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ABSTRACT This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with

schizophrenia. In the United States and India, 185 outpatients (18–60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were

randomized to 12 weeks of placebo (_n_=91) or TC-5619 (_n_=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12). The primary efficacy outcome measure was the

Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative

Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (_P_=0.036) in this

exploratory trial. SANS also statistically favored TC-5619 (_P_=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically

significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in

India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial

agonists for cognitive dysfunction and negative symptoms in schizophrenia. SIMILAR CONTENT BEING VIEWED BY OTHERS PHASE 1 RANDOMIZED STUDY ON THE SAFETY, TOLERABILITY, AND PHARMACODYNAMIC

COGNITIVE AND ELECTROPHYSIOLOGICAL EFFECTS OF A DOPAMINE D1 RECEPTOR POSITIVE ALLOSTERIC MODULATOR IN PATIENTS WITH SCHIZOPHRENIA Article Open access 17 November 2020 LOW-DOSE LITHIUM

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SCHIZOPHRENIA SYMPTOMS: A FOLLOW-UP PILOT STUDY Article Open access 14 October 2023 EFFECTS OF RISPERIDONE/PALIPERIDONE VERSUS PLACEBO ON COGNITIVE FUNCTIONING OVER THE FIRST 6 MONTHS OF

TREATMENT FOR PSYCHOTIC DISORDER: SECONDARY ANALYSIS OF A TRIPLE-BLIND RANDOMISED CLINICAL TRIAL Article Open access 10 June 2023 INTRODUCTION Schizophrenia is a heterogeneous mental

disorder associated with different pathological features, including positive and negative symptoms (DSM IV-TR; American Psychiatric Association, 2000)) and cognitive dysfunction (Reichenberg

and Harvey, 2007). The negative and cognitive symptoms may precede onset of positive symptoms by many years and persist despite the remission of psychosis (Addington and Addington, 1993;

Fleischhacker, 2000; O’Carroll, 2000; Ojeda, 2000; Reichenberg et al, 2010; Tandon et al, 2009). Positive symptoms are highly responsive to antipsychotic medications in the majority of

patients, but negative symptoms and cognitive dysfunction are much less effectively treated (Erhart et al, 2006; Gold, 2004; Marder and Fenton, 2004; Miyamoto et al, 2005; Stahl and Buckley,

2007) and hence may prevent many patients from functioning productively and independently (Gold, 2004; Stahl et al, 2007). In contrast to psychotic symptoms in which the D2 receptor is a

proven target, the pharmacology of cognitive and negative symptoms is not well defined. To this end, the National Institute of Mental Health sponsored the Measurement and Treatment Research

to Improve Cognition in Schizophrenia (MATRICS) initiative to develop a consensus battery of neuropsychological tests that could measure therapeutic effects of agents for cognitive

dysfunction in schizophrenia (CDS; Gold, 2004; Kern et al, 2008; Nuechterlein et al, 2004; Nuechterlein et al, 2008). In the wake of the MATRICS initiative, molecular targets for the

treatment of CDS have been proposed (Gray and Roth, 2007; Marder et al, 2004). Among the prioritized targets was the alpha7 neuronal nicotinic receptor (NNR; Freedman et al, 2008; Kucinski

et al, 2011; Olincy and Stevens, 2007). Initially, preclinical studies indicated that antagonists of this receptor could induce sensory gating deficits in rodents that were similar to those

observed in schizophrenia (Luntz-Leybman et al, 1992). Shortly thereafter, genetic linkage was found for this deficit and the alpha7 NNR gene (Freedman et al, 1997). Post-mortem studies of

individuals with schizophrenia further supported these findings by showing reduced expression of this receptor in the hippocampus (Freedman et al, 1995) and thalamic reticular nucleus (Court

et al, 1999). Several alpha7 NNR agonists have shown promising results in preliminary trials by demonstrating efficacy against surrogate electrophysiological markers

