Rethinking Schizophrenia—A Manageable Chronic Condition

This special edition is devoted to research on schizophrenia and how it informs treatment. Research in the field of schizophrenia has expanded dramatically since treatment with antipsychotic medications began 70 years ago. The adoption of early intervention programs for individuals experiencing their first episode of psychosis, the introduction of clozapine and newer second-generation antipsychotics, and the revolutionary progress in brain imaging and genetics have transformed our understanding of schizophrenia, its treatment, and its outcome. The papers in this special edition reflect the efforts in many of these areas of research. They provide a window on where we have been as a field and where we are heading.

It is fair to ask what have we learned from all this research and how has it impacted on the treatment of schizophrenia and the outcomes observed? Schizophrenia has often been viewed with therapeutic nihilism, as an illness without effective treatments that inevitably resulted in clinical deterioration. Research has clearly established that this is not the case. On the contrary, schizophrenia is a highly treatable illness. A majority of people with a first episode of schizophrenia will experience resolution of psychotic symptoms within the first month of treatment. ¹ When maintenance treatment is provided and adhered to, relapses are uncommon. ² The long-term course of schizophrenia is typically characterized by stability, not deterioration. ³ The substantial reduction in life expectancy that has been consistently associated with schizophrenia ⁴ is unlikely to be explained by the effects of the illness itself or the medications prescribed to treat it. It is likely due to factors that can be modified by comprehensive high-quality treatment: preventing suicide, providing maintenance antipsychotic treatment, reducing substance use, eliminating smoking, and ensuring access to high-quality medical care. ⁵ The course of schizophrenia need not involve recurring episodes of acute psychosis and hospitalizations. It need not involve ongoing clinical deterioration, problems with smoking and substance use, or diminished life expectancy. It now has a rightful place among other manageable chronic conditions.

Schizophrenia is without question a complex and challenging illness to experience and to treat. However, our most important treatments remain grossly underutilized: long-acting injectable antipsychotics,^6,7 clozapine, ⁷ and smoking cessation interventions. ⁸ We can do better. Papers in this special edition describe a number of ways that we can improve the care and outcomes for people with schizophrenia.

Lily Van and colleagues at the Centre for Addiction and Mental Health (CAMH) and the University of Toronto, together with senior author, Anne Bassett, describe the treatment that has been provided to 107 adults with 22q11.2 deletion syndrome and schizophrenia or schizoaffective disorder who have been followed for up to 25 years at Daiglish Family 22q Clinic in Toronto. Approximately 60% of their sample met criteria for treatment-resistant schizophrenia of whom 80% had a trial of clozapine. Clozapine remained the most commonly prescribed antipsychotic in this cohort. This work underscores how genetic characterization of individuals with schizophrenia can contribute to our understanding of treatment resistance. It also demonstrates that high levels of clozapine utilization can be achieved when devoted clinicians work closely with patients and their families to optimize treatment.

Faith Dickerson of Sheppard Pratt in Baltimore, Maryland, together with the research team led by Gail Daumit of Johns Hopkins University, describe their research into implementing tobacco cessation treatment in community mental health clinics in the USA. Tobacco smoking remains the leading cause of preventable mortality in this patient population. Dickerson and colleagues describe that rates of smoking remain 3 times as high as in the general population even though most smokers with serious mental illness would like to stop, and there are treatments available that have established efficacy in this population. Their study outlines the substantial level of interest in smoking cessation among people with serious mental illnesses and the kinds of challenges that need to be addressed to successfully implement smoking cessation treatment at the community level.

Benjamin Bond of the Institute of Psychiatry, Psychology, and Neuroscience at King's College, London, together with senior author, Marta Di Forti, build on their substantial work investigating the association between cannabis use and the development of psychosis. While cannabis was legalized in Canada in 2018, important questions remain about how cannabis use contributes to the incidence of psychotic disorders. Bond and colleagues found that former users of cannabis who had stopped cannabis 1 to 4 weeks earlier had a 7-fold increased risk of developing psychosis compared to never-users. Those who had stopped cannabis 37 or more weeks earlier did not differ in their risk of becoming psychotic compared to never users. This pattern of reduced risk following cessation is analogous to the reduction in the risk of health consequences associated with stopping smoking and drinking. Stopping cannabis may have the potential to prevent the development of psychosis.

Tyler Kaster and colleagues from CAMH and the University of Toronto together with senior authors Daniel Blumberger and Simone Vigod investigated the use of electroconvulsive therapy (ECT) in inpatients with schizophrenia spectrum disorders in Ontario, Canada, between 2006 and 2023. ECT may be of value for the management of schizophrenia when catatonia, suicidal behavior and aggression are present as well as in treatment-resistant schizophrenia (TRS) including clozapine-resistant schizophrenia. They report that ECT was utilized in less than 2% of admissions and that patient characteristics predictive of ECT use were consistent with current guidelines: depression, decreased oral intake, catatonia, command hallucinations and self-injurious behavior. However, their study also indicated that there may be inequitable access to ECT as the likelihood of receiving ECT was greater in those living in the highest income neighborhoods, and lower in those who were unmarried, experiencing family conflict, and living in rural environment. Addressing these inequities will allow ECT to be made available to those severely ill individuals who could benefit most from its use.

