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Cognitive deficits and poor functional outcomes in schizophrenia: clinical and neurobiological progress.

Globally, schizophrenia is the third leading cause of disability among adolescents and adults 15 to 44 years of age. Despite the availability of numerous antipsychotic medications for the past half century, functional outcomes for individuals with the disorder remain dismal.' Sustained clinical, vocational, and social improvement for those afflicted by the disorder remains the exception. As few as 1 in 7 patients (just under 14%) demonstrate concurrent symptomatic and social/voca-tional improvements that endure for at least 2 years,3 even in first-episode samples:: Annualized recovery rates suggest that only 1 or 2 out of every 100 patients qualify as "recovered" each yeaC It is discouraging to psychiatrists and other mental health professionals that the clinical and functional outcomes of schizophrenia have not improved over the last several decades despite the proliferation of various biopsychosocial interventions.3.5 The human burden of schizophrenia remains staggering, as most patients are unmarried, unemployed, and socially isolated.2 Homelessness, incarceration, stigma, hopelessness, and poor access to primary care are disproportionately common in patients with schizophrenia compared with the general population.

It is reasonable to conclude that controlling psychotic symptoms, which current antipsychotics do relatively well, is necessary but not sufficient to enable rehabilitation and recovery, and that other symptoms not addressed by antipsychotics, such as cognitive impairment, play a role in poor outcomes.2 Cognitive impairment in schizophrenia has received increasing attention in the past few decades as the field has come to recognize its importance.6 The ability to plan, attend to stimuli, filter out irrelevant stimuli, remember new information, and many other higher-order cognitive processes are critical to successfully navigating the world.'

Both Kraepelin and Bleuler included cognitive dysfunction in their seminal descriptions of the disorder that came to be known as schizophrenia.(6), (8), (9) However, in the years after their work, cognitive impairment among patients with schizophrenia was de-emphasized in research and diagnostic paradigms--particularly in favor of more dramatic positive symptoms.(6), (9) The past 3 decades have seen a resurgence in the field's awareness of the importance of cognitive dysfunction in schizophrenia, and it is now clearly recognized that severe and pervasive cognitive impairment is in fact a core component of this disabling syndrome.(6), (9)

Cognitive Impairment as a Core Feature of Schizophrenia

Neurocognition refers to our ability to think, learn, plan, and attend to important stimuli, and includes a range of specific and somewhat discrete abilities, such as speed of processing; vigilance and attention; verbal memory; working memory; reasoning and problem solving; and social cognition, or the mental operations underlying social interactions (such as the ability to correctly perceive and interpret the reactions of others).(10) Some patients with schizophrenia may be aware of and report cognitive difficulties, (11), (12) but at least half of patients with demonstrable cognitive deficits have no insight into the existence of these deficits.(13) Furthermore, there is limited association between patient-reported cognitive deficits and the actual presence and magnitude of cognitive impairment.(14) In research settings, formal neurocognitive testing is generally used to evaluate and quantify cognitive deficits in patients with schizophrenia.

Extensive literature on neurocognitive testing in patients with schizophrenia demonstrates that these patients suffer frdm a severe and generalized deficit in cognitive abilities in relation to healthy controls or normative data.(15), (16) As a group, patients are impaired on nearly all tasks assessing different domains of cognitive ability, and this impairment is quite severe, often 1 to 2 standard deviations below the average cognitive performance in the general population.(15) A standard approach in neuropsychology is to define cognitive impairment as a prespecified performance deficit as compared to normative data--typically 1 standard deviation below the mean on 1 or more areas of cognition. Using this type of definition, 70% to 80% of all patients with schizophrenia are classified as impaired.'7

However, resedrch has shown that the true impact of cognitive impairment is even greater than this, affecting up to 98% of all patients with schizophrenia (18) Studies demonstrate that patients who appear to be within the normal range of cognitive performance actually underperform in comparison to what would be expected based upon the performance of well-matched controls (19) or monozygotic twins discordant for the disorder (20) or performance predicted from maternal levels of educa-tion.(18) Thus, cognitive impairment is nearly universal in schizophrenia, even in those with seemingly normal cognitive abilities.

