Review

Negative symptoms of schizophrenia: new developments

and unanswered research questions
Silvana Galderisi, Armida Mucci, Robert W Buchanan, Celso Arango

Lancet Psychiatry 2018; Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on
5: 664–77 people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation
Published Online of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown
March 27, 2018
that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the
http://dx.doi.org/10.1016/
S2215-0366(18)30050-6 domains of avolition–apathy and expressive deficit. Failure to take this heterogeneity into account might hinder
Department of Psychiatry, progress in research on neurobiological substrates and discoveries of treatments for primary or enduring negative
University of Campania Luigi symptoms. Improvement in recognition and routine assessment of negative symptoms is instrumental for correct
Vanvitelli, Naples, Italy management of secondary negative symptoms that are amenable to treatment. If substantial progress is to be made
(Prof S Galderisi MD,
in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be
A Mucci MD); Maryland
Psychiatric Research Center, integrated into the design of future studies of these symptoms.
University of Maryland School
of Medicine, Baltimore, MD, Introduction two different subdomains within the negative symptom
USA (Prof R W Buchanan MD);
Negative symptoms have been recognised as core features dimension, evidence supporting the distinction between
and Department of Child and
Adolescent Psychiatry, of schizophrenia since the first descriptions of the primary and secondary negative symptoms, boundaries
Hospital General Universitario disorder.1–3 In contrast with positive symptoms, which are with other schizophrenia dimensions, and advances in
Gregorio Marañón, Centro de thought to reflect an excess or distortion of normal pathogenetic hypotheses, and it will provide an overview
Investigación en Red de Salud
functions (eg, auditory hallucinations), negative symp- of present and potential future treatments.
Mental, Instituto de
Investigación Sanitaria toms have been regarded as a reduction of normal
Gregorio Marañón, and School functions either related to motivation and interest, such Conceptualisation of negative symptoms
of Medicine, Universidad as avolition, anhedonia, and asociality, or to expressive Brief history of negative symptom conceptualisation
Complutense de Madrid,
Madrid, Spain
functions such as blunted affect and alogia. Traditional conceptualisations of negative symptoms
(Prof C Arango MD) Negative symptoms are frequently observed; two large have regarded these symptoms as a core component of
Correspondence to: cross-sectional retrospective studies4,5 involving more schizophrenia.1–3 Two aspects have dominated the
Prof S Galderisi, Department of than 1000 people with schizophrenia reported that over description of negative symptoms: the reduction of
Psychiatry, University of 50% of study participants had at least one negative emotional expression and the loss of motivation.
Campania Luigi Vanvitelli, Largo
symptom. They are associated with poor functional Eugen Bleuler1 described individuals with schizophrenia
Madonna delle Grazie,
80138 Naples, Italy outcome6,7 and pose a substantial burden on people with as having expressionless faces, being indifferent towards
silvana.galderisi@gmail.com schizophrenia, their families, and health-care systems. everything, and having no urge to do anything either on
In light of these associations, interest in negative their own initiative or at the bidding of another.
symptoms has grown over the past decade, and they have Emil Kraepelin3 reported emotional dullness and loss of
become a key target for the development of new mastery over volition. Dide and Guiraud14 introduced the
treatments. However, progress in relevant fields of concept of athymhormia, including loss of emotions and
research has been slow and negative symptoms remain a affect, and loss of drive. Delay and Deniker15 described a
crucial unmet therapeutic need. form of schizophrenia characterised by adynamia and
Although psychiatrists are familiar with the concept of indifference, as opposed to agitation and delusions. The
negative symptoms of schizophrenia, misconceptions concept of basic symptoms, though only partly applicable
and uncertainties about the correct identification and to current concepts of negative symptoms, also
management of these symptoms remain. contributed to raising the awareness of psychiatrists and
In the past decade, efforts to improve the con- researchers to negative symptoms.16
ceptualisation and assessment of negative symptoms The introduction of operational diagnostic criteria and
have contributed to reducing their overlap with other classification systems contributed to de-emphasising the
schizophrenia dimensions and identifying the areas in role of negative symptoms as a core component of
which borders are still poorly defined.8–10 The heterogeneity schizophrenia, mainly because of their presumed poor
of the negative symptom dimension is acknowledged and inter-rater reliability, while prioritising the role of positive
regarded as a potential confounder in research and symptoms and especially of first-rank symptoms (eg,
education, and an obstacle to correct management of though insertion, withdrawal or broadcasting, and
some secondary negative symptoms which are amenable delusions of control, influence, or passivity).17 Nevertheless,
to treatment.11–13 several researchers remained focused on the negative
This Review will cover the main advances in symptom dimension, and they proposed either a dimen­
conceptualisation and assessment of negative symptoms sional or a categorical approach to their conceptualisation.18–21
of schizophrenia, findings relevant to identification of The work of these groups contributed to the resurgence of

