The Role of Serotonin in Cognitive Function

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DOI: 10.1177/02698811134825312013 27: 575 originally published online 27 March 2013J PsychopharmacolPhilip Cowen and Ann C Sherwood

understanding depressionThe role of serotonin in cognitive function: evidence from recent studies and implications for

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Introduction

Cognitive function comprises various neurobiological processesinvolved in attention, learning, memory, planning and decision

making (Garcia-Carbonero and Paz-Ares 2002; Millan et al.,

2012). Impairment of cognitive function is a prominent feature of

many psychiatric and neurodegenerative illnesses and imposes

substantial disability. There is increasing interest in understanding

the neurobiology of cognition in healthy individuals in order to

identify therapeutic targets for improving symptomatic and func-

tional outcomes in impaired individuals with psychiatric disorders.

Symptoms of cognitive impairment such as poor concentration,

memory loss and difficulty with decision making are prevalent in

patients with depression but are not specific treatment targets, the

general assumption having been that any deficits will remit as the

patient recovers from depression (Garcia-Carbonero and Paz-Ares2002; Jaeger et al., 2006; McCall and Dunn 2003; Naismith et al.,

2007). However, the fact that patients can continue to demonstrate

cognitive impairments even when apparently clinically recovered

suggests that this view may be too sanguine (Hasselbalch et al.,

2011). Indeed, structural imaging studies have revealed consistent

evidence of hippocampal grey matter reductions in patients with

recurrent depression, which might be associated with persistent

problems in episodic memory (McKinnon et al., 2009). Similarly,

functional imaging studies of working memory also suggest

abnormal neural activation patterns in remitted depressed patients

(Kerestes et al., 2012; Schoning et al., 2009).

Drugs that potentiate serotonin (5-HT) function are the main-stay of depression treatment and are often prescribed for longer-

term maintenance therapy. However, our understanding of the

effects of serotonin on cognitive function in healthy humans and

depressed patients is incomplete. There are useful data from animal

studies investigating the modulatory effects of specific 5-HT

receptor subtypes on cognition in animal models but much less

data on effects in humans. Nevertheless, it is possible that future

antidepressant compounds with more selective actions at 5-HT

receptor subtypes may produce specific cognitive benefits in

depressed patients. The literature relevant to these topics is consid-

erable, and the objective of this article is to provide a concise over-

view for clinicians, focusing on how 5-HT impacts cognitive

function relevant to depressed patients. We will also briefly sum-marize animal studies linking specific 5-HT receptor subtypes with

cognitive function where relevant to psychotropic drug action.

The role of serotonin in cognitive function:evidence from recent studies and implicationsfor understanding depression

Philip Cowen1 and Ann C Sherwood2

AbstractBackground: Symptoms of cognitive impairment such as poor concentration, memory loss and difficulty with decision making are prevalent in patients

with depression, but currently are not specific targets for treatment. However, patients can continue to demonstrate cognitive impairments even

when apparently clinically recovered. Drugs that potentiate serotonin (5-HT) function, such as selective serotonin reuptake inhibitors (SSRIs), are

the mainstay of treatment for depression. Nevertheless, our understanding of the effects of SSRIs and other conventional antidepressant therapy on

cognitive function in healthy humans and depressed patients remains limited.

Objective: The purpose of this article is to provide a concise overview for clinicians on the impact of pharmacological manipulation of 5-HT on

cognitive function in healthy humans with additional reference to animal models where human data are lacking, particularly regarding specific 5-HTreceptor subtype modulation.

Findings: The most consistent observation following manipulation of serotonin levels in humans is that low extracellular 5-HT levels are associated

with impaired memory consolidation. Preclinical data show that agonism and antagonism at specific 5-HT receptors can exert effects in animal models

of cognition.

Conclusions: Larger, consistently designed studies are needed to understand the roles of 5-HT in cognition in healthy and depressed individuals.

Efforts to target specific 5-HT receptors to improve cognitive outcomes are warranted.

Keywords

Cognition, serotonin, tryptophan depletion, 5-HT receptor, antidepressants

1Warneford Hospital, Oxford, UK2The Medicine Group, New Hope, PA, USA

Corresponding author:

Philip Cowen, Neurosciences Building, Warneford Hospital, Oxford

OX3 7JX.

