Comment by Dr. Ofer Agid
Comment by Dr. Ashok Malla
The management of schizophrenia has traditionally focussed on a reduction in positive and negative symptoms with antipsychotic agents. However, this narrow focus does not adequately address other features that are important to patients and caregivers, such as social and occupational functioning, involvement in productive activities, and an ability to live independently. When the European Group on Functional Outcomes and Remission in Schizophrenia (EGOFORS) examined how psychiatrists, patients and caregivers viewed symptomatic remission, only 18% agreed in their assessment (Karow et al. Eur Psychiatry 2012;27:426-431). For clinicians, remission was largely defined as improvement in PANSS scores; whereas for patients, remission was characterized by good subjective well-being, and for caregivers it was a combination of improved well-being and symptom reduction.
Recovery has been defined by the Schizophrenia Society of Canada (SSC) as living life with meaning, purpose and hope (personal recovery), meaningful relationships and social inclusion (social recovery), and managing one’s illness through various treatment options (illness recovery). In a 2009 SSC survey, a majority of respondents stated that the pursuit of recovery goals was essential to enhancing quality of life (Schizophrenia Society of Canada, 2009. Full report at www.schizophrenia.ca/docs/FINALSSCQOLReport.pdf).
The advent of second-generation antipsychotics has resulted in broader efficacy and improved tolerability, with associated gains in functional outcomes and quality of life (Remington et al. CNS Drugs 2010;24:9-20). This has enabled psychiatrists to move beyond the medical-based model of symptom improvement, and to reconceptualize schizophrenia and the goals of treatment, as Remington and colleagues have noted (Remington 2010).
Thus, achieving treatment efficacy and tolerability are only the initial goals; thereafter, treatment success will necessarily include outcomes such as psychosocial and occupational functioning, cognitive performance and quality of life (Juckel & Morosini. Curr Opin Psychiatry 2008;21:630-639). After symptomatic recovery from an acute episode, the objective during the maintenance phase is to optimize functional recovery, which includes the ability to perform basic self-care and activities of daily living (ADL), social relationships, the ability to learn and work, patient satisfaction and quality of life (QoL) (Canadian Clinical Practice Guidelines for the treatment of schizophrenia. Can J Psychiatry 2005;50:1S-56S). Unfortunately, functional recovery is not addressed in the most recent CPA guidelines on pharmacotherapy or psychosocial interventions (Remington et al. Can J Psychiatry 2017;Jan 1:706743717720448. Norman et al. Can J Psychiatry 2017; Jan 1:706743717719894).
Functional recovery may be achieved with maintenance antipsychotic treatment in conjunction with psychosocial treatments. Recommended psychosocial initiatives include family interventions, supported employment programs, and cognitive-behavioural therapy (Norman 2017). A recent survey found that a majority (89.8%) of psychiatrists believe that functional recovery is a primary therapeutic goal and one that is achievable, however, only a minority (14.4%) routinely use rating scales to evaluate functional improvement (Lahera et al. Actas Esp Psiquiatr 2016;44:97-106).
Toward functional recovery
Clinical remission is a necessary but not sufficient prerequisite for achieving functional recovery. Remission has been defined as an absence (no greater than mild) of core symptoms of schizophrenia (positive, negative and disorganized symptoms), sustained for a minimum of six months (Andreasen et al. Am J Psychiatry 2005;162:441-449). An analysis of the Schizophrenia Outpatients Health Outcomes (SOHO) cohort (n=6516) reported that symptomatic remission was more common (38% at 12 months, 52% at 36 months) than functional remission (22% at both time points) (Haro et al. Psychiatry Res 2014;220:163-169). Patient QoL and social functioning were significantly higher among those in symptomatic remission; QoL showed greater improvement in patients in sustained remission compared to those with no or intermittent remission. Similarly, in the Prevention and Early Intervention Program for Psychoses in Montreal, Quebec, the duration of remission of positive and negative symptoms was found to be predictive of functioning at one- and two-year follow-up, underscoring the importance of long-term therapy to maintain remission, and of routine monitoring of treatment adherence (Jordan et al. J Clin Psychiatry 2014;75:e566-572).
Additional studies have also found that symptomatic remission is the key determinant of QoL and functional recovery (Kokaçya et al. Noro Psikiyatr Ars 2016;53:328-333). Moreover, clinical relapse has been reported to be the factor with the greatest impact on QoL (Briggs et al. Health Qual Life Outcomes 2008;6:105-13).
