psychopharmacological treatment of neurocognitive deficits in people with schizophrenia: a review of...

REVIEW ARTICLE

Psychopharmacological Treatment of Neurocognitive Deficitsin People with Schizophrenia: A Review of Old and New Targets

Anthony O. Ahmed • Ishrat A. Bhat

� Springer International Publishing Switzerland 2014

Abstract Neurocognitive impairments significantly con-

tribute to disability and the overall clinical picture in

schizophrenia spectrum disorders. There has therefore been

a concerted effort, guided by the discovery of neurotrans-

mitter and synaptic systems in the central nervous system,

to develop and test compounds that may ameliorate neu-

rocognitive deficits. The current article summarizes the

results of efforts to test neurocognitive-enhancing agents in

schizophrenia. Overall, existing clinical trials provide little

reason to be enthusiastic about the benefits of psycho-

pharmacological agents at enhancing neurocognition in

schizophrenia—a state of affairs that may reflect the

inadequacy of single neurotransmitter or receptor models.

The etiologic and phenomenological complexity of neu-

rocognitive deficits in schizophrenia may be better served

by psychopharmacological agents that (i) target neuro-

transmitter systems proximal in the causal chain to neu-

rocognitive deficits; (ii) enhance distal survival processes

in the central nervous system—neurogenesis, neuronal

growth, synaptogenesis, and connectivity; and (iii) coun-

teract the negative effects of aberrant neurodevelopment in

schizophrenia, such as neuroinflammation and oxidative

stress. Future efforts to develop psychopharmacological

agents for neurocognitive impairment in schizophrenia

should reflect the knowledge of its complex etiology by

addressing aberrations along its causal chain. Clinical trials

may benefit methodologically from (i) an appreciation of

the phenomenological heterogeneity of neurocognitive

deficits in schizophrenia; (ii) a characterization of the

predictors of treatment response; and (iii) a recognition of

issues of sample size, statistical power, treatment duration,

and dosing.

1 Introduction

Schizophrenia spectrum disorders are characterized by

persistent neurocognitive impairments that predate the

onset of classic positive and negative symptoms and are

present not just in patients but also their family members

[1–3]. These deficits are believed to reflect both general-

ized intellectual decline and impairments in domain-spe-

cific areas, including attention/vigilance, working memory,

processing speed, learning and memory, reasoning and

problem-solving, and social cognition [4, 5]. Neurocogni-

tive deficits have a neural foundation—reflecting structural

and functional aberrations and impairments in neural con-

nectivity and neurotransmission [6, 7].

Studies have demonstrated that neurocognitive impair-

ments are generally unresponsive to traditional antipsy-

chotic therapy beyond practice effects [8–10]. With

increasing evidence that neurocognitive deficits contribute

to symptom severity, relapse, and disability in schizo-

phrenia spectrum disorders [11, 12], recent innovations in

psychiatry have focused on the development of clinical

therapeutics to improve neurocognition. These innovations

encompass psychopharmacological, behavioral, and brain

stimulation-based strategies. The current article is a com-

prehensive review of ongoing efforts to test psychophar-

macological neurocognitive enhancement strategies. A

number of brief reviews of enhancement agents have been

conducted [13–16], with the most recent review published

in 2012. These reviews focused on a few compounds that

act on select single-receptor targets but do not include

A. O. Ahmed (&) � I. A. Bhat

Department of Psychiatry and Health Behavior, Medical College

of Georgia, Georgia Regents University, 997 Saint Sebastian

Way, Augusta, GA 30912, USA

e-mail: [email protected]

CNS Drugs

DOI 10.1007/s40263-014-0146-6

several compounds currently under investigation in recent

clinical trials. The reviews by Harvey [13, 14] and Harvey

and Bowie [13, 14] underscored failed clinical trials,

whereas the Friedman [16] review from 2004 focused on

only cholinergic targets. Moreover, none of the existing

reviews was informed by an emerging literature on the role

of several other influences on neurocognition in schizo-

phrenia. The current review seeks to (i) provide an update

on single-receptor mechanisms; (ii) evaluate other possible

targets; and (iii) address methodological issues in cogni-

tive-enhancement research. The review includes only a

brief discussion of cognitive remediation, a promising

behavioral strategy that focuses on rehabilitating neuro-

cognitive deficits through a guided and progressive training

of attention, working memory, problem solving, processing

speed, and other neurocognitive skills. The discussion

about cognitive remediation is with regard to its possible

capacity to enhance several neural targets. For a detailed

discussion of cognitive remediation and evidence of its

efficacy, we refer the reader to Wykes et al [17].

2 Psychopharmacological Neurocognitive-

Enhancement Strategies

The identification of neural targets and the development of

compounds that would improve neurocognition has been a

challenging endeavor in schizophrenia. MATRICS (Mea-

surement and Treatment Research to Improve Cognition in

Schizophrenia) and CNTRICS (Cognitive Neuroscience

Treatment Research to Improve Cognition in Schizophre-

nia) were two initiatives charged with the identification of

drug neural system targets that will elucidate the neuro-

chemical bases of neurocognition [18, 19]. The goals of the

initiatives also included the identification of models for

drug development and the testing of putative neurocogni-

tive enhancers. These initiatives, in conjunction with recent

findings, have highlighted targets associated with learning

and memory; targets shown to improve neurocognition in

other psychiatric disorders (e.g., attention-deficit/hyper-

activity disorder [ADHD]) or in healthy samples; and,

more recently, targets shown to foster neuroprotection and

neuroplasticity [20].

Guided by traditional models of target identification and

drug discovery, the MATRICS and CNTRICS efforts have

generally focused on implicating and elucidating the role of

aberrations in single neurotransmitters or receptor mecha-

nisms on neurocognitive functioning in schizophrenia [18,

19]. Subsequent research has used preclinical and clinical

models to identify and test candidate neural targets and com-

pounds. Preclinical modeling involves the neurochemical

disruption of normal receptor activity and function; the

genetic-level disruption of normal neurotransmission,

receptor function, or neurochemical expression; and a mea-

surement of their behavioral sequelae in animals [21]. As an

illustration, disruptions in N-methyl-D-aspartate (NMDA)

receptor activity have been implicated in schizophrenia-rela-

ted neurocognitive impairments primarily through the dem-

onstration that administration of NMDA antagonists such as

ketamine, phencyclidine, or dizocilpine (MK-801) produce

neurocognitive impairments in rodents and primates [22].

Clinical modeling involves testing agents that have been

developed in the context of other psychiatric or neurodegen-

erative disorders that are similarly characterized by neuro-

cognitive impairments. Several agents currently undergoing

studies to determine if they can improve neurocognition in

schizophrenia patients were initially developed and tested to

decrease impairments in other conditions. These compounds

include, among others, davunetide, memantine, and modafinil

and are tested for their neurocognitive benefits rather than their

ability to decrease classic schizophrenia symptoms. Clinical

research has identified risk factors that predict incidence,

clinical neuropathology, and neurocognitive impairments in

schizophrenia. Several of these risk factors that contribute

small, additive effects to both the incidence of schizophrenia

and neurocognition are encompassed by the neurodevelop-

mental model. The neurodevelopmental model implicates the

role of the early prenatal environment, obstetric complica-

tions, environmental risk factors, and several risk genes

(Table 1) with pleiotropic effects on neurodevelopment,

neurogenesis, synaptogenesis, and neural connectivity [23].

