Review

Negative symptoms of schizophrenia: new developments

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

Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on Lancet Psychiatry 2018
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
http://dx.doi.org/10.1016/
that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the
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,
A Mucci MD); Maryland
in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be
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);
and Department of Child and
Negative symptoms have been recognised as core features dimension, evidence supporting the distinction between
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
Mental, Instituto de
functions (eg, auditory hallucinations), negative symp- of present and potential future treatments.
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
Madonna delle Grazie,
symptom. They are associated with poor functional Eugen Bleuler1 described individuals with schizophrenia
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

www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6 1

 Review

interest in negative symptoms, although they have never overlap is minor, associations are weak and, despite
been regarded as core symptoms of schizophrenia in nearly all people with schizophrenia having some degree
classification systems. of cognitive impairment, only half of them experience
negative symptoms.22 Additionally, the possibility should
Current conceptualisation of negative symptoms be considered that avolition might lead to poor
In the past decade, negative symptoms have received performance on cognitive assessment tasks.26
increased attention because of their effect on real-life An association between conceptual disorganisation
functioning of people with schizophrenia. The dearth of and negative symptoms has sometimes been assumed27
effective therapeutic interventions and the inconsistency and might be partly due to the presence of items related
of research findings relevant to the neurobiological to conceptual disorganisation in instruments traditionally
underpinnings of negative symptoms have highlighted used to assess negative symptoms.
the need for a reconceptualisation of this dimension. The distinction between depression and negative
The association between negative and positive symp- symptoms is also challenging because of the commonalities
toms has been differently conceptualised over time. in clinical presentation, such as diminished emotional
John Hughlings Jackson2 regarded negative symptoms as expression, anhedonia, social withdrawal, and apathy.
the direct expression of the loss of function of the higher However, negative symptoms and depression are separable
nervous system levels; positive symptoms, instead, were symptom domains according to factor analysis studies,28
regarded as secondary—ie, due to the disinhibition of and they can be distinguished by accurate clinical
lower levels previously controlled by the higher ones. assessment.
Other authors have defended the independence of the Important progress has been made in the
two dimensions.15 The idea that a common patho­ acknowledgment of the heterogeneity of negative
physiology is at the origin of both negative and positive symptoms, the importance of differentiating primary
symptoms has not been supported by evidence, and from secondary and persistent from transient negative
several studies have indicated that negative symptoms symptoms, and the need to overcome diversities among
are independent from positive symptoms, cognitive research groups with respect to defining the main
dysfunctions, disorganisation, and depression.9 However, constructs to be included in the negative symptom
clear boundaries are not always possible to identify. dimension. A consensus has been achieved on the main
Despite the largely documented independence of constructs to be included in the negative symptom
negative from positive symptoms,22 substantial evidence dimension—ie, alogia, blunted affect, anhedonia,
indicates that the longer the duration of untreated asociality, and avolition.9 A brief definition of each
psychosis, the greater the severity of negative symptoms.23 symptom is provided in panel 1.
These data need to be further assessed in longitudinal In contrast, no consensus has emerged so far on
research designs to exclude the possibility that longer whether a categorical or a dimensional approach is better
duration of untreated psychosis in patients with negative suited to negative symptoms. Evidence supporting the
symptoms is the result of an insidious onset that might validity of the categorical approach has been produced
delay presentation of cases and entry into treatment.24 for the deficit schizophrenia construct (ie, the subtype of
Associations between positive and negative symptoms schizophrenia characterised by the presence of primary
might also result from assessments focusing on and persistent negative symptoms).29–32 However, evi-
behavioural aspects instead of internal experience. dence supporting the dimensional perspective is also
Regarding the boundaries between negative symptoms available; negative symptoms are observed in disorders
and cognitive impairments, it is important to point out apart from schizophrenia, such as schizoaffective
that both domains have strong associations with real-life disorder, depression, at-risk mental states, and in the
functioning; since many studies have used assessment general population.22,33 In the past 5 years, studies have
instruments that include poor attention as a component been done to identify which negative symptom domains
of the negative symptom construct, it is difficult to say are present in which disorder;34–36 however, the evolution
whether commonalities between the two dimensions are of definitions and assessment instruments has not
partly explained by this confounder. Some overlap cannot happened in the same way as for schizophrenia.
be excluded when considering, for instance, that an
impairment of executive function might interfere with Course of negative symptoms
goal-directed behaviour necessary for the acquisition of The available data indicate that negative symptoms are
reward, which is currently conceptualised as a mechanism present early in the course of illness, largely before an
contributing to avolition;25 poor verbal fluency (ie, a deficit acute psychotic episode leading to a diagnosis of
in the ability to retrieve information from memory) is schizophrenia,37–39 and, according to some findings, they
thought to underlie alogia and poor social cognition predict the eventual psychotic episode.39
might result in or be the result of asociality.25 However, Longitudinal and retrospective studies37,38,40–42 frequently
although further studies are needed to better define report the presence of asociality and trait anhedonia
boundaries, it should be stressed that the degree of since childhood and early adolescence, as well as in the