Email: [email protected]

JOP27710.1177/0269881113482531Journal of PsychopharmacologyCowena nd Sherwood

Review

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576 Journal of Psychopharmacology 27(7)

Serotonin and cognition

Tryptophan depletion studies

Tryptophan (TRP) is the amino acid precursor of 5-HT, and

depleting systemic levels of TRP effectively lowers 5-HT in the

central nervous system. Depletion is accomplished by oral admin-

istration of an amino acid mixture lacking TRP and enriched forother large, neutral amino acids (LNAA). As a result, circulating

TRP levels decrease while at the same time competition increases

for the LNAA transporter needed by TRP to cross the bloodbrain

barrier. In rats, TRP depletion results in an approximately 50%

reduction in 5-HT levels in the cortex, striatum, and hippocampus

(Mendelsohn et al., 2009).

A number of TRP depletion studies have assessed the relation

between lowered 5-HT levels and cognition in healthy adults

(Table 1). Most studies were small and used heterogeneous cog-

nitive testing methods, which revealed heterogeneous outcomes.

To increase the power to detect effects in these trials, Mendelsohn

et al. (2009) conducted a comprehensive review of 66 TRP deple-

tion studies published starting in 1966 through September 2008

(Mendelsohn et al., 2009). Fifty-nine trials included healthy indi-viduals and used a placebo drink or TRP loading as a comparator.

Circulating TRP levels were reduced by 4697%. There was no

evidence that TRP depletion affected mood in healthy volunteers

without a family history of depression. However, acute TRP

depletion impaired episodic memory, which the authors define as

acquisition and retention of memories for events and experiences

requiring conscious learning. The most consistent effects of TRP

depletion across the trials included in the analysis were impaired

consolidation of episodic memory, primarily that requiring

verbal learning. Some trials found small effects on encoding of

verbal learning. In addition, one study showed significant nega-

tive impact of TRP depletion on contextual episodic memory.

However, TRP depletion did not appear to affect spatial episodicmemory, or semantic or working memory. Indeed, semantic

memory tended to improve in the depleted state (Mendelsohn

et al., 2009).

The authors also noted results in the majority of studies did not

support specific effects of TRP depletion on executive function

(planning, decision making, and response inhibition) (Mendelsohn

et al., 2009) and showed minimal effects on sustained attention

(vigilance), selective attention, divided attention, or attentional

set-shifting (Lash et al., 2000; Mendelsohn et al., 2009).

Results using BOLD signals in fMRI to assess the function of

5-HT manipulation on the neural activity involved in cognitive

processes also are heterogeneous among themselves and variable

with respect to consistency with other approaches. Van der Veen

et al. (2006) used fMRI to compare the BOLD response afterdrinking a balanced amino acid mixture and after TRP depletion

in healthy male volunteers during visual verbal episodic memory

tasks. TRP depletion increased the number of positively rated

words and worsened word retrieval. The BOLD response was

diminished in brain regions normally activated during encoding

(right hippocampus) but was not affected the response in the

neurocircuitry activated during the retrieval phase (distributed in

frontal, parietal, temporal, cingulate, striatal and cerebellar

regions) (van der Veen et al., 2006). These findings are consistent

with evidence implicating 5-HT in consolidation of episodic

memory (Mendelsohn et al., 2009), and suggest that the key role

is during the encoding phase (van der Veen et al., 2006).

The same group investigated the impact of TRP depletion on

performance monitoring and response inhibition (Go/NoGo test),

two processes necessary for cognitive flexibility (Evers et al.,

2006). They compared the BOLD response in the dorsolateral pre-

frontal cortex with and without TRP depletion in 13 healthy male

volunteers. Although there was no difference in the number of

correct responses on the Go/NoGo tasks with and without TRP

depletion, after TRP depletion the BOLD response decreased dur-ing performance monitoring, but not during response inhibition

(Evers et al., 2006).