(EnVivo_Pharmaceuticals, 2009; Olincy et al, 2006) and cognitive and negative symptoms of schizophrenia (Freedman et al, 2008). TC-5619 (a benzofuran-substituted pyridylmethylquinuclidine)

is a highly selective alpha7 NNR partial agonist with a Ki at the alpha7 NNR of 1 nM. It is 1000–10 000 times less potent at other NNRs and at other receptor subtypes (eg, 5HT3, opioid). Two

phase 1 studies of TC-5619 in healthy male volunteers showed that single doses of TC-5619 were well tolerated up to 406 mg (limited by orthostatic hypotension) and that multiple doses of

204 mg are well tolerated (Targacept, data on file). The half-life (20 h) and time to _C_max (approximately 2 h) were independent of dose. Finally, the Cognitive Drug Research cognitive test

battery revealed a statistically significant improvement in power of attention (_P_<0.05) in subjects taking 6.8 mg TC-5619 (Targacept Study TC-5619-CLP-002 (data on file)). Based on

these clinical data as well as data from a preclinical model suggesting cognitive benefits at a human dose of approximately 3 mg (Hauser et al, 2009) (Targacept, data on file), a dose range

of 1–25 mg was determined to be safe and conservatively chosen to encompass the anticipated efficacious dose range. SUBJECTS AND METHODS SUBJECTS The study was Institutional Review

Board-reviewed, filed with the US Food and Drug Administration (FDA), and registered on www.clinicaltrials.gov (NCT01003379) before study initiation, and conducted according to the

Guidelines of the Declaration of Helsinki (2008). It was conducted by the sponsor (Targacept) at 12 sites in India and 7 sites in the United States. Enrollment began in November 2009 and was

completed in December 2010. A total of 185 subjects were enrolled and randomized (Figure 1; Table 1). Tobacco users were stratified approximately equally across the treatment arms; tobacco

use was verified by urinary cotinine levels >500 ng/ml, and non-use by urinary cotinine levels <50 ng/ml. In all, 46% were tobacco users. In total, 154 subjects completed the study

(Figure 1); the most frequent reason for discontinuation was withdrawal of consent (12 subjects). All subjects met DSM-IV criteria for schizophrenia, primarily paranoid type (92%). Subjects

were required to be outpatients with: stable housing, availability of caregivers with personal contact at least four times weekly, and stable schizophrenia, defined as a lack of psychiatric

hospitalization and no change in quetiapine or risperidone monotherapy dose for 2 months before screening and during the study. Quetiapine and risperidone were chosen for this preliminary

adjunctive treatment study because they are prototypical atypical antipsychotics that are widely used in the clinic. Use of a wider range of underlying antipsychotic treatments will be

adopted in future studies. Subjects could have: a score no >4 on the Positive and Negative Syndrome Scale (PANSS) items assessing delusions, hallucinations, unusual thought content, and

conceptual disorganization; a score no >5 on the Calgary Depression Scale for Schizophrenia (CDSS); and no significant suicidality as assessed by the Columbia Suicide Severity Rating

Scale (CSSRS). Subjects could have no other comorbid axis 1 or axis 2 DSM-IV disorder nor any unstable medical condition. All subjects signed a written informed consent. EXPERIMENTAL DRUG

AND MATCHING PLACEBO The experimental drug was a blend of TC-5619 and excipients in gelatin capsules. Placebo was manufactured to match the experimental drug TC-5619 in identical-appearing

capsules in size, color, and shape. EXPERIMENTAL DRUG PROTOCOL AND ASSESSMENTS At screening, all subjects were trained to use the CogState Schizophrenia Battery (CSB). They also had

assessments using the PANSS, Scale For Assessment of Negative Symptom (SANS), Subject Global Impression-Cognition (SGI-Cog; a subject-rated seven-point Likert scale assessing three items:

memory and learning, attention and concentration, and speed of thinking), and Clinical Global Impression-Severity (CGI-S) scales. Physical examination, vital signs, serum chemistry and

hematology, urinalysis, urine drug screen for illicit drugs, and ECG were performed. Assessments were also made using the Abnormal Involuntary Movements Scale (AIMS), the CSSRS, and the

