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Thinking and acting beyond the positive: the role of the cognitive and
negative symptoms in schizophrenia

Maren Carbon and Christoph U. Correll

CNS Spectrums / Volume 19 / Supplement S1 / December 2014, pp 35 - 53

DOI: 10.1017/S1092852914000601, Published online: 18 November 2014

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How to cite this article:

Maren Carbon and Christoph U. Correll (2014). Thinking and acting beyond the positive: the role of the cognitive and
negative symptoms in schizophrenia. CNS Spectrums, 19, pp 35-53 doi:10.1017/S1092852914000601

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CNS SPECTRUMS
CME Review Article
Thinking and Acting Beyond the Positive: The
Role of the Cognitive and Negative Symptoms
in Schizophrenia

This activity is sponsored by the Neuroscience Education Institute

 CME Information

Accreditation and Credit Designation Statements ∙ Incorporate psychosocial strategies into the overall
care of patients with schizophrenia
The Neuroscience Education Institute is accredited by the
∙ Enable patients to participate in their own recovery by
Accreditation Council for Continuing Medical Education to
establishing life goals
provide continuing medical education for physicians.
The Neuroscience Education Institute designates this
enduring material for a maximum of 1.0 AMA PRA Date of Release/Expiration
Category 1 CreditTM. Physicians should claim only the Released: December, 2014
credit commensurate with the extent of their participa- CME credit expires: November, 2017
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Sponsor
Target Audience
This activity is sponsored by the Neuroscience Education
This activity has been developed for prescribers specializing
Institute.
in psychiatry. There are no prerequisites. All other health
care providers interested in psychopharmacology are wel-
come for advanced study, especially primary care physicians, Acknowledgment of Financial Support
nurse practitioners, psychologists, and pharmacists. This activity is supported by an educational grant from
FORUM Pharmaceuticals, Inc.
Statement of Need
Schizophrenia is a debilitating disorder associated with Instructions
poor quality of life and huge adherence issues. There are
You are advised to review this activity from beginning to
identified competency areas that need to demonstrate as
end, evaluate the content presented, and then complete
a foundation for having a successful role in improving
the posttest and activity evaluation. The estimated time
outcomes for patients with schizophrenia: Unfortu-
for completion of this activity is 60 minutes.
nately, there are documented gaps between established
To receive your certificate of CME credit or participa-
best practices and actual practice with respect to these
tion, complete the posttest and activity evaluation,
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available only online at www.neiglobal.com/CME under
∙ Understand the impact of different symptom domains “CNS Spectrums”. If a score of 70% or more is achieved,
of schizophrenia on patient functioning you will be able to immediately print your certificate.
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ment of goals and strategies for recovery activity. If you have questions, please call 888-535-5600,
or email [email protected].
To help address these professional practice gaps and
improve outcomes for patients with schizophrenia, quality
improvement efforts need to provide education regarding Peer Review
(1) the presentation and assessment of different symptom
These materials have been peer reviewed to ensure the
domains of schizophrenia, particularly those that most
scientific accuracy and medical relevance of information
impact patient functioning and recovery, and (2) the
presented and its independence from commercial bias.
importance of partnering with patients to develop long-
NEI takes responsibility for the content, quality, and
term goals and strategies for recovery, including addressing
scientific integrity of this CME activity.
barriers and the incorporation of psychosocial strategies.

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∙ Recognize the impact of cognitive and negative individuals in a position to influence or control content
symptoms on functioning and outcomes for patients are required to disclose any financial relationships.
with schizophrenia Although potential conflicts of interest are identified
∙ Assess and monitor the cognitive and negative and resolved prior to the activity being presented, it
symptoms of patients over time remains for the participant to determine whether outside
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Steven S. Simring, MD, MPH, is a clinical associate
Authors
professor in the Department of Psychiatry at Columbia
Maren Carbon, MD, is a research scientist in psychiatry University College of Physicians and Surgeons, New York
research at The Zucker Hillside Hospital, North Shore– State Psychiatric Institute in New York, NY. Dr. Simring
LIJ Health System in Glen Oaks, NY. Dr. Carbon’s spouse has no financial relationships to disclose.
receives research support from Bristol-Myers Squibb,
Janssen/Johnson & Johnson, Novo Nordisk, and Otsuka; Program Development
and her spouse is a consultant/advisor to Actelion,
Sheri Mills is the director of program development at
Alexza, Bristol-Myers Squibb, Cephalon, Genentech,
the Neuroscience Education Institute in Carlsbad, CA.
Gerson Lehrman Group, Intra-Cellular Therapies, Janssen/
She has no financial relationships to disclose.
Johnson & Johnson, Lilly, Lundbeck, Medavante, Medscape,
Merck, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Steve Smith is the president and chief executive officer
Teva, and Vanda. at the Neuroscience Education Institute in Carlsbad, CA.
He has no financial relationships to disclose.
Christoph U. Correll, MD, is a professor of psychiatry
at The Zucher Hillside Hospital, North Shore-LIJ Health
System in Glen Oaks, NY; at the Hofstra North Shore-LIJ Disclosure of Off-Label Use
School of Medicine in Hempstead, NY; at the Feinstein
This educational activity may include discussion of
Institute for Medical Research at Manhasset, NY; and at
unlabeled and/or investigational uses of agents that are
the Albert Einstein College of Medicine in the Bronx, NY.
not currently labeled for such use by the FDA. Please
Dr. Correll receives research support from Bristol-Myers
consult the product prescribing information for full
Squibb, Janssen/Johnson & Johnson, Novo Nordisk, and
disclosure of labeled uses.
Otsuka; and is a consultant/advisor to Actelion, Alexza,
Bristol-Myers Squibb, Cephalon, Genentech, Gerson
Lehrman Group, Intra-Cellular Therapies, Janssen/ Disclaimer
Johnson & Johnson, Lilly, Lundbeck, Medavante, Medscape,
Participants have an implied responsibility to use the
Merck, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda,
newly acquired information from this activity to enhance
Teva, and Vanda.
patient outcomes and their own professional develop-
No writing assistance was utilized in the production of
ment. The information presented in this educational
this article.
activity is not meant to serve as a guideline for patient
management. Any procedures, medications, or other
Content Editor courses of diagnosis or treatment discussed or suggested
Meghan M. Grady, BA, is the director of content in this educational activity should not be used by
development at the Neuroscience Education Institute in clinicians without evaluation of their patients’ condi-
Carlsbad, CA. She has no financial relationships to tions and possible contraindications or dangers in use,
disclose. review of any applicable manufacturer’s product infor-
mation, and comparison with recommendations of other
authorities. Primary references and full prescribing
CNS Spectrums Peer Review
information should be consulted.
All CME articles are peer reviewed in accordance with
the strict standards of CNS Spectrums and in accordance
Cultural and Linguistic Competency
with requirements and recommendations of the Interna-
tional Committee of Medical Journal Editors. The A variety of resources addressing cultural and linguistic
Editorial policies of the journal CNS Spectrums and peer competency can be found at this link: www.neiglobal.
review of all articles that appear in the journal is com/go/cmeregs
CNS Spectrums (2014), 19, 38–53. © Cambridge University Press 2014
doi:10.1017/S1092852914000601

