Focusing on the negative

In 1919 in Dementia Praecox and Paraphrenia, Kraepelin wrote that ‘The most important of these changes is their emotional dullness’. He described the indifference of patients towards relationships, work and pleasure as ‘not seldom the first and most striking symptom of the onset of disease’.

Kraepelin wrote that ‘The most important of these changes is their emotional dullness’

Prof Armida Mucci, University of Campania 'Luigi Vanvitelli', Italy, noted that many years after this work, in 1974, negative symptoms in schizophrenia were proposed as a separate domain with distinctive pathophysiological and therapeutic implications. Despite the impact of this broad constellation of psycho-behavioral phenomena on quality of life and functional outcomes, no effective treatment is available. This was also highlighted by Prof Andrea Raballo, University of Oslo, Norway.

Prof Raballo acknowledged that the revamped attention to the negative symptoms of schizophrenia has led to a number of important developments and a focus on behavioral expressivity. But in-depth phenotypic characterization remains partly unaddressed. Also, the clinical intertwining with non-productive clinical features - such as cognitive-perceptual basic symptoms - may be overlooked.

Evolution of assessment

There is still controversy regarding the definition and assessment of negative symptoms.

Prof Mucci described the evolution of the negative symptom assessment instruments - from the Brief Psychiatric Rating Scale (BPRS) in the 1960’s to the second generation instruments such as the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Motivation and Pleasure Scale - Self Report (MAP-SR) in the past four years. But there is still controversy regarding the definition and assessment of negative symptoms.

Motivation and expression

Recent data point to two domains of negative symptoms, as described by the National Institute of Mental Health (NIMH) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). There are motivation-related symptoms (anhedonia, asociality, and avolition or apathy) and those that are deficits in expression (alogia and blunted effect). They reflect different pathophysiological mechanisms and, importantly, have different impacts on a patient’s functional outcomes. Prof Mucci urged that these two domains need to be better assessed in clinical trials. She illustrated this point by referring to the Positive And Negative Syndrome Scale (PANSS) Negative subscale rating, which cannot be used to assess new treatments to increase motivation.

Primary vs secondary - implications for treatment development

Identifying treatable causes of secondary negative symptoms will improve patient care.

Prof Mucci described two categories of negative symptoms - a concept which has major implications for treatment development. Primary, idiopathic negative symptoms are those that are etiologically related to the core pathophysiology of schizophrenia. Secondary negative symptoms, on the other hand, are due to identifiable factors such as the effect of drugs or depression. Identifying treatable causes of secondary negative symptoms will improve patient care. She proposed an improved definition and assessment of the core, persistent, primary negative symptoms, in which the main sources of secondary symptoms (positive, depressive and extrapyramidal symptoms) are excluded by setting threshold values.

Negative symptoms and neuroimaging

Brain volume changes in schizophrenia may relate to psychopathology and functional outcome.

Since the mid 1970’s, we started to use imaging to discover how the brain differs in schizophrenia¹. Prof Paolo Brambilla, University of Milan, Italy, highlighted the role of translational imaging in the stratification of schizophrenia subtypes. For example, Krepelinian patients, those with very poor outcome and persistence of negative symptoms, have larger ventricles and reduced white matter volumes. There is also evidence of interhemispheric dysconnectivity.

Gray matter volume may predict the clinical response.

Prof Brambilla presented preliminary data from a longitudinal study of how brain volume changes in schizophrenia may relate to psychopathology and functional outcome. Seventeen individuals were included in each of three groups - patients with predominantly positive symptoms, patients characterized by negative symptoms, and healthy controls.

Compared to controls, both patient groups had decreased gray matter volume in the frontal lobe, bilaterally. Interestingly, compared to patients with positive symptoms, those with negative symptoms had deficits in gray matter volume in a large frontal pole and in the left limbic lobe (anterior cingulate). Prof Brambilla proposed that gray matter volume may predict the clinical response to certain treatments.