That said, functional recovery is a multidimensional construct not fully captured by clinical efficacy measures (Oorschot et al. Br J Psychiatry 2012;201:215-220). Of importance are broad domains of day-to-day functioning, such as productive activities, residential and self-maintenance activities, and social relationships (Harvey & Bellack. Schizophr Bull 2009;35:300-306). Social, occupational and psychological functioning are commonly evaluated with the Global Assessment of Functioning (GAF), now replaced by the WHO Disability Assessment Schedule (WHODAS 2.0) in DSM-V; and the Social and Occupational Functioning Assessment Scale (SOFAS) (Goodman et al. Am J Psychiatry 1992;149:1148-1156).
Several studies have examined functional recovery in individuals with schizophrenia. A multi-site study in Ontario found that the rate of functional recovery (SOFAS score >60) from first-episode psychosis was 51% at one year (Menezes 2009). In the ConstaTRE open-label study, significant improvements in SOFAS scores were seen with risperidone long-acting injectable and oral quetiapine (Rouillon et al. Acta Neuropsychiatr 2013;25:297-306). A two-year trial of olanzapine oral or long-acting injectable (LAI) found that about 25% of subjects in each group achieved a good level of functioning (Ascher-Svanum et al. Neuropsychiatr Dis Treat 2014;10:1125-1131).
More recently, the Canadian ReLiAM study (Real-life assessment of Abilify Maintena® in Schizophrenia) evaluated functional status in early-phase subjects (< 5 years) with schizophrenia treated with aripiprazole LAI (Bougie et al. Value in Health, May 2017;20:A293). At 12 months, there was a significant 10-point improvement from baseline in mean GAF score, which represents a change from severe to moderate symptoms, or severe to moderate difficulty in social/occupational functioning. Higher functional improvement was also seen in early-phase compared to later-phase psychosis. There was a mean 9-point change in SOFAS score, representing improvement from severe impairment to moderate difficulty in social, occupational or school functioning. Treatment with aripiprazole LAI also resulted in decreased hospital admissions in both early and later phases.
These findings are supported by the results from the QUALIFY trial, which examined social, occupational, and psychological functioning using the QLS in patients with schizophrenia treated with aripiprazole LAI and paliperidone LAI (Naber et al. Schizophr Res 2015;168:498-504). Functional improvement with aripiprazole LAI was observed in the first month of treatment; QLS scores with aripiprazole LAI were significantly superior to paliperidone LAI beginning at week 8 and continuing until endpoint (See also Quality of life in schizophrenia: the QUALIFY trial, with commentary by Dr. Ofer Agid, NeuroSens, October 14, 2015.) The odds of being ready for work at endpoint (week 28) were significantly higher with aripiprazole LAI versus paliperidone LAI (odds ratio 2.67) (Potkin et al. Int J Neuropsychopharmacol 2017;20:40-49; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5578804/pdf/pyw093.pdf). A separate analysis from QUALIFY found that the rate of sexual dysfunction was significantly lower with aripiprazole LAI versus paliperidone LAI (odds ratio 0.33 in men, 0.14 in women). Among those with baseline sexual dysfunction who improved with treatment, there was a corresponding trend to greater improvements in QLS total scores (Potkin et al. Int Clin Psychopharmacol 2017;32:147-154; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5378005/pdf/yic-32-147.pdf).
Moreover, patients demonstrated sustained improvement in QLS scores during the 24-week QUALIFY extension (Naber et al. Schizophr Res 2017; epublished April 19, 2017, free full text at www.schres-journal.com/article/S0920-9964(17)30199-8/pdf). At the end of one year (core + extension), the mean change from baseline in QLS score was 11 points, which is more than double the minimally clinically important difference.
Taken together, these results suggest that sustainable functional recovery is achievable with effective LAI antipsychotic therapy. While social/occupational functioning is necessarily variable throughout the life course of the illness, higher functional improvements can be achieved in younger individuals. In addition, one study of older individuals with schizophrenia (mean age 59 years) living in the community found that while their functional status was worse than that of healthy age-matched subjects, 73% were living in a house or apartment and were able to manage most of their daily needs, 43% drove a car, and 30% were employed at least half of their adult lives (Palmer et al. Schizophr Res 2002;55:205-215). This challenges the notion that functional impairment is an inevitable and irremediable consequence of schizophrenia. Significant gains in functional performance and patient quality of life are realistic goals with early treatment to achieve clinical remission, and long-term maintenance of pharmacological and psychosocial interventions.
Dr. Ofer Agid: The early 1950s are considered to be the beginning of the ‘biological era’ in psychiatry. Antipsychotics were introduced to the market and became the cornerstone of treatment for schizophrenia. While antipsychotics aim to control the positive symptom domain and prevent psychotic relapse, other domains affected by schizophrenia (e.g. negative, cognitive) were never considered to be treatable by psychopharmacological compounds. Unfortunately, the impact of the illness on these domains is a major contributor to the functional impairment common in patients with schizophrenia.
