
The HPA system was also assessed and showed marked hyperactiv- it has been argued that antidepressants may exert multiple effects
ity before treatment which then normalized. on neural processes underlying emotion processing and cognitive
Another study that analyzed treatment effects over a relatively function. It has been recently argued that antidepressant actions
long time determined the effects of SSRIs (escitalopram) and SNRIs resulting in increased 5-HT (SSRI) may lead to a decreased
(duloxetine) on memory tasks and mental processing speed reactivity in emotion processing as opposed to antidepressants
(Herrara-Guzman et al., 2009). Both antidepressants improved resulting in increased NA (SNRI) which may lead to increased
the episodic memory and to a lesser extent, working memory, regulation of emotions (Outhred et al., 2013). These findings
mental processing speed and motor performance. Treatment with suggest a differential effect of antidepressants on emotion proces-
SNRI was superior to treatment with SSRI at improving episodic sing and subsequently on cognitive function depending on the
and working memory. These findings are contradictory to the valence of emotional stimuli. In addition, it has been suggested
studies that only examined the effects of duloxetine and did not that antidepressants such as reboxetine not only ameliorate
find improvement in cognition (Raskin et al., 2007; Robinson et al., negative perception and memory biases in unmedicated depressed
2014). patients, but may also occur very early during successful treatment
A comparison of the effects of fluoxetine and the NRI rebox- (Harmer et al., 2009c). Along similar lines of evidence for impacts
etine on attention and memory in late-onset major depression on neural processes, it has been reported that antidepressants (e.g.
showed that both drugs equally improved the outcomes of the venlafaxine and fluoxetine) may induce changes in the prefrontal
Table 2
Effects of SSRE and SNRI-antidepressant therapy on cognitive performance and functional ability in depression.
Klasik Determine the effect of 3-Month observation Assessed one day before the first Comparison between all three times
et al. tianeptine on short-term dose of tianeptine, and 1 and of measurements:
(2011) memory, reaction time and 3 months after the first dose:
attention
20 Patients (18–50 years) with current MDD, SDT, UBS, RTI, SBS ↑UBS (p o 0.001)
3 months
Tianeptine (37.5 mg/day) HAM-D ↑SBS (p o 0.004)
↑SDT (p o 0.001)
↑RTI (po 0.001)
Correlation between cognitive tests
and HAM-D:
SDT ratio accurate to delayed
responses
r ¼ 0.46 (p ¼0.044)
Alls other tests: n.s. correlations
Saiz-Ruiz Determine the acceptability, Open multicentre study Assessed on days 0, 14, 28 and 3 Months to baseline:
et al. safety and efficacy of 84:
(1998) tianeptine in elderly
depressives
63 Elderly patients (44♀, 19♂, 20 drop-outs, M ¼ 68.8 MADRS, CGI, HAM-A, MMSE, ↑MMSE (p ¼ 0.004)
years) with depressive symptoms (55.6% MDD, 44% Zung Depression s–r scale
dysthymia), 4–7 days placebo washout, 3 months
Tianeptine (25 mg/day) CHESS-84, Blood pressure ↑ MADRS (76.7% response after
3 months)
Response ¼MADRS score r 50% to baseline Assessed at inclusion, after ↑Zung Depression s–r scale
1 month and at end of (p o0.001)
treatment:
Body weight, ECG, EEG ↑HAM-A (p o0.001)
↑CHESS-84 (p o0.001)
2Blood pressure
2Body weight
2ECG
2EEG
Oakes Assess functional ability after Two double-blind, randomized, placebo-controlled Assessed at weeks 8 and 12: At baseline:
et al. treatment with duloxetine trials conducted under the same protocol;
(2012)
Screening phase (5–30 days), a 9-month, double-blind SDS, SASS, CGI-Severity, POMS SASS score lower in duloxetine
treatment phase and followed by an optional 2-week Brief total score and subscales group than in placebo group
taper off
Trial I (Duloxetine 4placebo)
Evaluated weekly for the first ↑HAM-D item 7 only at week 4
three visits, biweekly for one (p o0.05)
visit, and then monthly to study
end:
Drug phase HAM-D, HAM-D Maier subcscale,↑HAM-D Maier subscale at weeks
HAM-D item 7 (work/activities)
4 and 8 (po 0.01), and at week 12
(p o0.05)
Trial I Standard laboratory parameters, Week 12:
AEs, vital signs
384 Patients (233♀, 151♂, M ¼ 42.7 years) with MDD, ↑SASS (p ¼0.001)
8 weeks
N ¼257: duloxetine (60 mg/day) 2SDS
N ¼127: placebo ↑HAM-D (p ¼0.013)
Trial II ↑CGI-Severity (p ¼ 0.032)
392 Patients (256♀, 136♂, M¼ 44.4 years) with MDD, ↑POMS total (p ¼ 0.007)
8 weeks
N ¼261: duloxetine (60 mg/day) ↑POMS Tension/Anxiety (p ¼0.020)
N ¼131: placebo ↑POMS Depression/Dejection
(p ¼0.010)
↑POMS Anger/Hostility (p¼ 0.010)
Response ¼reduction in HAM-D450% to baseline POMS Vigor/Activity differences n.s.
Remission ¼HAM-D total scoreo 7 POMS Fatigue/Inertia differences n.s.
POMS Confusion/Bewilderment
differences n.s.
Patients completing 12-week acute
phase (p ¼0.04)
Response:
Week 8: placebo 44%, duloxetine
53% (n.s.)
38% (n.s.)
Remission:
29% (n.s.)

