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The Scale for the Assessment of Negative Symptoms (SANS) was the first instrument developed in order to provide for comprehensive assessment of negative symptoms in schizophrenia (Andreasen, 1982, 1983). It consists of five scales that evaluate five different aspects of negative symptoms: alogia, affective blunting, avolition-apathy, anhedonia-asociality, and attentional impairment. Each of these negative symptoms can be rated globally, but in addition detailed observations are made in order to achieve the global rating. It is complemented by a Scale for the Assessment of Positive Symptoms (SAPS), which permits detailed evaluation and global ratings of hallucinations, delusions, positive formal thought disorder and bizarre behaviour (Andreasen, 1984). Taken together, the two scales provide a comprehensive set of rating scales in order to measure the symptoms of schizophrenia and to assess their change over time.

The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.

This paper reviews the penomenology of schizophrenia to acquaint non-clinicans (pharmacology researchers) with the characteristic features of this disorder. Schizophrenia is noted to be a disorder with onset usually during early adult life in individuals who often have been at least mildly abnormal prior to the time of onset. The disorder is characterized by both positive symptoms, particularly delusions, hallucinations, thought disorder, and motoric symptoms, as well as negative symptoms, particularly affective flattening, avolition/apathy, and asociality. In most cases, schizophrenia leads to considerable psychosocial disability. Despite important advances in treatment, individuals who fully recover from schizophrenia remain relatively rare. New drugs are needed to treat this illness.

Negative symptoms have been assessed in 34 cases of major endogenous depression (RDC) using the Scale for Assessment of Negative Symptoms. Correlation coefficients between negative symptoms and improvement rated on a 5-point scale were determined. Poverty of speech, affective flattening and avolition-apathy were found to be related with poor outcome. There was also a negative relationship between improvement and certain frequently occurring negative symptoms: inability to feel emotions, feelings of emptiness in thinking and feeling of avolition. High total negative symptom scores predicted poor outcome.

Schizophrenia is a complex and multifactorial disorder generally diagnosed in young adults at the time of the first psychotic episode of delusions and hallucinations. These positive symptoms can be controlled in most patients by currently-available antipsychotics. Conversely, they are poorly effective against concomitant neurocognitive dysfunction, deficits in social cognition and negative symptoms (NS), which strongly contribute to poor functional outcome. The precise notion of NS has evolved over the past century, with recent studies – underpinned by novel rating methods – suggesting two major sub-domains: “decreased emotional expression”, incorporating blunted affect and poverty of speech, and “avolition”, which embraces amotivation, asociality and “anhedonia” (inability to anticipate pleasure). Recent studies implicate a dysfunction of frontocortico-temporal networks in the aetiology of NS, together with a disruption of cortico-striatal circuits, though other structures are also involved, like the insular and parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic–glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoidergic transmission may be involved. Several agents are currently under clinical investigation for the potentially improved control of NS, including oxytocin itself, N-Methyl-d-Aspartate receptor modulators and minocycline. Further, magnetic-electrical “stimulation” strategies to recruit cortical circuits and “cognitive–behavioural–psychosocial” therapies likewise hold promise. To acquire novel insights into the causes and treatment of NS, experimental study is crucial, and opportunities are emerging for improved genetic, pharmacological and developmental modelling, together with more refined readouts related to deficits in reward, sociality and “expression”. The present article comprises an integrative overview of the above issues as a platform for this Special Issue of European Neuropsychopharmacology in which five clinical and five preclinical articles treat individual themes in greater detail. This Volume provides, then, a framework for progress in the understanding – and ultimately control – of the debilitating NS of schizophrenia.

Neuroleptics have been the main form of treatment of schizophrenia since their introduction three decades ago. Their use in thousands of clinical studies has pro-vided extensive data with which to evaluate their contribution to the treatment of the schizophrenic syndrome. The evidence for their effectiveness in treating some aspects of the schizophrenic syndrome, e.g., positive symptoms such as delusions and hallucinations, and prevention of relapse and rehospitalization in a large percentage of schizophrenics is unequivocal (Lipton and Burnett 1979). It is also clear that these agents do not completely alleviate delusions and hallucinations in many schizophrenics or have any effect on them in others, and that many aspects of the schizophrenic syndrome, e.g., negative symptoms such as withdrawal, flat affect and avolition are not as effectively treated by neuroleptics as are positive symptoms (Meltzer 1985).

To investigate the components of emotional blunting, we factor-analyzed an emotional blunting scale, and examined the relationships between the derived factors and several clinical variables in two patient samples. Two factors were identified, corresponding to “lack of emotional expression” and “avolition.” The “avolition” factor was strongly related to clinical improvement after treatment. Discriminant analyses indicated that schizophrenics could be differentiated from manics by emotional expression and from depressives by avolition. Scores on two shorter scales derived from the factors were also highly predictive of clinical improvement and diagnosis. These results indicate that emotional blunting can be differentiated into two easily measured components which may have different clinical significance.