CME REVIEW ARTICLE

Thinking and acting beyond the positive: the role of the

cognitive and negative symptoms in schizophrenia
Maren Carbon1 and Christoph U. Correll1–4*

1
Psychiatry Research, The Zucker Hillside Hospital, North Shore—Long Island Jewish Health System, Glen Oaks, New York, USA
2
Psychiatry and Molecular Medinine, Hofstra North Shore LIJ School of Medicine, Hempstead, New York, USA
3
Psychiatric Neuroscience Center of Excellence, The Feinstein Institute for Medical Research, Manhasset, New York, USA
4
Psychiatry, Albert Einstein College of Medicine, Bronx, New York, USA

Since currently available antipsychotic medications predominantly treat hallucinations, delusions, disorganized thoughts and
behavior, and related agitation/aggression, attention has traditionally been focused on managing positive symptoms.
However, prominent negative symptoms and clinically relevant cognitive impairment affect approximately 40% and 80% of
people with schizophrenia, respectively. Moreover, negative and cognitive symptoms are closely related to functional
outcomes, and contribute substantially to the overall illness burden. Therefore, approaches to describe, measure, and manage
these symptom domains are relevant. This article summarizes the phenomenology, prevalence, assessment, and treatment of
negative and cognitive symptoms in patients with schizophrenia, including pharmacologic and nonpharmacologic
management strategies that can be used in clinical care now, as well as pharmacologic approaches that are being tested.
Currently, no approved treatments targeting negative or cognitive symptomatology in schizophrenia are available. It is hoped
that progress in the understanding of the neurobiology of these important symptom domains of schizophrenia will help
develop effective treatment strategies in the future. However, until this goal is achieved, clinicians should avoid therapeutic
nihilism. Rather, the severity and impact of negative and cognitive symptoms should be determined, quantified, and
monitored. Further, psychosocial treatments have shown therapeutic benefits. Thus, cognitive behavioral therapy, cognitive
remediation, social skills training, and computer-assisted training programs should be offered in conjunction with
antipsychotic treatment. Several non-antipsychotic augmentation strategies can be tried off-label. Treatment plans that
incorporate currently available management options for negative and cognitive symptomatology in patients with
schizophrenia should be adapted over time and based on the individual’s needs, with the aim to enhance overall outcomes.

Received 9 September 2014; Accepted 8 October 2014; First published online 18 November 2014
Key words: Assessment, cognition, negative symptoms, schizophrenia, treatment.

Introduction prevalence of negative symptoms and of cognitive symp-

toms in patients with schizophrenia. This is followed by a
Despite decades of research and the relevance of negative summary of available, as well as currently tested, manage-
and cognitive symptoms for functional outcomes in ment approaches, and description of their utility for each
patients with schizophrenia, treatments for schizophrenia of the 2 symptom domains. Although the hypotheses and
have largely been limited in their efficacy to treat emerging findings of the biological underpinnings of
hallucinations, delusions, disorganized thoughts and beha- negative symptoms and cognitive symptoms are relevant
vior, and related agitation/aggression. By contrast, due to and help inform the testing of novel pharmacologic
their functional relevance, assessing and managing nega- treatment approaches, these aspects are covered elsewhere
tive and cognitive symptoms is relevant when treating and beyond the scope of this article.
individuals with schizophrenia. This article summarizes
the phenomenology, clinical diagnosis, measurement, and
Negative Symptoms
* Address for correspondence: Christoph U. Correll, MD, The Zucker
Hillside Hospital, Psychiatry, 75-59 263rd Street, Glen Oaks, NY 11004, USA. Phenomenology
(Email: [email protected])
This activity is supported by an educational grant from Envivo Negative symptoms in schizophrenia include asociality,
Pharmaceuticals, LLC (a.k.a. FORUM Pharmaceuticals, Inc) avolition, consummatory and anticipatory anhedonia,
 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 39

affective flattening, and alogia.1 These symptoms can be do not resolve, but persist during an otherwise stable
consistently separated from positive symptoms, affective illness period, are termed persistent or enduring negative
symptoms (depression and anxiety), and disorganized symptoms.7 Two additional terms to characterize sub-
thought, speech, and behavior.2 Factor analyses have groups include the following:
shown that the classical 5 symptoms weigh on 2 factors:
1. Prominent negative symptoms: ratings of moderate
(1) reduced emotional expression (blunted affect, alogia)
symptom severity on ≥3 Positive and Negative
and (2) reduced motivation and pleasure (avolition,
Syndrome Scale (PANSS) negative subscale items or
anhedonia, asociality).2,3 In fact, avolition as the clinical
ratings of moderately severe on ≥2 negative subscale
correlate of reward system deficits has been proposed as
items8,9
the core negative symptom domain.4 Anhedonia, speci-
2. Predominant negative symptoms: a score ≥60 on the
fically “anticipatory anhedonia,”5 may lead to avolition,
Scale for the Assessment of Negative Symptoms
in that patients with schizophrenia are able to experience
(SANS) concomitant with a score ≤50 on the Scale
pleasure similar to controls,4 but fail to anticipate these
for the Assessment of Positive Symptoms (SAPS) [ie,
activities as controls would do, seemingly forgetting the
corresponding to less than moderately ill Clinical
positive valence that would drive goal-directed behavior
Global Impressions-Severity (CGI-S)].10
toward enjoyable activities.6
Buchanan7 proposed the differentiation of “persistent
Clinical diagnosis of negative symptoms
negative symptoms in schizophrenia” (ie, any primary
For clinical purposes, it is particularly important to negative symptoms of at least moderate severity on an
separate primary negative symptoms from secondary accepted rating scale, eg, PANSS/SANS, which are stable
negative symptoms, as the latter are amenable to treatment for a period of time) from “schizophrenia with deficit
changes (Figure 1). To make this differential diagnosis in a syndrome.” For the latter diagnosis, patients present
patient with schizophrenia, comorbid psychiatric condi- throughout their illness course predominantly with
tions, including depression, anxiety, dementia, and mental negative symptoms, ie, ≥2 at of the following 6 at a
retardation, as well as paranoia that might lead to social clinically significant severity persisting for ≥12 months:
withdrawal, need to be ruled out/addressed. Moreover, (1) restricted affect, (2) diminished emotional range,
antipsychotic-related side effects, like sedation and EPS; (3) poverty of speech, (4) curbing of interest, (5) diminished
medical conditions, like chronic pain or sleep apnea; and sense of purpose, or (6) diminished social drive. Notably,
environmental deprivation, understimulation, or antici- different from persistent negative symptoms, negative
pated stigma may present as secondary negative symptoms. symptoms that are part of schizophrenia with deficit
While secondary negative symptoms typically respond syndrome must have been present throughout the
to treatment of the underlying cause, there are currently majority of the individual’s illness, although they may
only limited treatment options for primary negative be difficult to detect during transient episodes of acute
symptoms. Primary or secondary negative symptoms that psychotic disorganization or decompensation.

