Secondary negative symptoms — A review of mechanisms, assessment and treatment

Abstract

Negative symptoms in schizophrenia may be classified as primary or secondary. Primary negative symptoms are thought to be intrinsic to schizophrenia, while secondary negative symptoms are caused by positive symptoms, depression, medication side-effects, social deprivation or substance abuse. Most of the research on secondary negative symptoms has aimed at ruling them out in order to isolate primary negative symptoms. However, secondary negative symptoms are common and can have a major impact on patient-relevant outcomes. Therefore, the assessment and treatment of secondary negative symptoms are clinically relevant. Furthermore, understanding the mechanisms underlying secondary negative symptoms can contribute to an integrated model of negative symptoms. In this review we provide an overview of concepts, evidence, assessment and treatment for the major causes of secondary negative symptoms. We also summarize neuroimaging research relevant to secondary negative symptoms. We emphasize the relevance of recent developments in psychopathological assessment of negative symptoms, such as the distinction between amotivation and diminished expression, which have only rarely been applied in research on secondary negative symptoms.

Introduction

Negative symptoms are a core deficit in schizophrenia and can be considered to represent two dimensions (Blanchard and Cohen, 2006, Liemburg et al., 2013, Strauss et al., 2014). First, the motivational dimension, which we refer to as amotivation, combines anhedonia, avolition, and asociality. Second, the diminished expression dimension includes blunted affect and alogia. Negative symptoms contribute strongly to poor functional outcome and reduced quality of life (Milev et al., 2005, Strauss et al., 2010, Strauss et al., 2013, Galderisi et al., 2013, Galderisi et al., 2014). An important causal distinction has been made between primary and secondary negative symptoms (Fig. 1). Primary negative symptoms are thought to be intrinsic to schizophrenia, while secondary negative symptoms are caused by positive symptoms, depression, medication side-effects, social deprivation and substance abuse (Carpenter et al., 1985, Kirkpatrick, 2014). Most research employing this distinction has focused on the definition of primary and persistent negative symptoms or deficit symptoms and has not focused on secondary negative symptoms as a primary outcome measure (Carpenter et al., 1988, Kirkpatrick et al., 1989). However, secondary negative symptoms have considerable clinical relevance for two reasons. First, secondary negative symptoms are more prevalent than primary negative symptoms and occur in more than half of patients with schizophrenia (Bobes et al., 2010, Lyne et al., 2015). Second, since secondary negative symptoms have often clearly defined causes, they should be easier to treat than primary ones.

At a clinical level both types of negative symptoms often appear to have similar or even identical phenomenology. Therefore, they are not easily distinguished with negative symptom scores without additional information about other symptom dimensions or environmental factors (Kirkpatrick, 2014). However, in clinical practice it is crucial to be aware of the mechanisms underlying secondary negative symptoms. Hence, our primary aim is to review the evidence and treatment options for each individual cause of secondary negative symptoms in schizophrenia.

In addition to the clinical relevance, it is important to elucidate the underlying pathophysiological mechanisms of secondary negative symptoms for two reasons. First, given the fact that both primary and secondary negative symptoms have strongly overlapping phenomenological properties one would expect some shared pathophysiology. Thus, the study of secondary negative symptoms could benefit the development of a pathophysiological model of symptoms such as apathy and diminished expression. Second, these pathophysiological states are likely to be influenced by different biological and environmental factors depending on the type of negative symptom. The study of secondary negative symptoms can thus help to differentiate causal pathways affecting the underlying physiology. However, despite growing insights into the pathophysiology of negative symptoms, such an integrated approach for primary and secondary negative symptoms has yet to be developed (Barch and Dowd, 2010, Kirkpatrick, 2014, Kirkpatrick et al., 2001, Kring and Barch, 2014, Strauss et al., 2014). Therefore, an additional aim of this review is to consider how current neuroimaging research provides initial evidence on shared and divergent pathophysiological mechanisms of primary and secondary negative symptoms.

Finally, we recommend how future research could address secondary negative symptoms and provide an updated clinical approach to assess and treat these debilitating symptoms.