There is evidence that stress and immune-response circuits are

implicated in the pathophysiology of schizophrenia, exerting

effects on clinical symptoms, neuropathology, and neuro-

cognitive functioning [24, 25]. They may therefore represent

alternative therapeutic targets to single-receptor mechanisms

for alleviating neurocognitive deficits in schizophrenia.

Table 2 summarizes several single-receptor psychophar-

macological targets linked to neurocognition and findings

from clinical trials of drugs associated with the identified

mechanism [26–76]. Enhancement strategies have included

fostering agonist activity by stimulating receptors, fostering

the release of neurotransmitters, blocking the reuptake of

neurotransmitters, inhibiting enzyme activity, or blocking

neurotransmitter action [77]. There have been few represen-

tative studies of each mechanism, and the results of published

clinical trials have been generally less than promising, with

several failed trials. The results of these studies are often

mixed; moreover, studies that obtained significant improve-

ments in neurocognition with the putative enhancer over

placebo suggest no more than small effects [13].

2.1 Dopaminergic Targets

The benefits of two dopaminergic enhancers have been

studied in schizophrenia patients to date—dihydrexidine

A. O. Ahmed, I. A. Bhat

(DAR-0100) and sonepiprazole (U101387). Dihydrexidine

crosses the blood–brain barrier and acts as a D1 receptor

agonist directly on D1 receptors. In contrast, sonepiprazole

is a highly selective D4 receptor antagonist that is unable to

penetrate the blood–brain barrier. Both enhancers have

received very little study in schizophrenia. George et al.

[26] obtained no evidence of neurocognitive benefits in 20

stable outpatients assigned to receive either a 20 mg sub-

cutaneous dose of dihydrexidine or placebo. Similarly,

Corrigan et al. [27] found no clinical or neurocognitive

benefits to prescribing sonepiprazole to 467 hospitalized

patients with schizophrenia in a 6-week placebo-controlled

trial. In the absence of evidence of their efficacy, there

have been no further attempts to evaluate the benefits of

these enhancers with schizophrenia patients. The limited

efficacy of dihydrexidine with schizophrenia patients is

puzzling, given evidence of its benefits for patients with

schizotypal personality disorder. Siever et al. [78] reported

on pilot data obtained from 14 patients with schizotypal

personality disorder who received 15 mg of DAR-0100A

(an enantiomer of dihydrexidine) or placebo. They found

that DAR-0100A produced improvements in working

memory and context processing. It may be that the less

severe neurocognitive impairments in schizotypal person-

ality disorder patients are more responsive to potential di-

hydrexidine treatment than impairments in schizophrenia.

Lisdexamfetamine dimesylate (LDX) is the precursor

and inactive form of dextroamphetamine, a psychostimu-

lant used for the treatment of ADHD [79]. On ingestion,

LDX is metabolized into its active components—L-lysine

and D-amphetamine [80]. Like other amphetamines,

D-amphetamine is believed to enhance neurocognition by

acting as a dopamine and norepinephrine agonist, either by

fostering their release or blocking their reuptake into pre-

synaptic neurons [80]. LDX has received little study in

schizophrenia. In a recent open-label trial, Lasser et al. [81]

examined the benefits of adjunctive LDX (20–70 mg/day)

for 92 schizophrenia outpatients with predominant negative

Table 1 Risk factors with potential pleiotropic effects for schizophrenia and neurocognition

Risk factor class Risk factors

Obstetric complications

Second trimester is vulnerable to adverse exposures that impact neuronal

migration, glial-neuronal interactions, and cortical connectivity

Fetal growth retardation: reduced head circumference

Small-for-gestational age measures

Fetal hypoxia–oxygen deprivation

Intrauterine infections and pro-inflammatory cytokines:

influenza, Coxsackie B, rubella, and toxoplasmosis

Malnutrition: (e.g., exposure to famine during the Nazi

blockade of northern Netherlands)

Nutritional deficiencies e.g., hypovitaminosis D

Placentation abnormalities

Environmental

Certain environmental factors may contribute to neurocognitive impairments

by interfering with normal neurodevelopment

Cannabis use

Toxin exposure (e.g., lead poisoning)

Genetic

Several genes code for receptor systems that influence neurocognition directly.

Many act indirectly by exerting effects on neurogenesis, proliferation,

maturation, synaptogenesis, synaptic connectivity, neuroinflammation, and

neural development

Serotonin 2A receptor (5-HTR2A)

Dopamine D1 (DRD1), D2 (DRD2), and D3 (DRD3) receptor

genes

Disrupted-in-schizophrenia 1 and 2 (DISC1 and DISC2)

Dystrobrevin-binding protein 1

Neuregulin 1

Regulator of G-protein signaling 4

Catechol-O-methyl-transferase

Brain-derived neurotrophic factor

Inflammatory Interleukin-1

Interleukin-6

Interleukin-8

Tumor necrosis factor alpha

Polyinsosini:polycytidic acid

C-reactive protein

Helper T cell 1

Psychopharmacological Treatment of Neurocognitive Deficits in Schizophrenia

Table 2 Psychopharmacological single-receptor targets for neurocognitive enhancement

Mechanism and

target

Example drugs Studies Notes

Dopaminergic

D1 receptor

agonist

Dihydrexidine

(DAR-0100)

George et al. [26] 20 stable outpatients with schizophrenia received

20 mg sc dose or PL. Good tolerability but no

improvements in cognition

D4 antagonist Sonepiprazole

(U101387)

Corrigan et al. [27] No neurocognitive efficacy in 467 acute pts

treated for 6 weeks

D4 agonist A-412997 n/a No studies in schizophrenia pts

COMT

inhibition

Tolcapone n/a No currently published studies in schizophrenia

pts

Other

dopaminergic

LDX n/a No available neurocognitive data

Cholinergic

M1 muscarinic

receptor

agonist

Galantamine Buchanan et al. [28], Lee et al. [29], Lindenmayer

and Khan [30], Deutsch et al. [31]

Buchanan et al. obtained improvements on the

WAIS-III digit symbol task and the CVLT

verbal learning task but no improvements on

global cognition in 86 pts treated for 12 weeks

No neurocognitive benefits in other trials

Cholinesterase

inhibitor

Rivastigmine

Donepezil

Sharma et al. [32], Kumari et al. [33], Friedman

et al. [34], Tugal et al. [35], Mazeh et al. [36],

Fagerlund et al. [37], Lee et al. [38], Keefe et al.

[39]

No benefits of rivastigmine on neurocognition.

Donepezil demonstrates good tolerability but no

benefits as adjunct to several antipsychotics on

neurocognition

Akhondzadeh et al. [40], Chung et al. [41] No improvements on neurocognitive scores on the

MCCB battery

a-7 nicotinic

receptor

agonist

DMXB-A Olincy et al. [42], Freedman et al. [43] Possible benefits on neurocognition but not

replicated

a4b2 nicotinic

agonist

RJR2403 n/a No published studies in schizophrenia pts

AZD3480 Velligan et al. [44] Good tolerability but no benefits on

neurocognition or functional outcomes in a

sample of 440 pts treated for 12 weeks

Glutamergic

NMDA

receptor

agonist

Glycine, D-

cycloserine, D-

serine

Buchanan et al. [45], Weiser et al. [46], D’Souza

et al. [47]

In the Buchanan et al. study, there were no

neurocognitive benefits from adjunctive glycine

or D-cycloserine over adjunctive PL in 157 pts.