If remission of psychotic symptoms in people with schizophrenia is to be sustained with maintenance antipsychotic treatment, it will be very important to identify the minimum doses required for effective treatment so that adverse effects can be minimized over the long-term. Findings from our research group at CAMH and the University of Toronto published in this special edition (Zipursky et al.) suggest that trough paliperidone levels can be measured reliably in patients receiving monthly long-acting injections. While plasma levels at trough varied 15-fold in our sample, many participants had levels at the lower end of the therapeutic range proposed for oral paliperidone and risperidone (i.e. 20 ng/mL). Research underway in our program is aimed at determining prospectively whether minimum trough plasma levels can be established that will prevent recurrence of psychotic symptoms.

Daniel Devoe and colleagues together with senior author, Jean Addington, of the University of Calgary, investigated factors that mediated treatment outcomes in a randomized controlled 18-week trial comparing treatment with cognitive behavior social skills (CBSST) training to supportive therapy to improve social and role function in youth at clinical high-risk for psychosis (CHR). While it was previously reported that no significant differences between interventions were found at the end of treatment, the only measure that was found to mediate the effect of treatment on social functioning, role functioning and negative symptoms was the positive symptom score on the Scale of Psychosis-risk Symptoms (SOPS). CHR youth are a heterogeneous group of whom only a minority will develop psychosis on follow-up. The findings of this study suggest that the severity of attenuated psychotic symptoms may limit the ability of individuals at risk for psychosis to engage in and benefit from psychosocial interventions such as CBSST. The authors propose that CHR youth with more prominent attenuated psychotic symptoms may benefit from pre-treatment with brief individual therapy such as CBT in order to benefit more from CBSST.

Mohammed Alarabi and colleagues at CAMH and the University of Toronto with senior author, Gary Remington, investigated the association between formal thought disorder and neurocognition in individual with TRS treated with clozapine. There has been great interest in understanding the extent to which different symptom domains and cognitive deficits contribute to clinical outcomes in people with schizophrenia. The answer to this question would be expected to vary with sample selection as many factors including treatment and response will impact on outcomes. They report that the total score on the Thought and Language Disorder (TALD) Scale was significantly correlated with both cognitive functioning as well as social and occupational functioning. It is notable that in this sample of clozapine-treated subjects with TRS, formal thought disorder may be a critical indicator of poor outcome. It is likely that efforts to further improve outcomes in this group will require treatments that impact on thought disorder.

Lejia Fan and colleagues at the Second Xiangya Hospital of Central South University in Changsha, China, together with senior author, Lena Palaniyappan, from McGill University, obtained brain MRI scans from 49 antipsychotic-naïve participants with schizophrenia. The goal of their study was to determine whether the structural brain measures present at the time of the first episode of schizophrenia, conceptualized as brain age gap (BAG), is a determinant of antipsychotic response and to determine whether poor responders show progressive worsening of BAG compared to responders. Previous research has suggested that that lower grey matter volumes may be associated with poor treatment response but interpretation has been limited by exposure to antipsychotic medication prior to scanning. In this study, Fan et al. found that the patient group as a whole had significantly higher BAG at baseline and after 12 weeks of treatment, and that greater BAG at baseline was associated with less improvement in functioning. These findings support the view that increases in BAG are present at the time of the first episode of schizophrenia prior to any treatment, and that these difference in brain structure may be more common in those who experience less improvement in symptoms and functioning. Future progress in MRI imaging may help to distinguish responders from non-responders.

Ana Weidenauer and colleagues at McGill University with senior author, Romina Mizrahi, report on a novel positron emission tomography (PET) study to investigate if stressful life events are associated with the activity of brain fatty acid amid hydrolase (FAAH), an enzyme involved in the degradation of endocannabinoids, in 30 subjects with a first episode of psychosis and 35 healthy participants. The radioligand [11C]CURB was used to measure FAAH activity. The first episode psychosis group had more Stressful Recent Life Events; a significant association was found between FAAH and the measure of Recent Life Events scores in this group but not in healthy controls. The authors interpret their work as suggesting that first episode psychosis patients have intact endocannabinoid homeostasis that results in increased FAAH in response to higher stress levels. This, in turn, may lead to lower circulating endocannabinoids to enable response to stress.

Vitall Korann and colleagues at CAMH and the University of Toronto, with senior authors Margaret Hahn and Mahavir Agarwal, report on their work investigating the glymphatic system in schizophrenia using MRI with Diffusion-Weighted Imaging. The glymphatic system is a recently described macroscopic waste clearance system for eliminating metabolites and soluble proteins from the central nervous system. Understanding whether disturbances in glymphatic function are present in individuals with psychosis may be important to understanding the pathophysiology of schizophrenia as well as the mechanisms that underlie the adverse effects of antipsychotic medications. They studied 13 patients with a history of psychotic symptoms with a history of minimal exposure to antipsychotic medication and found that they had a decrease in glymphatic function on average compared to healthy control values. This finding is of particular interest given the very modest exposure to antipsychotic treatment in their sample. Further work in this area will benefit from larger samples sizes and community controls.

Sarah Barber of King's College London and colleagues together with senior author, Ashok Malla, of McGill University draw our attention to the care of people with schizophrenia, and women in particular, in the Global South. Just as we are appreciating how schizophrenia can be effectively treated in wealthy countries with well-resourced systems for providing psychiatric services, it is timely for the field to be broadening its view to understand how the needs of people with schizophrenia worldwide can be best addressed. As this goal is undertaken, their paper reminds us to heed the wisdom of Mary Seeman, to whom this special edition is dedicated, to ensure that understanding and addressing the complex needs of women with schizophrenia be a priority.