38% (n.s.)
AEs:
↑Nausea (p¼ 0.001)
Trial II (Duloxetine 4placebo)
↑HAM-D item 7 at week 8
(po 0.001), and 12 (p o 0.05)
↑HAM-D Maier subscale at week 4
(po 0.05), 8 and 12 (po 0.01)
Week 12
↑SASS (p ¼0.006)
↑SDS (p ¼ 0.005)
↑HAM-D (p o0.001)
↑CGI-Severity (p o 0.001)
↑POMS total (p ¼0.031)
2POMS Tension/Anxiety
↑POMS Depression/Dejection
(p¼ 0.005)
↑POMS Anger/Hostility (p ¼ 0.019)
POMS Vigor/Activity differences n.s.
POMS Fatigue/Inertia differences n.s.
POMS Confusion/Bewilderment
differences n.s.
Patients completing 12-week acute
phase (p ¼0.093 n.s.)
Response:
53% (p ¼0.040)
63% (p ¼0.016)
Remission:
Week 8: placebo 17%, duloxetine 31%
(p¼ 0.007)
35% (p¼ 0.022)
AEs:
↑Nausea (po 0.001)
↑dry mouth (p ¼ 0.038)
Raskin Compare the effects Double-blind, placebo-controlled trial Cognitive measures Duloxetine4 placebo
et al.
(2007)
of duloxetine vs placebo on 311 Patients (185♀, 126♂, median age of 72) with
Assessed before random Cognitive measures
cognition, depression, and recurrent MDD, 8 weeks assignment and at last visit of
pain treatment:
N ¼207: duloxetine (60 mg/day) MMSE,VLRT, DSST, TDCT, LNST VLRT learning trials (p ¼ 0.03)
N ¼104: Placebo Depression and pain measures VLRT delayed recall (p ¼ 0.02)
Response ¼HAM-D decrease450% from baseline to Assessed before random Other tests n.s.
endpoint assignment and at every visit of
treatment phase:
RemissioN ¼HAM-D total score r 7 at endpoint HAM-D, GDS, CGI, VASP Depression and pain measures
Safety and tolerability measures HAM-D after weeks 4 and 8
(po 0.001)
Patients were visited at beginning and after 1, 2,4 Recorded at every visit: GDS after weeks 1 and 2 (p o 0.01)
and 8 weeks of treatment
AEs, concomitant medications, GDS after weeks 4 and 8 (p o 0.001)
weight, blood pressure, heart rate
Collected at screening and last CGI after week 2 (p o 0.01)
visit of treatment:
ECH, urine sample, blood sample CGI after weeks 4 and 8 (p o 0.001)
Back pain mean change (po 0.01)
Time in pain while awake mean
change (p o0.05)
Overall pain, only after 4 weeks
(po 0.05)
Safety and tolerability measures
Duloxetine more side effects than
placebo:
Discontinuation because of lack of
efficacy (p o 0.03)
Decrease in weight (p ¼0.009)
Increase of alkaline phosphatase
(po 0.02)
Dry mouth (p o0.001)
Nausea (p o 0.02)
Diarrhea (p o0.05)
Robinson Compare the efficacy of Randomized, placebo-controlled, double-blind trial Assessed at weeks 4, 8, 16, 20 Cognitive measures
et al. duloxetine with placebo on and 24:
(2014) depression in elderly
patients with MDD 299 Patients (191♀, 108♂, M ¼ 73 years) with MDD, VLRT, DSST, TDCT, TT B Differences between duloxetine and
24 weeks placebo n.s.
N ¼204: 12 weeks duloxetine (30 mg/day for HAM-D, HAM-D Maier subscale, HAM-D:
1 week, forced titration to 60 mg/day) MMSE, MADRS, GDS, BPI, CGI-
Severity, PGI-I, NRS
week 12-20: placebo rescue or dose optimization Blood Pressure, Pulse, Weight Duloxetine4 placebo at weeks 4, 8,
possible 16 and 20 (p ¼ 0.007 at week 20)
N ¼95: placebo HAM-D Maier subscale:
Response ¼HAM-D reduction Z50% compared to Duloxetine4 placebo only at weeks
baseline 4,8,16 and 20; at week 24 n.s.
Remission ¼HAM-D total score r 7 and r 10 GDS:
Duloxetine4 placebo at weeks
2,4,8,16 and 24 (p o 0.01 at week 24)
CGI:
Duloxetine4 placebo at weeks 4, 8,
16, 20 and 24 (p o 0.01 at week 24)
PGI-I:
Duloxetine4 placebo at weeks 4 and
8 (p o 0.001)
BPI/ NRS during acute phase:
Duloxetine4 placebo (p o 0.05)
BPI/NRS during acute plus
continuation phase:
Duloxetine4 placebo on certain
items:
Average pain (p ¼ 0.013)
Mood (p¼ 0.002)
Walking (p¼ 0.04)
Normal work (p ¼ 0.014)
Relations (p¼ 0.01)
Sleep (p ¼ 0.005)
Enjoyment of life (p o 0.001)
Back pain (p¼ 0.013)
Interference with daily activities
(p ¼0.019)
Time in pain while awake (p¼ 0.036)
AEs
Discontinuation because of AEs:
duloxetine 4placebo (p ¼0.01)
Treatment-emergent AEs
(duloxetine 4placebo) during acute
phase:
Dry mouth, constipation, diarrhea
(p o0.05)
Treatment-emergent AEs
(duloxetine 4placebo) during
acuteþcontinuation phase:
Constipation, diarrhea, upper
respiratory infection (p o 0.01)
Dry mouth (p o0.05)
Physical measures
Diastolic blood pressure higher in
duloxetine group at week 12
(p ¼0.001)
Orthostatic change – diastolic blood
pressure lower in duloxetine group
at week 12 (p o 0.001) and 24
(p ¼0.05)
Pulse higher in duloxetine group at
week 24 (p ¼ 0.04)
Weight lower in duloxetine group at
week 12 (p¼ 0.003)
For Abbreviations see Table 1
cortex engagement when regulating negative affect that closely involved in modifying the ratio of negative to positive emotion
correlate with changes in depression severity over 6 months biases which may contribute to an overall positive effect of
(Heller et al., 2013). Taken together, antidepressant may be antidepressant on cognitive function (Harmer et al., 2009b).
In contrast, effects of antidepressants on neural processing of indicated that at the end of treatment, as well as at the 3-months
emotions and cognitions can be detrimental during antidepressant follow-up, patients showed lower residual depressive symptoms,
treatment as shown by various studies. In a recent study it was and increased occupational, as well as overall psychosocial func-
reported that SSRI-treated patients with MDD were less sensitive tioning. Interestingly, improvements in executive functioning were
to negative feedback (punishment) than either medication-naïve associated with improvements in occupational functioning
patients with MDD or HC subjects suggesting a decreased learning (Deckersbach et al., 2010).
from negative stimuli (Herzallah et al., 2013b). Other classes of Using a combined approach of psychological treatments and
antidepressants such as TCAs could exert their negative effects on antidepressants, a randomized study among patients with current
cognitive function via the anticholinergic effect as supported by major depressive episodes compared the effects of either treat-
the finding that greater anticholinergic effects were negatively ment with sertraline only, or psychodynamic psychotherapy only,
associated with cognitive improvement in verbal learning and or a combination of the two treatments (Klasik et al., 2012). The
processing speed in depressed elderly adults (Doraiswamy et al., mean dose of sertraline was 50 mg/day. The psychodynamic
2003). Similarly, other studies have reported that the use of psychotherapy consisted of five 90-min group sessions and two
anticholinergic drugs negatively affect cognitive performance such 1-h individual sessions per week. The best improvement of short-
as episodic verbal memory (Fortin et al., 2011) and anticholinergic term memory and attention after 8 weeks was found in the group
drugs may particularly impair cognitive abilities that depend on in which combined psychotherapy and pharmacotherapy was
the medial temporal lobe (Herzallah et al., 2010). applied. A similar study determined the effects of Sahaj Yoga
Taken together, antidepressants may exert differential effects Mediation on attention span, visuo-motor speed, short-term
on emotion processing and cognitive processes during the treat- memory, working memory and executive functions in currently
ment of depression depending on their action on neural networks depressed patients (Sharma et al., 2006). Sahaj Yoga is a form of
in the brain and depending on their pharmacological profile Kundalini Yoga which describes a technique to arouse the latent
(Table 4). potential of man by a simple meditative process. One-half of the
included patients were treated with antidepressant medication
4.1. Neuropsychological approaches for the improvement of only (TCAs and SSRIs). The other half was additionally treated with
neuropsychological functioning and functional ability in depression 30 min of Sahaj Yoga Meditation three times a week. As a result,
there was significant decrease in several tests assessing mood,
We only found five studies that examined the effects of attention and executive functioning in both groups but improve-
cognitive approaches on neuropsychological functioning in ment was significantly more marked in the group that was treated
depression which is considerably less than the research that has with antidepressants and Sahaj Yoga Meditation (Table 5).
been conducted in the same field in schizophrenia. Three studies
analyzed the effects of cognitive remediation. In one of these
studies, the effects of the Neuropsychological Educational
Approach to Remediation (NEAR) were examined (Naismith et 5. Discussion
al., 2010). This treatment model incorporates compensatory stra-
tegies and uses information about relative cognitive strengths and This review describes the available research on possible improving
weaknesses together with increased understanding about one's effects of antidepressant therapy and cognitive approaches on neu-
learning style (Revheim and Marcopulos, 2006). Sixteen patients ropsychological impairment and functional ability in depressed adult
with MDD were allocated to treatment or waitlist control condi- patients. The literature shows that pharmacological studies have been
tions. The treatment consisted of 10-weeks of twice weekly carried out nearly exclusively in major depressive disorder, while two
cognitive training using NEAR. Participants in the treatment non-pharmacological studies included depressed patients with bipolar
condition showed greater improvements on tests of memory disorder in addition to MDD patients. Hence, the published evidence
encoding and memory retention than the waitlist control group for pharmacological studies is restricted to MDD. It is important
but there were no observable benefits in terms of affective however, to consider that unipolar and bipolar depressions form
symptoms, psychomotor speed, executive functions or in self- distinctly different psychopathological entities and a “bipolar signa-
reported levels of disability. In the second study, the authors ture” (clinical admixture of psychomotor-retarded melancholic signs
administered a computerized cognitive retraining package (PSSCo- and symptoms, “atypical” features, and psychosis) (Mitchell et al.,
gReHab) with demonstrated efficacy to 12 stable patients with 2001) which is suggestive that treatments useful for unipolar depres-
recurrent MDD (Elgamal et al., 2007). In this computerized sion may not be useful for bipolar depression (Mansell et al., 2005).
cognitive training, participants perform simple tasks in a single The pharmacological studies in MDD show that a variety of classes of
cognitive domain initially, followed by multi-domain tasks and, antidepressants exert improving effects on cognitive function across
once successful, graduate to complex tasks that rely upon several cognitive domains. Specifically, studies suggest that SSRIs, the
problem-solving skills. Twelve matched patients with MDD and SSRE tianeptine, the SNRI duloxetine, and other antidepressants such
a group of healthy control participants were included for compar- as bupropion and moclobemide may exert certain improving effects
ison but they did not receive the intervention. Patients who on cognitive function in depression. The multimodal antidepressant Lu
received PSSCogReHab improved on a range of neuropsychological AA21004 has shown an improving effect on cognitive performance in
tests targeting attention, verbal learning and memory, psychomo- learning and memory and executive function. Class-specific cognitive
tor speed and executive function without improving in depressive domains or specific dose–response relationships were not identified
symptom scores. yet. Although still preliminary, comparative studies indicate that SSRIs
In a third study using cognitive remediation (CR), employed are as good as SSREs, but superior to TCAs while duloxetine might be
patients with residual depressive symptoms of bipolar disorder superior to escitalopram at improving episodic and working memory.
underwent a comprehensive intervention with cognitive remedia- Only a few non-pharmacological studies including cognitive orien-
tion to tests whether improvement of cognitive impairment would tated treatments and cognitive remediation therapy were carried out
be associated with improvement in psychosocial functioning. In showing promising results for the improvement of cognitive impair-
total, 18 individuals with DSM-IV bipolar disorder were enrolled ment in depression (in both MDD and Bipolar Depression). Several
of which 14 patients completed the study with 14 individual methodological constraints of most studies limit generalizability of the
50 min-treatment sessions of CR over a period of 4 months. Results results and caution the interpretation of current studies in the field.
Table 3
Effects of other antidepressants and pharmacological agents on cognitive performance and functional ability in depression.
Han et al. Examine the relationship between a A prospective cohort study with Assessed at baseline and 3, 6 and 12 Total: 1027 antidepressant
(2011) range of antidepressant medication database linkage months after discharge: prescriptions filled
and long-term cognitive effects in
older medical patients with different
depression diagnoses
MMSE, HAM-D MDD
281 Patients (68.15%♀, M ¼79.11 M ¼ 5.9 prescriptions
years) diagnosed with minor (N ¼51)
or major depression (N ¼ 121) or no
depression (N ¼ 109)
Antidepressant medication 2MMSE
was ascertained from a provincial Minor depression
prescription database and quantified
as cumulative exposures over each
follow-up interval
M ¼ 2.3 prescriptions
↑MMSE (p¼ 0.018 across 3 follow-
up intervals)
No depression
M ¼ 1.8 prescriptions
2MMSE
Butters et al. Examine the cognitive response to Case-control clinical study Assessed before and after 45 patients (36♀,9♂, M ¼72.9
(2000) antidepressant treatment treatment: years) achieved remission after 12
(nortriptyline, paroxetine) for patients weeks, 17 did not. Remitters were
with late-life depression reassessed following 12 weeks of
treatment with the new drug
62 Non-demented, elderly patients HAM-D, GAF, MMSE, MDRS At baseline
with MDD
45 Achieved remission after 12 weeks HAM-D score slightly higher in
of antidepressant treatment (earlier non-remitters than in remitters
randomized to nortriptyline or (p o 0.06)
paroxetine)
CG: 20 elderly healthy controls Remitters
Remission ¼ HAM-D scoreo10 for 2MMSE
3 consecutive weeks
↑MDRS total (po 0.03)
↑HAM-D, GAF (p o0.0001)
10 Patients with cognitive
impairment (MDRS)
35 Patients no cognitive
impairment
Patients with cognitive impairment
↑MDRS (p o 0.001)
Older than patients without
cognitive impairment (po 0.007)
and CG (po 0.007)
Less educated than patients
without cognitive impairment
(p o 0.004) and CG (po 0.001)
Lower GAF score than patients
without cognitive impairment
(p o 0.001)
n.s. differences between groups in
terms of gender, racial distribution,
HAM-D score
Herrera- Examine the cognitive predictors of Clinical trial Assessed before and after 12 rResponders, 8 Non-responders
Guzmán treatment response to bupropion and treatment:
et al. its neuropsychological effects in
(2009) patients with MDD
20 (18♀, 2♂, M ¼24.46 years) Patients RAVLT, ID/ED, DMS, MTS, PAL, SRM, Responders:
with current MDD, 8 weeks RTI
bupropion (150 mg/day) HAM-D Older than non-responders
(p ¼0.009)
Responder ¼ HAM-D reduction4 50% Assessed only at onset: Higher HAM-D baseline score
(p ¼0.048)
WAIS III vocabulary subtest, FDS, Lower HAM-D score after
RDS, Spatial Span PRM, RVP, Stroop treatment (p ¼0.000)
Test, COWAT, SWM, SOC
Before treatment:
Non-responders 4Responders
PAL first trial (p ¼ 0.05)
PAL mean errors to success
(p ¼0.021)
PAL total errors (p ¼ 0.009)
PAL total trials (p ¼ 0.05)