2 www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6

 Review

prodromal phase, in people later diagnosed with

schizophrenia or schizophrenia-spectrum disorders. Panel 1: Definition of negative symptoms*
Asociality has also been reported37,43,44 as a prodromal Blunted affect
symptom of other non-psychotic disorders, such as major Decrease in the expression of emotion and reactivity to events
depressive disorder, of ultra-high-risk people who later do as observed during the spontaneous or elicited expression of
not convert to psychosis, and of anxiety disorders. The emotion (facial and vocal expression and expressive gestures)
instruments used to assess asociality in these studies
(eg, parent or teacher ratings or observation of the child or Alogia
adolescent’s social impairment) placed a strong emphasis Reduction in quantity of words spoken and in spontaneous
on behaviour, so whether the reported social impairment elaboration (ie, amount of information spontaneously given
was due to factors other than asociality (eg, poor cognitive beyond what is needed to answer a question)
abilities, social anxiety, or antisocial traits) is not clear. Asociality
Furthermore, the associations between the asociality Reduced social interactions and initiative due to decreased
ratings before and after the diagnosis of schizophrenia motivation for and interest in forming and maintaining
were not investigated. Only one study45 assessed childhood relationships with others
social withdrawal in people with deficit schizophrenia and
those with non-deficit schizophrenia, with the use of the Anhedonia
Child Behaviour Checklist to obtain a retrospective Reduced experience of pleasure for a variety of activities or
assessment of parent-rated social withdrawal (with parents events, during the activity or event (consummatory
blind to the categorisation). The study found more severe anhedonia) and for future anticipated activities or events
social withdrawal in deficit schizophrenia than in non- (anticipatory anhedonia)
deficit schizophrenia. Avolition
For anhedonia, the trait measures used in prepsychotic Reduced initiation and persistence of goal-directed activity
periods showed no association with negative symptoms due to reduced motivation
in adults with schizophrenia-spectrum or other psychotic
disorders.46,47 No retrospective or longitudinal study *Following the National Institute of Mental Health–Measurement and Treatment
Research to Improve Cognition in Schizophrenia (NIMH–MATRICS) consensus statement9
has investigated the association of trait anhedonia
with primary and enduring negative symptoms.
Cross-sectional studies48,49 reported greater severity of trait manifestations of the underlying pathophysiology of
anhedonia in people with deficit schizophrenia than schizophrenia or secondary to other factors. Primary and
people with non-deficit schizophrenia. secondary negative symptoms can be transient or
Only a few long-term longitudinal studies50,51 have enduring, although distinguishing primary and transient
examined symptom stability. The course of broadly negative symptoms from secondary negative symptoms
defined negative symptoms was heterogeneous over a is not always possible. Primary and enduring negative
10-year follow-up in participants with first episode symptoms have been termed deficit symptoms.21 Several
psychosis, with various diagnoses. In more than half of studies12,29,32,53 have shown the validity of subgrouping
the sample, negative symptoms had a continuous people with schizophrenia into those with deficit
(134 of 496, 27%) or relapsing (129 of 496, 26%) course. symptoms (deficit schizophrenia) and those without
Predictors of the continuous course were moderate deficit symptoms (non-deficit schizophrenia).
severity of the negative symptoms and presence of Negative symptoms might be secondary to positive,
disorganisation symptoms at baseline, schizophrenia affective, or extrapyramidal symptoms, antipsychotic-
diagnosis, male gender, and poor premorbid adjustment.51 induced sedation, environmental deprivation, and other
A meta-analysis52 including 89 studies reported an illness-related and treatment-related factors.54
overall improvement of negative symptoms over time Differentiation of primary and secondary negative
with all treatments (including placebo); however, those symptoms has important treatment implications since
studies did not attempt to assess pseudospecificity no known effective treatments exist for primary negative
(ie, whether improvement was related to changes in or deficit symptoms. In contrast to primary negative
other aspects of the syndrome, such as depression, symptoms, secondary negative symptoms might be
positive symptoms, or extrapyramidal side-effects). responsive to available treatments;13,54 for example,
Elevated stability of deficit features (ranging from 67% to negative symptoms secondary to positive symptoms
more than 80%) was found in longitudinal studies.12, 53 might be responsive to effective antipsychotic treatment,
whereas negative symptoms secondary to depression
Heterogeneity of negative symptoms might be responsive to antidepressant treatment. The
Primary and secondary negative symptoms failure to differentiate primary from secondary negative
Negative symptoms are a heterogeneous group of symptoms has complicated efforts to develop effective
symptoms that might differ in cause, longitudinal treatments for negative symptoms because including
course, and treatment.21 They are either primary secondary negative symptoms might lead to apparent