Anxiety d/o,
Depression
Social Anxiety
Dementia Substance
Misuse

Mental
Retardation Primary Paranoia
Negative or Cognitive
Environmental Symptoms
Deprivation EPS

Stigma Sedation
Chronic Pain Sleep Apnea

FIGURE 1. Differential diagnosis of primary versus secondary negative or cognitive symptoms.

40 M. CARBON AND C. U. CORRELL

While an illness course characterized by persistent all 5 consensus-based negative symptom domains
negative symptoms is generally recognized, the concept (asociality, avolition, consummatory and anticipatory
of deficit syndrome schizophrenia as a separate neuro- anhedonia, affective flattening, and alogia). In contrast
biological entity remains debated.11 to the currently used scales, the CAINS is a semistruc-
tured, 7-point, 23-item interview using prompts and
follow-up questions for each item, as well as clear
Measurement of negative symptoms
anchors for ratings.3,18 The Brief Negative Symptom
In clinical research, valid and reliable quantification of Scale19 has also been developed along novel negative
symptomatology is achieved using standardized clinical symptom concepts, particularly emphasizing multiple
assessments, but these are only very rarely utilized in facets of anhedonia and avolition, but in contrast to
clinical practice, although scales support the objective, the CAINS, this scale is also intended for clinical
less observer-dependent monitoring of the disease settings. Thirteen items are organized into 6 subscales,
course and treatment efficacy.12,13 Since individuals and ratings may be based on an interview of about
with schizophrenia are typically not aware of negative 20 minutes.19
symptoms, and rarely report these as a chief complaint,14
it is very important to (1) observe the patient’s
Prevalence of negative symptoms
expression and attention during the interview,
(2) systematically ask questions regarding frequency/ Baseline data from the large Clinical Antipsychotic Trials
intensity of social contacts and of other enjoyable of Intervention Effectiveness (CATIE) study showed
activities, and (3) interview family members/informants. prominent negative symptoms in 40% of participants
Several interviews and scales have been developed and with chronic schizophrenia.9 One-half of this subgroup
used in research to measure negative symptoms showed prominent negative symptoms without promi-
(Table 1). Two reliable and valid negative symptom nent positive symptoms, and the other half showed
scales have been the standard for clinical trials15: the prominent negative symptoms plus prominent positive
SANS (25 items, covering the 5 domains of affective symptoms.9 In the European Cardiovascular, Lipid,
flattening, alogia, avolition/apathy, anhedonia/asocial- and Metabolic Outcomes Research in Schizophrenia
ity, and attention, each rated from 0/absent to 5/severe) (CLAMORS) study, 18% of treated subjects presented
and the PANSS negative symptoms subscale (7 items, with all 5 negative symptoms.20 The most frequent
covering blunted affect, emotional withdrawal, poor negative symptom seems to be social or emotional
rapport, passive social withdrawal, difficulty in abstract withdrawal,14,22,23 followed by diminished expression
thinking, lack of spontaneity and flow of conversation, and inattention-alogia. Importantly, negative symptoms
and stereotyped thinking, each rated from 1/absent to are not only present in chronic schizophrenia, but have
7/extreme). However, both scales incorporate a cogni- been clearly recognized in early psychosis24 and during
tive item (SANS: attention; PANSS: difficulty in abstract the prodromal period.25 Persistent negative symptoms
thinking), which should no longer be counted to the can be found in up to 25% during the first 2 years
negative symptom, but to the cognitive domain.16 after first-episode schizophrenia, demonstrating high
The Negative Symptom Assessment Scale, NSA-16,16 or within-subject consistency.26 The prevalence of negative
its shortened version, NSA-4,17 additionally captures symptoms was higher in men27 and in subjects who were
social interest and sense of purpose, but has not been unemployed, single, had reduced functioning, and were
widely used yet. The Clinical Assessment Interview for taking higher antipsychotic dosages.
Negative Symptoms (CAINS),3 the preliminary product
of an ongoing National Institute of Mental Health
Impact on outcome
(NIMH)-initiated scale development process, covers
Surprisingly, patients with prominent negative symp-
toms showed higher ratings of subjective quality of life
TABLE 1. Interviews and scales used for the assessment of negative and of subjective mental health than subjects with
symptoms in schizophrenia predominant positive symptoms, even though they had
Rating instrument Reference a significantly higher functional impairment for everyday
chores.9 This discrepancy that may be related to low
Positive and Negative Syndrome Scale (PANSS) Negative Subscore 184 levels of insight questions the sole use of external ratings,
PANSS Negative Symptom Marder Factor 185 and highlights the need for subjective ratings of well-
Scale for the Assessment of Negative Symptoms (SANS) 186 being in clinical studies.
The Brief Negative Symptom Scale 19
Moreover, a higher burden of negative symptoms is
Clinical Assessment Interview for Negative Symptoms (CAINS) 3
Negative Symptom Assessment Scale (NSA-16) 187 a consistent predictor of negative short-term,28
mid-term,26,29 and long-term treatment response and
 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 41

