Defining, understanding, and treating lack of motivation in schizophrenia
Lead Research Organisation:
University of Cambridge
Department Name: Psychiatry
Abstract
Schizophrenia is a barely understood brain disorder. Over the last fifty years, psychiatry has defined schizophrenia as a psychotic disorder, meaning suffering from delusions and hallucinations. Medication (antipsychotics) has been developed with some success. Paradoxically, most people with schizophrenia remain unable to work or have a family life even after psychosis is successfully treated. The reason is the poorly understood negative symptoms (along with cognitive symptoms). Negative symptoms refer to a lessening or absence of a previous function, namely motivation and emotional life. There is no licenced medication for its treatment.
In this proposal I will focus on defining, understanding and treating poor motivation in schizophrenia.
My impression is that the current scales for measuring motivation in schizophrenia are not fit for purpose. As 'negative symptoms', it is not a patient-friendly term, it is often avoided by clinicians, and other fields like neurology use different terms such as apathy (preventing joining forces in studies the same phenomenon as we have different words). Additionally, the approach to describe and treat poor motivation have not considered significant limitations. Poor motivation is the 'end point' behaviour but could be either a primary feature or secondary to other factors. These include medication-induced sedation, psychosis itself (avoidance), or a comorbid depressive state requiring completely different pharmacological non-pharmacological intervention.
Working with world leaders in the field and under the partnership with Pr. Peter Jones, I have three primary aims in this proposal.
First, to explore which of the novel measures of poor motivation can be used in clinical practice. We gather data in an international study to then work with experts by experience to define the best strategy to describe these symptoms in clinical practice in the future.
Second, to describe the different steps of motivation (e.g. coming up with ideas, evaluation of effort needed or self-esteem level) using computer tasks. Then, to evaluate which secondary factor impacts each step of motivation. For instance, we anticipate that someone suffering from depression will consider too much effort to initiate any activity. In contrast, someone distracted with psychosis will not develop ideas or struggle to put a plan to establish them in place. Deconstructing the different steps and their secondary causes will inform clinicians to implement personalised interventions.
Finally, we will explore how medication impacts motivation using novel statistical techniques. For instance, we have already found that a drug (clozapine) improves motivation by improving secondary factors: reducing psychosis severity and sedation (when clozapine is reduced). We can now analyse the impact of over 20 different medications on motivation using our cohort of patients carefully characterised. The end goal is to have detailed information to design a future clinical trial and help clinicians decide which medication is more effective for each aspect.
This ambitious proposal builds upon two decades of experience treating people with schizophrenia and on three ethically approved research projects to be completed by 2022, 2023 and 2024, respectively. Funds are requested to ringfence time to analyse results and apply to a clinical trial formulated on the results. The study group is patients with chronic schizophrenia (>5 years since illness onset). They are disproportionally affected by motivation and emotional dysfunction compared to those with the first episode of psychosis. They are the core group seen at the Cambridge Psychosis Centre, an NHS unit that I lead.
In this proposal I will focus on defining, understanding and treating poor motivation in schizophrenia.
My impression is that the current scales for measuring motivation in schizophrenia are not fit for purpose. As 'negative symptoms', it is not a patient-friendly term, it is often avoided by clinicians, and other fields like neurology use different terms such as apathy (preventing joining forces in studies the same phenomenon as we have different words). Additionally, the approach to describe and treat poor motivation have not considered significant limitations. Poor motivation is the 'end point' behaviour but could be either a primary feature or secondary to other factors. These include medication-induced sedation, psychosis itself (avoidance), or a comorbid depressive state requiring completely different pharmacological non-pharmacological intervention.
Working with world leaders in the field and under the partnership with Pr. Peter Jones, I have three primary aims in this proposal.
First, to explore which of the novel measures of poor motivation can be used in clinical practice. We gather data in an international study to then work with experts by experience to define the best strategy to describe these symptoms in clinical practice in the future.