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 Review

improvements in the negative symptom outcome symptoms that are not conceptually related to negative
measure, which reflect indirect or pseudospecific symptoms are excluded.58 The two factors that emerge
changes in negative symptoms rather than a direct from these studies suggest that negative symptoms
therapeutic effect of the study intervention.55 might be subdivided into two independent dimensions:
Unfortunately, secondary negative symptoms might not avolition–apathy, and expressive deficit.
be responsive to treatment of their underlying cause. Three studies59–61 have examined the factor structure of
A substantial number of people with schizophrenia have negative symptoms in people with deficit schizophrenia.
primary or secondary negative symptoms, enduring over The Schedule for the Deficit Syndrome (SDS)62 was used
time.12,56 The attempt to identify people with enduring to assess six negative symptoms. The avolition–apathy
primary or secondary negative symptoms for purposes of and expressive deficit factors were each defined by
research into the pathophysiological cause or treatment three symptoms (panel 2).
of negative symptoms has led to additional conceptual The two-factor solution has also been found in people
models for defining negative symptoms, the two most with schizophrenia with a combination of primary and
important of which are the concept of predominant and secondary negative symptoms.8,10,30,61,63 In these studies,
persistent negative symptoms.12,56 Both constructs lead to negative symptoms were assessed with the Brief Negative
the identification of a population of people with Symptom Scale (BNSS),8,63 the SDS,30,61 and the Clinical
schizophrenia with disabling negative symptoms, which Assessment Interview for Negative Symptoms (CAINS).10
is markedly larger than the population with deficit The delineation of two independent negative symptom
schizophrenia. dimensions has at least two important implications. First,
Research participants with predominant negative the two dimensions might differ in their associations
symptoms are characterised by moderate to severe with course of illness and other psychopathological
negative symptoms of greater relative severity than dimensions.25 In a study61 of almost 200 participants
co-occurring positive symptoms—ie, rating scale scores with schizophrenia, the avolition–apathy factor was
greater for negative than positive symptoms—but with no differentially associated with increased positive symp-
attempt to limit the absolute severity of positive symptoms toms, increased rates of hospital admission, poorer social
or other symptom domains. In contrast, people with function, and greater social cognition impairment
schizophrenia with persistent negative symptoms are also compared with the expressive deficit factor. Second, the
characterised by moderate to severe negative symptoms, two dimensions might differ in their response to
but upper limits are placed on the severity of positive, therapeutic interventions. In a study64 of cognitive therapy
affective, and extrapyramidal symptoms.56 The combin- for negative symptoms, cognitive therapy significantly
ation of the two sets of persistent negative symptom improved the Scale for the Assessment of Negative
criteria leads to the enrichment of the study sample, with Symptoms (SANS) avolition–apathy item, but it had no
respect to people with deficit schizophrenia.56,57 The other effect on measures of emotional expression. Similarly, in
major advantage associated with use of the persistent a study65 of the selective monoamine oxidase B inhibitor,
negative symptom construct is that it allows for control of rasagiline, the observed negative symptom benefit was
potential sources of indirect changes to negative symptoms largely due to its effect on the SANS avolition–apathy
during the course of clinical trials. item. These results suggest that future studies of
innovative therapeutic interventions might want to assess
Negative symptom domains the effect of the experimental intervention on each of the
Interest in whether negative symptoms represent a two negative symptom dimensions separately.
monolithic construct or have a multidimensional
structure has been considerable. The results of factor Theories of causation
analysis studies have supported two-factor, three-factor, Pathophysiological mechanisms of negative symptoms
or five-factor models of negative symptoms.58 However, a are still unclear.25,33 The increasing acknowledgment of
two-factor solution tends to be more likely when the heterogeneity of negative symptoms has fostered the
construction of separate hypotheses for the avolition–
Panel 2: Deficit symptom factor structure apathy and expressive deficit domains; however, only
rarely have these models been tested in participants with
Avolition–apathy: persistent and primary negative symptoms.
• Curbed interests
• Diminished sense of purpose Avolition–apathy domain
• Diminished social drive In present conceptualisations, avolition–apathy is hypo-
Expressive deficit: thesised to be related to deficits in different aspects of
• Restricted affect motivation (panel 3).66,67 The neural bases of motivation
• Diminished emotional range are shown in figure 1.66,67 People with schizophrenia are
• Poverty of speech often impaired in reward anticipation, valuation of
stimuli and actions, and incentive learning (over short