functional outcome.30,31 Importantly, the presence of with schizophrenia spectrum disorders, but the largest
persistent negative symptoms has also been related to deficits were noted in verbal memory, speed of proces-
prolonged duration of untreated psychosis,26 which in of sing, and working memory scores, with large effect sizes
itself is a very robust predictor of poor treatment amounting to standard mean differences of 1.03, 1.03,
response.32 and 0.97, respectively. Importantly, this pattern of
results in antipsychotic-naïve patients is consistent with
an earlier meta-analysis including 43 separate samples of
Cognitive Symptoms 2204 medicated FE schizophrenia patients.52 While the
cognitive profile of schizophrenia is clearly worse than in
Phenomenology
controls, there remains some uncertainty regarding the
Neurocognitive deficits have been well established in distinction relative to other psychoses. Earlier studies
schizophrenia as independent disease characteristics in supported the notion that cognitive deficits are most
addition to positive and negative symptoms.33–35 pronounced in schizophrenia compared to other
However, the exact nature and structure of cognitive psychiatric diagnoses.54,55 For example, when matched
deficits has long been a topic of debate. Consensus on the for clinical symptoms, subjects with schizophrenia
major domains affected by schizophrenia was reached 10 performed 0.5 SD below patients with bipolar disorder.55
years ago36 and yielded the Measurement and Treatment By contrast, a later meta-analysis compared cognitive
Research to Improve Cognition in Schizophrenia performance from 31 studies and 1979 subjects with
(MATRICS) battery, which covers 7 key domains: work- schizophrenia to 1314 subjects with affective psychosis
ing memory, attention/vigilance, verbal learning and or schizoaffective disorder, finding only minimal
memory, visual learning and memory, reasoning and differences in the domains verbal memory, executive
problem solving, speed of processing, and social cogni- functioning, mental speed, and general IQ.56 However,
tion. Although antipsychotic treatment may interfere the authors emphasized that design and population
with neurocognitive function,37 neurocognitive impair- characteristics may have influenced the results, as
ment has been clearly demonstrated as a core feature of schizophrenia patients had larger deficits in studies with
schizophrenia, and not merely a result of positive a higher proportion of males, subjects with early disease
symptom interference or treatment side effects.36 These onset, and subjects with pronounced negative symptoms.
deficits are present during all phases of the illness, While a comprehensive assessment clearly needs the
including clinical high-risk cohorts,37–40 first episode broad, but time-consuming, measurement of all
(FE) schizophrenia,33,41–43 and chronic schizophre- domains, these are by no means entirely independent of
nia.44–49 Deficits have remained mostly stable in each other. Indeed, a principal components analysis
longitudinal studies with follow-up from FE to chronic (PCA) of CATIE baseline cognitive data48 showed
illness phases, without clear further age-inappropriate considerable correlation among all domains, and PCA
cognitive decline,50,51 at least at group means. However, identified a single factor accounting for 45% of the test
some cognitive decline may occur in the early illness variance. This finding suggests that neurocognitive
period, ie, from the prodrome until 3–5 years of ill- batteries could be considerably shortened to yield one
ness.43,52 Cognitive deficits have also been demonstrated representative measure of cognition in a short testing
in first-degree relatives of patients with schizophrenia,53 period, which would have relevant clinical practice
suggesting that cognitive deficits represent a trait char- implications. Moreover, although recent concepts of
acteristic of the illness. In addition to the overall stability of schizophrenia advocate for a clear separation of cognitive
cognitive deficits in schizophrenia, this notion of a trait deficits and negative symptoms, cognitive impairment
characteristic is supported by the observation that measures also modestly correlated with negative
cognitive measures did not correlate with the longitudinal symptom severity (r = 0.13−0.27) in this48 and earlier
change in negative symptom severity.47 studies,33,45–47,56,57 whereas correlations with positive
Cognitive impairment profiles vary considerably. The symptom severity were almost absent.48
most recent meta-analysis on this topic42 focused on
antipsychotic-naïve patients with schizophrenia-
Clinical diagnosis of cognitive symptoms
spectrum disorders and included cognitive data from
23 studies, published from 1992–2013, including Despite the relevance of cognition to neurobiology,
1106 patients and 1385 controls. Test data were sorted outcome, and treatment in schizophrenia, the diagnosis
according to the MATRICS domains.36 The domain and quantification of cognitive deficits has been
reasoning/problem solving was not sufficiently repre- relatively neglected in clinical practice.58 This neglect
sented in the assessed studies and had to be replaced by does not necessarily reflect a lack of knowledge regard-
other executive functioning tests. Across all domains, ing the existence and relevance of cognitive deficits
controls performed significantly better than subjects in schizophrenia, but psychiatrists may refrain from
42 M. CARBON AND C. U. CORRELL

referring patients to a lengthy paper-and-pencil neuro- in a paper-and-pencil test that takes about 30 minutes to
psychological assessment, as it is often not feasible administer and covers the areas of immediate and
during acute illness periods. In more stable patients, the delayed (verbal) memory, visuospatial/constructive
relevance of a detailed cognitive assessment may be abilities, language, and attention.60 The battery was
questioned, as results would not necessarily lead to a originally not developed for use in schizophrenia, but
specific treatment or recommendation. However, as with still has shown some utility in this population. Subjects
negative symptoms, clinicians need to differentiate with schizophrenia underperformed controls by 0.78 SD
primary from secondary cognitive deficits (Figure 1). on this scale,61,62 and a clear separation from affective
Therefore, the clinical interview should at least be psychoses was demonstrated.54 Moreover, the RBANS
extended to include open questions regarding the cogni- has been widely used to detect effects of treatment on
tive domains (such as, “Have you been having trouble cognition in schizophrenia.54,63–65 Nevertheless, the
memorizing items on shopping lists or names of celeb- covered domains differ from the 7 MATRICS domains66;
rities?” or “Have you been feeling less sharp lately?”). in particular, the RBANS lacks a measure of reasoning
Moreover, as long as standardized, brief neuropsychologi- and problem solving, even though executive functioning
cal bedside screening instruments are not used (see below), deficits have long been recognized as a core cognitive
cognitive deficits should always be part of the diagnostic deficit in schizophrenia.67
interview and be documented by the respective mental The Brief Assessment of Cognition in Schizophrenia
status exam component (ie, orientation, serial 7, 5-minute (BACS) was much later developed and only shortly before
3 word recall, memory, abstract thinking/reasoning). the MATRICS initiative was started.68 The BACS covers
Finally, since the correlation matrix from the CATIE the domains of verbal memory, working memory, motor
baseline sample suggests that the removal of any of the speed, attention, executive functions, and verbal fluency,
domain scores from the composite had little effect on the ie, those cognitive functions that are clearly impaired in
reliability of the composite score,48 it may also be schizophrenia. Moreover, the BACS was designed to be
reasonable to bridge the aforementioned research–practice easily applicable during clinical trials. It can be used by
gap by adding the Hopkins Verbal Learning test59 to the minimally trained personnel and requires only about
baseline mental status exam. For this test, individuals need 30 minutes of testing time plus minimal extra time for
to memorize as many words as possible from a list of scoring.68 The BACS showed high reliability and sensi-
12 words read aloud by the tester. First, verbal memory, in tivity for cognitive impairment in schizophrenia,68–72
general, and the Hopkins Verbal Learning test, in discriminatory power from cognitive deficits in affective
particular, showed a high correlation with other domains psychoses,54,71,72 and has been widely utilized in clinical
and ranged among the highest correlations for the studies.73–75
composite score.48 Second, this test is similar to already Because of limited progress in the development of
used, freely interpreted 5-minute recall tests and is easy to effective treatments for cognitive symptoms, the
administer and score. Third, it is well tolerated even by National Institute of Mental Health (NIMH) started the
significantly impaired individuals. The assessment takes Measurement and Treatment Research to Improve
approximately 5 minutes with a 25-minute delay to Cognition in Schizophrenia (MATRICS) project, which
complete (which can be used for other parts of the involved, among other projects, the development of the
psychiatric interview) and takes not more than 2 minutes MATRICS Consensus Cognitive Battery.66,76 This
to score. Additional tests that may be clinically useful battery, as a paper-and-pencil test, measures working
include the Clock Drawing Test, the Trail Making Test, and memory (2 items), attention/vigilance (3 items), verbal
the 10-minute Montreal Cognitive Assessment (MoCA), learning and memory (2 items), spatial learning
which includes both the Clock Drawing Test and the Trail (3 items), reasoning and problem solving (4 items),
Making Test. speed of processing (3 items; one from the BACS), and
social cognition (4 items). Compared to the RBANS and
the BACS, testing with the MATRICS battery takes much
Measurement of cognitive symptoms
longer (about 1 hour), but for use in clinical trials, this
A variety of neuropsychological batteries have been in amount is still considered appropriate, considering that
use for the detection and quantification of cognitive the MATRICS battery covers a broad spectrum.
deficits in schizophrenia, but these often are not MATRICS battery data have shown high sensitivity,
standardized, can be administered only by specially reliability, and validity, as well as successful application
trained personnel, and take over 2 hours to administer. in large clinical trials.48,77–82
Thus, efforts have been made to develop more easily As an alternative to performance-based tests, in which
applicable batteries (Table 2). outcome measures may be difficult to understand for
The Repeatable Battery for the Assessment of affected subjects, caretakers, and clinicians, interview-
Neuropsychological Status (RBANS) consists of 12 tasks based measures of the impact of cognitive function on
 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 43

