Journal of Psychopharmacology

http://jop.sagepub.com/ The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression
Philip Cowen and Ann C Sherwood J Psychopharmacol 2013 27: 575 originally published online 27 March 2013 DOI: 10.1177/0269881113482531 The online version of this article can be found at: http://jop.sagepub.com/content/27/7/575

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2013

JOP27710.1177/0269881113482531Journal of PsychopharmacologyCowen and Sherwood

Review

The role of serotonin in cognitive function: evidence from recent studies and implications for understanding depression
Philip Cowen1 and Ann C Sherwood2

Journal of Psychopharmacology 27(7) 575583 The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881113482531 jop.sagepub.com

Abstract

Background: 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-HT receptor 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

Introduction
Cognitive function comprises various neurobiological processes involved in attention, learning, memory, planning and decision making (Garcia-Carbonero and Paz-Ares 2002; Millan etal., 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 functional 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-Ares 2002; Jaeger etal., 2006; McCall and Dunn 2003; Naismith etal., 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 etal., 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 etal., 2009). Similarly, functional imaging studies of working memory also suggest abnormal neural activation patterns in remitted depressed patients (Kerestes etal., 2012; Schoning etal., 2009). Drugs that potentiate serotonin (5-HT) function are the mainstay of depression treatment and are often prescribed for longerterm 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 considerable, and the objective of this article is to provide a concise overview for clinicians, focusing on how 5-HT impacts cognitive function relevant to depressed patients. We will also briefly summarize animal studies linking specific 5-HT receptor subtypes with cognitive function where relevant to psychotropic drug action.

1Warneford 2The

Hospital, Oxford, UK Medicine Group, New Hope, PA, USA

Corresponding author: Philip Cowen, Neurosciences Building, Warneford Hospital, Oxford OX3 7JX. Email: phil.cowen@psych.ox.ac.uk

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Journal of Psychopharmacology 27(7)

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 etal., 2006). They compared the BOLD response in the dorsolateral prefrontal 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 during performance monitoring, but not during response inhibition (Evers etal., 2006). Although there is no evidence that serotonin depletion is sufficient 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) therapy relapse under conditions of TRP depletion (>80% decrease in plasma TRP levels) (Delgado etal., 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 lowdose 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 etal., 2009; Hayward etal., 2005). In both of these studies, 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 etal., 2012). Conclusions drawn from TRP depletion studies are limited because serotonin manipulation is not specific to a particular serotonin 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 different serotonin functions.

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 administration of an amino acid mixture lacking TRP and enriched for other 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 etal., 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 cognitive testing methods, which revealed heterogeneous outcomes. To increase the power to detect effects in these trials, Mendelsohn etal. (2009) conducted a comprehensive review of 66 TRP depletion studies published starting in 1966 through September 2008 (Mendelsohn etal., 2009). Fifty-nine trials included healthy individuals 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 negative impact of TRP depletion on contextual episodic memory. However, TRP depletion did not appear to affect spatial episodic memory, or semantic or working memory. Indeed, semantic memory tended to improve in the depleted state (Mendelsohn etal., 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 etal., 2009) and showed minimal effects on sustained attention (vigilance), selective attention, divided attention, or attentional set-shifting (Lash etal., 2000; Mendelsohn etal., 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 etal. (2006) used fMRI to compare the BOLD response after drinking 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 etal., 2006). These findings are consistent with evidence implicating 5-HT in consolidation of episodic memory (Mendelsohn etal., 2009), and suggest that the key role is during the encoding phase (van der Veen etal., 2006).