SOC three movements (p ¼ 0.045)
SOC four movements (p ¼ 0.006)
Comparison before and after
treatment:
Responders 4Non-responders
MTS mean correct latency
(p ¼0.001)
All patients
↑PAL first trial, PAL total errors,
DMS mean correct latency, MTS
mean correct latency (p o 0.05)
Booij et al. Investigate the effects of different Double-blind, randomized, crossover Assessed at both sessions at High-dose ATD
(2005) extents of depletion on mood and design with two sessions, separated by þ4.75 h, and also before and after
cognitive tasks involving neutral and at least 4 days the whole procedure:
emotional stimuli.
20 Patients (9♀, 11♂, M ¼48.7 years) Stroop Word Colour Test, Emotional ↑Stroop Word Coulour Test
in remission or in partial remission Stroop Test, Left/Right Choice RTI, (p ¼0.002; responders¼ non-
from MDD TOL, Letter Fluency, APRT responders)
Patients were kept on a 24-h low-Trp Assessed at both sessions before, at ↑Emotional Stroop (positive)
diet (160 mg/day) before both þ6.5 h and þ24 h after depletion: (p ¼0.001; responders¼ non-
sessions; meals: 2300 kCal responders)
High-dose ATD (100 g) MADRS, HAM-D 2Left/Right Choice RTI, TOL (↑only
in females)
Low-dose ATD (25 g) Blood Plasma 2word fluency (↑only for word
production within the first 30s)
Caffeine consume was controlled, 2APRT
low-Trp lunch 3 h after drinking the
mixture
Response ¼ MADRS increase 46 point ↑MADRS (p ¼0.002)
↓total Trp ( 86.3%)
↓Trp/LNAA ratio ( 93.3%)
↑Tyrosine levels ( þ214.0%)
↑Tyrosine/LNAA ratio ( þ56.4%)
↓5-HIAA levels compared to –1 h (–
50.3%)
n.s. ↓HVA levels ( 23.6%)
Low-dose ATD
↑Stroop Word Color Test (p ¼ 0.002;
responders¼non-responders)
2Emotional Stroop (positive)
2Left/Right Choice RTI, TOL
2Word fluency
2APRT
MADRS
↓Total Trp ( 46.8%)
↓Trp/LNAA ratio ( 42.2%)
n.s. ↓tyrosine levels ( 2.0.0%)
n.s. ↑tyrosine/LNAA ratio (þ 11.2%)
Levkovitz Determine the effects of SAMe Double-blind, randomized clinical trial Assessed before and after SAMe:
et al. augmentation of serotonin-reuptake treatment:
(2012)
inhibitor antidepressants on cognitive 46 serotonin-reuptake inhibitor non- CPFQ (7 domains tested: ↑Ability to recall information
symptoms of MDD responders (27♀, 19♂, M ¼52.7 years) (1) motivation and interest, (p ¼0.04)
with MDD, 6 weeks (2) wakefulness, (3) energy,
(4) ability to focus, (5) ability to
recall information, (6)word-finding
ability, and (7) sharpness/mental
acuity)
N ¼ 27: SAMe pill (800 mg/day; after n.s.↑word-finding ability (p ¼0.09)
2 weeks 1600 mg/day)
N ¼ 19: dummy pills (800 mg/day; HAM-D, CGI-Severity and 2Rest of CPFQ-domains
after 2 weeks 1600 mg/day) improvement
Pelton et al. Evaluated whether, after 8 weeks of Randomized, double-blind, placebo- Assessed at baseline and the 8, 20, Phase A:
(2008) open antidepressant treatment, controlled pilot study and 52-weeks time points:
donepezil HCl (Aricept) would afford
added cognitive benefit compared to
placebo in a randomized 12-week trial
23 Elderly patients (56.5%♀, M¼ 67.7 BSRT, DSST, TT A&B, CFL 14 responders, 9 non-responders
years) with MDD and cognitive
impairment
Phase A: HAM-D, CGI, NPT for subjective Responders 4non-responders:
cognitive complaints BSRT immediate recall (p ¼0.02)
TESS
8-Week open treatment with n.s. differences for DSST,