Although there is no evidence that serotonin depletion is suf-

ficient to induce depression in healthy individuals, approximately

50% of patients with major depressive disorder (MDD) who are in

remission after selective serotonin reuptake inhibitor (SSRI) ther-

apy relapse under conditions of TRP depletion (>80% decrease in

plasma TRP levels) (Delgado et al., 1999). These findings suggest

that serotonin is essential for the maintenance of antidepressant

effects of SSRIs at least in some patients. However, use of a low-

dose TRP depletion protocol in which competition for the LNAA

transporter is reduced was able to induce immediate recall deficits

in recovered patients without affecting mood in two studies(Haddad et al., 2009; Hayward et al., 2005). In both of these stud-

ies, low-dose TRP depletion (between 64% and 70% reduction in

plasma TRP) was also associated with negative cognitive bias and

difficulties with autobiographical memory. Impaired specificity of

autobiographical memory was reported recently in a preliminary

study of healthy individuals with a family history of depression

following a 63% reduction in plasma TRP (Alhaj et al., 2012).

Conclusions drawn from TRP depletion studies are limited

because serotonin manipulation is not specific to a particular sero-

tonin pathway or brain region. However, taken together, the

results in healthy subjects and in patients with depression support

the hypothesis that mood and cognitive symptoms have different

thresholds for serotonin availability and may be mediated by dif-

ferent serotonin functions.

Serotonin reuptake inhibition

5-HT is removed from the synaptic cleft via the serotonin trans-

porter (SERT). It is generally accepted that SERT inhibition by

SSRIs increases serotonin availability in the synapse, thus increas-

ing serotonergic tone. In the short term, however, the increase in

5-HT activates 5-HT1A autoreceptors in the raphe nuclei, which

may initiate a transient compensatory inhibition of 5-HT release.

Although the activation of 5-HT1A autoreceptors inhibits seroto-

nin release, rat studies show that extracellular 5-HT levels in the

prefrontal cortex increase during acute and subchronic SSRI

administration (Ceglia et al., 2004). Thus, even in the short term,SSRI treatment is presumed to result in increased 5-HT levels in

the central nervous system in some brain regions. With chronic

exposure to SSRIs, overall 5-HT neurotransmission is increased.

In three small studies in healthy volunteers, acute (24 h) and

subchronic treatment (1422 days) with fluoxetine, paroxetine

and venlafaxine reduced vigilance (sustained attention) (OHanlon

et al., 1998; Ramaekers et al., 1995; Schmitt et al., 2002). To

determine if this effect is specific to SERT inhibition, the effects

of the highly selective SSRI citalopram were compared with those

of sertraline, an SSRI with some potential activity at the dopamine

transporter. Acute (24 h) and subchronic (Day 15) treatment with

citalopram (20 mg and 40 mg, respectively) impaired sustained

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Cowen and Sherwood 577

Table 1. Serotonin manipulation and cognitive effects in healthy individuals.

Serotonin

(5-HT) receptor

Study method Cognitive effects observed in healthy individuals

TRP depletion (Mendelsohn et al., 2009) (Meta-analysis of 59 trials) impaired consolidation of

episodic memory (verbal); did not appear to affect the

spatial episodic memory, semantic or working memory, or

executive function; minimal effects on sustained attention,

selective attention, divided attention, or attentional set-

shifting

Serotonin transporter

(SERT)

Citalopram (20 mg) (Nathan et al., 2000) (N= 9 males) Acute (14 h): Improved response time and

sustained attention vs. baseline

Citalopram (30 mg) vs. placebo and

atomoxetine (Chamberlain et al., 2006)

(N= 60 males) Acute (1.5 h) Impaired probabilistic learning

but not response inhibition

Citalopram (20 mg on days 18, 40 mg

on days 915) vs. sertraline or placebo

(Riedel et al., 2005)

(N= 24) Acute (24 h) and subchronic (14 days) treatment

with citalopram (20 mg and 40 mg, respectively) impaired

sustained attention

Citalopram 10 mg iv vs. placebo (Harmer

et al., 2002)

(N= 24 females) Acute


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attention in 21 healthy subjects. However, sertraline (50 mg

acutely, and 100 mg subchronically) did not affect sustained atten-

tion (vigilance) in healthy subjects (Riedel et al., 2005).

It should be pointed out that decrements in sustained attention

have not always been found in healthy individuals treated with

citalopram. Harmer and colleagues (2002) conducted a rand-

omized, placebo-controlled study of citalopram in 24 healthy

women. Testing was initiated 45 min after infusing either 10 mgcitalopram or placebo. There was no citalopram effect on

sustained attention or immediate recall. The reasons for the differ-

ences may reflect the small sample sizes, different study popula-

tions (both sexes vs. only women), different testing methods, or

different drug administration. Perhaps, however, the more inter-

esting finding in the latter study is that acute citalopram treatment

enhanced memory consolidation compared with the placebo

group (Harmer et al., 2002). Once again, these results suggest that

memory consolidation may be inversely correlated with extracel-

lular 5-HT levels.