Serotonin reuptake inhibition

5-HT is removed from the synaptic cleft via the serotonin transporter (SERT). It is generally accepted that SERT inhibition by SSRIs increases serotonin availability in the synapse, thus increasing 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 serotonin release, rat studies show that extracellular 5-HT levels in the prefrontal cortex increase during acute and subchronic SSRI administration (Ceglia etal., 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 etal., 1998; Ramaekers etal., 1995; Schmitt etal., 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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Table 1. Serotonin manipulation and cognitive effects in healthy individuals. Serotonin (5-HT) receptor Study method TRP depletion (Mendelsohn etal., 2009) Cognitive effects observed in healthy individuals (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 setshifting (N = 9 males) Acute (14 h): Improved response time and sustained attention vs. baseline (N = 60 males) Acute (1.5 h) Impaired probabilistic learning but not response inhibition (N = 24) Acute (24 h) and subchronic (14 days) treatment with citalopram (20 mg and 40 mg, respectively) impaired sustained attention (N = 24 females) Acute <24 h: No effect on sustained attention; enhanced delayed recall and recognition (N = 20 males) Acute (24 h): Impaired contextual information processing; no effect at 28 days (N = 16) Acute (<24 h): Treatment impaired divided attention (N = 40) Acute (24 h): Slower reaction times to warning if first treatment; faster response times if escitalopram was second treatment Subacute (7 days): Participants receiving escitalopram first had significant slower reaction times in incongruent trials with escitalopram compared with placebo, whereas participants starting with placebo had significant shorter reaction times in incongruent trials with escitalopram (N = 36) Acute and repeated administration did not affect inhibition of already initiated responses and response reengagement (N = 8) Acute (3.56 h): Fluvoxamine shortened response time without decreasing the accuracy of the responses (N = 24) 24 h and subchronic (14 days) did not affect sustained attention (N = 12) Subchronic (14 d): Did not affect choice reaction time, psychomotor coordination, visual memory span, or ability to detect discrete sensory data (N = 12 males) 14 days; also had no effect on sustained attention or psychomotor functions (N = 9) Acute (14 h): No effect on sustained attention or response time vs. baseline (N = 12) Treatment for 7 days had no effect on sustained attention or psychomotor functions (N = 16) Increased impairment in immediate verbal recall when combined with an SSRI (N = 60) 1.5 and 3.5 h: No effects on memory, executive planning, impulse control, decision making or cognitive flexibility (N = 18 males) Acute (<24 h): No significant effects were observed on aspects of executive function (N = 16) Acute (<24 h): Increased impairment in spatial working memory in combination with SSRI (escitalopram 20 mg)

Serotonin transporter (SERT)

Citalopram (20 mg) (Nathan etal., 2000) Citalopram (30 mg) vs. placebo and atomoxetine (Chamberlain etal., 2006) Citalopram (20 mg on days 18, 40 mg on days 915) vs. sertraline or placebo (Riedel etal., 2005) Citalopram 10 mg iv vs. placebo (Harmer etal., 2002) Citalopram 20 mg/day vs. placebo for 28 days (Almeida etal., 2010) Escitalopram 20 mg (Wingen etal., 2007a) Escitalopram 10 mg/d or placebo (Drueke etal., 2009)

Escitalopram 10 mg/d (Drueke etal., 2010) Fluvoxamine (100 mg) (Hasbroucq etal., 1997) Sertraline 50 mg on days 18, 100 mg on days 915 (Riedel etal., 2005) Sertraline 50 mg (Siepmann etal., 2003)

5HT1A

Venlafaxine 75 mg/d for 7 days followed by 150 mg/day for 7 days (Siepmann etal., 2008) Venlafaxine 37.5 mg (Nathan etal., 2000) Milnacipran 100 mg (Poirier etal., 2004) Non-selective receptor agonist (pindolol 10 mg) (Wingen etal., 2007b) Receptor agonist (buspirone, 20 mg or 30 mg vs. placebo) (Chamberlain etal., 2007b) Antagonist (tandospirone 20 mg) (Takahashi etal., 2010) 5-HT2A receptor antagonist (ketanserin 50 mg) (Wingen etal., 2007b)

5-HT2A

TRP = tryptophan; SSRI = selective serotonin reuptake inhibitor.