Weiser et al. obtained no neurocognitive

benefits for 2 g/day dosage of adjunctive D-

serine over PL

AMPA

receptor

agonist

AMPAkines (e.g.,

CX-516)

Goff et al. [48] No neurocognitive benefits of adjunctive CX-516

in 105 pts

Metabotropic

glutamate

receptor

agonist

mGluR2/3(e.g.,

LY2140023),

Patil et al. [49], Kinon et al. [50] Neurocognitive data not reported

mGluR5 (e.g.,

CDPPB)

n/a No studies in schizophrenia pts available

Glycine

reuptake

inhibitors

Sarcosine Lane et al. [51] Neurocognitive data not reported in the Lane

et al.’ study

Org-24598 n/a No currently published clinical trials in

schizophrenia

Glutamate

inhibition

Lamotrigine Goff et al. [52] Possible benefits on neurocognition

Memantine Lieberman et al. [53], Lee et al. [54] No neurocognitive benefits with adjunctive

memantine


Table 2 continued

Mechanism and

target


Noradrenergic

a-2 receptor

agonist

Guanfacine Friedman et al. [55] Adjunctive guanfacine improved spatial working

and attention relative to PL

NE reuptake

inhibitor

Atomoxetine Friedman et al. [56], Kelly et al. [57]c Adjunctive atomoxetine produced no benefits over

PL

Reboxetine Poyurovski et al. [58] As olanzapine adjunct, no neurocognitive benefits

over PL

GABAergic

GABAA a2

agonists

MK-0777 Lewis et al. [59] In the Lewis et al. study, improvements in delayed

memory and attention but no other domains

Buchanan et al. [60] In the Buchanan et al. study, MK-0777 recipients

performed worse than PL group on visual

memory and reasoning/problem-solving. No

differences in other neurocognitive domains

Flumazenil Menzies et al. [61] Improvements on N-back relative to PL in 11 pts

GABAAa5

antagonist

BL-1020 Geffen et al. [62] At 30 mg, the antipsychotic BL-1020 produces

greater improvements on neurocognition than

risperidone and PL

L-655708 n/a No existing clinical trials in schizophrenia

Serotonergic

5HT1A agonist Tandospirone,

buspirone

Sumiyoshi et al. [63] Adjunctive tandospirone (30 mg) produced

greater improvements on executive functions

and verbal memory than PL adjunct

Sumiyoshi et al. [64] Adjunctive buspirone produced improvements in

attention but no other cognitive domains relative

to PL adjunct

Piskulic et al. [65] No benefits of semi-acute administration of

buspirone over PL in chronic schizophrenia

5HT1A

antagonist

WAY100635 n/a No existing clinical trials in schizophrenia

5HT2A

antagonist

M100907 DePaulis [66] Discontinued following phase II trials due to

limited efficacy

5HT3

antagonist

Ondansetron Zhang et al. [67] In the Zhang et al. study, adjunctive ondansetron

(8 mg/day) improved negative symptoms,

cognition, and global clinical impression over

adjunctive PL

Akhondzadeh et al. [68] Adjunctive ondansetron (8 mg/day) was

associated with improvements in negative

symptoms and visual memory as measured by

the WMS-R in the Akhondzadeh et al. study

Cannabinoid Rimonabant Boggs et al. [69] Relative to PL, rimonabant (20 mg) improved

reinforcement learning but rimonabant group

performed worse on the RBANS total score at

post-treatment

Other mechanisms

Promotion of

histamine

release

Modafinil Scoriels et al. [70], Turner et al. [71] Modafinil improves attention, memory, and

executive function in early course pts

Sevy et al. [72], Freudenreich et al. [73] Adjunctive modafinil produces no benefits over

adjunctive PL in chronic pts

Armodafinil Bobo et al. [74], Kane et al. [75] No neurocognitive benefits from adjunctive

armodafinil


symptoms. Participants received LDX for 10 weeks and

completed the Positive and Negative Syndrome Scale

(PANSS) and the Scale for the Assessment of Negative

Symptoms (SANS-18). LDX use was associated with

improvements on the SANS-18 scores and the abstract

thinking and judgment/insight subscales of the PANSS.

The robustness of the effects of LDX on neurocognition is

yet to be determined in the absence of trials that incorpo-

rate performance-based neurocognitive tests.

2.2 Cholinergic Targets

Several cholinergic agents have been developed and eval-

uated as putative neurocognitive enhancers for schizo-

phrenia. The most heavily studied of these enhancers is

galantamine. Galantamine is a competitive and reversible

cholinesterase inhibitor that also acts as an M1 muscarinic

acetylcholine receptor agonist or a modulator at alpha-4

and alpha-7 nicotinic receptors that has been used primarily

in the treatment of early-stage vascular dementia and

Alzheimer’s disease [82]. Galantamine has produced neu-

rocognitive benefits in only one study with schizophrenia

patients [28]—whereas Buchanan et al. [28] found that

galantamine improved working memory and verbal learn-

ing over placebo in 86 schizophrenia patients, no other

study has found good evidence of its precognitive benefits

[29–31]. Two other cholinesterase inhibitors—rivastigmine

and donepezil—have similarly failed to demonstrate ben-

efits as neurocognitive enhancers in schizophrenia in sev-

eral placebo-controlled trials [32–41]. However, in a

12-week open-label trial, Chung et al. [41] found that 28

schizophrenia patients who received up to 10 mg/day of

donepezil as an adjunct to atypical antipsychotics demon-

strated improvements in attention, memory, psychomotor

speed, and mental set-shifting. 3-(2,4-dimethoxy-benzyli-

dene)-anabaseine (DMXB-A) is an a-7 nicotinic receptor

partial agonist that demonstrated positive benefits on neu-

rocognitive functions—particularly attention—in a proof-

of-concept study that used a randomized, double-blind,

cross-over design to study 12 schizophrenia patients [42].

However, in the phase II study, Freedman et al. [43] found

no benefits of DMXB-A over placebo on neurocognition in

31 patients with schizophrenia. They attributed the failure

of the phase II trial to the possibility that strong practice

effects across the study arms may have obscured any

DMXB-A benefits on neurocognition.

2.3 Glutamatergic Targets

Several clinical trials have examined the neurocognitive

enhancement benefits of a group of amino acids that act as

glutamate agonists by binding to the glycine site on NMDA

receptors. These NMDA receptor agonists include glycine,

D-cycloserine, and D-serine; D-serine has even stronger

binding properties to the glycine site than glycine. As

shown in Table 2, none of the currently published studies

produced evidence that the adjunctive use of these com-

pounds improves neurocognition [45, 46]. In a recent

study, D’Souza et al. [47] provided D-serine (30 mg/kg) or

placebo to patients who participated in a 12-week cognitive

remediation program (5 h/week). Although tolerable, they

found no added benefit for the enhancement of cognitive

remediation with D-serine over cognitive remediation plus

placebo; meaning that D-serine did not provide any addi-

tional benefit over cognitive remediation. Goff et al. [52]

reported on the results of two clinical trials that examined

the benefit of preventing, rather than promoting, glutamate

release. They studied lamotrigine (100–400 mg/day), an

anticonvulsant that blocks sodium channels and inhibits the

spontaneous release of glutamate. They found that in their

second sample of 212 patients, lamotrigine was associated

with significant improvements in neurocognitive function-

ing but found no effects in the first sample.