CDSS. On day 1, all subjects meeting eligibility criteria including absence of illicit drugs were randomized in a double-blind manner (subjects, caregivers, staff, sponsor were blinded)

using a 1 : 1 allocation to receive either TC-5619 or placebo orally once daily, in addition to quetiapine or risperidone monotherapy. The random allocation method was based on a blinded

sequence method applied by an independent statistician employed by an outside vendor. Approximately equal numbers of tobacco users and non-users were stratified and randomized to each

cohort. Blood samples were taken before and approximately 3 h after study drug was administered in the clinic, and these were processed for PK analyses of TC-5619 and for measuring blood

levels of quetiapine and risperidone. ECG and vital signs measurements were obtained just before each PK blood sample. Subjects in the TC-5619 cohort were to take 1 mg TC-5619 qd from day 1

to week 4; 5 mg qd from week 4 to 8; and 25 mg qd from week 8 to 12. Subjects were instructed to take their daily dose of study drug each morning, at least 90 min before tobacco use (if a

user) and at least 30 min before taking quetiapine or risperidone. Subjects returned for clinic visits at weeks 1, 4, 8, and 12 for safety and efficacy assessments. Subject compliance for

TC-5619 was monitored by pill counts at each visit. Compliance with quetiapine, risperidone, and other concomitant medications was monitored by subject self-report. Urinary drug screens were

used to monitor illicit drug use, and urinary cotinine levels discriminated tobacco use from non-use. There was a final clinic visit at week 14 for follow-up. Disposition of subjects is

shown in Figure 1. PLASMA LEVELS OF TC-5619, QUETIAPINE AND RISPERIDONE Serial and sparse blood sampling from a subset of subjects (_n_=62) was performed pre-dose and post-dose on day 1 and

weeks 4, 8, and 12 to estimate TC-5619 PK parameters and to document plasma levels of the concomitant antipsychotic medication with and without TC-5619 co-administration. Sample analyses

were performed using LC-MS/MS methods at Tandem Laboratories. All plasma samples were analyzed for TC-5619 levels (Salt Lake City, UT). All pre-dose samples were analyzed for either

quetiapine or risperidone and 9-hydroxy-risperidone (active metabolite) levels (Trenton, NJ). PK parameters were estimated for TC-5619, including _C_max, _T_max, and AUC to last collected

sample (8 h post-dose) and the dosing interval (extrapolated to 24 h post-dose). Plasma levels of the antipsychotic medication in the pre-dose samples were examined by cohort. STATISTICAL

ANALYSES The prospectively defined primary efficacy outcome measure was the change from day 1 to weeks 4, 8, and 12 in the Groton Maze Learning Task (GMLT) of the CSB, as filed to FDA and to

clinicaltrials.gov before study initiation. The CSB rather than other cognitive test batteries was used because of its shorter time for completion (20 min), its culturally neutral

computerized tasks (important for India), and its assessment of the seven cognitive domains judged important to CDS by the MATRICS initiative. The GMLT was chosen because it measures

executive function, the highest domain of cognitive function, and because CogState analyses of other alpha7 NNR agonists in previous studies showed that the GMLT was sensitive to effects

produced by this pharmacological class. Secondary outcomes included the CSB composite score, and scores for SANS, CGI-S, Clinical Global Impression-Global Improvement (CGI-I), and SGI-Cog.

Additional analyses included individual items of the CSB. Efficacy analysis was based on a mixed model repeated-measures methodology. The model considered change from baseline to weeks 4, 8,

and 12 as the response variable and included fixed effects for treatment, visit and treatment by visit interaction as well as baseline score and a random effect for center. Values reported

here use a 2-tailed test with an alpha of 0.05 in order to determine statistical significance. As this was an exploratory study, within-company success criteria for drug development

discussions were prospectively defined as _P_-values<0.10 (one-tailed) as specified in the FDA-submitted protocol. Outcomes were not corrected for multiplicity in this exploratory study.

