Schizophrenia: a positive spin on negative symptoms

The next interview in our 'in depth' series, with key people in the field, looking at their work and what it says about the future of applied neuroscience.

Silvana Galderisi is professor of psychiatry and director of the Training School in Psychiatry at the University of Naples SUN, Italy, and director of the Emergency Unit of the Department of Mental Health. 

As a leading figure in schizophrenia research, Professor Galderisi has an important role in many leading organisations. Impressively, she is Chair of the ECNP Schizophrenia Network, the European Psychiatric Association (EPA) Section on Schizophrenia and the World Psychiatric Association (WPA) Section on Neuroimaging. What’s more, she is President Elect of the EPA, taking on the mantle of leadership next year.

We spoke to Professor Galderisi to dive into her exemplary career in schizophrenia.

Could you tell us a little bit about your journey with schizophrenia research over the years? Broadly speaking, have you seen a shift in the focus/areas of interest for treatment in recent times?
My interest in research on schizophrenia dates back to the beginning of my training in psychiatry, when I was fascinated with the complexity of the disorder and the variety of its presentations in real clinical cases. I understood very soon that pharmacological treatments available at that time (in the late 70s, only first generation antipsychotics were available) were powerful in some cases, useful in others, but of very little help in the remaining ones.

In particular, I noticed that in some cases delusions and hallucinations improved, but the person did not seem to gain enough autonomy and interest in social, work and leisure activities. Apathy and difficulties in everyday life drew my attention to neurocognitive and negative symptom domains. Initially, I mainly looked at their biological correlates, trying to improve knowledge on pathophysiological mechanisms. At that time these research topics did not receive the widespread attention they receive nowadays, and this has certainly represented an important shift in the focus of schizophrenia research and treatment.

Looking to the present day, is it fair to say that negative symptoms are the major challenge still in schizophrenia treatment, relating more strongly to functional outcomes than positive symptoms?
Unfortunately yes. We don’t know enough about pathomechanisms of negative symptoms, which remain a major challenge in the treatment of those suffering from the disorder. The recognition of the key role of negative symptoms in patients’ functional outcome is increasingly acknowledged. However, diversities among research groups in concepts, assessment instruments and experimental models relevant to negative symptoms has slowed the progress of research in this area.
The current activities of the ECNP Schizophrenia Network are aimed to overcome these diversities and create the basis for large-scale research projects.

What about the importance of primary/secondary negative symptoms?
The distinction between primary-negative and secondary-negative symptoms has important implications for both research into pathophysiological mechanisms and therapeutic approaches. Primary negative symptoms, sometimes referred to as ‘deficit symptoms’, are considered as core aspects of the illness, often predating the full blown psychosis, and present during and between periods of positive symptom worsening. They are not significantly improved by currently available treatment approaches.

Secondary negative symptoms are caused by identifiable factors, most commonly represented by depression, psychotic symptoms, social anxiety and extrapyramidal side effects. This distinction might have important clinical and research implications: adequate information on identifiable and treatable underlying causes of secondary negative symptoms might translate into better care for people with schizophrenia.

However, more systematic research is needed to establish effective treatments strategies. Primary and secondary negative symptoms likely have different pathomechanisms, but we need more studies focusing on differential and shared pathophysiological mechanisms of primary and secondary negative symptoms to draw sound conclusions.

Can you expand on the concept of ‘deficit’ schizophrenia and of avolition? Does either category have an impact on functional outcome?
Different approaches to the identification of primary negative symptoms have been proposed. The one elaborated by Carpenter et al. in 1988, i.e. the concept of deficit schizophrenia (DS), has been very influential. The diagnosis of deficit schizophrenia is based on the presence of at least two negative symptoms, for at least one year. These symptoms should not be due to anxiety, drug effects (especially extrapyramidal side effects), suspiciousness and other psychotic symptoms, or depression. Persons with deficit schizophrenia, when compared to those with non-deficit schizophrenia, have a poorer functional outcome, an insidious onset of the illness, a lower prevalence of dysphoria, hostility, suicidal ideation, depressive symptoms and substance abuse, more neurological soft signs and spontaneous movement disorders. 

A generalised cognitive deficit, reflected by a low IQ, has repeatedly been reported in subjects with DS. It is not clear whether it reflects a true cognitive deficit or poor mental effort, often associated to negative symptoms. The diagnosis of deficit schizophrenia has shown high reliability and stability. However, research based on this approach has proven difficult: information about the longitudinal course of the symptoms may be unavailable making the distinction between primary and secondary negative symptoms challenging, especially in first-episode patients.

Avolition, currently defined as reduced initiation and persistence of goal-directed activity, is increasingly regarded as the negative symptom with the strongest impact on functional outcome. It is a multifaceted construct, including deficits of reward prediction and valuation, effort valuation, encoding of action-outcome contingency, and an impaired decision-making processes. The term is often used to refer to one of the two factors in which individual negative symptoms tend to cluster: avolition or experiential factor, and diminished expression or expressive factor. The avolition factor includes, besides avolition itself, the negative symptom domains of anhedonia and asociality. It is important to highlight that most studies on cognitive and neural basis of avolition are relevant to the avolition factor including asociality and anhedonia.

Tying in with this, can you tell me about the 900+ patient study you conducted in Italy to examine the relationship between personal resources, symptom severity and psychosocial functioning? Are there factors that seemed to contribute the most to symptom severity/quality of life?
The goal of the Italian multicentre study involving 921 patients with schizophrenia living in the community was to identify factors contributing the most to real-life functioning of these persons. To this aim, based on the existing literature and clinical experiences, we selected several factors likely to influence real-life functioning of people with schizophrenia and grouped them into three categories: illness-related variables, personal resources and context-related factors. Some of these variables were never investigated before in relationship with real-life functioning.

We found that neurocognitive impairment exhibited the strongest association with real-life functioning. Of the two negative symptom factors, avolition proved to have significant direct and indirect effects, while diminished expression was only indirectly and weakly related to real-life functioning. The impact of avolition was independent of other psychopathological dimensions, cognitive deficits or functional capacity.

Several other variables contributed to the variance of real-life functioning: availability of a disability pension and access to social and family incentives, positive symptoms, disorganisation, social cognition, functional capacity, resilience, internalised stigma and engagement with mental health services. The complexity of this picture highlights the importance of integrated and personalised treatment programs for people with schizophrenia.

Looking to your wider work/research – what are the most important facets in this arena to focus on moving forward, and what emphasis would you like to see from others?
The priority has to be given to research on early intervention. Several studies, for instance, reported a relationship between the duration of untreated psychosis and the severity of negative symptoms. In addition, I would like to see large multicentre studies trying to elucidate the molecular and circuit alterations underlying the two domains of negative symptoms; they might contribute to identify novel treatment approaches. In addition to this, psychopathological and neurobiological research should also focus on individual symptoms: in fact, while it is conceivable that common mechanisms contribute to all symptoms in the same domain, the presence of specific mechanisms underlying an individual symptom cannot be ruled out.

For more on this topic, be sure to attend the symposium on ‘Negative symptoms of schizophrenia: pathophysiological mechanisms and relevance to functional outcome’ (S.09), taking place on Sunday at the 29th ECNP Congress.

Focused on the impact of different negative symptom dimensions on functional outcome, the session will highlight the role of the avolition domain, neuroimaging data relevant to pathomechanisms (e.g. the importance of white matter abnormalities), as well as pharmacological and non-pharmacological treatment options currently available or under development.