Mild to moderate cognitive impairment can be demonstrated before the onset of psychotic symptoms for individuals who have yet to convert to schizophrenia.(21), (22) In adolescence, premorbid IQ levels among individuals who go on to develop schizophrenia are roughly 8 points below those of healthy comparison subjects (based upon an effect size generated in a meta-analysis and adjusted for a control mean IQ of 100), (21) while subtly poor academic performance compared to peer performance is evident as early as first grade in follow-back studies of school records of those with schizophrenia; this relatively poor academic performance becomes more pronounced during middle school and high schoo1. (23) The initial development of psychosis is associated with further cognitive deterioration, as exemplified by additional IQ decline of about 6 points from premorbid levels. (22) Although less is known about the longitudinal course of cognition during the illness, following this initial decline at illness onset, cognitive impairment appears relatively stable. Cross-sectionally, neurocognitive test score deficits among first-episode populations are already comparable to those of chronic patients, (24), (25) supporting longitudinal analyses that suggest cognitive impairment is stable through the course of illness during nonelderly adulthood. (26)

While there may be some additional cognitive impact of excessive dopamine blockade, studies have demonstrated a similar magnitude of cognitive impairment in both treatment-naive patients and those treated with antipsychotic medication.(27) Cognitive impairment also is not a phenomenon due to, or secondary to, positive or disorganized symptoms--cross-sectional correlations between positive symptoms and cognition are negligible, (28-

30) and positive symptom improvement is not correlated with cognitive change in clinical trials. (31) (Modest relationships do exist between negative symptoms and cognition.(28-31) Thus, impaired cognition appears to be an independent and core feature of the illness that will need directed therapeutic intervention.

Cognitive Impairment Leads to Poor Functional Outcomes

The robust relationship between cognitive impairment and functional outcomes was described clearly in influential reviews and analyses by Green and his colleagues in 1996 and 2000. (32), (33) These analyses demonstrated consistent relationships between measures of cognitive ability such as verbal memory, attention, and executive functioning and outcomes such as community functioning, skill acquisition, and problem-solving skills (32), (33); these relationships tended to manifest with medium effect sizes. (33) Composite neurocognitive variables, indexing performance across multiple domains of intellectual performance, were even stronger predictors of functional outcome. (33Interestingly, and somewhat counterintuitively, neurocognitive abilities were consistently strong predictors of functional outcomes, whereas hallucinations and delusions were not. (32)

Since this work, the robust relationship between cognition and functional outcome has been demonstrated many times over. These results encompass the premorbid phase, in which neurocognitive performance of "clinical high-risk" subjects predicted social and academic/vocational functioning, but the magnitude of these individuals' attenuated positive symptoms did not (34); recent-onset schizophrenia, in which full recovery and adequate social and vocational functioning after 5 years' follow-up were predicted by baseline cognitive abilities after initial stabilization of a first episode of psychosis (4); and in more chronic illness, in which unemployed patients exhibited poorer cognitive functioning than did employed patients. (35) Longitudinal studies also demonstrate that better cognitive functioning at baseline predicts community functioning months to years later. (36) It is clear that cognitive impairment is a rate-limiting factor in successful rehabilitation and return to baseline functioning.

Our understanding of how cognitive abilities translate into functional outcomes has grown increasingly sophisticated in the last decade. For one thing, more than a dozen studies have provided evidence that social cognition mediates the relationship between basic cognition and functional outcomes, suggesting neurocognitive impairments may exert their negative influence on functional status via adverse effects on social cognition instead of directly affecting functional outcomes themselves.(10) Furthermore, a relatively strong prediction of functional outcome for patients can be generated by models that start with early perceptual problems leading to struggles with neurocognitive-mediated social cognition, motivational negative symptoms, and finally, outcomes, (37) suggesting both ability and motivation are necessary for appropriate role functioning and the 2 influence each other on a single direct path that begins with basic perception and cognition. One implication of a model such as this is that it suggests an intervention directed at early elements of the pathway could have beneficial effects on subsequent processing stages and functional outcome. It also suggests that a single intervention targeted at perception or cognition might lead directly to improved outcomes. (37)