For a number of CogState tasks (detection, identification, 1-card learning, and 1-back), data integrity criteria were specified _a priori_ to identify responses that reflect poor subject

cooperation. The analysis excluded subjects who failed to meet these criteria. Sample size calculations showed that 60 subjects should complete week 12 of the study to have a 90% power of

detecting a signal using a one-tailed test with an alpha of 0.10. As this study examined the efficacy of TC-5619 in both a tobacco user and a non-user cohort, 120 subjects were needed (60

per cohort) in order to be able to detect a signal in either of these cohorts. RESULTS EFFICACY PRIMARY EFFICACY OUTCOME MEASURE A blinded review by CogState during the study’s treatment

phase indicated a potentially greater-than-expected variance in the GMLT data, and analysis after database lock confirmed the existence of a positive skew to the GMLT data in the intent to

treat (ITT) population (sample skewness _g_1=1.03 in all patients at baseline). Consequently, a log (10) transformation of the GMLT data was performed (_g_1=−0.02). The treatment effect was

statistically significant in favor of TC-5619 (_P_=0.036, Week 4; Table 2), and the magnitude of the effect did not diminish following 12 weeks of randomized treatment (Cohen’s d for week 12

compared with day 1=0.40). The treatment effect in US patients (mean difference=0.082, 0.040, and 0.080 at 4, 8, and 12 weeks) was greater than the effect in Indian patients (mean

difference=0.020, 0.009, and 0.011 at 4, 8, and 12 weeks); this effect was significant at weeks 4 and 12 for US patients (_P_=0.0072, _P_=0.0044, respectively) but not for the Indian

patients (_P_>0.4 for all visits). The test for country (United States or India) by treatment interaction was not statistically significant (_P_=0.1577). This effect of TC-5619 was also

typically greater in tobacco users (Table 3). SECONDARY EFFICACY OUTCOME MEASURES Statistically significant results favoring TC-5619 in the ITT population were found in the SANS (_P_=0.030,

week 12; Cohen’s d for week 12 compared with day 1=0.26; Table 2). In the SGI-Cog, although the total score was not statistically significant, the attention/concentration item favored

TC-5619 (_P_=0.042). There was no drug effect identified in the ITT population in the other secondary outcome measures. The effect of TC-5619 was typically stronger in tobacco users (Table

3). The result in the SANS was driven by the avolition/apathy (_P_=0.110), anhedonia (_P_=0.062), and affective flattening (_P_=0.036) items. COGSTATE ANALYSES, TRAIL-MAKING TEST (TMT) A AND

B, DIGIT-SYMBOL SUBSTITUTION TEST (DSST) No measures in the CogState test battery, nor in the TMT or DSST, were statistically significant at the 0.05 level in the ITT population (Table 2).

A subgroup analysis of these data by tobacco use (Table 3) showed statistical significance in favor of TC-5619 in tobacco users on the 1-back test (ONB, a test of working memory: _P_=0.040,

week 12; Table 3). SAFETY AND TOLERABILITY ADVERSE EVENTS (AES) In all, 26% of subjects in the placebo cohort and 32% of subjects in the TC-5619 cohort reported AEs. All AEs were mild or

moderate in severity. AEs that were present in at least three subjects in either cohort were: constipation (2% placebo _vs_ 4% TC-5619); nausea (0% placebo _vs_ 5% TC-5619); body temperature

increased (2% placebo _vs_ 3% TC-5619); decreased appetite (5% placebo _vs_ 4% TC-5619); somnolence (2% placebo _vs_ 3% TC-5619); (worsening of) schizophrenia (2% placebo _vs_ 3% TC-5619);

headache (2% placebo _vs_ 3% TC-5619); and insomnia (0% placebo _vs_ 3% TC-5619). Nausea did not lead to discontinuation, and it was mild (_n_=4) or moderate (_n_=1) in severity. SERIOUS