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 Review

trials); they also show excessive effort-discounting,

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

Internal context and

Expressive deficit domain action retrieval

Pathophysiological mechanisms of blunted affect and

Figure 1: The neural bases of the different aspects of motivation
alogia have been investigated less than those related For motivational salience, dopamine neurons are activated for both positive and negative aspects; whereas for the
to avolition–apathy. In particular, these negative motivational value system, dopamine neurons are activated only for positive aspects. *National Institute of
symptoms are hypothesised to be related to neuro- Mental Health research domain criteria, positive valence system.
cognitive or social cognition deficits.25 An association of
expressive deficit with neurocognitive impairment has associations of avolition–apathy and expressive deficit
been found in patients experiencing their first psychotic with cognitive impairment should be further investigated.
episode and in those with chronic schizophrenia.7,72
In drug-naive participants with deficit schizophrenia, Assessment of negative symptoms
expressive deficit was associated with soft neurological Assessment of negative symptoms in the research context
signs73 suggesting a relation of the domain with has a long history. Several validated instruments are
subtle, diffuse neurodevelopmental abnormalities. The available with good to excellent psychometric properties.74

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 Review

disorganisation (table 1), is assessment of the avolition–

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

6 www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6

 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

to shared pathophysiological mechanisms; the evidence is primary and secondary negative symptoms is of the
insufficient to draw any firm conclusions. Panel 4 utmost importance, as is the state versus trait
summarises the main sources of secondary negative (persistent) characteristics of the negative symptoms,
symptoms and tips for assessment. and the concept of persistent or predominant negative
symptoms.
Management of negative symptoms with No treatments have shown robust efficacy in treating
non-pharmacological treatments primary and enduring negative symptoms. Thus, negative
When interpreting clinical trials assessing negative symptoms are less amenable to treatment than other
symptoms in schizophrenia, the distinction between 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 framework and personalised treatment planning showed
Psychosocial approaches to treating negative symptoms significant improvements compared with when based on
in schizophrenia include individual psychological, standard treatment in avolition–apathy (d=0·66). The
psychoeducational, and family interventions.81 The most central goals of this cognitive therapy were to undercut
studied by far has been social skill training (SST). One nihilistic beliefs and con­comitantly increase motivation
review82 and one meta-analysis83 have found SST to be for constructive activity. Recent approaches include
better than other interventions. However both review packages that combine several different interventions (eg,
and meta-analysis point that the studies included have environmental support, CBT, and SST).88
important methodological limitations, such as small Direct comparisons of different psychosocial inter-
sample sizes, lack of standardisation of negative ventions for the treatment of negative symptoms in
symptom assessments, and short follow-ups.81 schizophrenia seem to favour SST over the other
Family interventions, alone or in combination with other interventions.83 However, more controlled trials with
treatments, such as psychoeducation, communication negative symptoms as the primary outcome are clearly
training, behavioural problem solving, and crisis manage­ needed before any conclusions can be drawn. The
ment, have shown initial promising results.84–86 However, recommendations made to assess efficacy for negative
variation in the type of family intervention complicates the symptoms in clinical trials should apply not only to
interpretation of these studies. pharmacological trials, but also to trials of psychosocial
Cognitive behavioural therapy (CBT) applied to interventions.89
schizophrenia was originally developed for the treatment
of positive symptoms. Even though few studies Management of negative symptoms with
have focused primarily on negative symptoms, two meta- psychopharmacological treatments
analyses of negative symptoms as a secondary outcome Dopamine antagonists and dopamine agonists
indicate a significant effect of CBT.87 In a study by Grant The only mechanism of action common to all drugs
and colleagues,64 cognitive therapy based on a goal-directed used to treat psychosis is dopamine antagonism. In

8 www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6

 Scale for the Assessment of Negative Positive and Negative Syndrome Scale– Brief Negative Symptom Scale (BNSS)* Clinical Assessment Interview for Negative Symptoms
Symptoms (SANS) 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