664 www.thelancet.com/psychiatry Vol 5 August 2018


interest in negative symptoms, although they have never
been regarded as core symptoms of schizophrenia in
classification systems.
Current conceptualisation of negative symptoms
In the past decade, negative symptoms have received
increased attention because of their effect on real-life
functioning of people with schizophrenia. The dearth of
effective therapeutic interventions and the inconsistency
of research findings relevant to the neurobiological
underpinnings of negative symptoms have highlighted
the need for a reconceptualisation of this dimension.
The association between negative and positive symp-
toms has been differently conceptualised over time.
John Hughlings Jackson2 regarded negative symptoms as
the direct expression of the loss of function of the higher
nervous system levels; positive symptoms, instead, were
regarded as secondary—ie, due to the disinhibition of
lower levels previously controlled by the higher ones.
Other authors have defended the independence of the
two dimensions.15 The idea that a common patho­
physiology is at the origin of both negative and positive
symptoms has not been supported by evidence, and
several studies have indicated that negative symptoms
are independent from positive symptoms, cognitive
dysfunctions, disorganisation, and depression.9 However,
clear boundaries are not always possible to identify.
Despite the largely documented independence of
negative from positive symptoms,22 substantial evidence
indicates that the longer the duration of untreated
psychosis, the greater the severity of negative symptoms.23
These data need to be further assessed in longitudinal
research designs to exclude the possibility that longer
duration of untreated psychosis in patients with negative
symptoms is the result of an insidious onset that might
delay presentation of cases and entry into treatment.24
Associations between positive and negative symptoms
might also result from assessments focusing on
behavioural aspects instead of internal experience.
Regarding the boundaries between negative symptoms
and cognitive impairments, it is important to point out
that both domains have strong associations with real-life
functioning; since many studies have used assessment
instruments that include poor attention as a component
of the negative symptom construct, it is difficult to say
whether commonalities between the two dimensions are
partly explained by this confounder. Some overlap cannot
be excluded when considering, for instance, that an
impairment of executive function might interfere with
goal-directed behaviour necessary for the acquisition of
reward, which is currently conceptualised as a mechanism
contributing to avolition;25 poor verbal fluency (ie, a deficit
in the ability to retrieve information from memory) is
thought to underlie alogia and poor social cognition
might result in or be the result of asociality.25 However,
although further studies are needed to better define
boundaries, it should be stressed that the degree of
www.thelancet.com/psychiatry Vol 5 August 2018 665
Review
overlap is minor, associations are weak and, despite
nearly all people with schizophrenia having some degree
of cognitive impairment, only half of them experience
negative symptoms.22 Additionally, the possibility should
be considered that avolition might lead to poor
performance on cognitive assessment tasks.26
An association between conceptual disorganisation
and negative symptoms has sometimes been assumed27
and might be partly due to the presence of items related
to conceptual disorganisation in instruments traditionally
used to assess negative symptoms.
The distinction between depression and negative
symptoms is also challenging because of the commonalities
in clinical presentation, such as diminished emotional
expression, anhedonia, social withdrawal, and apathy.
However, negative symptoms and depression are separable
symptom domains according to factor analysis studies,28
and they can be distinguished by accurate clinical
assessment.
Important progress has been made in the
acknowledgment of the heterogeneity of negative
symptoms, the importance of differentiating primary
from secondary and persistent from transient negative
symptoms, and the need to overcome diversities among
research groups with respect to defining the main
constructs to be included in the negative symptom
dimension. A consensus has been achieved on the main
constructs to be included in the negative symptom
dimension—ie, alogia, blunted affect, anhedonia,
asociality, and avolition.9 A brief definition of each
symptom is provided in panel 1.
In contrast, no consensus has emerged so far on
whether a categorical or a dimensional approach is better
suited to negative symptoms. Evidence supporting the
validity of the categorical approach has been produced
for the deficit schizophrenia construct (ie, the subtype of
schizophrenia characterised by the presence of primary
and persistent negative symptoms).29–32 However, evi-
dence supporting the dimensional perspective is also
available; negative symptoms are observed in disorders
apart from schizophrenia, such as schizoaffective
disorder, depression, at-risk mental states, and in the
general population.22,33 In the past 5 years, studies have
been done to identify which negative symptom domains
are present in which disorder;34–36 however, the evolution
of definitions and assessment instruments has not
happened in the same way as for schizophrenia.
Course of negative symptoms
The available data indicate that negative symptoms are
present early in the course of illness, largely before an
acute psychotic episode leading to a diagnosis of
schizophrenia,37–39 and, according to some findings, they
predict the eventual psychotic episode.39
Longitudinal and retrospective studies37,38,40–42 frequently
report the presence of asociality and trait anhedonia
since childhood and early adolescence, as well as in the
 Review
Panel 1: Definition of negative symptoms*
Blunted affect
Decrease in the expression of emotion and reactivity to events
as observed during the spontaneous or elicited expression of
emotion (facial and vocal expression and expressive gestures)
Alogia
Reduction in quantity of words spoken and in spontaneous
elaboration (ie, amount of information spontaneously given
beyond what is needed to answer a question)
Asociality
Reduced social interactions and initiative due to decreased
motivation for and interest in forming and maintaining
relationships with others
Anhedonia
Reduced experience of pleasure for a variety of activities or
events, during the activity or event (consummatory
anhedonia) and for future anticipated activities or events
(anticipatory anhedonia)
Avolition
Reduced initiation and persistence of goal-directed activity
due to reduced motivation
*Following the National Institute of Mental Health–Measurement and Treatment
Research to Improve Cognition in Schizophrenia (NIMH–MATRICS) consensus statement9
prodromal phase, in people later diagnosed with
schizophrenia or schizophrenia-spectrum disorders.
Asociality has also been reported37,43,44 as a prodromal
symptom of other non-psychotic disorders, such as major
depressive disorder, of ultra-high-risk people who later do
not convert to psychosis, and of anxiety disorders. The
instruments used to assess asociality in these studies
(eg, parent or teacher ratings or observation of the child or
adolescent’s social impairment) placed a strong emphasis
on behaviour, so whether the reported social impairment
was due to factors other than asociality (eg, poor cognitive
abilities, social anxiety, or antisocial traits) is not clear.
Furthermore, the associations between the asociality
ratings before and after the diagnosis of schizophrenia
were not investigated. Only one study45 assessed childhood
social withdrawal in people with deficit schizophrenia and
those with non-deficit schizophrenia, with the use of the
Child Behaviour Checklist to obtain a retrospective
assessment of parent-rated social withdrawal (with parents
blind to the categorisation). The study found more severe
social withdrawal in deficit schizophrenia than in non-
deficit schizophrenia.
For anhedonia, the trait measures used in prepsychotic
periods showed no association with negative symptoms
in adults with schizophrenia-spectrum or other psychotic
disorders.46,47 No retrospective or longitudinal study
has investigated the association of trait anhedonia
with primary and enduring negative symptoms.
Cross-sectional studies48,49 reported greater severity of trait
666 www.thelancet.com/psychiatry Vol 5 August 2018
anhedonia in people with deficit schizophrenia than
people with non-deficit schizophrenia.
Only a few long-term longitudinal studies50,51 have
examined symptom stability. The course of broadly
defined negative symptoms was heterogeneous over a
10-year follow-up in participants with first episode
psychosis, with various diagnoses. In more than half of
the sample, negative symptoms had a continuous
(134 of 496, 27%) or relapsing (129 of 496, 26%) course.
Predictors of the continuous course were moderate
severity of the negative symptoms and presence of
disorganisation symptoms at baseline, schizophrenia
diagnosis, male gender, and poor premorbid adjustment.51
A meta-analysis52 including 89 studies reported an
overall improvement of negative symptoms over time
with all treatments (including placebo); however, those
studies did not attempt to assess pseudospecificity
(ie, whether improvement was related to changes in
other aspects of the syndrome, such as depression,
positive symptoms, or extrapyramidal side-effects).
Elevated stability of deficit features (ranging from 67% to
more than 80%) was found in longitudinal studies.12, 53
Heterogeneity of negative symptoms
Primary and secondary negative symptoms
Negative symptoms are a heterogeneous group of
symptoms that might differ in cause, longitudinal course,
and treatment.21 They are either primary manifestations
of the underlying pathophysiology of schizophrenia or
secondary to other factors. Primary and secondary
negative symptoms can be transient or enduring,
although distinguishing primary and transient negative
symptoms from secondary negative symptoms is not
always possible. Primary and enduring negative
symptoms have been termed deficit symptoms.21 Several
studies12,29,32,53 have shown the validity of subgrouping
people with schizophrenia into those with deficit
symptoms (deficit schizophrenia) and those without
deficit symptoms (non-deficit schizophrenia).
Negative symptoms might be secondary to positive,
affective, or extrapyramidal symptoms, antipsychotic-
induced sedation, environmental deprivation, and other
illness-related and treatment-related factors.54
Differentiation of primary and secondary negative
symptoms has important treatment implications since no
known effective treatments exist for primary negative or
deficit symptoms. In contrast to primary negative
symptoms, secondary negative symptoms might be
responsive to available treatments;13,54 for example,
negative symptoms secondary to positive symptoms
might be responsive to effective antipsychotic treatment,
whereas negative symptoms secondary to depression
might be responsive to antidepressant treatment. The
failure to differentiate primary from secondary negative
symptoms has complicated efforts to develop effective
treatments for negative symptoms because including
secondary negative symptoms might lead to apparent