TABLE 2. Interviews and scales used for the assessment of cognitive symptoms in schizophrenia
Test Cognitive domains Administration time Pros/cons Reference

Neuropsychological tests
Measurement and Treatment to Speed of processing 60 min Interview-based rating scale 78
Improve Cognition in Attention/vigilance Strong correlation with functional outcome
Schizophrenia (MATRICS) Working memory
Verbal learning
Visual learning
Reasoning/problem solving
Social cognition
Clinical Global Impression of Speed of processing 30 min Interview-based rating scale 98
Cognition in Schizophrenia Attention/vigilance Strong correlation with functional outcome
(CGI-CogS) Working memory
Verbal learning
Visual learning
Reasoning/problem solving
Social cognition
CogState Schizophrenia Battery Speed of processing 35 min Valid measurement of MATRICS cognitive domains 188
Attention/vigilance Designed for clinical trial use
Working memory
Verbal learning
Visual learning
Reasoning/problem solving
Social cognition
CogState 12-Minute Battery Executive function 12 min Designed for clinical trial use
Psychomotor function
Visual attention
Visual learning
Schizophrenia Cognition Rating Speed of processing 12–14 min for each of 3 Excellent correlations with performance and functional outcomes 83
Scale (SCoRS) Attention/vigilance interviews (patient, Appropriate for clinical use
Working memory informant, and
Verbal learning interviewer)
Visual learning
Reasoning/problem solving
Repeatable Battery for Assessment Immediate memory 25–45 min Lacks measures of motor, executive, and working memory 189
of Neuropsychological Status Visuospatial/constructional ability Appropriate for clinical use
(RBANS) Language
Attention
Delayed memory
Brief Assessment of Cognition in Reasoning/problem solving <35 min Appropriate for clinical use 68
Schizophrenia (BACS) Verbal fluency
Attention
Verbal memory
Working memory
Motor speed
Brief Cognitive Assessment Tool for Attention 10–11 min Appropriate for clinical setting 190
Schizophrenia (B-CATS) Language
Processing speed
5-Minute Digit Symbol Coding Task Processing speed 5 min Limited to 1 domain 191
Appropriate for clinical setting
Montreal Cognitive Assessment Orientation 10 min Appropriate for clinical setting 192, 193
(MoCA) Language
Short-term memory
Visuospatial abilities
Executive functions
Phonemic fluency
Verbal abstraction
Attention
Working memory
Questionnaires/interviews
Behavior Rating Inventory of Behavioral Regulation Index (BRI): Inhibit, Shift, 10–15 minutes (as per Scale consists of an 86-question real-world, task-related 194
Executive Functioning (BRIEF) and Emotional Regulation subdomains. authors) Parent Form and an 86-question Teacher Form.
Metacognition Index (MCI): Initiate, Working, Questions are answered as “never,” “sometimes,” or “often”
Memory, Plan/Organize, Organization of
Materials, and Monitor subdomains.
Global Executive Composite
(GEC) = BRI + MCI
New York Assessment of Adverse Working memory 5–7 minutes Clinician interview integrates informant data, patient self-report (separate 195
Cognitive Effects of Attention/vigilance forms), and indirect assessment based on real-life observations/impact. 7
Neuropsychiatric Treatment (NY- Verbal learning/memory probes/items rated “not present,” “a little bit bothersome,” “somewhat
AACENT) Visual learning/memory bothersome,” “quite bothersome,” “very bothersome” (Note: validation underway)
Reasoning and problem solving Appropriate for clinical use
Speed of processing
Social cognition
44 M. CARBON AND C. U. CORRELL