Several other small studies assessed SSRI effects on various

cognitive functions. Almeida et al. (2010) compared the acute and

chronic effects of citalopram 20 mg administered once daily onimpulsive responding and contextual information processing in

healthy controls. Acute administration (24 h) impaired perfor-

mance on the Delayed Non-Matching to Sample Task (DNST), a

measure of working memory. The effect was no longer apparent

after 28 days. In this study, citalopram treatment did not affect

performance on Degraded Symbol Continuous Performance Test,

a measure of impulsive responding, at either time point. The

authors suggested that the transient effects on the DNST are likely

attributable to activation of 5-HT1A receptors in the entorhinal

cortex and hippocampus (Almeida et al., 2010).

Effects of subchronic sertraline administration on cognitive

function were evaluated in a randomized, double-blind, cross-

over study in 12 healthy male volunteers (Siepmann et al., 2003).

Subjects received sertraline 50 mg or placebo once daily for 14days. In this trial, subchronic sertraline did not affect choice reac-

tion time, psychomotor coordination, visual memory span, or abil-

ity to detect discrete sensory data. The lack of effect has been

attributed to sertraline actions on dopamine levels that may coun-

ter the impact of 5-HT1A activation. On the other hand, it may

simply be that SSRIs produce relatively small and inconsistent

effect on cognition in healthy participants. Similarly, daily admin-

istration of a dual serotonin norepinephrine reuptake inhibitor,

venlafaxine 75 mg/day for 7 days followed by 150 mg/day for

another 7 days, did not significantly alter choice reaction time,

psychomotor function or memory in healthy subjects (Siepmann

et al., 2008). Overall, the most consistent observation following

manipulation of serotonin levels by TRP depletion or SERTblockade seems to be that low extracellular 5-HT levels are asso-

ciated with impaired memory consolidation.

Serotonin receptors and cognition data from animal and human studies

5-HT receptors comprise seven subfamilies including 14 sub-

types, and some subtypes are expressed as multiple isoforms. All

are G-protein-linked except 5-HT3 receptors, which are iono-

tropic. Most 5-HT receptors are present in brain regions associ-

ated with learning and memory. However, within any particular

region, they may be expressed on different neuronal subtypes and

in different layers of the region as heteroreceptors (Puig and

Gulledge 2011). This diversity allows for complex cellular and

regional mechanisms for regulation of receptor activity. Generally,

it is has been suggested that effects of 5-HT receptor subtype

manipulation on learning and memory are exerted through altera-

tions in the release of neurotransmitters such as acetylcholine and

glutamate, which have been more directly implicated in cognitivefunction than 5-HT itself (King et al., 2008). Although selective

agonists and antagonists have been developed for many 5-HT

receptor subtypes, agents tested in healthy humans tend to be rela-

tively non-selective. Nonetheless, evidence supports the potential

therapeutic value of targeting one or more 5-HT receptors to

enhance learning and memory in humans.

5-HT1A receptors

5-HT1A receptors are widely expressed in the prefrontal cortex,

hippocampus, and septum, areas associated with learning and

memory, and in the raphe nuclei, the primary location of 5-HT cell

bodies in the central nervous system (Albert and Francois 2010).

Generally, 5-HT1A agonists impair learning in animals, although

data from 5-HT1A knockout mice are not consistent with this.

Delivery of 5-HT1A receptor agonists to the rat medial raphe

nuclei enhanced cognitive performance, whereas performance

was impaired following systemic delivery or infusion into the hip-

pocampus. This suggests that activation of 5-HT1A autoreceptors

improves cognitive function by decreasing 5-HT release, and the

opposite effect is produced by drugs acting directly at post-synaptic

5-HT1A receptors (Warburton et al., 1997). However, systemic

delivery of F15599, an agonist that is highly selective for post-

synaptic 5-HT1A receptors, did not induce cognitive deficits in

rats and, unlike non-selective agents, partially reversed phencycli-

dine-induce impairment of working and reference memory(Depoortere et al., 2010).