improvements in the negative symptom outcome
measure, which reflect indirect or pseudospecific changes
in negative symptoms rather than a direct therapeutic
effect of the study intervention.55
Unfortunately, secondary negative symptoms might not
be responsive to treatment of their underlying cause.
A substantial number of people with schizophrenia have
primary or secondary negative symptoms, enduring over
time.12,56 The attempt to identify people with enduring
primary or secondary negative symptoms for purposes of
research into the pathophysiological cause or treatment
of negative symptoms has led to additional conceptual
models for defining negative symptoms, the two most
important of which are the concept of predominant and
persistent negative symptoms.12,56 Both constructs lead to
the identification of a population of people with
schizophrenia with disabling negative symptoms, which
is markedly larger than the population with deficit
schizophrenia.
Research participants with predominant negative
symptoms are characterised by moderate to severe
negative symptoms of greater relative severity than
co-occurring positive symptoms—ie, rating scale scores
greater for negative than positive symptoms—but with
no attempt to limit the absolute severity of positive
symptoms or other symptom domains. In contrast,
people with schizophrenia with persistent negative
symptoms are also characterised by moderate to severe
negative symptoms, but upper limits are placed on the
severity of positive, affective, and extrapyramidal
symptoms.56 The combin-ation of the two sets of
persistent negative symptom criteria leads to the
enrichment of the study sample, with respect to people
with deficit schizophrenia.56,57 The other major advantage
associated with use of the persistent negative symptom
construct is that it allows for control of potential sources
of indirect changes to negative symptoms during the
course of clinical trials.
Negative symptom domains
Interest in whether negative symptoms represent a
monolithic construct or have a multidimensional
structure has been considerable. The results of factor
analysis studies have supported two-factor, three-factor,
or five-factor models of negative symptoms.58 However, a
two-factor solution tends to be more likely when
symptoms that are not conceptually related to negative
symptoms are excluded.58 The two factors that emerge
from these studies suggest that negative symptoms
might be subdivided into two independent dimensions:
avolition–apathy, and expressive deficit.
Three studies59–61 have examined the factor structure of
negative symptoms in people with deficit schizophrenia.
The Schedule for the Deficit Syndrome (SDS)62 was used
to assess six negative symptoms. The avolition–apathy
and expressive deficit factors were each defined by
three symptoms (panel 2).
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Review
Panel 2: Deficit symptom factor structure
Avolition–apathy:
• Curbed interests
• Diminished sense of purpose
• Diminished social drive
Expressive deficit:
• Restricted affect
• Diminished emotional range
• Poverty of speech
The two-factor solution has also been found in people
with schizophrenia with a combination of primary and
secondary negative symptoms.8,10,30,61,63 In these studies,
negative symptoms were assessed with the Brief Negative
Symptom Scale (BNSS),8,63 the SDS,30,61 and the Clinical
Assessment Interview for Negative Symptoms (CAINS).10
The delineation of two independent negative symptom
dimensions has at least two important implications. First,
the two dimensions might differ in their associations
with course of illness and other psychopathological
dimensions.25 In a study61 of almost 200 participants
with schizophrenia, the avolition–apathy factor was
differentially associated with increased positive symp-
toms, increased rates of hospital admission, poorer social
function, and greater social cognition impairment
compared with the expressive deficit factor. Second, the
two dimensions might differ in their response to
therapeutic interventions. In a study64 of cognitive therapy
for negative symptoms, cognitive therapy significantly
improved the Scale for the Assessment of Negative
Symptoms (SANS) avolition–apathy item, but it had no
effect on measures of emotional expression. Similarly, in
a study65 of the selective monoamine oxidase B inhibitor,
rasagiline, the observed negative symptom benefit was
largely due to its effect on the SANS avolition–apathy
item. These results suggest that future studies of
innovative therapeutic interventions might want to assess
the effect of the experimental intervention on each of the
two negative symptom dimensions separately.
Theories of causation
Pathophysiological mechanisms of negative symptoms
are still unclear.25,33 The increasing acknowledgment of
the heterogeneity of negative symptoms has fostered the
construction of separate hypotheses for the avolition–
apathy and expressive deficit domains; however, only
rarely have these models been tested in participants with
persistent and primary negative symptoms.
Avolition–apathy domain
In present conceptualisations, avolition–apathy is hypo-
thesised to be related to deficits in different aspects of
motivation (panel 3).66,67 The neural bases of motivation
are shown in figure 1.66,67 People with schizophrenia are
often impaired in reward anticipation, valuation of
 Review