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attention in 21 healthy subjects. However, sertraline (50 mg acutely, and 100 mg subchronically) did not affect sustained attention (vigilance) in healthy subjects (Riedel etal., 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 randomized, placebo-controlled study of citalopram in 24 healthy women. Testing was initiated 45 min after infusing either 10 mg citalopram or placebo. There was no citalopram effect on sustained attention or immediate recall. The reasons for the differences may reflect the small sample sizes, different study populations (both sexes vs. only women), different testing methods, or different drug administration. Perhaps, however, the more interesting finding in the latter study is that acute citalopram treatment enhanced memory consolidation compared with the placebo group (Harmer etal., 2002). Once again, these results suggest that memory consolidation may be inversely correlated with extracellular 5-HT levels. Several other small studies assessed SSRI effects on various cognitive functions. Almeida etal. (2010) compared the acute and chronic effects of citalopram 20 mg administered once daily on impulsive responding and contextual information processing in healthy controls. Acute administration (24 h) impaired performance 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 etal., 2010). Effects of subchronic sertraline administration on cognitive function were evaluated in a randomized, double-blind, crossover study in 12 healthy male volunteers (Siepmann etal., 2003). Subjects received sertraline 50 mg or placebo once daily for 14 days. In this trial, subchronic sertraline did not affect choice reaction time, psychomotor coordination, visual memory span, or ability to detect discrete sensory data. The lack of effect has been attributed to sertraline actions on dopamine levels that may counter 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 administration 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 etal., 2008). Overall, the most consistent observation following manipulation of serotonin levels by TRP depletion or SERT blockade seems to be that low extracellular 5-HT levels are associated with impaired memory consolidation.

Journal of Psychopharmacology 27(7)

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 alterations in the release of neurotransmitters such as acetylcholine and glutamate, which have been more directly implicated in cognitive function than 5-HT itself (King etal., 2008). Although selective agonists and antagonists have been developed for many 5-HT receptor subtypes, agents tested in healthy humans tend to be relatively 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 hippocampus. 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 etal., 1997). However, systemic delivery of F15599, an agonist that is highly selective for postsynaptic 5-HT1A receptors, did not induce cognitive deficits in rats and, unlike non-selective agents, partially reversed phencyclidine-induce impairment of working and reference memory (Depoortere etal., 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 etal., 2007a; Takahashi etal., 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 surprisingly) that the effects of partial agonists on cognition might depend on underlying state of 5-HT neurotransmission (Sumiyoshi etal., 2000, 2001, 2007). It has been suggested that 5-HT1Amodifying drugs might also be helpful for the cognitive impairments in Alzheimers disease. However, development of single-receptor agents that showed promise for improving cognition 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).

Serotonin receptors and cognition data from animal and human studies
5-HT receptors comprise seven subfamilies including 14 subtypes, and some subtypes are expressed as multiple isoforms. All are G-protein-linked except 5-HT3 receptors, which are ionotropic. Most 5-HT receptors are present in brain regions associated with learning and memory. However, within any particular

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 etal., 2004). In rats, ()-2,5-dimethoxy-4iodoamphetamine (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 receptor antagonist EMD 281014 improved working memory function in rhesus monkeys (Terry, Jr. etal., 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 etal., 2004). However, it has been difficult to show that atypical antipsychotic drugs, many of which potently block 5-HT2A receptors, are better at improving cognitive function than conventional antipsychotic agents (Selva-Vera etal., 2010; Wittorf etal., 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 etal., 2010). Receptor mRNA has been localized to GABAergic, glutamatergic and dopaminergic neurons in the frontal cortex, hippocampus, hypothalamic nuclei, substantia nigra, nucleus accumbens, striatum and the raphe nuclei (Jensen etal., 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 paradoxically, the 5-HT2C agonist CP-809101 has been shown to enhance novel object recognition learning in animal models (Siuciak etal., 2007). Mirtazapine antagonizes 5-HT2C receptors in addition to acting at alpha-2 receptors. In a small study (N = 18) in healthy individuals, 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 in this placebo-controlled cross-over study (Wingen etal., 2006). However, adjunctive mirtazapine may enhance cognition in patients with schizophrenia (Cho etal., 2011; Stenberg etal., 2010, 2011). In one study, mirtazapine improved cognitive performance in patients with recurrent depression. Although depressive symptoms improved with treatment, cognitive improvement did not correlate with change in depressive symptoms (Borkowska etal., 2007). However, whether these procognitive effects are mediated by 5-HT2C receptors has not been determined. function in age-related memory decline in humans. However, there are some hints of cognitive benefit in patients with schizophrenia (Akhondzadeh etal., 2009; Levkovitz etal., 2005).