daily life functioning are being developed.83 While being to real-world skills, have shown higher predictive
easier to understand, treatment suggestions based on value.85,98,99 For example, work skills could be predicted
such a measure are expected to yield wider acceptance, in a model that included neuropsychological function-
and association with outcome measures can be estab- ing, functional capacity, and depression in schizophre-
lished more easily. The Schizophrenia Cognition Rating nia.100 Another confound of cognitive assessment that
Scale (SCoRS) parallels the MATRICS domains (except has been highlighted101,102 is motivation, which clearly
social cognition), including 18 items as questions, to affects real-life functioning. Moreover, social cognition
which scaled answers are given by the patient and an has been shown to mediate the association of neurocog-
informant/caregiver separately, as well by the inter- nitive capacity and functional outcome.103 In an over-
viewer (with 1 for least difficulty to 4 for severe difficulty view of 15 studies including 1559 patients, the authors
with the respective issue). Initial measures of inter-rater showed that 25% of the variance in functional outcome
reliability and associations to measures of real-world could be explained in the social cognition mediation
functioning were high, but only the interviewer’s global model. However, as mentioned above, the effect of
rating correlated most significantly with objective cognition on psychosocial functioning should be con-
measures of cognition.83 Due to the everyday life sidered in association with intrinsic motivation.104
association of the questions, this interview-based scale
has high face validity for patients, but the insight into
cognitive deficits is limited in patients with schizophrenia, Management of Negative and Cognitive Symptoms
such that objective cognitive measures showed little The management of negative and cognitive symptoms
correlation with the perceived deficits as measured with requires the adequate recognition and separation of
the SCoRS.84 By contrast, administrators’ SCoRS ratings primary and secondary negative symptoms to facilitate
correlated with PANSS total scores, Global Assessment of corresponding treatment adaptations. Similarly, the knowl-
Functioning (GAF) scores, and psychosocial functioning,85 edge of the individual’s baseline and recent psychosocial
possibly pointing to a lack of specificity of the global and cognitive functioning and any recent changes should
SCoRS rating. Nevertheless, in a clinical study, SCoRS guide management strategies. Interventions for cognitive
proved to be sensitive enough to document within-group, and negative symptoms partly overlap, and a combination
treatment-related changes in cognition after 3 weeks of of psychopharmacological and psychosocial interventions
treatment with lurasidone or ziprasidone.86 is needed to address individual needs of patients.

Prevalence of cognitive impairment in schizophrenia Psychosocial techniques

Cognitive deficits are so common in schizophrenia that the As part of an overarching approach, general behavioral
inclusion of cognitive impairment was considered as a interventions, which target exercise, sleep hygiene,
diagnostic criterion for the Diagnostic and Statistical social engagement, meditation/relaxation, and psycho-
Manual of Mental Disorders, Fifth Edition (DSM-5).87 social as well as cognitive stimulation, should be used.105
However, as cognitive decline precedes full-blown mani- Different, specific psychosocial techniques have been
festation of psychosis,38,43 and because similar cognitive designed to support functional status and ideally recovery.
reductions can be found in affective psychoses,56 cognitive Cognitive behavioral therapy (CBT),106 adapted for
impairment is not a defining criterion of schizophrenia. patients with psychosis,107,108 was originally developed to
As many as 73% of subjects with schizophrenia were treat persistent positive symptoms, but currently CBT also
deemed cognitively impaired based on clinical neuropsy- aims to change poor motivation and anhedonia together
chological assessment,88 and up to 98% performed worse with negative and defeatist beliefs. This technique uses the
cognitively than would be predicted by their parents’ individual’s strengths and actively engages those strengths
education level.89 to define and achieve goals.109 A positive, though
moderate impact of CBTon negative symptoms (adjunctive
to antipsychotic treatment), with a reduction of apathy and
The impact of cognitive deficits on outcome
enhanced motivation, was shown particularly using indivi-
Cognitive function closely relates to real-world commu- dual sessions.107,110,111
nity functioning.90,91 However, although several studies Cognitive remediation therapy (CRT) targets neurocog-
showed an association of single, objectively measured nition and social cognition,112 and has demonstrated
cognitive characteristics and longitudinal functional modest efficacy, with mean effect sizes for cognition of
outcome parameters,92–95 a comprehensive synthesis of 0.45 and some cognitive training effects outlasting active
studies failed to demonstrate consistent or specific treatment.113 Various variants of CRT have also demon-
predictive associations.96,97 Nevertheless, interview- strated modest negative symptom improvements, in
based measures, which are already more closely related particular in avolition/amotivation.110,112,114 Interestingly,
 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 45

in addition to influencing cognition and negative symp- Although clozapine has been associated in some studies
toms, therapeutic benefits of CRT were associated with with negative symptom benefits,132 results have not been
increased time to relapse in one study that included 55 universal,133 and it remains unclear if these are due to very
subjects with up to 5 years retrospective observation.115 low extrapyramidal side effect liability, greater adherence,
Social skills training targets negative symptoms by and longer follow-up, or whether these findings relate to
educating patients about expressive and interactive skills the unique pharmacologic mechanisms of clozapine.
needed in community functioning, such as reciprocal use Similarly, although some studies found isolated benefits
of verbal and nonverbal exchanges.110,116 With the focus of specific antipsychotics for cognition in different groups
on social cognition, this treatment approach partly over- of patients with schizophrenia, including aripiprazole,134
laps with approaches for treating cognitive symptoms. lurasidone,135 and even perphenazine,136 differences were
There is evidence to support group social skills training for generally restricted to specific tests, which were small and
negative symptoms,110,117 even in early psychosis.118 not universally replicated.
Ongoing efforts target computer-assisted training Based on the limited effects of antipsychotics, multi-
programs for cognitive deficits in schizophrenia.119 A ple adjunctive treatments added to ongoing antidopami-
recent meta-analysis of 16 such studies120 found that nergic antipsychotic treatment have been tried, but to
computer-assisted training programs improved general date no add-on treatments for cognitive or negative
cognition, with a mean effect size of 0.38. Social symptoms have been approved.
cognition improved, with a significant medium effect size
of even 0.64. Additionally, verbal memory, working
Antidepressants
memory, attention, and processing speed improved with
small effect sizes. Further refinement of computer-assisted Several meta-analyses support the adjunctive use of
programs is expected, as they are likely to be improved with antidepressants in subjects with predominant negative
gamification of the learning tasks. Accessibility is a further symptoms137 and patients with mixed positive and
advantage. Nevertheless, it remains to be determined negative symptoms.138,139 In a recent meta-analysis of
whether or not persisting and generalizing treatment 4 studies (n = 149), however, add-on 5-HT1A partial
effects beyond task-specific training can be achieved. agonists did not improve negative symptoms more than
placebo.140
Psychopharmacology of negative and cognitive symptoms
Serotonergic mechanisms for cognition. 5HT1A agonism
Antipsychotics
was used to improve attention and motor performance
Currently available antipsychotics have only limited with buspirone141 and to improve verbal memory and
efficacy for negative and cognitive symptoms.121,122 More- executive function with tandospirone.142 The 5HT3
over, the exact structural and neurochemical correlates of antagonists ondansetron143 and tropisetron144 were
primary negative and cognitive symptoms in schizophrenia associated with significant cognitive improvement in
are a topic of ongoing research.11,123,124 Therefore, the some domains, and 5HT6 antagonists improved execu-
development of novel targets relies on mechanisms that tive functioning.145 However, a recent meta-analysis
are still being investigated.121,125,126 suggested only weak and mostly nonsignificant effects
A line of preclinical studies has shown that acute of serotonergic and other antidepressants for cognitive
treatment with some SGAs, but not first generation deficits in schizophrenia.146
antipsychotics (FGAs), selectively relieved experimentally
induced N-methyl-D-aspartate-receptor (NMDAR)-
Glutamatergic mechanisms
mediated psychosis, including negative symptoms at
cellular and behavioral levels.127,128 However, the hopes A meta-analysis (studies = 18, subjects = 358) of the
for efficacy of SGAs for negative symptoms have only effects of glutamatergic substances, such as glycine,
insufficiently been fulfilled. In a meta-analysis, the 4 SGAs D-serine, D-cycloserine, and AMPAkines,147 showed ther-
amisulpride, clozapine, olanzapine, and risperidone were apeutic effects for negative symptoms only for glycine and
more efficacious than FGAs for negative symptoms, while D-serine. In a later, large study, no significant effect on
the other 5 studied SGAs (aripiprazole, quetiapine, negative or cognitive symptoms was found for either
sertindole, ziprasidone, and zotepine) were not.129 Never- D-cycloserine or glycine.147 Next, D-cycloserine showed
theless, most of the studies in this meta-analysis were not improvements for memory consolidation, but worsened
conducted in patients with predominant negative symp- negative symptoms148 and failed other treatment tar-
toms. Moreover, the results of the CATIE follow-up study gets.149 The mGlu2/3-R agonist pomaglumetad methionil
suggest only slight efficacy of SGAs for negative symptoms was efficacious in a proof-of-concept study,150 but failed to
in patients with chronic schizophrenia, with a probable show efficacy for negative symptoms in a subsequent larger
small advantage for clozapine.130,131 clinical study.151 A selective modulator at the mGlu2 site,
46 M. CARBON AND C. U. CORRELL