www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6

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
Review

9
 Review

amisulpride and ziprasidone seem to show the largest

Panel 4: Secondary negative symptoms—tips for assessment effect sizes.81 However, the studies done cannot rule out
Negative symptoms secondary to positive symptoms the possibility that the improvement was due to secondary
Social withdrawal and reduced engagement in pleasurable, work, or school activities might negative symptoms.94 A 26-week randomised controlled
be due to insufficient motivation or interest, or they could be secondary to positive trial95 comparing people with schizophrenia with
symptoms. In particular, persecutory delusions, ideas of reference or distress due to predominant negative symptoms showed a significant
passivity experience (mind reading, thought insertion, or delusions of being controlled), as reduction in negative symptoms for cariprazine compared
well as command auditory hallucinations, might induce these symptoms. with risperidone. Since participants randomly assigned
to risperidone also showed reductions in negative
The identification of negative symptoms secondary to positive symptoms requires
symptoms, and with no placebo control group, further
investigation of the internal experience of the patients. Individuals with schizophrenia
studies are needed to assess the efficacy of cariprazine for
can clearly indicate whether their social withdrawal is due to distress and positive
the treatment of negative symptoms.
symptoms (“I would like to meet my friends, but I am afraid of being mocked and the
On the contrary, some studies suggest that dopamine
voices tell me not to do so”) or due to lack of motivation (“I have no interest in going out
agonists, such as methylphenidate, amphetamine, lis-
or meeting friends”) or whether they hang around just passing the time with no interest
dexamfetamine, selegiline, modafinil, and armodafinil,
in what they do.
might improve negative symptoms without any worsening
Negative symptoms secondary to depression of positive symptoms in people with schizophrenia.81
In schizophrenia, depression can occur as a reaction to its burden, when psychotic However, for all these drugs, there is an absence of
symptoms are substantially reduced or remitted, or in response to stressful life events. independent validation or at least one study reporting
In clinical practice, the presence of the subjective component of depressed mood and
negative results.
other psychological features of depression, such as hopelessness, guilt, and suicidal
ideation, favour the diagnosis of depression and should be clinically assessed, whereas the
Serotoninergic and noradrenergic drugs
presence of blunted affect is more characteristic of negative symptoms.
A meta-analysis96 of 23 trials from 22 publications
(n=819 participants) assessing the efficacy of different
Negative symptoms secondary to drug-induced parkinsonism types of serotoninergic or noradrenergic drugs, or both
The retrospective or prospective assessment of the course of blunted affect and alogia with (SSRIs, mirtazapine, reboxetine, mianserin, trazodone,
respect to changes in antipsychotic treatment (either dose or drug changes) will assist in and ritanserin) for negative symptoms reached the
the differential diagnosis. Drug-induced blunting of emotional response and alogia follows conclusion that these drugs adjunctive to dopamine
dose increases, especially for first-generation antipsychotics, and it is associated with other antagonists work better than placebo. The overall
signs (extrapyramidal tremor or rigidity, gate instability), which are not part of the negative standardised mean difference was modestly in favour
symptom phenomenology. In case of progressive worsening, reducing the doses or of serotoninergic or noradrenergic drugs, or both
changing the class of antipsychotics (eg, switching from first to second generation or to a (d=0·33). One of the major problems with many of
D2/D3 partial agonist) can be useful to see whether the symptoms improve. these studies is that depression was not an exclusion