sertraline TT A&B, CFL
Phase B: 12-week randomized, Phase B:
double-blind, placebo-controlled
donepezil augmentation for patients
with persistent subjective cognitive
complaints
N ¼ 12:donepezil (5–10 mg/day) Donozepil:↑BSRT immediate recall
(p ¼0.05)
N ¼ 9: placebo(5–10 mg/day) 2 DSST, TT A&B, CFL
Phase C: 32-week extended open Combined Phases B þC:
donezepil treatment, open,
naturalistic follow-up
N ¼ 6: donezepil Week 8:
N ¼ 6: no donezepil Donezepil 4no-donezepil for
HAM-D score (p ¼0.04)
n.s. differences for NPT scores
Group by time effect:
Donezepil 4no donezepil: ↑BSRT
immediate recall (p ¼0.03)
Somatic side effects
n.s. differences between donezepil
group and placebo group,
respectively no-donezepil group
for TESS during Phase B and C
Holtzheimer Assess the safety and efficacy of Double-blind, randomized, placebo- Assessed at baseline, 12 weeks and Time effect:
et al. galantamine augmentation of controlled pilot study 24 weeks:
(2008) antidepressant treatment for
depressive and cognitive symptoms in
older adults
38 Patients (34.2%♂, M¼ 66 years) RBANS, MMSE ↑RBANS total (p¼ 0.0001)
with MDD receiving venlafaxine XR
(37.5 mg/day; after 1 week: 75 mg/
day; if no response after 3 weeks:
150 mg/day; if no response after
9 weeks: 225 mg/day); if no response
after 12 weeks or intolerable, they
received citalopram (10 mg/day in
week 1, 20 mg/day in weeks 2–4,
40 mg/day in
weeks 5–6, and 60 mg/day in weeks Assessed at baseline, then every ↑RBANS immediate memory
7–12) 2 weeks: (p ¼0.0002)
N ¼ 19: galantamine (8 mg/day; after HAM-D, CGI-Improvement, ↑RBANS visuospatial/construction
1 month: 16 mg/day) PGI–Improvement, AEs (p ¼0.019)
N ¼ 19: placebo (8 mg/day; after ↑RBANS language (p¼ 0.011)
1 month: 16 mg/day)
Response ¼ decrease in HAM-D450% ↑RBANS attention (p ¼0.033)
to baseline
↑RBANS delayed memory
(p o 0.0001)
Differences between galantamine
and placebo n.s. for the above tests
↑HAM-D (p o 0.0001); only at
week 2: galantamine 4 placebo
(p ¼0.05)
Patients that experienced 41 AEs:
Placebo: 17; galantamine: 11
Discontinuation rates:
Week 12: placebo 16%,
galantamine 53% (p ¼ 0.01)
Week 24: placebo 32%,
galantamine 63% (p ¼ 0.03)
Venlafaxine dose lower in
galantamine than in placebo group
(p ¼0.03)
6. Effects of pharmacological treatment on cognitive function antidepressant drug action (Harmer et al., 2009a). According to
and functional ability in depression this model, negative biases in information processing are consis-
tently found in depression, and this model argues that a mode of
The mechanisms by which antidepressants exert effects on the action of antidepressant drugs is to remediate these biases
neurobiology of cognitive function remain to be fully understood. providing a more positive social environment in which the patient
A possible explanation is a neuropsychological model of can relearn emotional associations fostering later improvement in
Table 4
Studies comparing the effects of two or more antidepressants on cognitive performance and functional ability in depression.
Bondareff Evaluate the comparative efficacy Randomized, double-blind, parallel Assessed at baseline and after 12 Sertraline4nortriptyline
et al. and safety of sertraline and group design weeks of treatment:
(2000) nortriptyline for the treatment of
major depressive disorder in older
adults
210 Patients (124♀, 86♂, M ¼ 67.85 DSST, MMSE, SLT, QOL Enjoyment and MMSE (p ¼ 0.01)
years) with current MDE, 1-week, Satisfaction Questionnaire
single-blind placebo washout period,
12 weeks treatment
N ¼ 105: Sertraline (50–150 mg/day) HAM-D, HAM-A, CGI, POMS, DSST (p ¼0.002)
N ¼ 105: Nortriptyline (25–100 mg/ Blood pressure, AEs, concomitant SLT no. of items recalled
day) medications (p¼ 0.0001)
Collected on day 1 of the placebo SLT no. retrieved of long-term recall
washout period and after 1, 3, 6, and (p¼ 0.001)
12 weeks of treatment:
Blood samples SLT size of learned list (p¼ 0.02)
SLT long-term storage (p0.0002)
POMS vigor (p ¼ 0.03)
POMS fatigue (p ¼ 0.006)
QOL physical health (p ¼0.01)
QOL psychological health (p ¼ 0.01)
QOL Leisure time satisfaction
(p¼ 0.02)
QOL social health satisfaction
(p¼ 0.004)
Mean dosages after 12 weeks
Sertraline: 96 mg/day
Nortriptyline; 78 mg/day
Discontinuation rate:
Sertraline: 20, nortriptyline: 19
Depressive symptoms:
↑HAM-D, CGI (n.s. differences
between groups)
↑POMS (sertraline4nortriptyline
p o0.05)
Levkovitz Test whether treatment with the Single-blind, randomized study Assessed at the beginning, and 3 and Prozac
et al. SSRI fluoxetine would be 6 weeks after the beginning of the
(2002) advantageous in improving memory treatment:
functions over treatment with the
selective noradrenergic tricyclic
antidepressant drug desipramine
17 Patients (7♀, 10♂, M¼ 47.1 years) RBMT, RCFT, PAL, DSST, FDS ↑RBMT at 6 weeks (p o0.05)
with a current MDE
N ¼ 8: Fluoxetine (20 mg/day) HAM-D, CGI 2RCFT
N ¼ 9: Desipramine (125–200 mg/day) ↑PAL at 6 weeks (p o 0.05)
MPI: 2FDS
Based only on the more ↑DSST at 6 weeks (p o 0.01)
discriminative tasks, i.e., those with
high initial variability as indicated by
stepwise regression (FDS, CFT, PAL,
and the RBMT subtests: recall of a
name (private name and family
name), immediate recall of a story
and delayed recall of a story)
↑HAM-D, CGI at 3 and at 6 weeks
(po 0.01)
Deprexan
2RBMT, CFT, PAL
↑FDS at 3 weeks (p o0.05)
↑DSST at 6 weeks (p o 0.05)
↑HAM-D, CGI at 3 and at 6 weeks
(po 0.01)
2MPI
MPI
n.s. difference between groups at
beginning of treatment
Mean improvement over time:
fluoxetine4desipramine (p o 0.02)
Culang- Compare the impact of nortriptyline Randomized, double-blind medication Assessed at baseline and at the end of Comparison Baseline – end of
Reinlieb to sertraline on change in trial, parallel group design week 12 or upon early termination: treatment
et al.
(2012)
CF in depressed older adults Sertraline
63 Patients (60% ♀, M ¼ 64.2 years) Medical Outcomes Study, MMSE,

with MDD, 1 week single-blind Purdue Pegboard, CPT, TT A&B, Stroop
placebo, 12 weeks Test, BSRT
N ¼ 33: Sertraline (1st week 50 mg/ Assessed at the end of placebo week ↑BSRT (p¼ 0.001)
day, 100 mg/day for the next 4 weeks, and every visit thereafter:
then if no remission 150 mg/day; if no
response by week 9 200 mg/day)
N ¼ 30: Nortriptyline (1 mg/kg; 1/3 HAM-D, MADRS, BDI, CGI 2Other neuropsychological tests
given on days 1–3, 2/3 on days 3–6,
and full dose was given on day 7)
RemissioN ¼ HAM-Do 10 Assessed at end of weeks 2, 4 and 8: Responders (33%)
HAM-A Nortriptyline
Assessed only at baseline: 2neuropsychological tests
CIRS-G Responders (53%)
Uher et al. Test the hypothesis that Multicentre part-randomized open- Assessed at baseline, then weekly: 105 Participants switched to the
(2009) escitalopram and nortriptyline differ label design other antidepressant and another
in their effects on observed mood, 4 switched to originally allocated
cognitive and neurovegetative drug after 12 weeks because of poor
symptoms of depression tolerance and/or lack of effect.
811 Patients (514♀, 297♂, M ¼ 42.5 MADRS, HAM-D, BDI 179 Drop-outs because of adverse
years) with moderate to severe MDD, reactions, lack of effect,
12 weeks improvement, death, and other
reasons
468 were randomized, 343 were non- Nortriptyline, randomly:
randomly allocated
N ¼ 458 (233 randomly, 225 non- Highest drop-out and switching
randomly): Escitalopram (10 mg/day, rates
increased to 15 mg/day within first
2weeks, could be further increased to
max. 30 mg/day)
N ¼ 353 (235 randomly, 118 non- s–r Adherence 98% (n.s. differences
randomly): Nortriptyline (50 mg/day, between groups)
increased to 100 mg/day within first
2 weeks, could be further increased to
max. 200 mg/day)
MADRS, HAM-D, BDI original scales:
n.s. differences between groups
Symptom dimensions:
Observed mood:
escitalopram4nortriptyline
(po 0.001)
Cognitive symptoms:
escitalopram4nortriptyline
(po 0.001)
Neurovegetative symptoms:
nortriptyline 4escitalopram
(po 0.001)
Predictors for less improvements on
all measures: older age, history of
taking antidepressants
AEs and adverse reactions:
Nortriptyline
1 suicide, 1 hospital admission due
to suicide risk, 1 manic episode,
1 unintentional overdose with full
recovery, dry mouth (80%),
orthostatic dizziness (32%),
drowsiness (27%), and constipation
(24%)
Escitalopram
1 deadly accident, 1 hospital
admission due to suicide risk,
nausea and vomiting (15%), and
sexual dysfunction (30%)
Nebes et al. Examine the effects of paroxetine Randomized, double-blind clinical trial Assessed at baseline and at week 1, 4, 32 Responders (14 nortriptyline, 18
(2003) and nortriptyline on cognition in 6 and 12 after baseline: paroxetine)
older depressed patients
12 Weeks DSST, N back test, TT A & B, RAVLT Cognitive tests
73 Patients (67%♀, M ¼ 70.3 years) HAM-D Improvement over time did not
with MDD were drawn from a differ between depressed patients
randomized double-blind treatment and CG
trial with nortriptyline and
paroxetine,
randomization was stratified by Only assessed at baseline:
inpatient–
outpatient status and by cognitive MMSE, DRS