mADX-71149, which is under investigation, was beneficial Sex hormones

for negative symptoms in a small study of 47 subjects with
Dehydroepiandrosterone (DHEA) is a precursor of estrogens
predominant negative symptoms.152 Some efficacy for
and androgens and has androgenic effects. Three rando-
cognitive symptoms was found in small/proof-of-concept
mized studies (n = 100) found significant effects, mainly on
studies with acetylcysteine153 and D-serine.154
negative symptoms.168–170 In another small study, DHEA
improved visual sustained attention as well as visual and
Glutamate transporter inhibitors. After encouraging pilot movement skills.171 Estrogen augmentation strategies
data for both negative and cognitive symptoms with showed favorable effects on negative symptoms in 4 double-
glycine transporter-1 inhibitors,155,156 recent results blind, placebo-;controlled, randomized studies with 214
have been disappointing. In a phase 2b study of 323 female patients.172 Adjunctive pregnenolone, a neurosteroid,
patients with predominant negative symptoms, the gly- showed improvements in working memory and attention.173
cine transporter-1 inhibitor bitopertin was associated
with a significant reduction in negative symptoms at the Psychostimulants
2 lower doses and in per protocol analyses only, and
showed a trend for functional improvement in the lowest Stimulant medications are known to improve cognition
dose treatment group relative to placebo.157 Subse- in healthy subjects and are sometimes administered for
quently, however, in 3 large phase-3 trials in patients refractory negative symptoms. In schizophrenia, they
with predominant negative symptoms, bitopertin failed have been shown to improve working memory, language,
to provide any therapeutic benefit at 6 months.126 These and selective attention.174 In a recent review, the authors
results, together with 3 negative studies for exacerbated concluded that stimulants used adjunctively to effective,
positive symptoms, has led to a halting of the bitopertin stable antipsychotic treatment show some evidence for
development program. the improvement of primary negative symptoms without
As an alternative mechanism, inhibition of D-serine exacerbation of positive symptoms in carefully selected
degradation via the D-amino-acid-oxidase inhibitor benzo- patients.175 This notion was also supported in a subsequent
ate158 may improve prefrontal glutamatergic signaling and open-label study of adjunctive lisdexamfetamine in 92
both cognitive and negative symptoms. In a recent, small, patients with predominant negative symptoms,176 but fear
randomized, double-blind, placebo-controlled study regarding exacerbation of psychosis upon non-adherence
(n = 52),159 benzoate showed large effect sizes (range with antipsychotics may make this option most feasible in
1.16–1.69) for negative and cognitive symptoms. patients on long-acting injectable antipsychotics. By con-
In summary, interventions targeting the glutamatergic trast, hopes for efficacy of modafinil or armodafinil have
system with improved regional specificity and a focus on not been supported by recent double-blind, placebo-
D-serine may be one of the most promising drug targets controlled studies of repeated doses of these agents.177–179
for the treatment of negative and cognitive symptoms in
schizophrenia.121,160 Repetitive transcranial magnetic stimulation (rTMS)

The most recent expert consensus guideline on the

Cholinergic mechanisms therapeutic use of rTMS assigned B-level evidence to high
Both central muscarinic (mAChR) and nicotinic frequency rTMS of the left dorsolateral prefrontal cortex as
(nAChR) acetylcholine receptor agonists can enhance an augmentation strategy for negative symptoms in schizo-
cognitive functioning in schizophrenia.161 For example, phrenia.180 The effect size for this technique was deemed
xanomeline,162 acting via the muscarinic receptor, moderate (0.53)181; however, the need for daily stimula-
improved verbal learning, memory function, and atten- tion sessions by well-trained clinical personnel may
tion. Acetylcholinesterase inhibitors donepezil and prevent a broad translation into clinical practice.
galantamine showed small procognitive effects,163–165
but were ineffective in a meta-analysis.166,167 Miscellaneous agents
Currently, at least 3 alpha-7 nicotinic receptor agonists
are still being investigated in phase 2 and 3 trial programs Although very preliminary, agents such as the antibiotic
for cognition in schizophrenia: encenicline (EVP-6124), minocycline182 and N-acetylcysteine183 have been associated
AQW-051, and nelonicline (ABT-126). Clinical efficacy with some negative symptom benefits.
results are not available yet for AQW-051 and nelonicline
(ABT-126), although a phase 2b study was recently
Summary and Conclusions
completed for nelonicline.126 However, in a proof-of-
concept and a phase 2b trial, adjunctive encenicline Prominent negative symptoms and clinically relevant
(EVP-6124) was associated with improvements in cogni- cognitive impairment are prevalent in schizophrenia,
tion and negative symptoms.126 affecting around 40% and 80% of subjects, respectively.
 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 47