ADVERSE EVENTS (SAES) Two SAEs were reported in the study, one in the placebo group (gastritis) and one in the TC-5619 group (acute exacerbation of schizophrenia). Both were considered not

drug related by the investigator. The subject with gastritis became dehydrated and was hospitalized to receive intravenous fluids. The subject with acute exacerbation of schizophrenia

stopped taking quetiapine and a week later was found wandering in the streets and acting bizarrely. He was hospitalized and treated. AES LEADING TO DISCONTINUATION Seven AEs led to

discontinuation, three in the placebo group and four in the TC-5619 group. All were considered not drug related by the investigator. In the placebo group, the events were: gastritis

(moderate), dermatitis (mild), and worsening schizophrenia (moderate). In the TC-5619 group, the events were: gastroenteritis (moderate), exacerbation of schizophrenia (two, moderate), and

exacerbation of psychotic symptoms (moderate). RESULTS OF THE CSSRS AND CDSS The CSSRS detected very low levels of suicidality during the trial between any visits, and all changes were in

the placebo cohort. The CDSS showed no meaningful change either within or between cohorts in the very low level of depression during the study. PHYSICAL EXAMINATION, AIMS, VITAL SIGNS,

LABORATORY ANALYTES, AND ECG There were no clinically meaningful changes between cohorts in physical examination, vital signs, orthostatic blood pressure changes, or urine or serum

laboratory measurements. The AIMS revealed no difference between cohorts in the very low mean severity of involuntary movements (AIMS score 0.1 in both cohorts on day 1 and at week 12).

There was no clinically meaningful difference in any ECG parameters or interpretations between cohorts. Mean QTcF values changed by a small and similar way in the cohorts between the

beginning (placebo: 394.4 ms pre-dose day 1; TC-5619: 392.9 ms pre-dose day 1) and end of the study (placebo: +1.6 ms post-dose week 12; TC-5619: +0.8 ms post-dose week 12). No QTcF values

were>480 ms in either cohort. PHARMACOKINETICS TC-5619 EXPOSURE LEVELS AND PHARMACOKINETIC PARAMETERS TC-5619 exposure, measured by steady-state concentrations (pre-dose (1.5–41.9 ng/ml)

and at _T_max (15.3–142 ng/ml)) and AUC24 h (129–1504 ng × hr/ml, estimated by extrapolation from 8-h collection time point), increased in a dose-dependent manner over the dose range. _T_max

(1.0–1.8 ng/ml) remained independent of dose. An analysis of the PK parameters of tobacco users and non-users was similar and could not account for differences in the effect of TC-5619

observed in the two sub-populations in the study. ANTIPSYCHOTIC EXPOSURE LEVELS Plasma levels of the concomitant antipsychotic were monitored in some subjects (_n_=62) to ensure that a

significant pharmacokinetic drug interaction could not contribute to observed efficacy. Levels of quetiapine and the ‘active moiety’ of risperidone (risperidone+9-hydroxy-risperidone levels;

(Risperdal prescribing information)) are presented (Table 4). Subjects were allowed to take any approved dose of antipsychotic, which contributed to the variability in levels. In addition,

several subjects in each antipsychotic subgroup did not have quantifiable antipsychotic levels, indicating either low doses or noncompliance with antipsychotic therapy. Subjects receiving

TC-5619 appeared to have lower (range of mean values: 208 to 284 nM) quetiapine levels than subjects receiving placebo (range of mean values: 512–743 nM). The number of subjects in the

analyzed quetiapine subgroup is small and differences in quetiapine doses or compliance across the two subgroups may have contributed to the observed differences in quetiapine levels between

the cohorts. Levels of active moiety of risperidone were similar among subjects receiving placebo and TC-5619. These findings indicate that a drug interaction did not contribute to the

effects observed in this study, because a lower quetiapine level in the TC-5619 group would be anticipated to produce smaller rather than greater beneficial effects in this cohort.