Memantine, typically prescribed to enhance neurocog-

nition in Alzheimer’s disease, has several mechanisms of

action. It operates as a weak, non-selective antagonist of

glutamatergic NMDA receptors, during which memantine

mitigates the neuronal excitotoxicity due to glutamatergic

deregulation by curbing the prolonged opening of calcium

channels and the prolonged influx of Ca2? [53, 54]. Me-

mantine also exerts weak, non-selective blocking action at

5HT3 receptors and nicotinic acetylcholinergic receptors

(particularly alpha-7) and agonist action at dopamine D2

receptors. There have been two studies of the possible

Table 2 continued

Mechanism and

target


Promotion of

neurogenesis

Davunetide Javitt et al. [76] Good tolerability but no benefits over PL on

neurocognition

COMT catechol-O-methyltransferase, CVLT California Verbal Learning Test, D dopamine, DMXB-A 3-2,4-dimethoxybenzylideneanabaseine,

GABA c-aminobutyric acid, GlyT glycine transporter, LDX lisdexamfetamine dimesylate, M muscarinic, MCCB MATRICS Consensus Cognitive

Battery, mGluR metabotropic glutamate receptor, n/a clinical evidence not available to date, NE norepinephrine, NMDA N-methyl-D-aspartate,

PL placebo, pt(s) patient(s), RBANS Repeatable Battery for the Assessment of Neuropsychological Status, sc subcutaneous, WAIS-III Wechsler

Adult Intelligence Scale-Third Edition, WMS-R Wechsler Memory Scale—Revised, 5-HT serotonin


precognitive benefits of memantine in schizophrenia. Lie-

berman et al. [53] examined the benefits of adjunctive

memantine (20 mg/day for 8 weeks) provided to 139

patients receiving olanzapine, risperidone, aripiprazole,

ziprasidone, or quetiapine sometimes in conjunction with a

mood stabilizer versus placebo for at least 3 months. They

found that adjunctive memantine did not produce any

benefits on schizophrenia symptoms measured by the

PANSS, or neurocognition as measured by the Brief

Assessment of Cognition in Schizophrenia (BACS), over

adjunctive placebo. In addition, memantine resulted in an

increased risk of adverse events. Lee et al. [54] similarly

found no benefits to adjunctive memantine provided to

patients receiving conventional antipsychotics. They ran-

domized 26 medicated patients who completed the Korean

version of the Mini Mental Status Exam (MMSE) as a

measure of neurocognition and the PANSS for schizo-

phrenia symptoms. They noted some improvements in

negative symptoms among patients who received meman-

tine, but the benefits were marginal. Unsurprisingly, there

were little gains on the MMSE as an outcome measure of

neurocognition. The MMSE has a high ceiling effect in

schizophrenia clinical trials and the data obtained with the

measure have a very small dispersion that makes it virtu-

ally impossible to obtain treatment effects on the measure.

2.4 Noradrenergic Targets

Three compounds that target adrenergic receptors have been

evaluated for their putative procognitive benefits in people

with schizophrenia. All three compounds have been used for

treating attention problems in children with ADHD. Guanfa-

cine is a selective agonist of central a-2A adrenergic receptors

originally indicated for the management of hypertension. In

the only clinical trial with schizophrenia patients to date,

Friedman et al. [55] randomized individuals receiving second-

generation antipsychotics to receive adjunctive guanfacine or

placebo for 4 weeks. There were no significant differences at

post-treatment between groups but there appeared to be an

association between guanfacine use and improvements in

working memory and vigilance. In contrast, atomoxetine and

reboxetine, both norepinephrine reuptake inhibitors, have

demonstrated no hint of possible efficacy with schizophrenia

patients in published clinical trials [56–58].

2.5 Gamma-Aminobutric Acid (GABA)-ergic Targets

A number of compounds have been developed to influence

c-aminobutric acid (GABA) activity, but most of these

compounds have failed to demonstrate neurocognitive

benefits in large clinical trials [59–62]. Lewis et al. [59]

examined the benefits of MK-0777, a GABAA a2 receptor

agonist, on neurocognition in 15 patients with

schizophrenia. They found improvements on the N-back

and the continuous performance test (CPT) but no effects

on the Repeatable Battery for the Assessment of Neuro-

cognitive Status (RBANS) subtests except delayed mem-

ory. Similarly, in a larger sample (n = 60), Buchanan et al.

[60] found no benefits for MK-0777 over placebo on the

MATRICS Consensus Cognitive Battery global cognition

score, the N-back, the CPT, or on the UCSD Performance-

Based Skills Assessment (UPSA), a measure of functional

capacity. In one study, Menzies et al. [61] found that flu-

mazenil, a GABAA antagonist, improved performance on

the N-back relative to placebo, and relative to lorazepam, a

GABAA agonist that actually worsened N-back perfor-

mance. However, the study sample was small (n = 11 for

schizophrenia patients) and would benefit from replication.

Recently, Geffen et al. [62] demonstrated that BL-1020, an

antipsychotic (D2L blockade, 5HT2A affinity) enhanced with

GABA agonist activity, had procognitive benefits in schizo-

phrenia patients. BL-1020 was comparable to risperidone at

attenuating psychotic symptoms; moreover, its benefits on

neurocognition were slightly greater than those of risperidone.

2.6 Serotonergic Targets

Of the six currently published studies of compounds targeting

serotonergic systems, three have focused on 5-HT1A agonism.

Sumiyoshi et al. [63] found that adjunctive tandospirone

(30 mg/day) contributed to improvement in executive func-

tioning and verbal reasoning compared with adjunctive pla-

cebo. However, there has been no replication of the study that

would suggest that the precognitive effects of tandospirone are

robust. Two studies that evaluated buspirone suggest that

there is little reason to be enthusiastic about any putative

precognitive benefits of the compound for schizophrenia [64,

65]. There appears to be little impetus for continued study of

5HT1A and 5HT2A antagonism as targets for neurocogni-

tion—WAY100635 has yet to be studied in schizophrenia and

M100907 was discontinued following phase II trials due to its

poor efficacy [66]. Two studies have evaluated the adjunctive

benefits of ondansetron, a 5-HT3 receptor antagonist [67, 68].

Both studies found this compound at 8 mg/day to be quite

promising for addressing negative symptoms and neurocog-

nitive impairments in chronically ill patients.

2.7 Histaminergic Targets

There has been recent interest in the possible procognitive

effects of modafinil, a wakefulness-promoting medication,

with an as yet unclear mechanism of action. As a treatment

for sleep disorders (e.g., narcolepsy), modafinil appears to

confer therapeutic effects by increasing the expression of

histamine in the hypothalamus [83]. It also appears to

operate as a dopamine agonist by inhibiting the reuptake of


dopamine by the dopamine transporter [84]. Both mecha-

nisms may involve the activation of orexin neurons that

project into the hypothalamus and from the hypothalamus

into frontal areas and other central nervous system struc-

tures [85]. Modafinil may thus promote wakefulness by

activating orexin neurons and fostering the release of his-

tamine and the expression of cortical serotonin and cate-

cholamines in the hypothalamus [86].

Modafinil has been shown in some studies to improve

attention, memory, and executive functioning in people

with schizophrenia but several studies have also found no

benefits to modafinil. The benefits of modafinil seem to be

more robust in studies of first-episode patients [70],

whereas no benefits have been found in patients with

chronic schizophrenia [71–73]. It may be that neurocog-

nitive impairments are more amenable to modafinil treat-

ment in early schizophrenia than in chronic schizophrenia

when impairments may have worsened over time.