representation, impaired incentive learning (for both

Panel 3: Motivation from a neuroscientific perspective outcome-stimulus and outcome-action associations), or
Motivation is a complex construct related to the instigation of goal-directed behaviour, and reduced integration of goal-directed behaviour and
it includes directional (approach or avoidance) and energetic aspects (vigour and persistence experienced value. Although functional and structural
in pursuing an outcome).66,67 A general motivation to act is related to aversive and rewarding abnormalities in the corticostriatal components of the
salient, attention-grabbing stimuli or events. motivational salience and value systems have been
reported in schizophrenia,68–71 only rarely have they been
Motivation toward a specific outcome—ie, instigation of a specific goal-directed
related to anticipatory anhedonia, avolition, or asociality.
behaviour—is modulated by the expected and experienced value of the outcome.
Further studies are needed to support these findings and
The presence of a cue associated with a valued outcome increases motivation
clarify the role of different striatal regions in different
(expected value), but the value of the outcome might change due to the individual’s
motivation-related processes.
state or external contingencies (experienced value–eg, our preferred pizza is less
Two possible mechanisms and circuits could be
valuable when we are satiated or see a bug on it).
involved in avolition–apathy (figure 2). One mechanism
Stimulus-outcome and action-outcome associations need to be learned (incentive learning) hypothesises involvement of the motivational value
to activate and guide behaviour. system, resulting in impairment in anticipatory pleasure,
A further aspect that influences motivation is effort discounting: an outcome requiring a valuation of action and stimuli, and instrumental
high degree of effort is devalued. learning. The other mechanism hypothesises involve-
ment of the motivational salience circuit, resulting in
Different dopamine neurons are involved in the so-called motivational salience circuit, in
impairment in orienting to salient stimuli, cognitive
which dopamine signals both rewarding and aversive events, and in the motivational
activation, and general motivation.
value system or reward system (corresponding to the Research Doman Criteria of the
The two mechanisms might benefit from completely
Positive valence system) figure 1.
different treatment approaches. In the first case (part A,
figure 2), it could be useful to increase the salience of
Motivational salience Motivational value stimuli and activate cognition through pharmacological
Positive situations Positive situations
Negative situations
and psychosocial interventions, whereas in the second
Anterior cingulate
Representation case (part B, figure 2), enhancement of instrumental
Net value Medial orbitofrontal of stimulus
(benefit minus cost) cortex cortex learning and provision of external rewards might be
value and
Ventromedial prefrontal inhibition of needed to improve motivation.
cortex
Representation
response In its present conceptualisation, asociality is related to
Dorsolateral prefrontal
of action value,
cortex
reduced interest and motivation for social interactions.
goal selection, and
cognitive–emotional Ventrolateral prefrontal Neither the pathophysiological mechanisms involved nor
cortex Dorsomedial Action–outcome
integration caudate associations their associations with social cognition deficits, often
found in patients with schizophrenia, are clear.25
Salience (including Avolition might also be related to general impairment
incentive salience) Nucleus accumbens Nucleus accumbens Valuation and
core shell prediction error
in decision making and executive control of behaviour;
however, findings are contradictory and the issue
Ventral tegmental area Ventral tegmental area
Dorsolateral substantia
deserves further investigation.25,33
Ventromedial substantia
nigra pars compacta nigra pars compacta
Expressive deficit domain
Pathophysiological mechanisms of blunted affect and
Hippocampus Central amygdala alogia have been investigated less than those related
External context
Experienced value to avolition–apathy. In particular, these negative
Insula symptoms are hypothesised to be related to neuro-
Internal context and cognitive or social cognition deficits.25 An association of
action retrieval expressive deficit with neurocognitive impairment has
been found in patients experiencing their first psychotic
Figure 1: The neural bases of the different aspects of motivation
For motivational salience, dopamine neurons are activated for both positive and negative aspects; whereas for the episode and in those with chronic schizophrenia.7,72
motivational value system, dopamine neurons are activated only for positive aspects. *National Institute of In drug-naive participants with deficit schizophrenia,
Mental Health research domain criteria, positive valence system. expressive deficit was associated with soft neurological
signs73 suggesting a relation of the domain with
stimuli and actions, and incentive learning (over short subtle, diffuse neurodevelopmental abnormalities. The
trials); they also show excessive effort-discounting, associations of avolition–apathy and expressive deficit
choosing low-effort options.25,33 Avolition in schizophrenia with cognitive impairment should be further investigated.
can be related to impairment of the energetic aspects of
motivation (reduced activation and persistence of goal- Assessment of negative symptoms
directed behaviour, with accentuated effort discounting) Assessment of negative symptoms in the research context
or of the motivation value system, with poor value has a long history. Several validated instruments are

668 www.thelancet.com/psychiatry Vol 5 August 2018


available with good to excellent psychometric properties.74
However, in clinical practice most psychiatrists are less
skilled in the assessment of these symptoms than in the
assessment of positive and disorganised symptoms.
In the following sections, we describe how negative
symptoms are assessed and rated by two of the most
frequently used instruments and by the two newest scales,
developed after the Measurement and Treatment Research
to Improve Cognition in Schizophrenia (MATRICS)
consensus initiative on negative symptoms,9 designed to
improve assessment. Assessment in routine clinical
practice is discussed with particular reference to the
identification of negative symptoms secondary to positive
symptoms, depression, and extrapyramidal side-effects.
Validated rating scales used in the research context
A comprehensive review on the evolution of negative
symptom assessment is beyond the scope of this paper,
although other reviews74,75 do cover this topic. This section
discusses two of the most widely used and well established
instruments (SANS, and the Positive and Negative
Syndrome Scale, PANSS; table 1)74,75 to highlight the
advantages and limitations they share with other
established instruments, and the newest scales developed
and proposed for research on negative symptoms (table 2).
The main limitation of the SANS and PANSS, apart from
inclusion of items assessing cognition and disorganisation
(table 1), is assessment of the avolition–apathy domain at
the behavioural level only, which leads to substantial
overlap with functioning and might bias the interpretation
of results from clinical trials on negative symptoms
(table 1 and table 3).76,77 In fact, SANS or PANSS–Negative
scores might not have improved due to specific environ-
mental factors, such as insufficient job opportunities or
stigma, rather than poor efficacy of the therapeutic
intervention. A further limitation of the PANSS is poor
assessment of the avolition–apathy domain (table 3).
Two instruments were developed after the MATRICS
consensus initiative:9 the BNSS and the CAINS (table 2).8,10
Detailed information on the two scales can be found in
Strauss and Gold.78 CAINS assessment of anhedonia does
not include the experiential aspect, and the alogia
subscale does not include reduced spontaneous
elaboration. The two scales are validated, and they provide
the best assessment of negative symptoms and of the
avolition–apathy and expressive deficit domains (table 3).78
Use of the newer instruments might improve assessment
of the effects of pharmacological and non-pharmacological
treatments on the avolition–apathy domain, for which
the older instruments provided the least appropriate
assessment. Sensitivity to change, for both total and
domain scores, needs to be established in clinical trials.
Assessment of negative symptoms in routine clinical
practice
Although primary negative symptoms still represent an
unmet need of schizophrenia treatment, secondary
www.thelancet.com/psychiatry Vol 5 August 2018 669
Review
A Dysfunctional motivational value circuit
Dopamine neurons signal reward and aversion Dopamine neurons signal reward
Dorsolateral substantia nigra pars compacta Ventromedial substantia nigra pars compacta
Ventral tegmental area Ventral tegmental area
Motivational salience Nucleus accumbens core Nucleus accumbens shell
circuit
Orienting
General motivation
Dorsal striatum Dorsal striatum
Cognitive activation
Dorsolateral prefrontal cortex Ventromedial prefrontal cortex
B Dysfunctional motivational salience circuit
Dopamine neurons signal reward and aversion Dopamine neurons signal reward
Dorsolateral substantia nigra pars compacta Ventromedial substantia nigra pars compacta
Ventral tegmental area Ventral tegmental area
Nucleus accumbens core Nucleus accumbens shell Motivational value
circuit
Positive motivation
Valuation
Dorsal striatum Dorsal striatum
Instrumental
learning
Dorsolateral prefrontal cortex Ventromedial prefrontal cortex
Figure 2: Hypothetical dysfunctions subtending the avolition–apathy domain of negative symptoms in
schizophrenia
Dysfunction or lesion located in the circuit, leaving the circuit inactive (red crosses).
negative symptoms could be ameliorated and prevented,
with an overall improvement of quality of life and
functional outcome.13,54
Psychotic exacerbation can mimic the avolition–apathy
domain.13 In routine clinical practice, it is helpful to
investigate the retrospective course of negative symptoms
to verify whether they worsen during acute psychotic
decompensation phases and improve during periods
of clinical stability. The presence of a stable level of
impairment suggests primary negative symptoms.
Depression is one of the dimensions introduced by
DSM-5 into the complementary dimensional assessment
of disorders because of its frequent occurrence and
relevance to clinical management. In people with
schizophrenia, depression might present with substantial
anhedonia, an absence of initiative, social isolation, and
motor retardation, and can be misdiagnosed as negative
symptoms.79,80
The expressive deficit domain of negative symptoms
might be particularly difficult to distinguish from
drug-induced parkinsonism. The issue is complicated by
the occurrence of parkinsonism in patients with primary
and persistent negative symptoms, independent of their
medication status.73 It is unclear whether the co-occurrence
of parkinsonism and primary and persistent negative
symptoms is due to their phenomen­ological similarity or
to shared pathophysiological mechanisms; the evidence is
 Review