The Schedule for the Deficit Syndrome (SDS) is an instrument for categorizing schizophrenic patients into those with and those without the deficit syndrome. In a study of 40 schizophrenic patients diagnosed by DSM-III criteria, raters using the SDS demonstrated good interrater reliability for this categorization, as well as for individual negative symptoms and a rating of global severity.

The authors provide a rationale for distinguishing the primary, enduring negative symptoms of schizophrenia (termed "deficit symptoms") from the more transient negative symptoms secondary to other factors. They argue that the former are more likely to provide a basis for meaningful subtyping of the schizophrenic syndrome, while the latter are more likely to respond to currently available treatments. They describe their experience in using clinical judgment based on longitudinal observations to identify deficit and nondeficit subtypes of schizophrenic patients and propose criteria for defining schizophrenia with the deficit syndrome.

The authors explored the clinical correlates of ventricular enlargement in schizophrenia by comparing 16 patients with "large" ventricles (ventricles more than I SD above the control mean) with 16 patients with the smallest ventricles from a sample of 52 schizophrenic patients. Patients with ventricular enlargement showed some impairment in the sensorium and had a preponderance of "negative" symptoms (e.g., alogia, affective flattening, avolition, anhedonia), while those with small ventricles were characterized by "positive" symptoms (e.g., delusions, hallucinations, positive formal thought disorder, bizarre behavior). These findings suggest that combining a measure of brain structure with the clinical picture may provide a useful new approach to the classification of schizophrenia.

Negative symptoms occur in several major mental health disorders with undetermined mechanisms and unsatisfactory treatments; identification of their neural correlates might unveil the underlying pathophysiological basis and pinpoint the therapeutic targets. In this study, participants with major depressive disorder (n=24), schizophrenia (n=22) and healthy controls (n=20) were assessed with ten frequently-used negative symptom scales followed by principal component analysis (PCA) of the scores. A linear model with the prominent components identified by PCA was then regressed on gray and white matter volumes estimated from T1-weighted magnetic resonance imaging (MRI). In depressed patients, negative symptoms such as blunted affect, alogia, withdrawal and cognitive impairment, assessed mostly via clinician-rated scales were inversely associated with gray matter volume in the bilateral cerebellum. In patients with schizophrenia, anhedonia and avolition evaluated via self-rated scales inversely related to white matter volume in the left anterior limb of internal capsule/anterior thalamic radiation and positively in the left superior longitudinal fasiculus. The pathophysiological mechanisms underlying negative symptoms might differ between depression and schizophrenia. These results also point to future negative symptom scale development primarily focused on detecting and monitoring the corresponding changes to brain structure or function.

In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research.

To the Editor.— We were intrigued by the findings of Watson et al 1 regarding schizophrenic birth seasonality, particularly their suggestion that an increase in the number of winter births is demonstrable in schizophrenics with severe process disorder but not in schizophrenics with good prognoses and reactive syndromes. We have arrived at a parallel finding from a different direction, in which we examined the hypothesis, advanced by Andreasen and Olsen, 2 that schizophrenics with positive syndromes (eg, a predominance of florid symptoms such as thought disorder, hallucinations, and delusions) and schizophrenics with negative syndromes (eg, a predominance of symptoms such as impoverished speech and thinking, affective flattening, avolition, and anhedonia) represent distinct subtypes. When comparing groups of well-characterized schizophrenics who met our criteria for a positive v negative syndrome, we reported 3 that the patients with negative syndromes displayed more primitive cognitive modes on developmental tests and greater psychomotor retardation, despite equivalent

• Recently, a renaissance of interest in "negative symptoms," eg, affective flattening or impoverishment of speech and language, has occurred. Although some investigators believe that these symptoms are important indicators of outcome, of response to treatment, and perhaps of a distinct, underlying pathologic process, research on the negative-symptom syndrome in schizophrenia has been handicapped because no standard instrument existed to assess it. This investigation reports on the developed Scale for the Assessment of Negative Symptoms. When symptoms are defined by objective behavioral indices, they have excellent interrater reliability. Furthermore, the five symptom complexes defined by the scale (affective flattening, alogia, avolition, anhedonia, and attentional impairment) have good internal consistency, which indicates that the conceptual organization of the scale is also cohesive.

• We developed criteria for dividing the schizophrenic syndrome into three subtypes: positive, negative, and mixed schizophrenia. Positive schizophrenia is characterized by prominent delusions, hallucinations, positive formal thought disorder, and persistently bizarre behavior; negative schizophrenia, by affective flattening, alogia, avolition, anhedonia, and attentional impairment. In mixed schizophrenia either both negative and positive symptoms are prominent, or neither is prominent. We explored the validity of these criteria in a variety of ways. Significant differences between the three types were noted using external validators such as premorbid adjustment, indices of cognitive dysfunction, ventricular brain ratio, and course in hospital. The correlational structure of the symptom complexes also provided further support for our approach to subtyping.