3 Problems and Prospects of Psychopharmacological

Enhancement

Save for a few exceptions, pharmacological-enhancement

strategies for neurocognition have generally had limited

success in schizophrenia. These include several failed trials

of compounds targeting dopaminergic, cholinergic, gluta-

matergic, GABAergic, and noradrenergic systems. Harvey

and Bowie [14] identified several factors that may account

for the limited efficacy of psychopharmacological agents

(Table 3). It may be that psychopharmacological agents are

simply ineffective for treating neurocognitive deficits—the

ubiquitous neurological impairments that precede the onset

of psychosis and further neuropathological changes asso-

ciated with the neurotoxic effects of frank psychosis may

render neurocognitive impairments intractable to medica-

tion treatment. There is some evidence that schizophrenia,

much like neurodegenerative diseases, is characterized by

deviant neuronal apoptosis that results in the loss of sub-

stantial receptor targets [87, 88]. Such loss may limit the

efficacy of agonist-induced receptor stimulation necessary

for the action of several agents as receptor targets are

limited in availability [88]. It may be that enhancement

strategies should begin by promoting survival processes

that activate neurogenesis, neural growth, and synaptic

connectivity (e.g., davunetide) before receptor sites can

become viable targets for agonist action. The efficacy of

some drugs (e.g., DAR-0100, modafinil) in early but not

chronic phases of schizophrenia may suggest that a dete-

riorating course of schizophrenia may limit the efficacy of

neurocognitive enhancers due to profound neuropathology.

It may be that most neurocognitive enhancers are more

efficacious during the first episode or prodromal phases

than the chronic phase of illness. Clinical trials that recruit

and compare patients from various phases of illness may be

particularly informative in this regard.

The concurrent use of antipsychotics and cognitive-

enhancing drugs may have pharmacodynamic interactions

that limit the efficacy of enhancing agents. For example,

antagonist action at D2 and 5-HT2A receptor sites may have

a downstream effect on the plasticity and efficiency of

other neurotransmitter and receptor systems implicated in

schizophrenia, including other serotonergic, cholinergic,

dopaminergic, adrenergic, glutamatergic, and histaminer-

gic systems [89].

Another issue is the pharmacokinetic properties of

enhancement drugs. It is possible that enhancement drugs

have failed to produce neurocognitive benefits in people

with schizophrenia because higher dosages would have

been needed to obtain improvements. However, higher

dosing may be untenable due to the increased risk of side

effects that may render a combined regimen of an anti-

psychotic and a neurocognitive enhancer intolerable.

Similarly, there is reason to be concerned about the rela-

tively short duration of several clinical trials in which

enhancing agents are provided as adjuncts to antipsychotics

for no more than a few weeks. While shorter trial durations

are reasonable in proof-of-concept studies, it may be that

adequate improvements in neurocognition may not be

observable unless the regimen is sustained for months

Table 3 Rate-limiters for the efficacy of neurocognitive-enhancing drugs in schizophrenia

Profound neuropathology: the severity and ubiquity of schizophrenia-related neuropathology may limit the effectiveness of single-receptor

enhancers

Receptor availability: neuronal apoptosis depletes the actual availability of receptor target sites for neurocognitive enhancers; a state of affairs

that may be particularly problematic for compounds with agonist properties

Antagonistic drug interactions: the impact of combining antipsychotics with neurocognitive-enhancing agents on the efficacy of the regimen

is currently unknown. Antipsychotics and neurocognitive enhancers may interact pharmacodynamically in a way that detracts from the

efficacy of one or both

Inadequate dosing: psychopharmacological neurocognitive enhancers may be inadequately dosed in existing clinical trials. Only a few studies

actually provided a snapshot of the impact of dosing on the efficacy of enhancers

Delivery and pharmacokinetics: promising agents delivered peripherally fail to cross blood–brain barrier or have a very short half-life that

limits their efficacy


rather than a few weeks. A longer-tem course of treatment

is consistent with the recommendations of the MATRICS

consensus guidelines for phase III clinical trials that rec-

ommend that such studies last for at least 6 months [14].

4 Neuroinflammation and Oxidative Stress as Putative

Treatment Targets for Neurocognition

Neurodevelopmental models of schizophrenia posit a role for

acute maternal infections in utero, such as maternal influenza.

Studies have produced evidence that increased expression of

inflammatory cytokines in the second trimester of pregnant

women increased the risk of schizophrenia in their offspring

[90, 91]. Viral exposure can result in reductions in the density

of receptors relevant to neurocognition, such as D1 receptors

in the frontal areas and NMDA receptors in the hippocampus,

reductions in protein kinase B (Akt) expression, and reduced

axonal integrity [92, 93]. Proinflammatory cytokines such as

interleukin (IL)-6 are elevated in schizophrenia [94], and have

been shown to cross the blood–brain barrier and influence

specific brain regions, including the prefrontal cortex, medial

temporal regions, and long-term potentiation in the hippo-

campus [95]. IL-6 increases oxidative stress, which may

disrupt the expression of inhibitory GABA interneurons and

impact executive functioning [96]. At least one study has

demonstrated that expression levels of C-reactive protein

(CRP), an inflammatory biomarker, are associated with neu-

rocognitive deficits but not necessarily symptom severity in

people with schizophrenia [97]. Neuroinflammation impacts

the activity-dependent transport of brain-derived neurotro-

phic factor (BDNF), a neuroplasticity-regulating protein that

promotes neurogenesis, synaptogenesis, and dendritic growth

[98, 99]. Akt, which is activated by BDNF signaling, similarly

influences neuroplasticity and downstream activity of NMDA

and GABA receptor pathways that in turn influence neuro-

cognitive functioning [98, 99]. Given their impact on neuro-

cognition, neuroinflammation and oxidative stress are

potential targets for psychopharmacological enhancement of

neurocognition. Preliminary studies suggest that anti-

inflammatory drugs and anti-oxidants may demonstrate

moderate efficacy for positive and negative symptoms of

schizophrenia, particularly early during the course of illness

(i.e., within the first 5 years) in people with altered immune

functioning [100, 101]. However, there have been very few

evaluations of their benefits on neurocognition. Following are

a few compounds that are being evaluated for their precog-

nitive benefits for schizophrenia patients (Table 4).

4.1 Minocycline

Minocycline is a long-acting tetracycline antibiotic tradi-

tionally prescribed for the treatment of bacterial infections

(e.g., spotted fever, typhus fever, etc.). There has been

recent interest in the possible anti-inflammatory, anti-oxi-

dative, and neuroprotective benefits of minocycline in

people with neurodegenerative disorders and people with

schizophrenia. Studies show that minocycline does have

anti-inflammatory properties in its ability to decrease the

expression of inflammatory cytokines such as tumor

necrosis factor (TNF)-a and IL-1b [102]. Several mecha-

nisms for its anti-inflammatory and neuroprotective action

have been suggested. One possibility is that minocycline

inhibits the apoptotic action of the enzyme 5-lipoxyge-

nase—an enzyme involved in the synthesis of both proin-

flammatory leukotrienes and anti-inflammatory lipoxins

[103]. Minocycline appears to inhibit T-cell-induced

cytokine signaling by preventing T cells from activating

microglia [104]. Minocycline may also act directly on

microglia by down-regulating its major histocompatibility

complex class (MHC)-II expression through an inhibition

of interferon (IFN)-c, interferon regulatory factor (IRF)-1,

and protein kinase C (PKC)-a/bII phosphorylation [105]. As

an antioxidant, minocycline may act by (i) attenuating lipid

peroxidation and associated peroxynitrite-related DNA

damage; (ii) supporting the upregulation of superoxide dis-

mutase in response to NMDA; and (iii) in the glutamatergic

system by inhibiting nitric oxide synthase activity, nitric oxide

synthesis from L-arginine, and, subsequently, preventing nitric

oxide-related neurotoxicity [106].

