Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms.
A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy–avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit.
A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.
Schizophrenia is a complex and multidimensional disorder with an estimated point prevalence of 0.46% (Saha et al., 2005), but which other studies estimate affects up to 1% of the world's population; and which is a leading cause of disability (Chumakov et al., 2002, Switaj et al., 2012 and WHO, 2012). Data from clinical and population-based studies of schizophrenia suggest a lifetime prevalence of severe primary negative symptoms of 15–20%, which increases with age (Buchanan, 2007). Recent analyses of negative symptom dimensions support a division into two clusters of apathy–avolition (AA) and expressive deficits (DE) (Liemburg et al., 2013 and Strauss et al., 2013). AA includes amotivation, apathy and social withdrawal (46%); whilst DE includes emotional withdrawal (39%), poor rapport (36%), blunted affect (33%) and poverty of amount and content of speech (Bobes et al., 2010). Negative symptoms are associated with poorer functional outcomes and greater reductions in quality of life (QOL) than positive symptoms (Velligan et al., 1997, Norman et al., 2000, Lysaker and Davis, 2004, Lysaker et al., 2004, Kurtz et al., 2005, Milev et al., 2005 and Kirkpatrick and Fischer, 2006). Therefore, targeting the treatment of negative symptoms may have significant functional benefits. It should be noted that negative symptoms may have sufficient face validity that improvement in these symptoms alone would be sufficient to demonstrate the effectiveness of an intervention and specific assessment of function would not be required for medication registration. (Marder et al., 2013). To date, we do not have an established treatment for negative symptoms (Buckley and Stahl, 2007). However, some pharmacological and psychosocial interventions show promise (Arango et al., 2013 and Elis et al., 2013). This is an active area in therapeutic research with a search for "negative symptoms" and "schizophrenia" on Clinicialtrials.gov identifying 93 open and 226 closed, interventional studies (access access date December 7th 2014). Given the salience of negative symptoms for functional outcomes and quality of life, developing a definition of a clinically meaningful effect of treatment is needed (Kirkpatrick et al., 2006). There is no consensus in the field of how to define therapeutic “success” in the treatment of negative symptoms. This article will review concepts of clinical relevance (clinically meaningful effect) and then report on a conference whose goal was to apply these concepts to the domain of negative symptoms. (See Fig. 1.)
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Fig. 1.
Graphical representation of proposed research criteria for the assessment of a therapeutic benefit on negative symptoms of schizophrenia.