5-HT4 receptors
To date, few studies have evaluated the role of 5-HT4 receptors in healthy humans. However, preclinical studies (King etal., 2008; Marchetti etal., 2004; Terry, Jr. etal., 1998) demonstrated a role for 5-HT4 binding in learning and memory. Findings in rodents suggest that antagonism at 5-HT4 receptors impairs passive avoidance 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 etal., 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 etal., 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 etal., 2011). Preclinical data indicate that the 5-HT6 receptor regulates serotonergic modulation 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 etal., 2008). Paradoxically, both 5-HT6 receptor agonists and antagonists reverse memory deficits in animal models of cognitive impairment (Codony etal., 2011). However, antagonists have little or no cognitive-enhancing affect in healthy animals. Consistent with these findings, one study conducted in healthy humans found that the 5-HT6 receptor antagonist SB-742457 did not affect motor activation and fluency, adaptive tracking, subjective alertness, or delayed word recognition (Liem-Moolenaar etal., 2011). Several agents that are selective for 5-HT6 receptors are currently in development for treatment of cognitive symptoms in Alzheimers disease (Codony etal., 2011).

5-HT7 receptors
5-HT7 receptors are found on glutamatergic neurons in the superchiasmic nucleus of the hypothalamus, hippocampus, cortex, thalamus and raphe nuclei (Bonaventure etal., 2011). In a recent rat study, the selective 5-HT7 antagonist SB269270 prevented the negative effects of MK801 but not scopolamine on working memory. Moreover, in this same study, SB269270 inhibited MK801 stimulated glutamate release, but not dopamine (Bonaventure etal., 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 investigated 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

5-HT3 receptors
5-HT3 receptors are the only ionotropic 5-HT receptors. Within the 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 hippocampus (Walstab etal., 2010). 5-HT3 receptor antagonists such as ondansetron have been shown to improve learning and memory in rat (Hodges etal., 1996) and monkey (Terry, Jr. etal., 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 compelling evidence that 5-HT3 receptor antagonism improves cognitive

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do appear to have differential effects on cognitive function in individuals with depression that is separable from effects on depressive symptoms.

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(2011) found that residual deficits in processing speed and cognitive 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 etal., 2011). These clinical findings should be considered in the context of animal studies showing that SSRI treatment, for example, facilitates neuroplasticity and neurogenesis in the hippocampus (Malberg etal., 2000; Santarelli etal., 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 etal. (2010) found that patients with MDD who achieved remission with escitalopram (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 etal., 2009). Cognitive outcomes were assessed again 24 weeks after treatment withdrawal (Herrera-Guzman etal., 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 etal., 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 muscarinic-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 etal., 2008).

Cognitive symptoms in depression and antidepressant 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. Metaanalysis 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 etal., 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 etal., 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 studies (Hasselbalch etal., 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 symptoms such as poor motivation (Millan etal., 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 etal. (2006) found that a history 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 metaanalysis 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 etal., 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, represent a marker for vulnerability to MDD (Mannie etal., 2010). However, cognitive function assessments in adolescents with a history MDD have yielded mixed results (Castaneda etal., 2008; Hermens etal., 2011; Maalouf etal., 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 impairments in a range of domains are still detectable (Alexopoulos etal., 2003; Hasselbalch etal., 2011, 2012; Herrera-Guzman etal., 2008; McClintock etal., 2011) and are associated with impaired psychosocial functioning (Jaeger etal., 2006; McCall and Dunn 2003). A recent meta-analysis by Hasselbalch etal.

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 effects of this agent on white matter structure in a similar population (NCT01492621). One trial is assessing the effects of augmenting citalopram with methylphenidate, which acts through inhibition 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 partially 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

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transporter in vitro (Bang-Andersen etal., 2011; Westrich etal., 2012). In a study of 453 patients 65 years of age with recurrent MDD, vortioxetine improved baseline episodic memory (standardized 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 etal., 2012). Two trials are underway to determine whether this cognitive benefit can be replicated in adults aged 1865 years.

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

References
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Conclusions
Available evidence indicates that 5-HT plays in a role in modulating 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 manipulations on aspects of learning and memory, there are fewer studies of selective 5-HT ligands in humans, in whom effects appear modest 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 antidepressant treatment and symptomatic improvement lead to some resolution of cognitive deficit, current studies suggest that abnormalities 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 depression 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 pharmacological approaches may be needed. The ability of certain 5-HT receptor 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 provided 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.

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