criterion and, therefore, improvement in secondary
negative symptoms could not be ruled out. In
clinical trials with acute psychotic symptoms, old and randomised trials with primary and enduring negative
new dopamine antagonists significantly improved symptoms, in which depression was an exclusion
negative symptoms compared with placebo.90 In fact, criterion, drugs such as fluoxetine did not differ from
benefits for positive and negative symptoms seemed placebo.97
evenly spread among all dopamine antagonists.90
However, one meta-analysis91 reported that new Glutamatergic drugs
dopamine antagonists (d=0·54) had a significant effect Several presynaptic and postsynaptic mechanisms
on negative symptoms, but old ones did not. This result targeting glutamatergic transmission have emerged as
might have to do with the effect of new dopamine possible targets for treatment of negative symptoms
antagonists on secondary negative symptoms. These in schizophrenia.94 In a meta-analysis98 (n=343) of
drugs have relatively higher affinity for the 5-HT2 18 randomised placebo-controlled studies with glut-
(serotonin) receptor than for the D2 (dopamine) receptor, amatergic drugs, Tuominen and colleagues found a mean
which might help to minimise the adverse effects reduction of four points on the PANSS–Negative
associated with D2-receptor blockade; D2-receptor symptoms subscale. A more recent meta-analysis99
blockade causes negatives symptoms in rat models of reported that D-serine, N-acetyl-cysteine (NAC), and
psychosis and healthy controls.92,93 sarcosine (also known as N-methylglycine), as add-on
Although clozapine was initially claimed as effective therapy to dopamine antagonists other than clozapine,
not only for treatment of refractory positive symptoms improve negative symptoms.
but also negative symptoms, it does not seem to have an N-methyl-D-aspartate (NMDA)-receptor activity is
effect on primary negative symptoms.55 modulated in several ways, one being through the
In all previous studies with different dopamine obligatory glycine site on the NMDA receptor. Different
antagonists, mostly in acutely ill patients, those with small-sample randomised trials have shown positive

10 www.thelancet.com/psychiatry Published online March 27, 2018 http://dx.doi.org/10.1016/S2215-0366(18)30050-6

 Review

results for drugs that act at this site when added to Disappointingly, the two largest trials with glycine and
antipsychotics other than clozapine.94 Drugs such as D-cycloserine57 or D-serine100 did not show any difference
glycine, sarcosine, NAC, D-serine, and D-cycloserine compared with placebo.
have been shown to improve negative symptoms, Drugs that produce positive modulation of NMDA
although not all studies have been positive.94 receptors, such as the neurosteroid pregnenolone or
7-Oxo-dehydroepiandrosterone, have shown mixed
results.94 The latest studies have been industry-sponsored
Panel 5: other drugs with at least one positive study for randomised trials investigating a metabotropic glu-
the treatment of negative symptoms in schizophrenia tamate 2/3 (mGlu2/3) receptor agonist and glycine
• Monoamine oxidase B inhibitors: selegiline and rasagiline receptor inhibitors, with no evidence of improvement in
• α7 nicotinic receptor (partial) agonists: bradanicline or negative symptoms.81
encenicline, and α7 nicotinic receptor positive allosteric
modulators Other pharmacological approaches
• Intranasal oxytocin Several other psychopharmacological interventions,
• Minocycline: a tetracycline antibiotic with potential mostly as add-on strategies to dopamine antagonists,
neuroprotective properties against glutamate neurotoxicity have been studied with respect to efficacy for improving
• Oestrogens and selective oestrogen receptor modulators negative symptoms in schizophrenia. Results from
• Serotonin 5-HT3 receptor antagonists: ondansetron, studies including this array of drugs with different
granisetron, and tropisetron (also an α7 nicotinic mechanisms of action are ambiguous, and many of them
receptor agonist) have had negative symptoms as a secondary outcome. See
panel 5 for a list of drugs with at least one positive study.