Second, to describe the different steps of motivation (e.g. coming up with ideas, evaluation of effort needed or self-esteem level) using computer tasks. Then, to evaluate which secondary factor impacts each step of motivation. For instance, we anticipate that someone suffering from depression will consider too much effort to initiate any activity. In contrast, someone distracted with psychosis will not develop ideas or struggle to put a plan to establish them in place. Deconstructing the different steps and their secondary causes will inform clinicians to implement personalised interventions.
Finally, we will explore how medication impacts motivation using novel statistical techniques. For instance, we have already found that a drug (clozapine) improves motivation by improving secondary factors: reducing psychosis severity and sedation (when clozapine is reduced). We can now analyse the impact of over 20 different medications on motivation using our cohort of patients carefully characterised. The end goal is to have detailed information to design a future clinical trial and help clinicians decide which medication is more effective for each aspect.
This ambitious proposal builds upon two decades of experience treating people with schizophrenia and on three ethically approved research projects to be completed by 2022, 2023 and 2024, respectively. Funds are requested to ringfence time to analyse results and apply to a clinical trial formulated on the results. The study group is patients with chronic schizophrenia (>5 years since illness onset). They are disproportionally affected by motivation and emotional dysfunction compared to those with the first episode of psychosis. They are the core group seen at the Cambridge Psychosis Centre, an NHS unit that I lead.
Technical Summary
In my previous work, we have shown that using negative symptoms as a single entitle is not supported by evidence. Lack of motivation and poor emotional expression are the two main components, which is supported by psychometrical and biological evidence. In this project, I will focus on one of these two components: amotivation, also termed apathy in other specialities, such as neurology.
First, I will use information from the CASES international study I set up (n=200) for studying four different scales that measure motivation and apathy: 1) Brief Negative Symptoms Scale (BNSS, new gold standard for measuring motivation), 2) Positive and negative syndrome scale (old gold standard), both researcher-rated scales widely used in schizophrenia. We will so use the 3) Domain Criteria of Apathy, a novel clinician-rated scale from neurodegenerative disorders and the 4) Apathy Motivation Index (AMI) a service-user rated scale. We will explore the validity of these scales and the internal consistency and concurrent validity.
Second, we will deconstruct apathy in different phases using a cognitive neuroscience approach., from option generation to reward-effort evaluation and outcome prediction. We will use three different computer tasks (CHANSS study, n=100 and 200 controls) and derive measures from the tasks (eg. reward sensitivity or uniqueness in imagination) and compare cases and controls. Within the schizophrenia group, we will also generate linear mixed models that explain how much is secondary to other sources of negative symptoms, for instance, the influence of depression or antipsychotic-induced sedation, among others.
Third, using the clozapine database (n=240, 9 years follow-up and 3,000 face-to-face assessments), we will evaluate the influence of 23 different medications in apathy (BNSS-motivation). We will use longitudinal mediation models, which calculates the direct effect on motivation and the indirect effect due to sedation, psychosis or depression.
First, I will use information from the CASES international study I set up (n=200) for studying four different scales that measure motivation and apathy: 1) Brief Negative Symptoms Scale (BNSS, new gold standard for measuring motivation), 2) Positive and negative syndrome scale (old gold standard), both researcher-rated scales widely used in schizophrenia. We will so use the 3) Domain Criteria of Apathy, a novel clinician-rated scale from neurodegenerative disorders and the 4) Apathy Motivation Index (AMI) a service-user rated scale. We will explore the validity of these scales and the internal consistency and concurrent validity.
Second, we will deconstruct apathy in different phases using a cognitive neuroscience approach., from option generation to reward-effort evaluation and outcome prediction. We will use three different computer tasks (CHANSS study, n=100 and 200 controls) and derive measures from the tasks (eg. reward sensitivity or uniqueness in imagination) and compare cases and controls. Within the schizophrenia group, we will also generate linear mixed models that explain how much is secondary to other sources of negative symptoms, for instance, the influence of depression or antipsychotic-induced sedation, among others.
Third, using the clozapine database (n=240, 9 years follow-up and 3,000 face-to-face assessments), we will evaluate the influence of 23 different medications in apathy (BNSS-motivation). We will use longitudinal mediation models, which calculates the direct effect on motivation and the indirect effect due to sedation, psychosis or depression.