status (MMSE ¼ 24 or less vs 25þ)
washout of any psychoactive
medication (exception: lorazepam)
CG: 21 healthy controls (62%♀,
M ¼ 71.0 years)
Response ¼ HAM-D scoreo 10
Nickel et al. Comparison of the changes induced Double-blind, randomized, controlled Assessed on day 4 prior to ↑Alertness, selective attention,
(2003) by tianeptine and paroxetine on CF trial treatment, then weekly until end of problem-solving (differences
treatment: between tianeptine and paroxetine
n.s.)
44 Patients (23♀, 21♂, M ¼49.5 years) TAP: alertness, focused attention, ↑HAMD, MADRS, CGI, BDI
with MDE or BPD I or II, 42 days, divided attention, response selection (differences between tianeptine and
LCT: selective attention paroxetine n.s.)
washout period of at least 4 days CVLT: verbal learning
N ¼ 22: tianeptine (37.5 mg/day. Day Memory span: short-term memory, Combined DEX–CRH test
22: 75 mg/day if clinical WM
improvement (HAM-D) was o 50%)
N ¼ 22: paroxetine (20 mg/day. Day Cogpack: visual recognition Paroxetine:
22: 40 mg/day if clinical
improvement (HAM-D) was o 50%)
RSPM: visual problem-solving 2Basal ACTH value
HAM-D, MADRS, CGI, BDI ↓Basal cortisol value (p ¼ 0.043)
Assessed on days 4 and 1 prior to ↓AUC ACTH value (p¼ 0.025, only
treatment and on days 21 and 42: from days 21 to 42)
Combined DEX–CRH test ↓Cortisol AUC values (p¼ 0.013)
Tianeptine:
↓Basal ACTH value (p ¼ 0.027, only
from days 4 to 21; from days 4
to 42 n.s.)
↓Basal cortisol value (p ¼ 0.003)
↓AUC ACTH value (p¼ 0.023)
↓AUC cortisol value (p¼ 0.012)
Herrera- Determine the effects of SSRIs and Randomized, controlled trial Only assessed at onset: Both antidepressants measured
Guzmán SNRIs on memory tasks and mental together:
et al. processing speed
(2009)
73 Patients (59♀, 14♂, M¼ 33.1 years) WAIS III vocabulary subtest ↑RAVLT, 5th and 7th trial
with MDD antidepressant-drug naїve, (po 0.000)
24 weeks
N ¼ 36: escitalopram (10 mg/day) Assessed at onset and end of ↑RAVLT Recognition (p ¼ 0.027)
treatment:
N ¼ 37: duloxetine (60 mg/day) WAIS III digit span, RAVLT, PRM, PAL, ↑PAL, 1st trial (p ¼ 0.045)
DMS, SRM, RTI, Stroop test
HAM-D ↑PAL, total errors adjusted
(p¼ 0.042)
↑PAL, total trials adjusted
(p¼ 0.026)
↑Stroop colors named (p ¼0.003)
WAIS III digit span:
↑RDS (p ¼ 0.022)
↑Span length (p ¼0.032)
↑SWM between errors (p o 0.000)
↑SWM total errors (p ¼ 0.001)
↑SWM strategy (p ¼0.031)
↑HAM-D (63 patients full remitters,
10 partial remitters)
SNRI 4SSRI:
RAVLT, 5th and 7th trial and
recognition (p o 0.000)
PAL, total errors adjusted (p ¼ 0.045)
PAL, total trials adjusted (p ¼ 0.004)
PAL, mean trials to success
(p¼ 0.014)
WAIS III RDS (p ¼0.014)
Doraiswamy Analyze the effects of Two multicenter, double-blind studies Assessed at day 1 of washout, at Variables associated with worse
et al. antidepressants on CF in elderly baseline, at weekly intervals for first baseline cognitive test scores:
(2003) depression 4 weeks, at 2-week intervals
thereafter:
440 Elderly patients (255♀, 185♂, SLT, DSST, MMSE SLT:
M ¼ mean age) with MDD who
participated in one of two
multicenter, double-blind studies
Male gender, older age (p ¼0.0001)
N ¼ 217 (62%♀, M¼ 68.0 years): HAM-D, CGI-Severity, CGI-

sertraline Improvement
N ¼ 119 (51%♀, M ¼67.4 years): Severity scores for dry mouth and DSST:
fluoxetine constipation
N ¼ 104 (58%♀, M ¼ 67.9 years): Male gender (p ¼ 0.0124)
nortriptyline
Response ¼ CGI-Improvement score Older age (p ¼0.0001)
“much” or “very much”
Study 1: Higher systolic blood pressure
(p¼ 0.0150)
12-Week treatment with either MMSE:
sertraline (50 mg/day, could be
increased to 100 mg/day at week 4) or
fluoxetine (20 mg/day, could be
increased to 40 mg/day at week 4)
Study 2: Older age (p ¼0.0001)
12-Week treatment with either Higher baseline illness severity
sertraline (50 mg/day, could be (p¼ 0.0168)
titrated in increments of 50 mg every
3 weeks to max. 150 mg) or
nortriptyline (25 mg/day, could be
titrated in increments of 25 mg per
week to max. 100 mg)
Sertraline
Endpoint daily dose: M¼ 83.8 mg
75% Responders
Fluoxetine
66% responders
Nortriptyline
70% Responders
All groups
HAM-D endpoint score among
responders: M ¼8.3 (change
M ¼16.1)
BSRT (number recalled, number
retrieved, size of learned list)
Total group: sertraline,
fluoxetine4 nortriptyline (po 0.05)
Responders: sertraline,
Responders with baseline cognitive
impairment: differences between
groups n.s.
DSST
Total group: sertraline4fluoxetine
(po 0.05)
sertraline,
Responders: sertraline,
Responders with baseline cognitive
impairment: differences n.s.
MMSE
Differences between groups n.s.
Predictors of endpoint
improvement in the CF composite
score
Positive predictor: HAM-D change
score (p o 0.0001)
Negative predictor: anticholinergic
severity score (p o0.005)
Gallassi et al. Compare the effects of fluoxetine Randomized, controlled, single-blind Assessed before treatment and after 33 Remitters, 9 Non-Responders (4
(2006) and reboxetine on attention and study 6 months of treatment: fluoxetine, 5 reboxetine)
memory in late-onset major
depression
48 patients (36♀, 12♂, M ¼ 67.54, Attentional Matrices, WMS, Familial At baseline, MDD-patients
6 Drop-outs) with MDD, 18 months FR, Famous FR, SCT, autobiographical significantly worse than CG:
memory, MLT'88
N ¼ 21: fluoxetine (10 mg at T0, 20 mg HAM-D, GDS, MMSE MMSE, WMS, autobiographical
7 days later up to 40 mg) memory (p o 0.001)
N ¼ 21: reboxetine (4mg at T0, 6 mg At baseline, no significant
7 days later up to 8 mg) differences between MDD-patients
and CG:
Remitters¼ After 6 months HAM-D Attentional Matrices, MLT '88, SCT,

