Negative symptoms are a core aspect of psychopathology in schizophrenia. Currently available pharmacological agents have proven minimally efficacious for remediating negative symptoms. A promising treatment avenue is the intranasal administration of the neuropeptide oxytocin. However, there have been inconsistencies in effects of oxytocin on negative symptoms throughout the literature, and factors leading to inconsistent effects are unclear.
We conducted a systematic review and meta-analysis of randomized clinical trials to compare the effectiveness of oxytocin with placebo for the treatment of negative symptoms and determine moderators of treatment effect. Random effects meta-analyses and dose-response meta-analysis were performed on mean changes in negative symptoms.
In an initial analysis of all 9 identified randomized clinical trials, intranasal oxytocin showed no significant effect on negative symptoms. For higher doses (>40-80 IU), a beneficial effect on negative symptoms was found with a moderate effect size, but this effect disappeared after exclusion of 1 outlier study. The dose-response meta-analysis predicted that higher doses of oxytocin may be more efficacious for negative symptoms. For positive symptoms, no beneficial effect of oxytocin was found in the main meta-analysis, but the dose-response meta-analysis suggested a potential advantage of higher doses.
The present results show no consistent beneficial effect of intranasal oxytocin for the treatment of negative and positive symptoms. The dose-response meta-analysis does not allow drawing any firm conclusions but suggests that high doses of intranasal oxytocin may be more efficacious. If future studies are conducted, an effort to reach adequate CNS concentrations for a sufficient duration is required.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.

In the DSM5, negative symptoms are 1 of the 5 core dimensions of psychopathology evaluated for schizophrenia. However, negative symptoms are not pathognomonic-they are also part of the diagnostic criteria for other schizophrenia-spectrum disorders, disorders that sometimes have comorbid psychosis, diagnoses not in the schizophrenia-spectrum, and the general \"nonclinical\" population. Although etiological models of negative symptoms have been developed for chronic schizophrenia, there has been little attention given to whether these models have transdiagnostic applicability. In the current review, we examine areas of commonality and divergence in the clinical presentation and etiology of negative symptoms across diagnostic categories. It was concluded that negative symptoms are relatively frequent across diagnostic categories, but individual disorders may differ in whether their negative symptoms are persistent/transient or primary/secondary. Evidence for separate dimensions of volitional and expressive symptoms exists, and there may be multiple mechanistic pathways to the same symptom phenomenon among DSM-5 disorders within and outside the schizophrenia-spectrum (ie, equifinality). Evidence for a novel transdiagnostic etiological model is presented based on the Research Domain Criteria (RDoC) constructs, which proposes the existence of 2 such pathways-a hedonic pathway and a cognitive pathway-that can both lead to expressive or volitional symptoms. To facilitate treatment breakthroughs, future transdiagnostic studies on negative symptoms are warranted that explore mechanisms underlying volitional and expressive pathology.