Elsevier

The Lancet Psychiatry

Volume 5, Issue 8, August 2018, Pages 664-677
The Lancet Psychiatry

Review
Negative symptoms of schizophrenia: new developments and unanswered research questions

https://doi.org/10.1016/S2215-0366(18)30050-6Get rights and content

Summary

Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition–apathy and expressive deficit. Failure to take this heterogeneity into account might hinder progress in research on neurobiological substrates and discoveries of treatments for primary or enduring negative symptoms. Improvement in recognition and routine assessment of negative symptoms is instrumental for correct management of secondary negative symptoms that are amenable to treatment. If substantial progress is to be made in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be integrated into the design of future studies of these symptoms.

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

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,

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