In healthy humans, 5-HT1A partial agonists such as buspirone

and tandospirone have little or no effect on cognition, though the

data are somewhat inconsistent (Chamberlain et al., 2007a;

Takahashi et al., 2010). Interpretation of this effect is complex

because partial 5-HT1A receptor agonism might increase or

decrease 5-HT neurotransmission. In contrast, in patients with

schizophrenia, the same 5-HT1A partial agonists may produce

small improvements in cognition, suggesting (perhaps not surpris-

ingly) that the effects of partial agonists on cognition might

depend on underlying state of 5-HT neurotransmission (Sumiyoshi

et al., 2000, 2001, 2007). It has been suggested that 5-HT1A-

modifying drugs might also be helpful for the cognitive impair-

ments in Alzheimers disease. However, development of

single-receptor agents that showed promise for improving cogni-

tion in patients with Alzheimers disease was stopped. Lecozotan,

a selective 5-HT1A antagonist, and xaliproden, a 5-HT1A agonist,

both failed to complete FDA registration trials for treatment of

Alzheimers symptoms (Sabbagh 2009).

5-HT2 receptors

5-HT2A receptors, along with 5-HT1A receptors, are among the

most commonly expressed in the prefrontal cortex. Unlike 5-HT1A

receptors, however, 5-HT2A receptors are located exclusively



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postsynaptically. In the cortex, 5-HT2A receptors are localized to a

subset of GABAergic interneurons and projection neurons,

consistent with a role in cognition (de Almeida and Mengod 2007;

Santana et al., 2004). In rats, ()-2,5-dimethoxy-4iodoampheta-

mine (DOI), a 5-HT2A receptor agonist, impairs short-term

memory at low doses and long-term memory at higher doses,

whereas 5-HT2A antagonists improved long-term memory without

affecting short-term memory (Meneses 2007). The 5-HT2A recep-tor antagonist EMD 281014 improved working memory function

in rhesus monkeys (Terry, Jr. et al., 2005).

There is also limited evidence that drugs with 5-HT2A receptor

antagonist properties, such as mianserin, may produce benefit in

cognitive function in patients with schizophrenia (Roth et al.,

2004). However, it has been difficult to show that atypical antip-

sychotic drugs, many of which potently block 5-HT2A receptors,

are better at improving cognitive function than conventional

antipsychotic agents (Selva-Vera et al., 2010; Wittorf et al., 2008).

5-HT2C receptors appear to be expressed exclusively in the

central nervous system, and are subject to extensive RNA editing

leading to 14 different isoforms (Jensen et al., 2010). Receptor

mRNA has been localized to GABAergic, glutamatergic anddopaminergic neurons in the frontal cortex, hippocampus, hypo-

thalamic nuclei, substantia nigra, nucleus accumbens, striatum

and the raphe nuclei (Jensen et al., 2010). There are relatively few

studies on the effects of 5-HT2C receptor ligands on cognitive

function in animals. The 5-HT2C receptor antagonist SB 242084

improved reversal learning in rats. However, somewhat paradoxi-

cally, the 5-HT2C agonist CP-809101 has been shown to enhance

novel object recognition learning in animal models (Siuciak et al.,

2007).

Mirtazapine antagonizes 5-HT2C receptors in addition to act-

ing at alpha-2 receptors. In a small study (N= 18) in healthy indi-

viduals, verbal memory was impaired with acute (2 days and 9

days) and subchronic (16 days) treatment with mirtazapine 3045

mg/d. Escitalopram 1020 mg did not affect verbal memory inthis placebo-controlled cross-over study (Wingen et al., 2006).

However, adjunctive mirtazapine may enhance cognition in

patients with schizophrenia (Cho et al., 2011; Stenberg et al.,

2010, 2011). In one study, mirtazapine improved cognitive per-

formance in patients with recurrent depression. Although depres-

sive symptoms improved with treatment, cognitive improvement

did not correlate with change in depressive symptoms (Borkowska

et al., 2007). However, whether these procognitive effects are

mediated by 5-HT2C receptors has not been determined.

5-HT3 receptors

5-HT3 receptors are the only ionotropic 5-HT receptors. Withinthe brain, 5-HT3 receptors are primarily localized to GABAergic

interneurons in the prefrontal cortex, where they contribute to the

regulation of cholinergic, dopaminergic, and glutamatergic activity

(Meneses, 2007). 5-HT3 receptors are also found in the hippocam-

pus (Walstab et al., 2010). 5-HT3 receptor antagonists such as

ondansetron have been shown to improve learning and memory in

rat (Hodges et al., 1996) and monkey (Terry, Jr. et al., 1996)

models of impaired cognition. A rat model showed that treatment

with the 5-HT3 agonist mCPBG impaired short-term memory at

low doses and long-term memory at high doses (Meneses, 2007).