Scale for the Assessment of Negative Symptoms (SANS) Positive and Negative Syndrome Scale–Negative subscale (PANSS–Negative)
Different Appropriate item Inappropriate Basis for Different Appropriate item Inappropriate item Basis for
denom­ item ratings denom­ ratings
ination ination
Blunted affect– Affective Facial expression, Inappropriate Observation N1, blunted Diminished emotional responsiveness ·· Observation
expressive flattening spontaneous affect affect as characterised by a reduction in facial
deficit movements, expressive expression, modulation of feelings, and
gestures, eye contact, communicative gestures
affective non-
responsivity, vocal
inflections
Alogia– .. Poverty of speech Poverty of Observation N6, reduced Reduction in the normal flow of Defensiveness* or cognitive Observation
expressive content of spontaneity communication associated with deficit†
deficit speech, blocking, and flow of apathy, avolition, manifested by
increased latency conversation diminished fluidity and productivity of
of response the verbal–interactional process
Asociality– Anhedonia Intimacy and closeness, .. Behaviour N4, passive– Diminished interest and initiative in .. Behaviour
motivation and relationships with apathetic social interactions due to passivity,
asociality friends social apathy, anergy, or avolition, which leads
withdrawal to reduced interpersonal involvement
and neglect of activities of daily living
Anhedonia Anhedonia Recreational interests, .. Behaviour .. Not assessed .. ..
(consum­ and sexual interest
matory)– asociality
motivation
Anhedonia .. Not assessed .. .. .. Not assessed .. ..
(anticipatory)–
motivation
Avolition– Avolition– Grooming and hygiene, .. Behaviour N2, Lack of interest in, involvement with, .. Behaviour
motivation apathy no persistence at work, emotional and affective commitment to life’s and
physical anergia withdrawal events observation
Attention ·· ·· Social Behaviour .. Not assessed .. ..
impairment– inattentiveness,† and test
other* inattentiveness
during testing†
Difficulty in .. Not assessed .. .. N5, Impairment in the use of the abstract- .. Test
abstract difficulty in symbolic mode of thinking, evidenced
thinking– abstract by difficulty in classification, forming
other* thinking generalisations, and proceeding
beyond concrete or egocentric thinking
in problem-solving tasks
Stereotyped .. Not assessed .. .. N7, Decreased fluidity, spontaneity, and .. Observed
thinking– stereotyped flexibility of thinking, as evidenced in cognitive
other* thinking rigid, repetitious, or barren thought verbal
content processes
Poor rapport– .. Not assessed .. .. N3, poor Lack of interpersonal empathy, .. Observation
other* rapport openness in conversation, or sense of
closeness, interest, or involvement
with the interviewer; evidenced by
interpersonal distancing and reduced
verbal and non-verbal communication

*Disorganisation. †Cognitive impairment.

Table 1: Evolution of negative symptom definitions and assessment with older instruments used in clinical trials

insufficient to draw any firm conclusions. Panel 4
summarises the main sources of secondary negative
symptoms and tips for assessment.
Management of negative symptoms with
non-pharmacological treatments
When interpreting clinical trials assessing negative
symptoms in schizophrenia, the distinction between
primary and secondary negative symptoms is of the
utmost importance, as is the state versus trait
(persistent) characteristics of the negative symptoms,
and the concept of persistent or predominant negative
symptoms.
No treatments have shown robust efficacy in treating
primary and enduring negative symptoms. Thus,
negative symptoms are less amenable to treatment than
other psychopathological domains, such as psychotic
symptoms.