Treatment Options for Cognitive Impairment

How can clinicians effectively address our patients' cognition and functioning? First and foremost, it is important to remain aware of and assess both domains. (38) This may require clinical probing beyond typical symptomatic assessments. Asking patients about how they spend their free time or if they pursue favorite activities may help illuminate the depth of impoverishment in their lives, while queries about how they manage their shopping, their transportation, or even if they can use their smartphone (if they have one) can help illuminate cognition-limited functioning and point towards potential solutions.

No pharmacologic agent is currently approved for the treatment of cognitive impairment in schizophrenia. The cognitive benefits of second-generation antipsychotics, once hoped to represent a significant advance in improving the cognitive abilities of patients with schizophrenia, have been shown to be negligible. At best, it appears that second-generation and first-generation antipsychotics both have comparable and very modest benefits on neurocognition. (39), (40) The benefit evident in research studies may be attributable in part to practice or placebo effects.(41) Undoubtedly, patients receiving antipsychotics remain cognitively impaired. Although some individuals may cognitively benefft from a change in antipsychotic medication, there is no drug to which a switch is universally likely to improve cognition. (42)

The absence of a current pharmacologic option to improve cognition in schizophrenia should not be taken as evidence that cognitive deficits cannot be successfully treated. Cognitive remediation therapy (CRT), or cognitive training, is a set of tools and strategies that support adaptive behaviors by harnessing and promoting intact physiologic mechanisms of neuroplasticity. (43) Using techniques ranging from computer-based exercises to therapist-led problem-solving sessions, (43) CRT has been shown to be of benefit to patients with schizophrenia in improving cognition and social cognition (44); further, these benefits generalize to functioning, especially when paired with other psychosocial interventions such as vocational rehabilitation or social skills training. (45) The changes in cognitive functioning induced by CRT suggest that cognitive deficits are responsive to therapy, and that cognitive enhancement with a pharmacologic agent may also be feasible if the correct neurobiological mechanisms are targeted.

Beyond CRT, additional considerations to help support and maximize the cognitive functioning of patients with schizophrenia are limited. The risk-benefit ratio of prescribing an anticholinergic should be carefully considered, as these drugs have been shown to impair many cognitive abilities. (46), (47) Conversely, discontinuation of anticholinergic drugs has been associated with statistically significantly improved cognitive abilities. (46) Additionally, interventions designed to address common comorbidities, such as obesity, hypertension, and the metabolic syndrome, may all prove to have beneficial effects on cognition, (48) as greater cognitive impairment in patients is associated with the presence of these physical prob-lems. (49-51) Environmental manipulations such as signs, pill organizers, calendars, and checklists--either tailored to a patient's abilities and environment or generically available to patients--have been shown to bypass problems with organization, memory, and attention and improve overall functioning and specific target behaviors, such as hygiene and adherence. (39), (40)

Ongoing Research and Development

Research into and the development of novel pharmacologic agents that may reduce the cognitive burden of schizophrenia is ongoing and offers hope for clinicians and their patients. (52) The ongoing development of these agents was propelled by the MATRICS initiative, or the Measurement and Treatment Research to Improve Cognition in Schizophrenia program. (52), (53) This National Institute of Mental Health (NIMH)--sponsored collaboration among academia, industry, and government regulators established the current framework for conducting clinical trials that may support the ultimate regulatory approval of a drug.