r 11 points for patients aged over 65 Familial&Famous FR
and r7 if aged under 65 years,
without residual symptoms and with
recovery of effective psychosocial
functioning for at least 8 consecutive
weeks
CG: 15 (9♀, 6♂, M ¼69.33 years) Remitters:
↑WMS (p o0.001)
↑MMSE, Familial FR,
autobiographical memory, MLT '88
(po 0.01)
2Attentional Matrices, Famous FR,
SCT
No significant differences between
the effects of fluoxetine and
reboxetine
Allain et al. Compare the effects of three Double-blind, randomized, monocentre Assessed on days 3, 0, 14, 28, 42: At baseline:
(1992) antidepressant drugs on vigilance, clinical trial
attention and memory
37 Outpatients (27♀,10♂, M ¼27 RTI, CFF, SM9 battery of memory Recognition of familiar faces:
years) with MDD, 42 days viloxazine group4moclobemide
group (p o 0.05)
4-Day washout-period MADRS, QOL-scale, questionnaire for Moclobemide:
psychiatrist about overall efficacy, AEs
N ¼ 12: Moclobemide (450 mg/day) ↑CFF (p o 0.01)
M ¼ 12: Viloxazine (300 mg/day) ↑choice RTI from day 28 up to day
42 (p o 0.01)
N ¼ 13: Maprotiline (150 mg/day) ↑SM9 delayed verbal recall
(po 0.05)
↑SM9 recognition of familiar faces
( 4viloxazine, maprotiline p o 0.05)
↑SM9 recognition of unfamiliar
faces( 4viloxazine, maprotiline n.s.)
Viloxazine:
2CFF
↑SM9 delayed verbal recall
(po 0.05)
Maprotiline:
2CFF
↑Choice RTI at day 42 (p o 0.01)
All treatments combined:
↑Simple RTI (p o 0.05)
2Choice RTI
↑SM9 verbal recall (p o 0.01,
training effect)
↑SM0 immediate and delayed
design recall (p o0.05, training
effect)
↑SM9 semantic organization
(po 0.05, training effect)
2SM9 recognition
↑SM9 memory global score
(moclobemide 4viloxazine,
maprotiline)
↑MADRS (all patients non-
depressive at day 42)
↑QOL-scale
AEs: dry mouth, insomnia, nausea,
tremor, hypotension
(moclobemide 4viloxazine,
maprotiline)
Questionnaire efficacy: n.s.
differences between groups
Gorenstein Evaluate the cognitive performance Case-control study Assessed once: Memory tests: respective
et al. of depressed patients treated with controls4 MDD-patients
(2006) TCAs or SSRIs for at least 6 months
56 outpatients (42♀, 14♂, M ¼ 40.7 Memory SMQ:
years) with MDD
N ¼ 15: Imipramine (M ¼230 mg/day SMQ, Verbal recall, word appreciation Imipramine, fluoxetine, sertraline
for 2.4 years) task, FDS, RDS, Word stem (po 0.001)
completion, Visual Recall
N ¼ 9: Clomipramine (M ¼ 219 mg/day Psychomotor tests Clomipramine (p o 0.01)
for 2.8 years)
N ¼ 14: Fluoxetine (M ¼54 mg/day for DSST, Cancellation Test, Symbol Immediate and delayed verbal
1.8 years) Copying Test, Tapping Test, Inserting recall, FDS:
Pins, RTI
N ¼ 18: Sertraline (M ¼157 mg/day for Depression n.s. differences
1.5 years)
CG: 31 healthy subjects (22♀, 9♂, STAI, BDI RDS:
M ¼ 38.3 years), matched regarding
sex, age and educational level
CG not assessed: Sertraline (the difference varies
according to dose/weight)
CGI, HAM-D Visual recall:
Sertraline (p o0.05)
Word stem completion, familiar
words correct:
Clomipramine (the difference varies
Word stem completion, time:
Intragroup priming effect
(familiar new) in all groups
Psychomotor tests: respective
controls4MDD-patients
DSST, Symbol Copying Test,
Cancellation Test, simple choice
auditory and visual RTI, visual RTI/
auditory prestimulus, auditory RTI/
visual prestimulus:
n.s. differences
Tapping Test:
Clomipramine, fluoxetine (the
difference varies according to dose/
weight)
Inserting Pins:
Imipramine (p o 0.05)
Visual RTI/differential response:
Imipramine (p o 0.05)
Depression: MDD-patients had
higher scores than their respective
controls
STAI trait:
Clomipramine, imipramine,
fluoxetine, sertraline (p o 0.001)
STAI state:
Clomipramine, imipramine
(po 0.01)
Fluoxetine, sertraline (p o 0.05)
BDI:
Clomipramine, fluoxetine
(po 0.001)
Sertraline (p o0.01)
Imipramine (the difference varies
Katona et al. Compare the efficacy and safety of Randomized, double-blind, placebo- Measured at baseline and last Comparison Baseline – week 8
(2012) Lu AA21004 to duloxetine and controlled, duloxetine-referenced, assessment:
placebo in elderly patients with fixed-dose study
MDD
RAVLT, DSST Lu AA21004
435 Patients (297♀, 138♂, M ¼ 70.6 HAM-D, MADRS, HAM-A, CGI ↑DSST (p o0.05, 83% direct effect)
years) with a current MDE, 8 weeks
N ¼ 156: Lu AA21004 (5 mg/day) Assessed only before treatment: ↑RAVLT acquisition (p o 0.05, 71%
direct effect)
N ¼ 151 Duloxetine (60 mg/day) MMSE ↑RAVLT delayed recall (po 0.05, 72%
direct effect)
N ¼ 128: Placebo Assessed at each visit (weekly during ↑HAM-D (p o0.01,
the first 2 weeks of treatment and LuAA21004 4duloxetine and
then every 2 weeks): Placebo)
Weight, BMI, ECGs, C-SSRS, Adverse ↑MADRS, CGI (p o 0.001)
Events
↑HAM-A (po 0.01)
Adverse Events (compared to
Placebo):
Nausea (p o 0.01)
Duloxetine
2DSST (26% direct effect)
↑RAVLT acquisition (p o 0.01, 65%
direct effect)
↑RAVLT delayed recall (p o0.01, 66%