To date, there have been only two studies of minocycline

benefits in patients with schizophrenia. These studies robustly

demonstrated that minocycline may be beneficial for reducing

symptoms of schizophrenia; however, only one of those

studies examined the possible precognitive benefits of mino-

cycline. Levkovitz et al. [106] randomized 54 early-phase

schizophrenia patients who had been receiving second-gen-

eration antipsychotics for at least 2 weeks to receive adjunc-

tive minocycline (200 mg/day). They found that adjunctive

minocycline improved negative symptoms and executive

functions, including working memory, cognitive shifting, and

planning in schizophrenia patients.

4.2 Aspirin

Although traditionally used as an analgesic and an anti-

pyretic, acetylsalicylic acid (aspirin) has gained recent

interest as an anti-inflammatory agent. Aspirin operates as

a non-steroidal anti-inflammatory drug through its sup-

pression of prostaglandin and thromboxane syntheses and

its inhibition of cyclooxygenase (COX) pathways [107,

108]. Aspirin inhibition of both COX enzymes (COX-1 and

COX-2) directly suppresses the production of prostaglan-

din and thromboxane given that these enzymes are neces-

sary for their synthesis. The inhibition of prostaglandin E2

production is particularly critical for the restoration of the


activity balance between two types of helper T cells (TH)—

the anti-inflammatory TH2 cells and the proinflammatory

TH1 cells [101]. An aberration in the comparative expres-

sion levels of both types of TH cells is a marker of a pro-

inflammatory immune state that influences the tryptophan–

kynurenine pathway and upregulates the expression of

kynurenic acid with a downstream effect on glutamatergic

neurotransmission and NMDA antagonism. Aspirin-medi-

ated inhibition of prostaglandin may have the downstream

consequence of altering signal transduction in NMDA-type

glutamatergic receptors [109]. This occurs because free

prostaglandins inhibit the glutamate reuptake action of

certain astrocytes in the synaptic cleft, with the conse-

quence of fostering glutamatergic neurotransmission [110].

Aspirin may also wield its anti-inflammatory effects

indirectly by signaling the production of 15-epi-lipoxin A4.

The lipoxin in turn induces an increased expression of

nitric oxide [111, 112]. Aspirin stimulates the production

of other lipoxins that attenuate the expression of inflam-

matory biomarkers such as CRP, IL-6, and TNF-a [108].

Deng and Fang [113] demonstrated that aspirin triggers the

activation of G-protein coupled receptor (GPR)-35, which

is known to play a role in cell immune response circuits.

Laan et al. [101] conducted the only published study to

date that examined the benefits of adjunctive aspirin for

people with schizophrenia. The authors randomized

patients receiving antipsychotic medications to adjunctive

aspirin treatment (1,000 mg/day) or adjunctive placebo.

Outcome measures included schizophrenia symptoms

measured with the PANSS. Neurocognitive functions—

memory, attention, locomotor functioning, and psycho-

motor skills—were also assessed using the Ray Auditory

Verbal Learning Test, HQ Continuous Performance Test,

Purdue Pegboard test, and the Trail Making Test, respec-

tively. At 3-month follow-up, the aspirin group demon-

strated greater reductions in positive symptoms and total

symptoms as measured by the PANSS. However, there was

no difference across groups in other PANSS subscales and

no differences in any of the neurocognitive functions

assessed.

4.3 Statins

Hydroxymethylglutamyl coenzyme A (HMG CoA) reduc-

tase inhibitors (statins) are a family of drugs traditionally

prescribed to lower lipid or cholesterol levels. They

include, among others, atorvastatin, simvastatin, lovastatin,

mevastatin, fluvastatin, and rosuvastatin. Particular atten-

tion has been paid to the anti-inflammatory properties of

simvastatin and rosuvastatin [114–117], which decrease the

Table 4 Pharmacological agents with anti-inflammatory and antioxidant properties

Mechanism Sample drug Sample

studies

Notes

Antimicrobial Minocycline Levkovitz

et al. [106]

Minocycline improved working memory, cognitive set shifting, and planning

in 54 early-phase schizophrenia pts. Additional improvements in negative

symptoms, global clinical impression, and functioning over PL group

Nonselective

COX

inhibitor

Aspirin Laan et al.

[101]

Adjunctive aspirin use was associated with greater reductions in positive and

total symptoms than adjunctive PL. No differences in neurocognitive

outcomes

Statin Simvastatin Chaudhry

et al. [121]

Study outcomes are pending

Omega-3 fatty

acid

Ethyl EPA Fenton et al.

[126]

Adjunctive 3 mg/day ethyl EPA produced no improvements in symptoms or

neurocognitive functioning over PL

Reddy et al.

[127]

Adjunctive 2 mg/day ethyl EPA produced improvements in executive

functioning in the open-label study. No randomization

Supplement L-Carnosine Chengappa

et al. [128]

Adjunctive L-carnosine produced improvements in executive functions,

memory, attention, and motor speed over adjunctive PL

Glutathione

precursor

N-acetylcysteine Berk et al.

[129]

Farokhnia

et al. [130]

Gunduz-

Bruce et al.

[131]

Improvements in negative symptoms. No data on neurocognitive outcomes

have yet been studied

Gunduz-Bruce et al. found evidence of improvement in P-300 ERP component

B Vitamins Complex of folic acid,

cobalamine, and

pyridoxine

Levine et al.

[133]

Adjunctive administration of the combination of B vitamins produced

improvements in neurocognitive outcomes over PL

COX cyclooxygenase, EPA eicosapentaenoic acid, ERP event-related potential, PL placebo, pt(s) patient(s)


expression of pro-inflammatory cytokines such as TNF-a,

IL-1b, IFN-c, MHC-II, and nitric oxide synthase in animal

models. In human samples, rosuvastatin reduces IL-6,

TNF-a, and IFN-c levels [118].

Currently published studies of the benefits of statins for

people with schizophrenia evaluate their lipid-lowering

properties (e.g., Vincenzi et al. [119, 120] and Landry et al.

[119, 120]). Unfortunately, none of these studies examined

neurocognitive functioning as an outcome measure. Chaudhry

et al. [121] are conducting a clinical trial that evaluates the

benefits of adjunctive simvastatin (C20 mg/day) and/or

ondansetron (8 mg/day). They plan to recruit 216 people with

schizophrenia spectrum disorders. The study includes the

PANSS to measure schizophrenia symptoms and a battery of

neurocognitive tests that measure intelligence, memory,

learning, attention, processing speed, reasoning/problem

solving, and social cognition.

4.4 Omega-3 Polyunsaturated Fatty Acids

Omega-3 fatty acids include, among others, the essential

fatty acids—eicosapentaenoic acid (EPA), doc-

osahexanoieic acid (DHA), and linolenic acid. This group

of orthomolecules is known to be essential for normal

cortical expansion and maturation and functional integrity

during prenatal and postnatal phases and during adult

development [122]. Animal models suggest that omega-3

fatty acids may confer neuroprotection against neurotoxic

insults [123]. A rodent model provided evidence of the

anti-inflammatory action of EPA in inhibiting the expres-

sion of IL-6, IL-1a, IL-1b, and TNF-a in the microglia in

response to lipopolysaccharide insult [124].