Despite encouraging results in animal models, there is no compel-

ling evidence that 5-HT3 receptor antagonism improves cognitive

function in age-related memory decline in humans. However,

there are some hints of cognitive benefit in patients with schizo-

phrenia (Akhondzadeh et al., 2009; Levkovitz et al., 2005).

5-HT4 receptors

To date, few studies have evaluated the role of 5-HT4 receptors inhealthy humans. However, preclinical studies (King et al., 2008;

Marchetti et al., 2004; Terry, Jr. et al., 1998) demonstrated a role

for 5-HT4 binding in learning and memory. Findings in rodents

suggest that antagonism at 5-HT4 receptors impairs passive avoid-

ance memory, whereas agonism has rather complex effects but

does seem capable of reversing scopolamine-induced cognitive

deficits. The latter effects are thought to occur through modulation

of memory consolidation via regulation of cholinergic neurons

(Orsetti et al., 2003). In addition, animal studies suggest that

5-HT4 receptor activation elicits hippocampal synaptic plasticity.

Thus, 5-HT4 agonists are being considered for treatment of

Alzheimers disease (Russo et al., 2009).

5-HT6 receptors

The densest distribution of 5-HT6 receptors in rat brain is found

in the frontal and entorhinal cortices, hippocampus, nucleus

accumbens and striatum (Codony et al., 2011). Preclinical data

indicate that the 5-HT6 receptor regulates serotonergic modula-

tion of dopamine release in the prefrontal cortex and cholinergic

neurotransmission in the brain. Pharmacological studies in rats

have further implicated this receptor in memory retention (King

et al., 2008). Paradoxically, both 5-HT6 receptor agonists and

antagonists reverse memory deficits in animal models of cogni-

tive impairment (Codony et al., 2011). However, antagonists have

little or no cognitive-enhancing affect in healthy animals.

Consistent with these findings, one study conducted in healthyhumans found that the 5-HT6 receptor antagonist SB-742457 did

not affect motor activation and fluency, adaptive tracking, subjec-

tive alertness, or delayed word recognition (Liem-Moolenaar

et al., 2011). Several agents that are selective for 5-HT6 receptors

are currently in development for treatment of cognitive symptoms

in Alzheimers disease (Codony et al., 2011).

5-HT7 receptors

5-HT7 receptors are found on glutamatergic neurons in the super-

chiasmic nucleus of the hypothalamus, hippocampus, cortex,

thalamus and raphe nuclei (Bonaventure et al., 2011). In a recent

rat study, the selective 5-HT7 antagonist SB269270 prevented thenegative effects of MK801 but not scopolamine on working mem-

ory. Moreover, in this same study, SB269270 inhibited MK801

stimulated glutamate release, but not dopamine (Bonaventure

et al., 2011). These findings suggest that 5-HT7 receptor inhibition

may improve working memory in patients with glutamatergic

dysfunction for example, schizophrenia.

In summary, a relatively small number of studies have investi-

gated the role of specific serotonin receptors with cognition in

healthy humans. Similar to results in TRP depletion studies, in

most cases, little or no impact on cognition has been observed,

suggesting that serotonin homeostasis is difficult to perturb in

the healthy state. Nonetheless, some serotonin receptor modulators



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do appear to have differential effects on cognitive function in indi-

viduals with depression that is separable from effects on depres-

sive symptoms.

Cognitive symptoms in depression andantidepressant treatment

Cognitive symptoms are present in a substantial proportion of

patients with MDD and often persist after response and remission.

It is difficult to draw consistent conclusions from the numerous

studies performed to date, as most were small cross-sectional

studies using a wide variety of neuropsychological tests. Meta-

analysis of 15 study samples (N= 644) involving patients with a

first depressive episode revealed impaired psychomotor speed,

visual memory and learning, attention, and executive functioning

compared with healthy matched controls (Lee et al., 2011).

Impaired executive function was confirmed in a meta-analysis of

375 depressed patients whose mean performance was almost one

standard deviation below that of controls (Wagner et al., 2012).