direct effect)
↑HAM-D, MADRS, HAM-A, CGI
(po 0.001)
Adverse Events (compared to
Placebo):
Nausea, dry mouth (p o 0.001)
Constipation, Somnolence
(po 0.01)
Fatigue, Hyperhidrosis (p o 0.05)
C-SSRS n.s. changes between
treatment groups and placebo
mood (Harmer et al., 2009a; Harmer, 2010; Pringle et al., 2011). working memory, and attention improve through 5-HT1A receptor
Subsequently, cognitive processes and performance may improve stimulation and 5-HT3 receptor antagonism both of which
following these mood changes induced by antidepressants enhance cortical glutamatergic neuronal firing by disinhibition of
(McIntyre et al., 2013). Similarly, other authors suggest that y-aminobutyric acidergic interneurons (Puig et al., 2004; Llado-
antidepressant drugs and psychological therapies modify negative Pelfort et al., 2012). However, further clinical studies putting
biases that not only provide a common mechanism for under- cognitive dysfunction as the primary outcome in depression trials
standing treatments for depression, but that are also potentially are required to further support these initial promising findings on
useful in predicting, detecting and treating depression (Roiser et the proposed direct pharmacological effects of antidepressants
al., 2012). with multiple pharmacological targets on domains of cognitive
In addition, evidence has been put forward that the effects of function.
antidepressants are related to regional cerebral glucose metabo- An explanation for the superiority of SSRIs to TCAs could be the
lism. More specifically, response to antidepressant treatment was anticholinergic effect of TCAs which is supported by the finding
predicted by pre-treatment hypermetabolism in the rostral ante- that greater anticholinergic effects were negatively associated
rior cingulate in MDD compared to controls (Mayberg et al., 1997), with endpoint cognitive improvement in verbal learning and
suggesting a neurobiological mechanism between metabolism and processing speed in depressed elderly adults in a comparative
antidepressant action in the brain. Effects of antidepressants on study (Doraiswamy et al., 2003). Similarly, various studies have
neural processes represent another explanation of pharmacologi- found that the use of anticholinergic drugs negatively affects
cal effects on cognitive function. In a study of SSRI-treated cognitive performance such as episodic verbal memory (Fortin et
(Paroxetine) vs drug-naïve MDD patients vs healthy controls, it al., 2011) and anticholinergic drugs may particularly impair
was shown that SSRI treated patients had better sequence learning cognitive abilities that depend on the medial temporal lobe
but performed poorer on generalization of learned material as (Herzallah et al., 2010). A possible explanation for the superiority
compared to drug-naïve MDD patients (Herzallah et al., 2013c). of duloxetine over escitalopram may be that serotonergic and
Hence, antidepressants may exert beneficial effects on striatal noradrenergic mechanisms of the SNRI exert some kind of inter-
function required for sequence learning and thereby improve action, i.e. a synergistic effect in hippocampal formation, leading to
cognitive processes. Interestingly, the same study showed a detri- higher levels of memory recovery (Herrara-Guzman et al., 2009).
mental effect of Paroxetine on the hippocampus and other medial However, the exact mechanism remains to be discovered and is
temporal lobe structures which are critical for generalization of subject to further research.
learned material (Herzallah et al., 2013c), suggesting antagonistic In addition to the changes in cognitive performance, some
effects of this antidepressant on neural process and broader brain interventions have shown to improve social functioning and/or
functions. quality of life. Sertraline, citalopram and treatment with nortripty-
Although some of these neural effects of antidepressants line or paroxetine improved overall psychosocial functioning
suggest a subsequent improvement of cognitive performance (Butters et al., 2000; Rocca et al., 2005). Also, duloxetine was shown
following initial modification of emotion processing, antidepres- to improve overall social functioning and enjoyment of life which
sants have not been sufficiently studied to demonstrate robust might be partially due to the fact that it has a pain alleviating effect,
direct pro-cognitive effects in depression. While most of these should patients be affected by pain (Oakes et al., 2012; Robinson et
antidepressants primarily target the serotonin transporter (SERT), al., 2014). Moreover, sertraline seems to be superior to nortriptyline
other drugs combine multiple simultaneous pharmacologic at improving energy and most aspects of quality of life (Bondareff et
mechanisms in addition to SERT inhibition within the same al., 2000). However, the described findings must be taken with
molecule: vilazodone combines 5HT1A partial agonism with SERT caution because most of the included studies used a relatively small
inhibition; triple reuptake inhibitors combine norepinephrine and number of patients and a short observation time. Therefore it
dopamine reuptake inhibition with SERT inhibition, and vortiox- remains to be explored, if the observed correlations between
etine combines actions such as 5-HT1A and 5-HT1B partial treatment-induced changes are replicated in independent studies
agonism, 5-HT7 antagonism and 5-HT3 antagonism with SERT and remain stable over time. Many of the mentioned studies also
inhibition (Stahl et al., 2013). Therefore, in addition to mood lacked a control group and for some of the inserted cognitive tests,
improving effects, it has recently been suggested that vortioxetine parallel forms are not available which means that the observed
may exert direct effects on cognitive function through its multi- improvements in cognitive functions cannot be solely attributed to
modal pharmacological actions. Specifically, it was shown that the pharmacological treatment since it is possible that these changes
cognitive measures of processing speed, executive functioning, are, at least partially, due to practice effects. Besides, a lot of the
Table 5
Effects of cognitive interventions on neurocognitive performance and functional ability in depression.
Klasik et al. Evaluate the effectiveness of different forms of Randomized study, pretest–posttest design Assessed at onset and UBS-Test:
(2012) therapeutic methods on short-term memory and end of treatment:
attention
60 Subjects with current moderate depressive SDT, UBS-Test First/ second
episode examination:
N ¼20: PD psychotherapy (5 1.5-h PD psychotherapy
meetingsþ 2 1-h individual sessions per week) M ¼6.42/ 6.79,
Combined M¼ 4.55/
8.90, Sertraline M¼ 5.10/
8.25
N ¼20: sertraline (M¼50 mg/day)þ PD SDT:
psychotherapy (5 1.5-h meetings þ2 1-h
individual sessions per week)
N ¼20: sertraline (M¼50 mg/day) First/ second
examination:
8 Weeks PD psychotherapy
M ¼48.13/44.38,
Combined M¼ 35.35/
71.30, Sertraline
M ¼36.40/65.70
Sharma et al. Determine the effects of SY on attention span, visuo- Randomized study, pretest–posttest design Assessed at onset and SY-group:
(2006) motor speed, short-term memory, working memory end of treatment:
and executive functions
30 patients (11♀, 19♂, M¼ 31.8 years) with current LCT, TT A and B, RFFT, ↑LCT omission
MDD, 8 weeks FDS, RDS (p¼ 0.002)
N ¼15: conventional anti-depressant medication (9 HAM-D ↑LCT time (p ¼0.006)
TCA, 6 SSRI) þ SY meditation (3 times a week,
30 min)
N ¼15: conventional anti-depressant medication (8 ↑TT A (p¼ 0.019)
TCA, 7 SSRI)
↑TT B (p ¼0.002)
↑RDS (p¼ 0.04)
2RFFT, FDS
↑HAM-D (p o 0.001) (SY-
group4No SY-group,
p ¼0.003)
No SY-group:
↑LCT omission (p ¼0.03)
↑LCT time (p ¼0.01)
↑TT A (p¼ 0.017)
↑TT B (p ¼0.002)
2RDS
2RFFT, FDS
↑HAM-D (p o 0.001)
Naismith Determine the effects of NEAR on Preliminary randomized, single-blind study, pretest– Assessed at onset and ↑RAVLT learn (po 0.01)
et al. neuropsychological functioning and disability levels posttest design end of treatment,
(2010) assessors blinded to
group allocation:
16 Patients (14♀, 2♂, M¼ 33.5 years) with a lifetime WTAR ↑RAVLT delay (po 0.05)
diagnosis of MDD (14 unipolar, 2 bipolar-II),
Waitlist control design RAVLT, TT A&B, RCFT, 2 WTAR
COWAT
N ¼8: immediate treatment with NEAR, 10 weeks, BDQ 2TT A and B
twice weekly
N ¼8: waitlist Only assessed at 2RCFT
beginning of
treatment:
Semi-structured 2COWAT
interview including
HAM-D
DASS 2BDQ
Elgamal et al. Determine the effects of a computer-assisted CRT on Proof of principle study, pretest–posttest design Assessed at onset and PSSCogReHab group:
(2007) memory, attention, executive functioning and end of treatment:
psychomotor speed
24 patients with recurrent MDD and 22 healthy CVLT, RSAT 2&7, WAIS- ↑CVLT (po 0.001)
subjects (30♀, 16♂, M¼ 48.9 years), 10 weeks R FDS and RDS, WAIS-R
SS, TT A&B, COWAT
N ¼12: received PSSCogReHab training twice HAM-D, YMRS (only ↑RSAT 2&7 (p o 0.01)
weekly, 45–60 min MDD patients)
N ¼12: comparator group ↑WAIS-R FDS (po 0.05)
CG: N ¼ 22 healthy controls ↑TT A (po 0.01)
2WAIS-R RDS, TT B,
COWAT, WAIS-R SS
2HAM-D, YMRS
Comparator group:
↑CVLT (po 0.05)

2RSAT, WAIS-R FDS and
RDS, TT A&B, COWAT,
WAIS-R SS
2HAM-D, YMRS
CG:
↑CVLT (po 0.01)
↑TT A (po 0.05)
2RSAT, WAIS-R FDS and
RDS, TT B, COWAT, WAIS-
R SS
Deckersbach Determine whether a new CR treatment is Open trial, pretest–posttest design Assessed only at onset: ↑HAM-D (p ¼0.004)
et al. associated with improvement in depressive
(2010) symptoms, occupational functioning, and overall
psychosocial functioning in individuals with bipolar
disorder
18 Individuals with DSM-IV bipolar I or II disorder RBANS, D–KEFS, WTAR Pretreatment: M¼8.65,
(8♀, ♂6, M¼36.8years) enrolled; 17 patients met post-treatment: M ¼5.41,
criteria for ITT analysis; 14 patients completed the follow-up: M¼6.06
study; 13 patients were assessed at 4 months
follow-up, 14 individual sessions of CR (50 min)
Assessed at onset and Pretreatment– post-
end of treatment and tretament (po 0.05)
at 3-months follow up:
HAM-D, YMRS Pretreatment–follow-up
(po 0.05)
Absenteeism and 2YMRS
presenteeism
questions of WHO HPQ
LIFE-RIFT 2WHO HPQ
absenteeism
FrSBe ↑WHO HPQ
presenteeism (p¼ 0.005)
Pretreatment: M¼6.78,
post-treatment: M ¼5.10,
follow-up: M¼5.23
Pretreatment–post-
tretament (po 0.05)
Pretreatment–follow-up
(po 0.05)
↑WHO HPQ total lost
workday equivalents
(p¼ 0.001)
post-treatment:
M ¼7.04, follow-up:
M ¼7.38
tretament (po 0.05)
(n.s.)
↑LIFE-RIFT (p¼ 0.03)
post-treatment:
M ¼9.47
tretament (po 0.05)
(po 0.05)
↑FrSBe Executive
Dysfunctioning
(p¼ 0.003)
posttreatment:
M ¼57.76
tretament (po 0.05)
(po 0.05)
2FrSBe Apathy
2FrSBe Disinhibition