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 Review

Brief Negative Symptom Scale (BNSS) Clinical Assessment Interview for Negative Symptoms (CAINS)
Different Appropriate item Inapp­ropriate Basis for Different Appropriate item Inapp­ropriate Basis for ratings
denomination item ratings denomination item
Blunted .. Decrease in the observed .. Observation Expression Decreased observed expression of emotion .. Observation
affect– expression of emotion and (EXP) scale and reactivity, including facial expression,
expressive reactivity to events; based on vocal expression, and expressive gestures
deficit facial, vocal expression, and
expressive gestures
Alogia– .. Reduction in quantity of .. Observation Expression Reduced quantity of speech—ie, the .. Observation
expressive words spoken and in (EXP) scale amount of speech produced throughout
deficit spontaneous elaboration (the the interview (quantity of words spoken)
quantity of information given
beyond what is strictly needed
to answer a question)
Asociality– .. Reduced social initiative due .. Internal Motivation Reported reduced interest in, desire or ·· Internal experience
motivation to decreased interest in experience and Pleasure motivation for, and actual engagement in (interest and
forming close relationships (reduced (MAP) scale relationships motivation for
with others interest and relationships) and
desire for behaviour
close, social
bonds) and
behaviour
Anhedonia– .. Reduced subjective experience .. Internal Motivation Reported number of days that .. Frequency
motivation of pleasure for a variety of experience and Pleasure pleasurable social, or work or school of pleasurable
activities or events; reduced of pleasure (MAP) scale activities were experienced, as well as experiences, number
pleasure experience during the during the variety and daily frequency of pleasurable of expected
activity (consummatory activity or recreational activities (consummatory pleasurable
anhedonia), and reduced for future anhedonia); reported expected number of experience
pleasure experience for future activities pleasurable social or work, or school or
anticipated activities or events recreational activities (anticipatory
(anticipatory anhedonia) anhedonia)
Avolition– .. Reduced initiation and .. Internal Motivation The extent of interest, motivation, and .. Internal
motivation persistence of goal-directed motivation and Pleasure engagement in work or school and motivation and
activity and (MAP) scale recreational activities behaviour
behaviour

Table 2: Evolution of negative symptom definitions and assessment with the latest assessment instruments

Psychosocial interventions for negative symptoms
Psychosocial approaches to treating negative symptoms
in schizophrenia include individual psychological,
psychoeducational, and family interventions.81 The most
studied by far has been social skill training (SST). One
review82 and one meta-analysis83 have found SST to be
better than other interventions. However both review
and meta-analysis point that the studies included have
important methodological limitations, such as small
sample sizes, lack of standardisation of negative
symptom assessments, and short follow-ups.81
Family interventions, alone or in combination with other
treatments, such as psychoeducation, communication
training, behavioural problem solving, and crisis manage­
ment, have shown initial promising results.84–86 However,
variation in the type of family intervention complicates the
interpretation of these studies.
Cognitive behavioural therapy (CBT) applied to
schizophrenia was originally developed for the treatment
of positive symptoms. Even though few studies
have focused primarily on negative symptoms, two meta-
analyses of negative symptoms as a secondary outcome
indicate a significant effect of CBT.87 In a study by Grant
and colleagues,64 cognitive therapy based on a goal-directed
framework and personalised treatment planning showed
significant improvements compared with when based on
standard treatment in avolition–apathy (d=0·66). The
central goals of this cognitive therapy were to undercut
nihilistic beliefs and con­comitantly increase motivation
for constructive activity. Recent approaches include
packages that combine several different interventions (eg,
environmental support, CBT, and SST).88
Direct comparisons of different psychosocial inter-
ventions for the treatment of negative symptoms in
schizophrenia seem to favour SST over the other
interventions.83 However, more controlled trials with
negative symptoms as the primary outcome are clearly
needed before any conclusions can be drawn. The
recommendations made to assess efficacy for negative
symptoms in clinical trials should apply not only to
pharmacological trials, but also to trials of psychosocial
interventions.89
Management of negative symptoms with
psychopharmacological treatments
Dopamine antagonists and dopamine agonists
The only mechanism of action common to all drugs
used to treat psychosis is dopamine antagonism.

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672
Review

Scale for the Assessment of Negative Positive and Negative Syndrome Brief Negative Symptom Scale (BNSS)* Clinical Assessment Interview for Negative Symptoms
Symptoms (SANS) Scale–Negative subscale (PANSS–Negative) (CAINS)†
Items Items Limitations Items Items Limitations Items Items Limitations Items consistently Items Limitations
consistently inconsistently consistently inconsistently consistently inconsistently loading on the factor inconsistently
loading on the loading on loading on loading on the loading on the loading on the loading on the
factor the factor the factor factor factor factor factor
Expressive Facial Poverty of Poverty of N6 lack of G7 motor Motor Quantity of Lack of Lack of distress Facial expression, ·· ··
deficit expression, content of content of spontaneity, retardation, retardation, speech, distress inconsistently vocal expression,
domain spontaneous speech speech N3 poor G5 mannerisms mannerism, and spontaneous clusters with expressive gestures,
movements, inconsistently rapport, N1 and posturing, posturing, as elaboration, this factor and quantity of speech
expressive clusters with flat affect G13 avolition well as avolition, vocal its relationship
gestures, eye this factor and inconsistently expression, with negative
contact, or negative cluster with this expressive symptoms is
affective non- symptoms factor or gestures, facial controversial
responsivity, negative expression
vocal symptoms
inflections,
poverty of
speech
Avolition– No persistence ·· Basis for N4 passive or G16 active Basis for ratings Frequency of ·· ·· Motivation for close ·· Basis for ratings
apathy at work, ratings of the apathetic social of the items is pleasure during relationships with of anhedonia
domain physical items is social avoidance behaviour activities, family, motivation for (consummatory
anergia, behaviour withdrawal, manifested by intensity of close friendships and and
recreational manifested by N2 emotional the patient, pleasure during romantic anticipatory)
interests, sexual the patient, withdrawal leading to activities, relationships, does not include
interest, leading to substantial intensity of frequency of the experiential
intimacy and substantial overlap with expected pleasurable social aspect
closeness, overlap with functioning and pleasure from activities in the past
relationships functioning poor future activities, week, frequency of
with friends and poor discrimination of Avolition: expected pleasure
discrimination secondary internal from social activities
of secondary negative experience, in the next week,
negative symptoms, Avolition: motivation for work
symptoms insufficient behaviour, or school activities,
assessment of Asociality: frequency of expected
the 3 symptoms internal pleasure from work or
of the avolition– experience, school activities in the
apathy domain, Asociality: next week,
active social behaviour motivation for
avoidance recreational activities,
inconsistently frequency of
clusters with pleasurable
negative recreational activities
symptoms in the past week,
frequency of expected
pleasure from
recreational activities
in the next week

*The two-factor structure was not confirmed by one study.112 †Inconsistent structure reported by one study.113

Table 3: Factor structure of the two domains of negative symptoms as assessed by different rating scales