Both measures relate closely to real-world functional and 6. Cohen AS, Minor KS. Emotional experience in patients with
vocational outcomes. Effective management of these schizophrenia revisited: meta-analysis of laboratory studies.
Schizophr Bull. 2010; 36(1): 143–150.
pressing issues relies on a thorough clinical evaluation of
7. Buchanan RW. Persistent negative symptoms in schizophrenia: an
each individual with schizophrenia, as patients will not overview. Schizophr Bull. 2007; 33(4): 1013–1022.
actively complain about negative symptoms or cognitive 8. Kinon BJ, Noordsy DL, Liu-Seifert H, Gulliver AH, Ascher-Svanum H,
impairment. Ideally, the clinical diagnosis is comple- Kollack-Walker S. Randomized, double-blind 6-month comparison
mented by standardized screening and quantification of olanzapine and quetiapine in patients with schizophrenia or
schizoaffective disorder with prominent negative symptoms and
instruments, such as the CAINS for negative symptoms
poor functioning. J Clin Psychopharmacol. 2006;
and the BACS and SCoRS for cognitive impairment. 26(5): 453–461.
Importantly, psychosocial treatment programs have 9. Rabinowitz J, Berardo CG, Bugarski-Kirola D, Marder S. Association
repeatedly shown good therapeutic benefits, particularly of prominent positive and prominent negative symptoms and
for negative symptoms, which are not amenable to functional health, well-being, healthcare-related quality of life and
family burden: a CATIE analysis. Schizophr Res. 2013; 150(2–3):
antipsychotic treatment. Thus CBT, cognitive remedia-
339–342.
tion, or social skills training should be added to 10. Levine SZ, Leucht S. Identifying clinically meaningful symptom
antipsychotic treatment. Since treatment effects of response cut-off values on the SANS in predominant negative
psychosocial intervention have not reliably been shown symptoms. Schizophr Res. 2013; 145(1–3): 125–127.
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biological and treatment aspects. Eur Psychiatry. 2009; 24(8):
gical treatment is not expected to do), healthcare
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insurers should be urged to pay for repeated interven- 12. Correll CU, Kishimoto T, Nielsen J, Kane JM. Quantifying clinical
tions. Finally, several novel pharmacological strategies relevance in the treatment of schizophrenia. Clin Ther. 2011;
are currently being pursued. However, it is clear that 33(12): B16–39.
additional research is needed before the validity and 13. Kane JM. Tools to assess negative symptoms in schizophrenia.
J Clin Psychiatry. 2013; 74(6): e12.
clinical utility of these approaches will become clear.
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subjective and objective ratings for negative symptoms. J Psychiatr
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Disclosures 15. Marder SR, Alphs L, Anghelescu IG, et al. Issues and perspectives in
designing clinical trials for negative symptoms in schizophrenia.
Dr. Correll has been a consultant and/or advisor to or has
Schizophr Res. 2013; 150(2–3): 328–333.
received honoraria from: Actelion, Alexza, American 16. Alphs L, Summerfelt A, Lann H, Muller RJ. The Negative Symptom
Academy of Child and Adolescent Psychiatry, Bristol- Assessment: a new instrument to assess negative symptoms of
Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson schizophrenia. Psychopharmacol Bull. 1989; 25(2): 159–163.
Lehrman Group, IntraCellular Therapies, Lundbeck, 17. Alphs L, Morlock R, Coon C, Cazorla P, Szegedi A, Panagides J.
Validation of a 4-item Negative Symptom Assessment (NSA-4): a
Medavante, Medscape, Merck, National Institute of
short, practical clinical tool for the assessment of negative symptoms
Mental Health, Janssen/J&J, Otsuka, Pfizer, ProPhase, in schizophrenia. Int J Methods Psychiatr Res. 2011; 20(2): e31–37.
Roche, Sunovion, Takeda, Teva, and Vanda. He has 18. Forbes C, Blanchard JJ, Bennett M, Horan WP, Kring A, Gur R.
received grant support from BMS, Feinstein Institute for Initial development and preliminary validation of a new negative
Medical Research, Janssen/J&J, National Institute of symptom measure: the Clinical Assessment Interview for Negative
Symptoms (CAINS). Schizophr Res. 2010; 124(1–3): 36–42.
Mental Health, Novo Nordisk A/S, and Otsuka. Dr. Carbon
19. Strauss GP, Keller WR, Buchanan RW, et al. Next-generation negative
has the same disclosure information as Dr. Correll due to symptom assessment for clinical trials: validation of the Brief Negative
family relationship. Symptom Scale. Schizophr Res. 2012; 142(1–3): 88–92.
20. Bobes J, Arango C, Garcia-Garcia M, Rejas J; CLAMORS Study
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 COGNITIVE AND NEGATIVE SYMPTOMS IN SCHIZOPHRENIA 53

CME Posttest and Certificate

CME Credit Expires: November 30, 2017

CME Posttest Study Guide

NOTE: The posttest can only be submitted online. The below posttest questions have been provided solely as a study
tool to prepare for your online submission. Faxed/mailed copies of the posttest cannot be processed and will be
returned to the sender. If you do not have access to a computer, contact NEI customer service at 888-535-5600.

1. A 24-year-old patient with schizophrenia is being evaluated for cognitive and negative symptoms. Which of the
following is an interview-based measure of cognitive function?
A. Brief Assessment of Cognition in Schizophrenia (BACS)
B. MATRICS Consensus Cognitive Battery
C. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
D. Schizophrenia Cognition Rating Scale (SCoRS)

2. A 42-year-old patient with treatment-resistant schizoaffective disorder is currently enrolled in cognitive

remediation therapy (CRT). Recent evidence suggests that CRT may be effective in treating:
A. Cognitive symptoms of schizophrenia
B. Negative symptoms of schizophrenia
C. Both of the above
3. Among the pharmacological treatments under investigation for the treatment of negative symptoms of
schizophrenia, which of the following strategies currently shows the most promise?
A. Serotonergic modulation
B. Glutamatergic modulation
C. Cholinergic modulation

CME Online Posttest and Certificate

To receive your certificate of CME credit or participation, complete the posttest and activity evaluation, available only
online at www.neiglobal.com/CME under ‘‘CNS Spectrums’’. If a score of 70% or more is achieved, you will be able to
immediately print your certificate. There is no posttest fee nor fee for CME credits for this activity. Questions? call 888-
535-5600, or email [email protected]