A key deliverable of the MATRICS initiative was the MATRICS Consensus Cognitive Battery (MCCB), a brief, reliable, and clinically meaningful battery of cognitive tests that the US Food and Drug Administration (FDA) has accepted as a primary end point for clinical trials in cognition (Table), (52), (54), (55) In addition, during the MATRICS initiative, the FDA indicated that in order for a drug to be approved for cognitive improvement in schizophrenia, it would need to lead to positive changes not only in cognitive performance, but also demonstrate improvement on a functionally meaningful co-primary measure that would be more intuitive for consumers and clinicians than cognitive performance. (52)--such as standardized tests of functional capacity or interview-based assessments of cognition. (56)

Table. MATRICS Consensus Cognitive Battery (MCCB)(7), (55)

Domain                         Tests                Real-World
                                                    Example (7)

Speed ot processing  * Category Fluency    * Using a touch-screen
                     *BACS Symbol Coding   computer to record customer
                     * Trail Making, part  orders at a fast food
                     A                     restaurant

Attention/vigilance  * Continuous          * Being able to read a
                     Performance Test      book or pay attention to
                     (Identical Pairs      a movie
                     version)

Working memory       * Letter-Number A     * Remembering number just
                     phone Span            given to you
                     * WMS Spatial Span
                     Subtest

Verbal learning      * Hopkins Verbal      * Remembering  the items
                     Learning              someone told you to
                     Test-Revised,         purchase at the supermarket
                     immediate recall

Visual learning      * Brief Visuospatial  * Remembering where you put
                     Memory Test-Revised   something in a closet

Reasoning and        * NAB mazes           * Arriving on  time for work
problem solving                            even though your bus
                                           schedule has changed

Social cognition     * MSCEIT. managing    * Knowing by looking at
                      emotions             someone whether they are
                                           angry at you or not;
                                           being able to take someone
                                           else's perspective in a
                                           conversation

BAGS, Brief Assessment of Cognition ii Schizophrenia; MSCEIT,
Mayer-Salovey-Caruso Emotional Intelligence Test; NAI3,
Neuropsychological Assessment Battery; WMS, Wechsler Memory Scale.


A number of such options have been evaluated and found both reliable and valid. (56), (57) In addition, the MATRICS initiative led to guidelines about patient populations, length of treatment, and other elements of trial design for potentially cognitive-enhancing drugs. (53), (58)

Finally, MATRICS evaluated the most promising molecular mechanisms to target to improve cognition in schizophrenia. During this process, they identified several mechanisms of interest, including cholinergic, dopaminergic, and glutamatergic approaches (Box). Of the cholinergic approaches, a7 was identified as a top target of investigation. (52) The role of the a7 receptor can be informed by our evolving understanding of the neurobiology of cognitive impairment in schizophrenia.

Box. MATRICS-ldentifed Potential Mechanistic Targets for Treatment of Cognitive lmpaiment in Schizophrenia (52)

CHOLINERGIC

* [alpha]7 Receptor

*Muscarinic M1 mAChR

DOPAMINERGIC

*Dopamine D, receptor

GLUTAMATERGIC

*AMPA glutamatergic receptor

*NMDA glutamatergic receptor

*Metabotropic glutamate receptor

*Glycine uptake

OTHER

* [alpha]2 Adrenergic receptor

* GAB[A.sub.A] R subtype

AMPA. u-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA. gamma-aminobutyric acid: mAChR, muscarinic acetylcholine receptor: NMDA. A/-methyl-o-aspartate.

A Closer Look at the Neurobiology of Cognitive Impairment in Schizophrenia

Much like the neuropathology of schizophrenia as a whole, cognitive impairment in schizophrenia has been associated with numerous brain regions and neural pathways, including the basal ganglia, the prefrontal and frontal cortex, the auditory and parietal cortices, the magnocellular visual system, the limbic system, and the hippocampus (Figure 1). (59-690)

Postmortem neuroimaging studies have revealed decreased gray matter, white matter, and whole brain volume--as well as increased ventricular volume--in patients with both recent-onset and chronic schizophrenia. (70) Further, these analyses have uncovered evidence that suggests disrupted or altered synaptic connectivity, such as reduced neuropil and soma size (but not overall number of neurons) in the whole or prefrontal cortex; decreased dendritic spine density and length in some layers; glial atrophy; and layer-specific reductions in the density of pyramidal and nonpyramidal neurons in the prefrontal and anterior cingulate cortices. (70), (71) Subtle abnormalities in cellular positioning and orientation also have been observed, suggesting another potential contributor to altered synaptic connectivity in schizophrenia.(71)