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In clinical trials with acute psychotic symptoms, old and
new dopamine antagonists significantly improved
negative symptoms compared with placebo.90 In fact,
benefits for positive and negative symptoms seemed
evenly spread among all dopamine antagonists.90
However, one meta-analysis91 reported that new
dopamine antagonists (d=0·54) had a significant effect
on negative symptoms, but old ones did not. This result
might have to do with the effect of new dopamine
antagonists on secondary negative symptoms. These
drugs have relatively higher affinity for the 5-HT2
(serotonin) receptor than for the D2 (dopamine) receptor,
which might help to minimise the adverse effects
associated with D2-receptor blockade; D2-receptor
blockade causes negatives symptoms in rat models of
psychosis and healthy controls.92,93
Although clozapine was initially claimed as effective
not only for treatment of refractory positive symptoms
but also negative symptoms, it does not seem to have an
effect on primary negative symptoms.55
In all previous studies with different dopamine
antagonists, mostly in acutely ill patients, those with
amisulpride and ziprasidone seem to show the largest
effect sizes.81 However, the studies done cannot rule out
the possibility that the improvement was due to secondary
negative symptoms.94 A 26-week randomised controlled
trial95 comparing people with schizophrenia with
predominant negative symptoms showed a significant
reduction in negative symptoms for cariprazine compared
with risperidone. Since participants randomly assigned
to risperidone also showed reductions in negative
symptoms, and with no placebo control group, further
studies are needed to assess the efficacy of cariprazine for
the treatment of negative symptoms.
On the contrary, some studies suggest that dopamine
agonists, such as methylphenidate, amphetamine, lis-
dexamfetamine, selegiline, modafinil, and armodafinil,
might improve negative symptoms without any worsening
of positive symptoms in people with schizophrenia.81
However, for all these drugs, there is an absence of
independent validation or at least one study reporting
negative results.
Serotoninergic and noradrenergic drugs
A meta-analysis96 of 23 trials from 22 publications
(n=819 participants) assessing the efficacy of different
types of serotoninergic or noradrenergic drugs, or both
(SSRIs, mirtazapine, reboxetine, mianserin, trazodone,
and ritanserin) for negative symptoms reached the
conclusion that these drugs adjunctive to dopamine
antagonists work better than placebo. The overall
standardised mean difference was modestly in favour of
serotoninergic or noradrenergic drugs, or both (d=0·33).
One of the major problems with many of these studies is
that depression was not an exclusion criterion and,
therefore, improvement in secondary negative symptoms
could not be ruled out. In randomised trials with primary
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Review
Panel 4: Secondary negative symptoms—tips for assessment
Negative symptoms secondary to positive symptoms
Social withdrawal and reduced engagement in pleasurable, work, or school activities might
be due to insufficient motivation or interest, or they could be secondary to positive
symptoms. In particular, persecutory delusions, ideas of reference or distress due to
passivity experience (mind reading, thought insertion, or delusions of being controlled), as
well as command auditory hallucinations, might induce these symptoms.
The identification of negative symptoms secondary to positive symptoms requires
investigation of the internal experience of the patients. Individuals with schizophrenia
can clearly indicate whether their social withdrawal is due to distress and positive
symptoms (“I would like to meet my friends, but I am afraid of being mocked and the
voices tell me not to do so”) or due to lack of motivation (“I have no interest in going out
or meeting friends”) or whether they hang around just passing the time with no interest
in what they do.
Negative symptoms secondary to depression
In schizophrenia, depression can occur as a reaction to its burden, when psychotic
symptoms are substantially reduced or remitted, or in response to stressful life events.
In clinical practice, the presence of the subjective component of depressed mood and
other psychological features of depression, such as hopelessness, guilt, and suicidal
ideation, favour the diagnosis of depression and should be clinically assessed, whereas the
presence of blunted affect is more characteristic of negative symptoms.
Negative symptoms secondary to drug-induced parkinsonism
The retrospective or prospective assessment of the course of blunted affect and alogia with
respect to changes in antipsychotic treatment (either dose or drug changes) will assist in
the differential diagnosis. Drug-induced blunting of emotional response and alogia follows
dose increases, especially for first-generation antipsychotics, and it is associated with other
signs (extrapyramidal tremor or rigidity, gate instability), which are not part of the negative
symptom phenomenology. In case of progressive worsening, reducing the doses or
changing the class of antipsychotics (eg, switching from first to second generation or to a
D2/D3 partial agonist) can be useful to see whether the symptoms improve.
and enduring negative symptoms, in which depression
was an exclusion criterion, drugs such as fluoxetine did
not differ from placebo.97
Glutamatergic drugs
Several presynaptic and postsynaptic mechanisms
targeting glutamatergic transmission have emerged as
possible targets for treatment of negative symptoms
in schizophrenia.94 In a meta-analysis98 (n=343) of
18 randomised placebo-controlled studies with glut-
amatergic drugs, Tuominen and colleagues found a mean
reduction of four points on the PANSS–Negative
symptoms subscale. A more recent meta-analysis99
reported that D-serine, N-acetyl-cysteine (NAC), and
sarcosine (also known as N-methylglycine), as add-on
therapy to dopamine antagonists other than clozapine,
improve negative symptoms.
N-methyl-D-aspartate (NMDA)-receptor activity is
modulated in several ways, one being through the
obligatory glycine site on the NMDA receptor. Different
small-sample randomised trials have shown positive
results for drugs that act at this site when added to
 Review
antipsychotics other than clozapine.94 Drugs such as
glycine, sarcosine, NAC, D-serine, and D-cycloserine
have been shown to improve negative symptoms,
although not all studies have been positive.94
Disappointingly, the two largest trials with glycine and
Panel 5: other drugs with at least one positive study for
the treatment of negative symptoms in schizophrenia
• Monoamine oxidase B inhibitors: selegiline and rasagiline
• α7 nicotinic receptor (partial) agonists: bradanicline or
encenicline, and α7 nicotinic receptor positive allosteric
modulators
• Intranasal oxytocin
• Minocycline: a tetracycline antibiotic with potential
neuroprotective properties against glutamate neurotoxicity
• Oestrogens and selective oestrogen receptor modulators
• Serotonin 5-HT3 receptor antagonists: ondansetron,
granisetron, and tropisetron (also an α7 nicotinic
receptor agonist)
Panel 6: Negative symptoms—main achievements and controversial aspects
Achievements
1) The psychopathological dimension referred to as negative
symptoms is heterogeneous, and the failure to distinguish
between primary enduring and secondary negative
symptoms might hinder the research progress on
pathophysiological mechanisms and new treatment
discoveries, and might prevent attempts to adequately
address sources of secondary negative symptoms.
2) Established assessment instruments include items
irrelevant to the current conceptualisation of negative
symptoms, and they too often focus on behavioural
aspects ignoring internal experience, leading to an overlap
with psychosocial functioning and preventing conclusions
concerning the primary or secondary distinction.
Promising newer instruments are available and future
research might benefit from their use.
3) Factor analyses on many different datasets confirm that
negative symptoms tend to group in two factors: avolition–
apathy and expressive deficit, which suggests that future
studies should provide data on both factors instead of a
total score for negative symptoms.
4) A dimensional and a categorical approach to the study of
negative symptoms are reasonable approaches.
5) Available antipsychotic drugs are not an effective treatment
for primary and enduring negative symptoms.
6) Transnosographic studies of negative symptoms appear of
interest in the search for biomarkers and innovative
treatments, provided that recent advances in concepts and
assessment are taken into account.
7) Research on pathophysiological mechanisms and
biomarkers is rapidly progressing and might lead to the
development of innovative treatment strategies.
674 www.thelancet.com/psychiatry Vol 5 August 2018
D-cycloserine57 or D-serine100 did not show any difference
compared with placebo.
Drugs that produce positive modulation of NMDA
receptors, such as the neurosteroid pregnenolone or
7-Oxo-dehydroepiandrosterone, have shown mixed
results.94 The latest studies have been industry-sponsored
randomised trials investigating a metabotropic glu-
tamate 2/3 (mGlu2/3) receptor agonist and glycine
receptor inhibitors, with no evidence of improvement in
negative symptoms.81
Other pharmacological approaches
Several other psychopharmacological interventions,
mostly as add-on strategies to dopamine antagonists,
have been studied with respect to efficacy for improving
negative symptoms in schizophrenia. Results from
studies including this array of drugs with different
mechanisms of action are ambiguous, and many of them
have had negative symptoms as a secondary outcome. See
panel 5 for a list of drugs with at least one positive study.
Controversial aspects
1) Advances in the conceptualisation and assessment of
negative symptoms have not yet been taken into account
by drug regulatory authorities and, possibly as a
consequence, by designers of randomised controlled trials.
2) The frequent statement that negative symptoms are a core
aspect of schizophrenia is inconsistent with current major
classification systems that require the presence of at least
one psychotic symptom but not of a negative symptom for
the diagnosis of schizophrenia.
3) Schizophrenia with the presence of primary and enduring
negative symptoms and schizophrenia without primary and
enduring negative symptoms may differ in
etiopathogenesis, outcome, and response to treatment.
4) Despite the efforts aimed at clarifying the boundaries
between negative symptoms and other schizophrenia
dimensions, several controversial aspects remain, in particular,
the possibility that some, if not all, negative symptoms could
be better conceptualised as cognitive dysfunctions (eg, alogia
as an impairment of verbal fluency, or avolition–apathy as
impaired salience or reward processing).
5) Negative symptoms are present in diseases other than
schizophrenia; whether the constructs, their correlates, and
neurobiological underpinnings are homogeneous across
diagnoses remains to be clarified.
6) Systematic investigation of pathophysiological
mechanisms relevant to primary and to secondary
negative symptoms, requiring the inclusion of large
samples of participants with a broad range of negative
symptom severity, with and without comorbid conditions
(eg, depression), is still not adequately pursued.

