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,
ReviewNegative symptoms of schizophrenia: new developments and unanswered research questions
Introduction
Negative symptoms have been recognised as core features of schizophrenia since the first descriptions of the disorder.1, 2, 3 In contrast with positive symptoms, which are thought to reflect an excess or distortion of normal functions (eg, auditory hallucinations), negative symp-toms have been regarded as a reduction of normal functions either related to motivation and interest, such as avolition, anhedonia, and asociality, or to expressive functions such as blunted affect and alogia.
Negative symptoms are frequently observed; two large cross-sectional retrospective studies4, 5 involving more than 1000 people with schizophrenia reported that over 50% of study participants had at least one negative symptom. They are associated with poor functional outcome6, 7 and pose a substantial burden on people with schizophrenia, their families, and health-care systems. In light of these associations, interest in negative symptoms has grown over the past decade, and they have become a key target for the development of new treatments. However, progress in relevant fields of research has been slow and negative symptoms remain a crucial unmet therapeutic need.
Although psychiatrists are familiar with the concept of negative symptoms of schizophrenia, misconceptions and uncertainties about the correct identification and management of these symptoms remain.
In the past decade, efforts to improve the con-ceptualisation and assessment of negative symptoms have contributed to reducing their overlap with other schizophrenia dimensions and identifying the areas in which borders are still poorly defined.8, 9, 10 The heterogeneity of the negative symptom dimension is acknowledged and regarded as a potential confounder in research and education, and an obstacle to correct management of some secondary negative symptoms which are amenable to treatment.11, 12, 13
This Review will cover the main advances in conceptualisation and assessment of negative symptoms of schizophrenia, findings relevant to identification of two different subdomains within the negative symptom dimension, evidence supporting the distinction between primary and secondary negative symptoms, boundaries with other schizophrenia dimensions, and advances in pathogenetic hypotheses, and it will provide an overview of present and potential future treatments.
Section snippets
Brief history of negative symptom conceptualisation
Traditional conceptualisations of negative symptoms have regarded these symptoms as a core component of schizophrenia.1, 2, 3 Two aspects have dominated the description of negative symptoms: the reduction of emotional expression and the loss of motivation. Eugen Bleuler1 described individuals with schizophrenia as having expressionless faces, being indifferent towards everything, and having no urge to do anything either on their own initiative or at the bidding of another. Emil Kraepelin3
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, 38, 39 and, according to some findings, they predict the eventual psychotic episode.39
Longitudinal and retrospective studies37, 38, 40, 41, 42 frequently report the presence of asociality and trait anhedonia since childhood and early adolescence, as well as in the prodromal phase, in people later diagnosed with
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
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.
Assessment of negative symptoms
Assessment of negative symptoms in the research context has a long history. Several validated instruments are 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,
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
Dopamine antagonists and dopamine agonists
The only mechanism of action common to all drugs used to treat psychosis is dopamine antagonism. 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.
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
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.
Search strategy and selection criteria
References (100)
- et al.
Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms, and health status
World Psychiatry
(2012) - et al.
Dissecting negative symptoms of schizophrenia: history, assessment, pathophysiological mechanisms and treatment
Schizophr Res
(2017) - et al.
Primary and persistent negative symptoms: concepts, assessments and neurobiological bases
Schizophr Res
(2017) - et al.
Secondary negative symptoms—a review of mechanisms, assessment and treatment
Schizophr Res
(2017) - et al.
Huber's basic symptoms: another approach to negative psychopathology in schizophrenia
Compr Psychiatry
(1984) - et al.
Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders
Eur Neuropsychopharmacol
(2014) - et al.
Duration of untreated psychosis and negative symptoms—a systematic review and meta-analysis of individual patient data
Schizophr Res
(2012) - et al.
Persistent negative symptoms in first episode patients with schizophrenia: results from the European First Episode Schizophrenia Trial
Eur Neuropsychopharmacol
(2013) - et al.
Intrinsic motivation, neurocognition and psychosocial functioning in schizophrenia: testing mediator and moderator effects
Schizophr Res
(2008) - et al.
Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia
Schizophr Res
(2012)
Categorical and dimensional approaches to negative symptoms of schizophrenia: focus on long-term stability and functional outcome
Schizophr Res
Examining the latent structure of negative symptoms: is there a distinct subtype of negative symptom schizophrenia?
Schizophr Res
Modeling the role of negative symptoms in determining social functioning in individuals at clinical high risk of psychosis
Schizophr Res
Systematic meta-analysis of childhood social withdrawal in schizophrenia, and comparison with data from at-risk children aged 9–14 years
J Psychiatr Res
Cognitive functioning and anhedonia in subjects at risk for schizophrenia
Schizophr Res
Prodromal symptoms of schizophrenia in first-episode psychosis: prevalence and specificity
Compr Psychiatry
Characterization of premorbid functioning during childhood in patients with deficit vs non-deficit schizophrenia and in their healthy siblings
Schizophr Res
Anhedonia and negative symptomatology in chronic schizophrenia
Compr Psychiatry
Anhedonia and the deficit syndrome of schizophrenia
Psychiatry Res
Neurocognitive, social, and emotional dysfunction in deficit syndrome schizophrenia
Schizophr Res
Flat affect and social functioning: a 10-year follow-up study of first episode psychosis patients
Schizophr Res
Long-term trajectories of positive and negative symptoms in first episode psychosis: a 10-year follow-up study in the OPUS cohort
Schizophr Res
A two-factor structure for the Schedule for the Deficit Syndrome in schizophrenia
Psychiatry Res
Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome
J Psychiatr Res
The Schedule for the Deficit Syndrome: an instrument for research in schizophrenia
Psychiatry Res
The Brief Negative Symptom Scale (BNSS): independent validation in a large sample of Italian patients with schizophrenia
Eur Psychiatry
Dopamine in motivational control: rewarding, aversive, and alerting
Neuron
Corticostriatal control of goal-directed action is impaired in schizophrenia
Biol Psychiatry
Negative symptom subgroups have different effects on the clinical course of schizophrenia after the first episode: a 24-month follow up study
Eur Psychiatry
Defining and measuring negative symptoms of schizophrenia in clinical trials
Eur Neuropsychopharmacol
Dimensional structure of psychotic symptoms: an item-level analysis of SAPS and SANS symptoms in psychotic disorders
Schizophr Res
Two subdomains of negative symptoms in psychotic disorders: established and confirmed in two large cohorts
J Psychiatr Res
Psychosocial treatments for negative symptoms in schizophrenia: current practices and future directions
Clin Psychol Rev
Psychosocial treatments for negative symptoms in schizophrenia: current practices and future directions
Clin Psychol Rev
A randomized pilot study of MOtiVation and Enhancement (MOVE) Training for negative symptoms in schizophrenia
Schizophr Res
Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia
Schizophr Res
Pharmacological approaches to treating negative symptoms: a review of clinical trials
Schizophr Res
Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial
Lancet
Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis
Schizophr Res
Dementia praecox or the group of schizophrenias
Selected writings of JH Jackson
Dementia praecox and paraphrenia
Impact of negative symptoms on healthcare resource utilization and associated costs in adult outpatients with schizophrenia: a population-based study
BMC Psychiatry
Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study
J Clin Psychiatry
The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia
World Psychiatry
The brief negative symptom scale: psychometric properties
Schizophr Bull
The NIMH-MATRICS consensus statement on negative symptoms
Schizophr Bull
The Clinical Assessment Interview for Negative Symptoms (CAINS): final development and validation
Am J Psychiatry
Psychiatrie du médecin praticien
Méthodes chimiothérapiques en psychiatrie
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