Introduction

The negative symptoms of schizophrenia, defined as the absence or diminution of normal behaviors and functions, have been recognized since Kraepelin1 and Bleuler.2 Kraepelin’s description of the “avolitional syndrome,1” manifested as a “weakening of those emotional activities which permanently form the mainsprings of volition,” and resulting in “emotional dullness, failure of mental activities, loss of mastery over volition, of endeavor, and of ability for independent action,” represents one of the most elegant descriptions of negative symptoms. The work of Strauss and colleagues,3 separating schizophrenia symptoms into 3 specific complexes (ie, positive symptoms, negative symptoms, and disorders of relating) rekindled interest in the positive/negative classification of symptoms. Other models using the positive/negative symptom dichotomy ensued, such as, type I and type II schizophrenia4,5 and positive and negative schizophrenia.6,7 All these constructs were attempts to explain the heterogeneity of schizophrenia.

Negative symptoms account for much of the long-term morbidity and poor functional outcome of patients with schizophrenia.8-10 The development of a negative symptom treatment is a major challenge for the field. Negative symptoms, as broadly defined by such measures as the Brief Psychiatric Rating Scale (BPRS)11 anergia factor, Scale for the Assessment of Negative Symptoms (SANS),12 or Positive and Negative Symptom Scale (PANSS),13 improve during conventional and second generation antipsychotic drug treatment.14-18 However, in most of these studies, this effect has been observed in the context of, and correlated with, concurrent improvement of positive, depressive, and/or extrapyramidal symptoms.14-20 These are the major sources of secondary negative symptoms, and other sources of secondary symptoms are usually not even assessed. Thus, the use of negative symptoms broadly defined is unlikely to lead to the development of effective treatments for those negative symptoms, which persist during clinical stability and are associated with impaired role function performance.21

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There are 2 alternative approaches for defining negative symptoms in the context of clinical trials. The first approach is to restrict negative symptoms to primary, enduring negative symptoms or deficit symptoms.22 Deficit symptoms are highly correlated with impaired role function.8 The second approach is to include both primary negative symptoms and those secondary negative symptoms, which have not responded to appropriate treatments.23 Both these approaches have advantages over negative symptoms broadly defined for isolating those negative symptoms that are the most relevant treatment target.

In this article, we will review negative symptom definitions and terminology. We will contrast persistent negative symptoms with deficit symptoms and propose the use of persistent negative symptoms in pharmacological studies of negative symptoms. We will define persistent negative symptoms and propose study design guidelines for clinical trials. Finally, we will propose future areas of research for persistent negative symptoms. The ultimate goal is to facilitate the development of new drugs for this component of the illness.

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