Search strategy and selection criteria
We searched PubMed and PsycINFO for relevant publications
using the terms: “Schizophrenia” AND “negative symptom”
OR “avolition”, “apathy”, “anhedonia”, “asociality”, “social
withdrawal”, “blunted affect”, “affective flattening”,
“persistent negative symptom”, “primary negative
symptom”, “deficit schizophrenia”. The retrieved English
language publications were downloaded to an Endnote
library and further selected for their relevance to the topics of
negative symptom definition, assessment, treatment,
association with outcome, and pathophysiological models.
Further focused searches were carried out on the selected
topics. No date restrictions were applied to our search; date of
the last search was April 30, 2017.
Perspectives on negative symptom
management
After many years without any candidate mechanisms of
action or targeted interventions driven by pathophysiology
for treatment of negative symptoms, the past decade has
witnessed the emergence of several clinical trials with
negative symptoms in schizophrenia as a primary outcome.
Many studies have not followed proper methodology for
assessing primary and enduring negative symptoms92 and
have relied on small samples. Identification of biomarkers
able to define subgroups of people with negative symptoms,
who might benefit from specific mechanisms of actions
and assessment of specific negative symptoms across
different diagnoses, seem to be the next routes to follow.
Conclusions
Negative symptoms are present in more than 50% of
people with schizophrenia, have a great effect on their
real-life functioning, and pose a substantial burden on
them, their families, and health-care systems.
In light of these findings, over the past decade interest
in conceptualisation, assessment, and management of
negative symptoms has substantially increased. Main
achievements and controversial aspects requiring further
research and perhaps reconceptualisation are highlighted
in panel 6.
Contributors
SG and AM initiated, planned, and coordinated the Review. RWB and
CA provided input on project planning and several strategic decisions.
All authors reviewed the literature, drafted specific sections, and
contributed to the final version of the manuscript, providing comments
on all sections. RWB contributed to proofreading the different sections.
Declaration of interests
SG received honoraria and advisory board or consulting fees from
Angelini-Acraf, Gedeon-Richter, F Hoffman-La Roche, Janssen
Pharmaceuticals, Lundbeck, Otsuka, and Pierre Fabre. AM received
honoraria and advisory board or consulting fees from Janssen
Pharmaceuticals, Otsuka, Pfizer, and Pierre Fabre. RWB was a consultant
for Upsher-Smith Laboratories Incorporated and has received advisory-
board honoraria from AbbVie, Astellas, Boehringer Ingelheim-RCV,
ITI Incorporated, Lundbeck, and Takeda, and he has received data safety
www.thelancet.com/psychiatry Vol 5 August 2018 675
Review
monitoring board honoraria from Pfizer. CA was a consultant to or has
received honoraria or grants from CIBERSAM, Fundación Alicia Koplowitz,
Gedeon-Richter, Instituto de Salud Carlos III, Janssen Cilag, Lundbeck,
Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de
Economía y Competitividad, Otsuka, Roche, Servier, and Takeda.
Acknowledgments
CA was supported by the Madrid Regional Government
(S2010/BMD–2422 AGES), European Union Structural Funds,
and European Union Seventh Framework, and H2020 Programmes
under grant agreements FP7-HEALTH-2013-2·2·1-2-603196
(Project PSYSCAN), FP7-HEALTH-2013-2·2·1-2-602478 (Project METSY),
and Innovative Medicines Initiative 2 under grant agreement No. 115916
(Project PRISM).
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