Neurotransmitters in Brain Abnormalities in Schizophrenia

Synaptic and neuroanatomical brain abnormalities in schizophrenia have been linked with changes in neurotransmitter levels--including dysfunction in the dopaminergic, glutamatergic, and cholinergic pathways.(72)

THE DOPAMINE HYPOTHESIS

The traditional neurotransmitter model for schizophrenia is the "dopamine hypothesis."It holds that presynaptic striatal dopamine function is elevated in patients with schizophrenia and correlates with psychosis.(73)

Indeed, meta-analyses of data from numerous studies suggest that there is a modest increase (10% to 20%) in--striatal [D.sub.2] and [D.sub.3] receptors in schizophrenia independent of the effects of antipsychotic drugs.(73)

In the prefrontal cortex, however, dopaminergic transmission is primarily mediated by D, receptors, which are linked to cognitive impairment and negative symptoms in schizophrenia.(73) Thus, it has been suggested that [D.sub.1] receptor dysfunction may mediate some cognitive impairments and negative symptoms.(73)

This may be one reason why currently approved antipsychotics, all of which block [D.sub.2] receptors, reduce positive symptoms of the disease but have no effect on the cognitive impairment and negative symptoms of schizophrenia. (73), (74)However, it is increasingly clear that the broad manifestations of disease pathology seen in schizophrenia cannot be explained by changes in the dopamine neurotransmitter system alone.(75)

THE GLUTAMATE HYPOTHESIS

A growing body of evidence suggests that abnormalities in glutamate transmission contribute to the pathogenesis of schizophrenia, particularly cognitive and sensory processing deficits.(76) This theory is predicated on the fact that gluta-matergic N-methyl-o-aspartate (NMDA) antagonists, such as phencyclidine and ketamine, can induce psychosis and dull cognitive function associated with the prefrontal cortex in a manner similar to the disturbances seen with schizophrenia.(77), (78)

Indeed, the NMDA system is extensive and plays a key role in neuroplasticity, with NMDA receptors possibly mediating gamma-aminobutyric acid--ergic (GABAergic) control of cortical pyramidal cell activity related to cognitive function.(77), (79-82) Inadequate GABA inhibition may contribute to alterations in intemeuron-dependent network synchrony in schizophrenia, which may then lead to impaired neuroplasticity. (81), (82)

Impaired glutamatergic transmission is only one portion of a larger issue, however. Accumulating research shows that, for many individuals, the glutamatergic-mediated cognitive deficits may be, in turn, mediated by dysfunction in the acetylcholine (ACh) system.(83)

THE ACETYLCHOLINE HYPOTHESIS

Within the central nervous system, acetylcholinergic neurotransmission is integrally involved in aspects of memory formation, affect, and motivational and multiple volitional behaviors, all of which are affected in schizophrenia."" Coordination of these cognitive and behavioral functions requires proper signaling through muscarinic receptors (mAChRs) and nicotinic receptors (nAChRs). Therefore, altered ACh neurotransmission may contribute to the cognitive and behavioral symptoms of schizophrenia because the ACh system is also widespread throughout the cortex and acts at multiple mAChRs and nAChRs.(72)

Figure 2 shows a schematic diagram of cholinergic circuits (in red) and their projections within key brain areas implicated in schizophrenia. Specifically, it depicts the potential for direct and indirect interactions of the cholinergic system with dopaminergic. glutamatergic, and GABAergic projections in these brain regions.(83)

How do ACh receptors play into all of this? To better understand this, it may help to take a closer look at one of the 2 nAChR receptors--the a7 receptor.(72)

[alpha]7 Receptors as a Promising Target for Cognitive Impairment in Schizophrenia

The [alpha]7 receptor is an ACh-gated ion channel receptor with a homopentameric composition that is abundantly expressed in the hippocampus and cortex--key brain areas involved in cognition.(84) In addition to its shape, it has several characteristics that distinguish it from its coun-terpart--the [alpha]4[beta]2 receptor--including more rapid desensitization and higher calcium permeability.(72), (84)