Moreover, another meta-analysis in remitted MDD subjects (11

studies, 500 subjects) found evidence of residual impairment in

attention, memory and executive function or estimated global

cognitive function in patients vs. normal controls in 9 of 11 stud-

ies (Hasselbalch et al., 2011). Generally, cognitive deficits in

depression are broad based and extend into social cognition.

However, it is important to note that in acute depression, cognitive

performance can be compromised by other core depressive symp-

toms such as poor motivation (Millan et al., 2012). There is also

some evidence of correlations between depression severity and

the likelihood of experiencing cognitive symptoms (McDermott

and Ebmeier 2009).

Depression and cognitive impairment may have a bi-directional

causality. For example, in a meta-review and meta-regression of

case control and cohort studies, Ownby et al. (2006) found that ahistory of depression produced a twofold increase in risk for

subsequent development of Alzheimers disease. How far the

converse relationship holds is unclear. For example, a recent meta-

analysis found that patients with clinical dementia had a threefold

risk of experiencing depression. However, those with milder

cognitive impairment did not seem at greater risk of suffering

mood disorder (Huang et al., 2011).

Efforts to determine whether cognitive symptoms are present

before onset of depressive mood are inconclusive. One study

comparing healthy subjects aged 1620 with and without a family

history of MDD showed that overactivity, as measured by BOLD

response in brain regions associated with working memory, repre-

sent a marker for vulnerability to MDD (Mannie et al., 2010).

However, cognitive function assessments in adolescents with a

history MDD have yielded mixed results (Castaneda et al., 2008;

Hermens et al., 2011; Maalouf et al., 2011).

There is some evidence suggesting that cognitive symptoms

of depression do improve with antidepressant treatment.

Generally, the literature suggests that antidepressant treatment

improves cognitive function in depressed patients over time.

However, even after many months of treatment, cognitive impair-

ments in a range of domains are still detectable (Alexopoulos

et al., 2003; Hasselbalch et al., 2011, 2012; Herrera-Guzman

et al., 2008; McClintock et al., 2011) and are associated with

impaired psychosocial functioning (Jaeger et al., 2006; McCall

and Dunn 2003). A recent meta-analysis by Hasselbalch et al.

(2011) found that residual deficits in processing speed and cogni-

tive flexibility related to the cognitive domain of attention. The

STAR*D study found impaired concentration was one of the most

frequent residual symptoms in patients who showed an overall

treatment response (McClintock et al., 2011). These clinical find-

ings should be considered in the context of animal studies show-

ing that SSRI treatment, for example, facilitates neuroplasticity

and neurogenesis in the hippocampus (Malberg et al., 2000;Santarelli et al., 2003). Thus, despite the fact that longer-term

treatment with antidepressants appears to promote the kind of

neurobiological changes that would enhance cognitive function,

many depressed patients continue to show evidence of persistent

cognitive impairment even after long durations of therapy.

In a longitudinal study, Herrera-Guzman et al. (2010) found

that patients with MDD who achieved remission with escitalo-

pram (n = 36) or the serotoninnorepinephrine reuptake inhibitor

(SNRI) duloxetine (n = 37) showed improved episodic memory,

working memory, sustained attention and planning at the end of

24 weeks of therapy. However, patients in the duloxetine group

showed consistently better cognitive outcomes than those in the

escitalopram group (Herrera-Guzman et al., 2009). Cognitiveoutcomes were assessed again 24 weeks after treatment with-

drawal (Herrera-Guzman et al., 2010). At that time, the symptom

severity continued to improve from baseline throughout the

post-treatment phase. Moreover, during the post-treatment phase,

memory function continued to improve in those previously

treated with duloxetine, whereas the improvement in memory

remained stable in the group receiving escitalopram prior to

treatment withdrawal (Herrera-Guzman et al., 2010).

Quetiapine, an atypical antipsychotic agent, has antagonist

properties at 5-HT1A and 5-HT2A receptors as well as at dopamine

(D) 1 and D2, histamine 1, alpha-1- and -2-adrenergic and mus-

carinic-1 receptors. A small study (N= 18) tested the hypothesis

that patients who had cognitive symptoms and did not respond to

an SSRI alone would benefit from augmentation with quetiapine,in part through its dopamine antagonism. However, only small

benefit in cognitive function was observed (Olver et al., 2008).