pharmacological studies used fixed doses of the analyzed drugs, so it 2008). Major models suggest that this type of treatment may
remains unclear if optimized dosages for each patient would lead to involve restoration and/or compensation for impaired functions.
better outcomes. Moreover, the study comparing Lu AA21004 At a cellular level, preliminary research suggests that cognitive
(vortioxetine) to duloxetine is the only one that also conducted a training may influence spine density, synaptogenesis and vascular
path analysis to find out to which extent the drugs affect neurop- supply to the brain. Additionally, it may promote glial and
sychological performance directly or indirectly through the metabolic activity, brain-derived neurotrophic factor and hippo-
improvement of mood (Katona et al., 2012). Although not a primary campal neurogenesis (Fuchs et al., 2004; Sachdev and Valenzuela,
focus of this review, it is notable that antidepressants may exert 2009). Moreover, repeated stimulation of impaired cognitive
positive effects on cognitive function even in medical comorbidities functions through targeted, repetitive exercises has been shown
such as stroke. A study in post-stroke patients reported that stroke to improve cognitive performance in patients with psychiatric
patients treated with escitalopram showed improvement in global illness, most prominently schizophrenia (Bell et al., 2001, 2003;
cognitive functioning, specifically in verbal and visual memory Fiszdon et al., 2004); however, the mechanisms underlying func-
functions, as compared to patients who received placebo or under- tional change are poorly understood and require further clinical
went Problem Solving Therapy (Jorge et al., 2010). In this study, the and mechanistic research.
beneficial effect of escitalopram was independent of its effect on In addition to cognitive remediation, two other types of cogni-
depression (Jorge et al., 2010). Additional important factors that may tive approaches – the Psychodynamic psychotherapy and Sahaj
influence the cognitive response to antidepressant treatment might Yoga Meditation – have shown additional improvement in cognition
be age. Although studies have shown improving effects of antide- in patients treated with conventional antidepressants. However,
pressants on cognitive function in old age depression (Doraiswamy given the relatively small number of studies that analyzed the
et al., 2003), this group of patients may need to be regarded as effects of interventions addressing neuropsychological performance
different in their pathophysiology of depression, overall prognosis in depression and their methodological limitations, further research
and risk of developing dementia as compared to adult-onset of in this field is needed. At a mechanistic level, synergistic treatment
depression (Butters et al., 2000). Moreover, cognitive impairment in effects between antidepressants and psychological treatment may
depression appears to differ even before treatment commences be explained by a neuropsychological model of antidepressant drug
between young and older MDD patients groups with the older age action as suggested by Harmer et al. (2009a). It is argued that
group performing cognitively worse than the younger groups and antidepressants change the relative balance of positive to negative
bipolar depression patients showing consistently lower scores on emotional processing, which provides a platform for subsequent
cognition in young and older age groups (Burt et al., 2000). Hence, cognitive and psychological reconsolidation (Harmer et al., 2009a;
studies on antidepressant treatment effects on cognitive function Harmer, 2010). Similarly, it has been suggested that antidepressants
need to consider age effects on treatment response as both younger modify negative biases towards positive biases by which not only a
and older patients with depression have different baseline cognitive common mechanism for understanding various types of treatments
performances and might respond to antidepressants at varying for depression is provided, but also this can be regarded as a useful
degrees of cognitive function based on age effects. model to understand the synergistic effects between antidepressant
Taken the evidence on positive and negative effects of phar- treatment and psychotherapy, such as CBT (Roiser et al., 2012).
macological effects on cognitive dysfunction in depression Interestingly, cognitive behavioral therapy has shown positive
together, on balance the positive effects of the published results effects on cognitive performance in depression on its own. A study
seem to outweigh possible negative effects. Not only more studies in remitted bipolar disorder I patients showed that CBT affected not
have been published with positive than studies with negative only positively dysfunctional attitudes over 6 months, it also
effects of antidepressants on emotion and cognitive dysfunction in improved memory performance (Docteur et al., 2013). However,
depression as reviewed above, it has become evident in the past since this study was performed in remitted patients without current
few years that antidepressant exert their effects on emotion and clinical depression at the time of treatment, its comparability with
cognitive processing via different mechanisms including direct the studies of this review in acute depression is limited. Several
receptor modulation relevant to cognitive function, indirect effects other studies have reported positive effects of CBT on cognitive
via emotion modulation and via modulating specifically neural performance, however, mainly in psychiatric diagnostic groups (e.g.,
processes and brain network function. However, for clinical panic disorder or in depressed pregnant women) (Pearson et al.,
practice it is important to be aware that some antidepressants 2013; Reinecke et al., 2013) other than depression or they did not
do exert differential positive and negative effects on neural employ cognitive performance such as in memory, attention and
processing affecting both emotion and cognitive functions as well executive function as primary outcomes. Further research into the
as detrimental effects via anticholinergic effects of TCAs. role of CBT on cognitive performance of such domains is needed.
7. Effects of non-pharmacological treatment on cognitive 8. Future directions

function and functional ability in depression
Important future directions need to be considered for both
A small number of studies have reported on the effects of pharmacological and non-pharmacological treatments of cognitive
cognitive approaches in the treatment of cognitive dysfunction in dysfunction in depression. Regarding antidepressant therapy,
depression. As a part of cognitive remediation, three approaches, some unanswered important questions include (a) whether there
namely the Neuropsychological Educational Approach to Reme- is one group of antidepressants that is generally superior to others
diation (NEAR), a computerized cognitive retraining package in terms of improving neuropsychological performance, (b) if there
(PSSCogReHab) and a 4-months cognitive remediation program are specific pharmacological indications for antidepressant to
in patients with residual depressive symptoms in bipolar disor- target certain neuropsychological impairments, (c) if women and
ders, were shown to improve cognitive, occupational and social men or patients of different ages react differently to the same
functioning. While the mechanisms for improvement are drug, and (d) if the observed effects are direct or indirect, and if
unknown, these studies support the notion that cognitive reme- they remain stable over time. It is important to note that most
diation and training therapies may promote neuroplasticity and studies to date have not been designed to distinguish direct pro-
restore compromised neural processes (Maples and Velligan, cognitive effects of antidepressants from indirect effects on
cognition via improvements of mood e.g. by employing a agents. This is notable because most of the studies that are
path-analysis and by comparing multimodal vs monomodal included in this review on the treatment of cognitive deficits in
antidepressants. depression use different measures for the same cognitive domains
In summary, additional comparative studies are required, long- which make it harder to compare the studies to each other. These
itudinal studies with a representative sample and a control group lessons can be learned from the schizophrenia research field and
are needed to analyze the effects of antidepressant therapy and are worthwhile to be applied to future research on cognition in
compare groups of different ages, with different neuropsycholo- depression.
gical impairments, compare men and women to each other and In summary, studies have reported effects of various psycho-
control for mood effects on cognitive function. Importantly, pharmacological and cognitive approaches that improve neurop-
studies should assess the patients' functional ability and self- sychological performance in depression. However, more extensive
rated cognitive and general function and quality of life, because and improved research is needed to eventually implement reliable
if a drug is able to improve cognition but this change is not related and precise methods for the improvement of neuropsychological
to the patients' functioning in their everyday life, such treatment performance in the treatment of depression. It may be helpful for
effects might be negligible. researchers to agree on a standardized neuropsychological test
Regarding the cognitive approaches, more longitudinal studies battery for the measurement of neuropsychological impairment in
on a wider variety of treatments are needed. Since psychodynamic depression.
psychotherapy has shown to additionally improve cognition in
antidepressant-treated patients, it might be worthwhile examin-
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Psychiatry Research 219 (2014) 25–50

Contents lists available at ScienceDirect

Pharmacological and non-pharmacological interventions to improve

1. Introduction contrast, SSRI antidepressants such as citalopram have been sug-

Authors Aim of the study Study design Measures Results

Savaskan Investigate the antidepressive effects of Single-centre, randomized, open-label trial

Authors Aim of the study Study design Measures Results

N ¼ 72: sertraline (50 mg/day) ↑HAM-D, GDS, GAF

Authors Aim of the study Study design Measures Results

Authors Aim of the study Study design Measures Results

Week 12: placebo 35%, duloxetine

Authors Aim of the study Study design Measures Results

For Abbreviations see Table 1

Authors Aim of the study Study design Measures Results

Authors Aim of the study Study design Measures Results

PAL total trials (p ¼ 0.05)

Authors Aim of the study Study design Measures Results

8-Week open treatment with n.s. differences for DSST,

For Abbreviations see Table 1

Authors Aim of the study Study design Measures Results

Authors Aim of the study Study design Measures Results

63 Patients (60% ♀, M ¼ 64.2 years) Medical Outcomes Study, MMSE,

Authors Aim of the study Study design Measures Results

outpatient status and by cognitive MMSE, DRS

Authors Aim of the study Study design Measures Results

N ¼ 217 (62%♀, M¼ 68.0 years): HAM-D, CGI-Severity, CGI-

Authors Aim of the study Study design Measures Results

Remitters¼ After 6 months HAM-D Attentional Matrices, MLT '88, SCT,

Authors Aim of the study Study design Measures Results

Authors Aim of the study Study design Measures Results

↑RAVLT delayed recall (p o0.01, 66%

For Abbreviations see Table 1

Authors Aim of the study Study design Measures Results

Authors Aim of the study Study design Measures Results

↑CVLT (po 0.05)

For Abbreviations see Table 1

7. Effects of non-pharmacological treatment on cognitive 8. Future directions

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