DISCUSSION There has been great interest and much effort to develop novel medications for the treatment of the cognitive and negative symptoms for which antipsychotic drugs are ineffective

(Gray et al, 2007; Miyamoto et al, 2005). In this context, nicotinic cholinergic receptors have emerged as priority targets and particularly the alpha7 and alpha4 beta2 NNRs (Freedman et al,

2008; Kucinski et al, 2011; Olincy et al, 2007; Ripoll et al, 2004). Although studies of the latter have yielded mixed results (Buchanan et al, 2008), studies of the former, using DMX-B and

EVP6124, have shown therapeutic potential in subjects with schizophrenia (EnVivo_Pharmaceuticals, 2009, 2011; Freedman et al, 2008; Olincy et al, 2006). The results of this exploratory

trial with TC-5619 are generally consistent with those of prior studies of alpha7 NNR partial agonists, and indicated statistically significant effects on the primary efficacy outcome (GMLT,

executive function) and on some secondary efficacy outcomes including SANS (negative symptoms). The results on the CSB task assessing working memory were statistically significant in favor

of TC-5619 in tobacco users. Although TC-5619 produced a statistically significant benefit in the ITT population on executive function as measured by the GMLT, it did not produce a

statistically significant benefit in the ITT population on the other six cognitive domains as measured in the CSB. Interestingly, despite the absence of a statistically significant benefit

of TC-5619 on the other six cognitive domains in the ITT population, there were statistically significant effects of TC-5619 on some of these other domains (eg, working memory, as measured

by the identification task) in the tobacco user cohort. The reason(s) for stronger effects of TC-5619 on executive function than on other cognitive domains is (are) unknown. TC-5619 was

generally well tolerated. Except for nausea, there were similar numbers of AEs, SAEs, and AEs leading to discontinuation. There were no clinically meaningful differences between cohorts in

suicidality, depression, physical examination, AIMS, vital signs, lab measurements of serum or urine analytes, or ECG. No differences in the drug levels between tobacco users and non-users

were observed to account for differences in efficacy between the two sub-populations. Antipsychotic levels across the TC-5619 and placebo groups were similar for risperidone, and we do not

believe that the difference in quetiapine would account for the effects observed. It is intriguing that the positive effects of TC-5619 were stronger in tobacco users. This finding may

pertain to observations that tobacco use is considerably higher in patients with schizophrenia than in the general population (de Leon et al, 1995; Goff et al, 1992; Hughes et al, 1986),

suggesting that these patients derive an NNR-mediated therapeutic benefit from nicotine. It is possible that the relatively small number of subjects in the study population caused this

finding in tobacco users to arise by chance. However, if this observation is confirmed by subsequent studies, at least three hypotheses may be invoked to explain this finding. First, alpha7

NNRs may be upregulated by tobacco use. In patients with schizophrenia who smoke, mRNA encoding the alpha7 NNR subtype was shown to be upregulated by 250% in comparison with patients who did

not smoke, and there were a greater number of functional alpha7 NNRs in smokers (Mexal et al, 2010). This finding suggests that there could be more alpha7 receptors in tobacco-users on

which TC-5619 could act. Second, nicotine increases blood–brain barrier permeability to small molecules in preclinical models (Hawkins et al, 2004; Manda et al, 2010), and hence a greater

brain concentration of TC-5619 may be present in tobacco users. Third, nicotine can act at NNR subtypes other than alpha7 (eg, alpha4 beta2) to enhance the effect of TC-5619 (Targacept, data

on file). These observed differences between tobacco users and non-users further underscore the complex and incompletely understood pharmacodynamic mechanisms by which alpha7 NNR agonists

work (Buchanan and Schwarcz, 2011). Recent studies have demonstrated how differences in dosing and schedule of administration, in addition to variation in the intrinsic activities of alpha7

NNR agonists, can influence cognitive and neurophysiological responses (Castner et al, 2011; Tregellas et al, 2011). If future studies confirm that TC-5619 or other alpha7 NNR agonists work

primarily in tobacco-using patients, it will be important to determine the pharmacodynamic basis of this effect. There is weak evidence suggesting that the positive effects of TC-5619 on