Ongoing trials

Several available antidepressants alone or in combination are

currently in clinical trials to evaluate their procognitive effects

in patients with MDD. The effects of the SNRI desvenlafaxine

on cognition and work productivity are being investigated in

adults with depression who are aged 1955 years (clinical trial

NCT01468610). A second trial is evaluating the effec ts of

this agent on white matter structure in a similar population

(NCT01492621). One trial is assessing the effects of augment-

ing citalopram with methylphenidate, which acts through inhi-

bition of both dopamine and norepinephrine reuptake in older

patients (aged 60 years) (NCT00602290). The amphetamine

prodrug lisdexamfetamine, whose active metabolite also inhibits

dopamine and norepinephrine reuptake, is being studied in

another trial involving patients aged 1865 years who only par-

tially responded to an SNRI or an SSRI (NCT01148979).

A new multimodal serotonergic compound, vortioxetine (Lu

AA21004), is in development for treatment of adults with MDD.

Preclinical data show that vortioxetine functions as a 5-HT3,

5-HT7, and 5-HT1D receptor antagonist, a 5-HT1A receptor agonist,

a 5-HT1B receptor partial agonist, and an inhibitor of the 5-HT



8/10


transporter in vitro (Bang-Andersen et al., 2011; Westrich et al.,

2012). In a study of 453 patients 65 years of age with recurrent

MDD, vortioxetine improved baseline episodic memory (stand-

ardized effect size, 0.27 for acquisition and 0.24 for delayed

recall,p < 0.05) and psychomotor speed (standardized effect size,

0.25,p < 0.05) (Katona et al., 2012). Two trials are underway to

determine whether this cognitive benefit can be replicated in

adults aged 1865 years.

Conclusions

Available evidence indicates that 5-HT plays in a role in modulat-

ing cognitive function, even though the effects of global 5-HT

manipulation on learning, memory and executive function (for

example, TRP depletion or SSRI treatment) in healthy volunteers

are not particularly robust. This may be due in part to the complex

and differing roles of various 5-HT receptor subtypes in cognition.

However, it does appear that lowering 5-HT levels though TRP

depletion reliably impairs memory consolidation. Although animal

studies reveal clear actions of certain 5-HT receptor subtype manip-

ulations on aspects of learning and memory, there are fewer studiesof selective 5-HT ligands in humans, in whom effects appear mod-

est and often differ between healthy participants and patient groups.

It seems clearer that depressive disorders are associated with

significant and broad-based cognitive impairment, which leads to

the functional disability seen in patients with acute depression.

This presumably also makes it more difficult for severely depressed

patients to utilize certain forms of psychotherapy. Although anti-

depressant treatment and symptomatic improvement lead to some

resolution of cognitive deficit, current studies suggest that abnor-

malities in learning and memory and attention may persist even

after many months of treatment. These impairments are apparently

associated with occupational and social dysfunction.

The clinical data suggest that cognitive impairment in depres-sion is an important target for treatment that is not satisfactorily

managed by current antidepressant medications. It may be that, as

in patients with schizophrenia, cognitive dysfunction in depression

is neurobiologically distinct from other major symptom domains

that is, not purely secondary to low mood (though there does

appear to be a correlation between acute depression severity and

cognitive impairment). If this is the case, additional pharmacologi-

cal approaches may be needed. The ability of certain 5-HT recep-

tor subtypes to influence cognition makes these receptors plausible

targets for future pharmacological treatments designed to improve

both the emotional and cognitive aspects of depression.

Acknowledgements

This review was sponsored by the Takeda Pharmaceutical Company, Ltd,

as part of a joint clinical development program with H. Lundbeck A/S. Dr.

Cowen and Ann C. Sherwood, PhD (medical writer) drafted and reviewed

successive versions of the manuscript. Editorial support, including styling

and editing for journal submission, was provided by The Medicine Group,

New Hope, Pennsylvania.

Conflict of interest

PJ Cowen is a member of an advisory board for Lundbeck and has pro-

vided expert advice to legal representatives of GlaxoSmithKline. He

received no remuneration for the preparation of the paper.

Ann C Sherwood has no disclosures or conflicts of interest.

Funding

This work has been supported by Takeda and H. Lundbeck A/S,

Deerfield, IL.

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The Role of Serotonin in Cognitive Function

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