While both the [alpha]7 and [alpha]4[beta]2 receptor types have been implicated in cognitive functioning, the [alpha]7 receptor is not likely to be involved in smoking addiction.(85) The [alpha]7 receptor shows a markedly lower affinity for nicotine than does the [alpha]4[beta]2 receptor (>100-fold lower), and unbound brain concentrations of nicotine achieved by smoking seem to be too low to either inhibit or desensitize the [alpha]7 receptor.(86), (87) On the other hand, the high affinity of the [alpha]4[beta]2 receptor for nicotine can lead to saturation and desensitization of the receptor at unbound brain concentrations of nicotine achieved in smokers, leading to receptor upregulation, tolerance and addiction.(86), (88)

Research has shown that stimulating [alpha]7 receptors may enhance cognition, an effect thought to be mediated by effects on glutamate release and on NMDA cognitive circuits in the prefrontal cortex.(89), (90) Further, the stimulation of [alpha]7 receptors enhances glutamatergic and GABAergic transmission in both the hippocampus and the midbrain, the latter of which ultimately modulates the firing frequency of dopaminergic neurons.(84), (91), (92) However, postmortem studies have demonstrated decreases in [alpha]7 receptor density in the striatum, frontal cortex, and hippocampus of patients with schizophrenia.(93) Therefore, given this evidence, it may be reasonable to postulate that the [alpha]7 receptor may be a promising target for improving cognition in schizophrenia.(84), (89), (90)

Conclusion

In the last several decades, it has become evident that that cognitive defidts are a fundamental aspect of the schizophrenia syndrome and, perhaps more compellingly, that they limit the functional outcomes of patients with the disease.

Insights from clinical and neurobiologic research have led to a growing interest in treating cognitive impairment as a means to reduce disability in patients with schizophrenia. Research into the neurobiology of cognitive impairment has converged with our evolving models of how poor perceptual and cognitive processes result in enduring disability in patients, suggesting a cascade of poor higher-level processing built on basic perceptual deficiencies and culminating in deficits in abilities, motivation, and, ultimately, poor outcomes.

Ongoing investigations of multiple molecular mechanisms will hopefully culminate in pharmacologic interventions that may improve intrinsic cognitive abilities and set the stage for improved functional outcomes for patients.

From Brain Circuits to Impaired Functioning

The dysfunctional neurobiological processes highlighted in this article can be observed in differences in mismatch negativity (MMN) between patients with schizophrenia and healthy controls. (78), (94) Along with many other psychophysiologic measures, deficits in MMN help demonstrate that the neurobiological disruption in schizophrenia affects basic sensory regions as well as higher-order processing. Further, deficits in generation of MMN are associated with deficits in simple auditory functioning that lead to impairments in more complex processing, providing a model for how low-level perceptual problems can cascade into more downstream impairments.

Mismatch negativity, a measure of early auditory processing, is a component of the event-related potential that is sensitive to small changes in the acoustic environment, such as a tone change.(95), (96) The MMN is reduced in patients with schizophrenia compared to healthy controls, reflecting a sensory processing deficit that has been connected with impairment in cognitive and social function.(78), (97)

Deficits in MMN may underlie dysfunctional auditory communication by impairing speech perception, contributing to deficits in auditory short-term memory (which may make it difficult to follow conversation), and reducing the patient's ability to direct attention toward relevant stimuli.(95)

Mismatch negativity impairment in patients with schizophrenia is well established by at least 18 months into the disorder and, in patients with chronic schizophrenia, correlates with the severity of negative symptoms and functional outcomes, including such cognitive components as verbal memory deficits, executive functioning, and degree of social skills acquisition.(78), (94) Typical and atypical antipsychotics have no effect on MMN deficits.(78)

The MMN depends on intact NMDA receptor signaling, with multiple studies finding that NMDA receptor antagonists such as ketamine can induce MMN deficits in animals and healthy controls. (78), (96), (98) Thus, therapeutic approaches that target NMDA receptors may restore full MMN, possibly improving cognitive processing and negative symptoms, and ultimately, a patient's ability to function.