CogState items might be stronger in the United States than India, although the difference was not statistically significant. The modest difference between the effects in the US subjects

compared with Indian subjects could arise from the greater tobacco use in the US subjects (60%) than in the Indian subjects (38%). If the apparent difference in the magnitude of effect

between the US and Indian subjects is confirmed in future studies that equalize the percentage of tobacco users in the two geographic populations, it may instead reflect a cultural effect

and stem from relatively less familiarity of Indian subjects to computer-based tests. A number of caveats should be considered in the interpretation of this study. First, the number of

tobacco users in the study was relatively small (46% of the enrolled population), so the findings need to be replicated in larger studies. Second, approximately two-thirds of enrolled

subjects in this study were from sites in India, and therefore the findings need to be tested in other regions to assess translation into other populations, cultures, and ways of medical

practice. Nevertheless, these encouraging findings support the role of alpha7 NNR partial agonists like TC-5619 to treat the residual psychopathology of schizophrenia. An effective treatment

for these symptoms could be of great value for patients, their families and caregivers, and for the society and economy that could benefit from enhanced productivity of these individuals.

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Download references ACKNOWLEDGEMENTS We thank Gaston Farr for clinical operations, Grace Li for statistical programming, LaTonya Bufford for data management, Dorothea Gibbs for trial

document management, Pete Zorn for thorough and expert review of the manuscript, and Katherine Pickett for administrative assistance. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department

of Psychiatry, Columbia College of Physicians and Surgeons, New York, NY, USA Jeffrey A Lieberman, Ragy R Girgis & Naihua Duan * Clinical Development and Regulatory Affairs, Targacept,

Winston-Salem, NC, USA Geoffrey Dunbar, Anthony C Segreti, Frances Seoane, Jessica S Beaver & David A Hosford Authors * Jeffrey A Lieberman View author publications You can also search

for this author inPubMed Google Scholar * Geoffrey Dunbar View author publications You can also search for this author inPubMed Google Scholar * Anthony C Segreti View author publications

You can also search for this author inPubMed Google Scholar * Ragy R Girgis View author publications You can also search for this author inPubMed Google Scholar * Frances Seoane View author

publications You can also search for this author inPubMed Google Scholar * Jessica S Beaver View author publications You can also search for this author inPubMed Google Scholar * Naihua Duan

View author publications You can also search for this author inPubMed Google Scholar * David A Hosford View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to Jeffrey A Lieberman. ETHICS DECLARATIONS COMPETING INTERESTS Drs Girgis and Duan also have no personal financial disclosures that are relevant to this

work. Dr Lieberman serves on the Advisory Board of Bioline, Intracellular Therapies, and PsychoGenics. He does not receive direct financial compensation or salary support for participation

in research, consulting, or advisory board activities. He receives grant support from Allon, F Hoffman-La Roche, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, Psychogenics, Sepracor

(Sunovion) and Targacept; and he holds a patent from Repligen. Dr Segreti and Dr Hosford are employees of Targacept, own Targacept stock, and have Targacept stock options. The remaining

authors are employed by the sponsor of this study, Targacept, and own shares of the common stock and/or options to purchase shares of the common stock of Targacept. These data were

previously presented at the International Congress of Schizophrenia Research (Colorado Springs, CO; April 2011); at the NCDEU Annual Meeting (Boca Raton, FLA; June 2011); and at the American

College of Neuropsychopharmacology Annual Meeting (ACNP; Hawaii; December 2011). ADDITIONAL INFORMATION These data were previously presented at the International Congress of Schizophrenia

Research (Colorado Springs, CO; April 2011); at the NCDEU Annual Meeting (Boca Raton, FL; June 2011); and at the American College of Neuropsychopharmacology Annual Meeting (ACNP; Hawaii;

December 2011). POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lieberman, J., Dunbar, G., Segreti, A. _et

al._ A Randomized Exploratory Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) for Cognitive Enhancement in Schizophrenia. _Neuropsychopharmacol_ 38, 968–975 (2013).

https://doi.org/10.1038/npp.2012.259 Download citation * Received: 14 September 2012 * Revised: 30 November 2012 * Accepted: 03 December 2012 * Published: 18 December 2012 * Issue Date: May

2013 * DOI: https://doi.org/10.1038/npp.2012.259 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * schizophrenia * alpha7 nicotinic receptor * TC-5619

* cognitive function * negative symptoms * clinical trial