It has been demonstrated that omega-3 fatty acids may be

beneficial in decreasing the risk of a frank psychotic disorder

in ultra high-risk individuals, suggestive of possible neuro-

protective effects [125]. However, very few clinical studies of

omega-3 fatty acids have examined their neurocognitive

benefits. Fenton et al. [126] examined the clinical benefits of

adjunctive ethyl EPA for 87 people diagnosed with schizo-

phrenia or schizoaffective disorder. Participants were ran-

domized to receive either 3 mg/day of ethyl EPA or placebo.

Through the course of treatment and at post-treatment, there

were no differences between the ethyl EPA group and the

placebo group on schizophrenia symptoms, mood, clinical

global impression, and neurocognitive functioning. In a recent

open-label study, Reddy et al. [127] added 2 mg/day ethyl

EPA to the antipsychotic medication regimen of 27 people

with schizophrenia for 24 weeks. They found that this regi-

men produced improvements on the perseverative errors

index of the Wisconsin Card Sort Test—a test of executive

functioning. In the absence of positive results from a well

controlled study, the precognitive benefits of omega-3 fatty

acids for people with schizophrenia remain speculative.

4.5 Other Compounds

L-Carnosine is a dipeptide composed of b-alanine and L-

histidine and localized in the brain and muscle tissues. As

an antioxidant, L-carnosine targets inadequate antioxidant

defense at glutamatergic synapses were it is co-localized

with glutamate and other antioxidants such as vitamin E

and glutathione. In 75 chronic schizophrenia patients,

Chengappa et al. [128] found that the adjunctive L-carno-

sine, an antioxidant, improved executive functions, mem-

ory, attention, and motor speed.

N-Acetylcysteine is a precursor of glutathione, a com-

pound with antioxidant effects that modulates NMDA

receptor activity by virtue of its co-localization with glu-

tamate. Two studies demonstrated that adjunctive use of N-

acetylcysteine improved the negative symptoms of

schizophrenia [129, 130]. Although there have been no

direct examination of its neurocognitive benefits, one study

showed that N-acetylcysteine improved P-300 amplitudes

on event-related potential (ERP) in individuals with keta-

mine-induced psychotic symptoms [131].

4.6 Vitamins B6, B9, B12, and Homocysteine

The B vitamins are a family of water-soluble nutrients avail-

able in several foods and involved in metabolism. These

include pyridoxine (B6), folate (B9), and cobalamine (B12) that

all metabolize homocysteine (and other sulfur-based amino

acids) through methylation and are hence involved in main-

taining low levels in the body. B vitamin deficiency contrib-

utes to neurocognitive impairment in several pathways that

implicate elevated homocysteine [132]. Homocysteine indu-

ces oxidative stress through its action on glutamate receptors

(e.g., altering antioxidant defense at redox sites).

There has been one evaluation of the neurocognitive ben-

efits of B vitamins. Levin et al. [133] recruited 42 people with

schizophrenia with elevated ([15 lmol/L) plasma homo-

cysteine levels. Using a randomized design, they evaluated the

benefits of an adjunctive administration of a combination of

folic acid, cobalamine, and pyridoxine. They found that the

combination produced benefits on several neurocognitive

tests, including the Wisconsin Card Sort test.

5 Methodological Issues in Clinical Trials

5.1 The Etiologic Heterogeneity of Neurocognitive

Dysfunction as a Putative Mediator of Treatment

Response

The heterogeneity of the constellations of symptoms that

define the schizophrenia spectrum is widely acknowledged,

but this knowledge has done little to inform the clinical trials


or practice guidelines. (One exception is the identification of

refractory schizophrenia symptoms and the use of clozapine).

This state of affairs is even more germane to studies of

enhancement strategies for neurocognition. Some evidence

supports the variable etiology of neurocognitive dysfunction

in schizophrenia. Studies suggest that multiple sources of

genetic variation that include single nucleotide polymor-

phisms (SNPs) and copy number variations (CNVs) may

contribute to neurocognitive dysfunction in schizophrenia

[77, 134, 135]. As examples, there is some evidence (although

mixed) that the Val66Met SNP on the BDNF gene influences

the intracellular transport and activity-dependent expression

of the BDNF protein—necessary for neurogenesis, synapto-

genesis, long-term potentiation, neuroplasticity, and neuronal

integrity [136–139]. Similarly, the COMT Val158Met

impacts neural networks in the prefrontal cortex by modu-

lating the activation patterns in D1/D2 receptors, thereby

influencing dopamine activity [140, 141]. Both SNPs have a

downstream effect on neurocognitive functioning [142, 143]

and may influence response to cognitive-enhancement strat-

egies [142–145]. As demonstrated by Giakoumaki et al. [146],

it is possible that individuals homozygous for the Val allele on

the COMT gene for whom the pathology of neurocognitive

dysfunction stems from frontal dopamine depletion due to

COMT enzyme overactivity may benefit more from COMT

inhibition than from other enhancement strategies [146, 147].

Similarly, BDNF Met allele carriers may benefit more from

strategies that target BDNF expression, neurogenesis, and

synaptogenesis than Val homozygotes. As discussed above,

the pathophysiology of neuroinflammatory and oxidative

stress may similarly contribute to neurocognitive impairment

in schizophrenia. To the degree that neuroinflammation,

rather than other factors, accounts for neurocognitive deficits

in some schizophrenia patients, neurocognitive enhancers

with anti-inflammatory properties may be a more effective

strategy for attenuating neurocognitive impairments.

5.2 Profiles of Neurocognitive Impairment

and Psychopharmacological Enhancement

There is some evidence from multivariate statistical mod-

eling that the schizophrenia spectrum is characterized by

clusters or profiles of neurocognitive impairment [148–

150].1 Examples of clusters include patients with

generalized neurocognitive decline, patients neurocogni-

tively intact in all areas but executive functioning, patients

who experienced IQ decline from higher premorbid IQ, and

patients with low premorbid IQ. Other classifications have

identified subgroups characterized by the presence or

absence of memory impairment or decline. It is possible

that the nature of neurocognitive impairment may influence

responsiveness to psychopharmacological enhancement in

general or the choice of enhancing agent, but these possi-

bilities have yet to be examined in clinical trials. It seems

unlikely that patients with low premorbid IQ would readily

gain neurocognitively from psychopharmacological

enhancement. In contrast, it may be possible to enhance

neurocognition in individuals who experience decline from

higher premorbid IQ and individuals who experience

impairments in only circumscribed domains such as

memory and executive functioning. Interventions that

promote neurogenesis and synaptogenesis may be partic-

ularly indicated for situations of IQ decline. These asser-

tions are of course merely speculative and would need to be

subject to empirical testing in future clinical trials.