Panel 6: Negative symptoms—main achievements and controversial aspects

Achievements Controversial aspects
1) The psychopathological dimension referred to as negative 1) Advances in the conceptualisation and assessment of
symptoms is heterogeneous, and the failure to distinguish negative symptoms have not yet been taken into account
between primary enduring and secondary negative by drug regulatory authorities and, possibly as a
symptoms might hinder the research progress on consequence, by designers of randomised controlled trials.
pathophysiological mechanisms and new treatment 2) The frequent statement that negative symptoms are a core
discoveries, and might prevent attempts to adequately aspect of schizophrenia is inconsistent with current major
address sources of secondary negative symptoms. classification systems that require the presence of at least
2) Established assessment instruments include items one psychotic symptom but not of a negative symptom for
irrelevant to the current conceptualisation of negative the diagnosis of schizophrenia.
symptoms, and they too often focus on behavioural 3) Schizophrenia with the presence of primary and enduring
aspects ignoring internal experience, leading to an overlap negative symptoms and schizophrenia without primary and
with psychosocial functioning and preventing conclusions enduring negative symptoms may differ in
concerning the primary or secondary distinction. etiopathogenesis, outcome, and response to treatment.
Promising newer instruments are available and future 4) Despite the efforts aimed at clarifying the boundaries
research might benefit from their use. between negative symptoms and other schizophrenia
3) Factor analyses on many different datasets confirm that dimensions, several controversial aspects remain, in particular,
negative symptoms tend to group in two factors: avolition– the possibility that some, if not all, negative symptoms could
apathy and expressive deficit, which suggests that future be better conceptualised as cognitive dysfunctions (eg, alogia
studies should provide data on both factors instead of a as an impairment of verbal fluency, or avolition–apathy as
total score for negative symptoms. impaired salience or reward processing).
4) A dimensional and a categorical approach to the study of 5) Negative symptoms are present in diseases other than
negative symptoms are reasonable approaches. schizophrenia; whether the constructs, their correlates, and
5) Available antipsychotic drugs are not an effective treatment neurobiological underpinnings are homogeneous across
for primary and enduring negative symptoms. diagnoses remains to be clarified.
6) Transnosographic studies of negative symptoms appear of 6) Systematic investigation of pathophysiological
interest in the search for biomarkers and innovative mechanisms relevant to primary and to secondary
treatments, provided that recent advances in concepts and negative symptoms, requiring the inclusion of large
assessment are taken into account. samples of participants with a broad range of negative
7) Research on pathophysiological mechanisms and symptom severity, with and without comorbid conditions
biomarkers is rapidly progressing and might lead to the (eg, depression), is still not adequately pursued.
development of innovative treatment strategies.

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 Review

Acknowledgments
Search strategy and selection criteria CA was supported by the Madrid Regional Government
(S2010/BMD–2422 AGES), European Union Structural Funds,
We searched PubMed and PsycINFO for relevant publications using the terms: and European Union Seventh Framework, and H2020 Programmes
“Schizophrenia” AND “negative symptom” OR “avolition”, “apathy”, “anhedonia”, under grant agreements FP7-HEALTH-2013-2·2·1-2-603196
“asociality”, “social withdrawal”, “blunted affect”, “affective flattening”, “persistent (Project PSYSCAN), FP7-HEALTH-2013-2·2·1-2-602478 (Project METSY),
and Innovative Medicines Initiative 2 under grant agreement No. 115916
negative symptom”, “primary negative symptom”, “deficit schizophrenia”. The retrieved (Project PRISM).
English language publications were downloaded to an Endnote library and further
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