A panel of experts in the field of schizophrenia was convened in February 2014 to develop an educational curriculum for health care professionals about the importance of cognitive impairment in schizophrenia, particularly as it relates to patient outcome and functioning; this Steering Committee was convened by FORUM Pharmaceuticals. The contents of this supplement are derived. in large part, from the proceedings of that Steering Committee, and the authors are thus indebted to and extend their gratitude to its members, including Michael F. Green, Ph.D., John M. Kane, M.D., Anil K. Malhotra, M.D., Stephen R. Marder, M.D., Herbert Y. Meltzer, M.D., Alan F. Schatzberg, M.D., Nina R. Schooler, Ph.D., S. Charles Schulz, M.D., Dawn I. Velligan, Ph.D and Peter J. Weiden, M.D.

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DISCLOSURES

Dr Nasrallah receives or has received research support from Genentech, Inc., a Member of the Roche Group; Hoffmann-La Roche Inc.; Otsuka Pharmaceutical Co., Ltd.: and Shire PLC. He also serves or has served as a consultant for Boehringer Inge!helm GmbH; FORUM Pharmaceuticals; Genentech, Inc., a Member of the Roche Group; H. Lundbeck A/S; Hoffmann-La Roche Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novartis Corporation; Otsuka Pharmaceutical Co., Ltd.; and Sunovion Pharmaceuticals Inc. Dr Nasrallah serves or has served on the speaker bureaus for Janssen Pharmaceuticals, Inc.; Merck & Co.. Inc.; Novartis Corporation; Otsuka Pharmaceutical Co.. Ltd.; and Sunovion Pharmaceuticals Inc.

Dr Keefe serves or has served as a consultant or service provider for AbbVie Inc.; Akebia Therapeutics, Inc.; Amgen Inc.; AsteIlas Pharma US, Inc.; Asubio Pharmaceuticals, Inc.: Avineuro Pharmaceuticals, Inc.. a ChernRar company; BioLineRx; BioMarin Pharmaceutical Inc.; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Company; Eli Lilly and Company; FORUM Pharmaceuticals; Helicon Therapeutics, Inc.; H. Lundbeck NS; Hoffman-La Roche Inc.; Merck & Co., Inc.; Mitsubishi Tanabe Pharma Corporation; Otsuka Pharmaceutical Co., Ltd.; Pfizer Inc; Shire PLC; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceutical Company Limited; Targacept, Inc.; Worldwide Clinical Trials, Inc.; and Zinfandel Pharmaceuticals, Inc. He receives or has received research support from Alton Therapeutics Inc.; GlaxoSmithKline; the National Institute of Mental Health; Novartis Corporation; PsychoGenics; the Research Foundation for Mental Hygiene; and the Singapore National Medical Research Council. He is the founder of NeuroCog Trials, Inc., which provides rater training, data quality assurance, and consultation to several pharmaceutical companies and other consortia. He also receives or has received royalties from the following research projects: the Brief Assessment of Cognition in Schizophrenia (BACS), the MATRICS Consensus Cognitive Battery (MCCB), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT).

Dr Javitt serves or has served as a consultant for Bristol-Myers Squibb Company; Eli Lilly and Company; FORUM Pharmaceuticals; Omeros Corporation; Otsuka Pharmaceutical Co., Ltd.; SK Biopharmaceuticals Co., Ltd.; Sunovion Pharmaceuticals Inc.; and Takeda Pharmaceutical Company Limited. He receives or has received research support from Hoffmann-La Roche Inc. and Pfizer Inc. He owns or has owned shares in GlyTech, Inc.
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Author:Nasrallah, Henry A.; Keefe, Richard S.E.; Javitt, Daniel C.
Publication:Current Psychiatry
Article Type:Report
Geographic Code:4EXSI
Date:Jun 1, 2014
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