The linkage of etiology to psychopharmacological

enhancement strategies is consistent with ongoing efforts at

biosignature-based personalization of psychiatric treatment

[152]. The personalization of neurocognitive enhancement

in schizophrenia is indeed a desirable proposition that has

potential to be cost saving for the delivery of such inter-

ventions. However, the assertion that such efforts may

result in more promising outcomes in clinical trials remains

an empirical question that has yet to be addressed by

existing studies. Several psychopharmacological targets

remain unexplored—for example, no studies have evalu-

ated the possible neurocognitive benefits of COMT enzyme

inhibition (e.g., tolcapone) as a strategy for fostering

frontal dopamine activity at D1/D2 sites in schizophrenia

patients. There have been similarly few attempts to test

other compounds (besides davunetide) that enhance neu-

rogenesis and increase BDNF activity. Early studies of

antioxidants and anti-inflammatory drugs such as L-carno-

sine and minocycline are promising but would benefit from

replication. Moreover, the influence of oxidative stress and

neuroinflammation on neurogenesis, synaptogenesis, the

signaling of neuronal networks, and downstream neuro-

cognitive functioning potentiates the development and

evaluation of many more antioxidants and anti-inflamma-

tory drugs.

5.3 Outcome Assessments and Practice Effects

One limitation of cognitive-enhancement clinical trials has

been the absence of uniformity in the assessment of neu-

rocognition. There has been vast heterogeneity across

studies with regard to neurocognitive domains assessed and

1 The assertion that neurocognition in schizophrenia is underpinned

by profiles of neurocognitive impairment warrants qualification.

Indeed, the degree to which common neuropsychological tests assess

so-called ‘neurocognitive domains’ (e.g., attention, working memory,

processing speed, problem solving), as opposed to a unitary,

generalized neurocognitive structure, remains a point of controversy.

Recent work by Dickinson and Harvey [151] has questioned the

utility of neurocognitive domains with evidence that a general higher-

order cognitive factor demonstrated greater associations with schizo-

phrenia diagnosis than specific neurocognitive deficits.


the measures used for the assessment of such domains. One

of the original goals of the MATRICS initiative was to

develop an expert-informed uniform assessment battery to

measure neurocognition in schizophrenia clinical trials.

The development of a uniform measure for clinical trials

would allow for an easy evaluation of neurocognitive

outcomes across studies. The product of this MATRICS

objective was the development of the MATRICS Consen-

sus Cognitive Battery (MCCB), a battery of ten subtests

that assess attention, working memory, processing speed,

reasoning/problem-solving, visual learning, verbal learn-

ing, and social cognition. However, very few studies have

incorporated the MCCB as an outcome measure of neu-

rocognition since its publication. In the absence of studies

using uniform assessments, the differential sensitivity of

assessment instruments to neurocognitive change remains

an uncontrolled variable in clinical trials. Concerns have

been expressed about the degree to which the practice

effects of assessment measures may confound the results of

clinical trials. It has been suggested that the previously

assumed precognitive benefits of second-generation anti-

psychotics better reflected practice effects of the repeated

administration of neurocognitive tests [9]. Practice effects

may similarly conceal any possible neurocognitive gains

when such practice effects dwarf treatment-related neuro-

cognitive gains.

5.4 Cognitive Remediation as a Platform

for Pharmacological Enhancement Trials

The majority of psychopharmacological enhancement

studies may be predicated on the assumption that neuro-

cognitive impairment stems from receptor dysfunction and

can be treated through pharmacological means alone. This

assumption may be unfounded to the degree that neuro-

cognitive ability is influenced by the propensity and

opportunity to engage in thinking behavior. It is often the

case that patients in psychopharmacological-enhancement

trials are recruited from environments that are intellectually

unstimulating, and research protocols are lacking in neu-

rocognitively enriching activities that may recoup thinking

behavior. It may be that psychopharmacological enhance-

ment may robustly improve neurocognitive capacity but

only when combined with cognitive training such as that

found in cognitive remediation [14]. To date, the study by

D’Souza et al. [47] appears to be the only study to have

examined the putative benefits of combining psychophar-

macological enhancement with cognitive remediation.

Although efficacious, the D-serine enhancement of cogni-

tive remediation provided no added benefits over cognitive

remediation alone. However, the possible enhancing ben-

efits of a daily cognitive training platform, either through

cognitive remediation or through other neurocognitively

enriching experiences, is one that should be evaluated in

future psychopharmacological-enhancement trials.

Cognitive training not only provides a platform for the

evaluation of enhancing agents, but may also serve the

study of neural signaling cascades that influence neuro-

cognition. The robust effects of cognitive training suggest

that it may foster improvements regardless of the etiology

of neurocognitive impairment. An hypothesis yet to be

tested is whether cognitive remediation influences all of the

aberrant signaling systems that contribute to neurocogni-

tive deficits in schizophrenia. One study did show that

cognitive remediation led to an increased expression of

serum BDNF that was marginally correlated with

improvements in neurocognition and significantly corre-

lated with improvements in quality of life [153]. It would

be of similar interest to determine if cognitive remediation

leads to changes in immune system parameters such as the

upregulation of anti-inflammatory biomarkers and down-

regulation of pro-inflammatory biomarkers. Evidence of an

association between changes in immune system signaling

and neurocognitive improvements following cognitive

remediation will provide further evidence of the benefit of

the intervention. It will also further establish the role of

neuroinflammation in schizophrenia-related neurocognitive

impairments.

5.5 Sample Size and Power to Detect Treatment

Effects

Keefe et al. [15] have argued on methodological grounds

that the majority of published clinical trials were destined

to fail because of inadequate sample sizes to detect treat-

ment effects. This is indeed a critical issue—given the

severity of neurocognitive impairments observable in

schizophrenia, it may be reasonable to expect no more than

small to moderate gains in neurocognition in relatively

short clinical trials. In pre-to-post comparison of parallel

study arms, the required sample size to detect such effects

range from at least 142 to detect medium effects to at least

788 to detect small effects when statistical power is set at

0.80 (G*Power 3.1). Our own review confirms the assertion

of Keefe et al. that the sample sizes in the majority of the

published clinical trials may have been insufficient to

detect significant differences. However, this assertion is

tempered by the fact that a few adequately powered studies

also produced null results [27, 44, 45].

6 Conclusions

Consistent positive improvements in neurocognition have

not been found with psychopharmacological treatment in

people with schizophrenia. Although most efforts have


focused on dopaminergic, cholinergic, glutamatergic, nor-

adrenergic, GABAergic, and serotonergic mechanisms, the

impact of neuroinflammation and oxidative stress and their

downstream effect on neuroplasticity and D1 and NMDA

receptors suggests that they may be treatment targets for

neurocognition in schizophrenia. Clearly, the neurobio-

logical basis of neurocognitive deficits in schizophrenia is

quite complex, not limited to a single target but several

interconnected signaling systems. It may therefore be that

effective psychopharmacological enhancement would seek

to address neuroinflammation and oxidative stress, and

promote neurogenesis, in concert with targeting activity at

specific receptor sites. The variable etiology and phenom-

enology of neurocognitive dysfunction in schizophrenia

may very well contribute to the limited efficacy of

enhancing drugs. A delineation of the specific etiology of

neurocognitive impairments in schizophrenia and increased

efforts to link etiology to enhancement strategies may

improve neurocognitive outcomes in psychopharmacolog-

ical enhancement. There remains the possibility that sev-

eral clinical trials were underpowered due to the lack of

adequate sample sizes to detect what may amount to no

more than small to moderate effects on neurocognition.

However, a few adequately powered trials similarly pro-

duced null results.

Conflicts of Interest Dr. Ahmed and Dr. Bhat have no conflicts of

interest that are directly relevant to the content of this review.

Role of Funding Source No external sources of funding were used

to assist with the preparation of this review.

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