Despite significant advances in pharmacological and psychological treatments, schizophrenia is still considered to be one of the world’s most disabling illnesses, mainly because patients experience deficits in a variety of everyday functional domains. In many patients with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities and social relationships. Functional disability in schizophrenia is usually a result of a cascade of multiple influences, which lead to difficulties in performing in different areas/domains of functioning and resulting in functional impairment.
A number of factors, many of them interacting with each other, have a direct or less direct influence on the ability to function. These factors include: functional capacity (by itself influenced by demographic and cognitive factors); social cognition; symptoms of the illness (including positive, negative, affective and cognitive symptoms); awareness of illness; environmental factors; and health status, including side effects resulting from treatment, such as metabolic disorders, heart and pulmonary conditions, and their functional sequelae. While some of these factors can be modified by treatment and some cannot, symptomatic remission and recovery are achievable goals in schizophrenia.
The notion that patients with schizophrenia are destined for deterioration is unnecessarily pessimistic and stigmatizing. Growing evidence suggests that the course of illness is affected by several factors, including the promptness of effective treatment interventions. The goal of treatment is to help patients move beyond the devastating impact of schizophrenia and to engage in valued life roles. This progression of events is termed recovery, and it is the process whereby persons with schizophrenia can learn to live satisfying, hopeful, and contributory lives.
Rather than implying a cure, recovery means developing a new meaning and purpose in life despite the presence of schizophrenia. As with functional outcome – itself a part of recovery – many factors are likely to facilitate the recovery process.
While only some of the factors influencing functioning and recovery can be controlled by psychopharmacological and/or psychosocial interventions, it is important to note that the strongest evidence – and a critical factor in promoting optimal outcomes in schizophrenia – is for the availability of prompt and effective antipsychotic treatment. The lessening of psychotic symptoms and the reduction of relapse rates set the stage for symptomatic remission, functional recovery and improved long-term outcomes. Effective psychopharmacological treatment – right from the outset of the illness, with early use of LAIs to prevent relapse – contributes to the improvement in real-life functioning and to promoting recovery. Family interventions, supported employment programs, and cognitive-behavioural therapy can also promote functioning and recovery and improve long-term outcomes in schizophrenia.
Dr. Ofer Agid is Clinician Scientist and Psychiatrist in the Schizophrenia Program, Medical Leader of the Home Intervention for Psychosis (HIP) team at the Centre for Addiction and Mental Health, Toronto, and Associate Professor in the Department of Psychiatry at the University of Toronto.
Dr. Ashok Malla: The central objective of this special article is to highlight the importance of functional improvement above and beyond remission of symptoms in patients with schizophrenia and related psychotic disorders. It is argued that remission of symptoms and functional recovery are not the same thing; that there are different perspectives on ‘what is recovery’ from patients and families; that while remission of symptoms is possible for most patients, functional recovery lags behind; and that antipsychotic medication, especially long acting injectables (LAI), are helpful in maintaining remission and, therefore, supporting recovery.
The first important observation that needs consideration is that the patient’s view of recovery is usually multidimensional, especially in the early course of the illness. This subjective concept embraces domains of recovery from illness (symptoms), social recovery (work, education, social relationships, independent living) and personal recovery (general wellbeing, existential, such as identity) (Windell et al. Psychiatr Serv 2012;63:548-553). To this should be added physical health, given the well-recognized morbidity and early mortality associated with the illness (Meesters et al. Am J Geriatr Psychiatry 2016;24:272-277). These dimensions may vary with stage of illness and are facilitated and impeded by a variety of factors (Windell et al. Soc Psychiatry Psychiatr Epidemiol 2015;50:1069-1077).
The role of sustained remission, through avoiding relapses, is central as it explains the largest proportion of variance in functional (work, education and social relationships) outcomes (Jordan et al. J Clin Psychiatry 2014;75:e566-572). Remission is necessary, but not sufficient in itself, to achieve functional recovery (Cassidy et al. Schizophr Bull 2010;36:1001-1008). Even in patients treated for their first episode of psychosis (FEP) in an intensive early intervention service, full remission of both positive and negative symptoms is achieved only by just over one-half of the patients within the first two years (Cassidy 2010). Further, of those who achieve remission, less than one-half make a good functional recovery. The reasons for such low rates of recovery are unclear but possibly include a number of patient (e.g. social anxiety, self-stigmatization) and environmental (lack of employment support, low level of family involvement) characteristics.
The role of LAI antipsychotics is to promote sustained remission, which allows other interventions and supports to facilitate functional recovery. There are additional factors to examine, not least of which are what can best be termed as ‘capacity factors’. These include pre-morbid adjustment (Malla et al. Schizophr Res 2002;54:231-242), cognitive functioning (especially verbal memory) and brain grey-matter volume (Bodnar et al. Br J Psychiatry 2012;200:300-307). These variables pre-date the onset of psychosis and may have their impact partly mediated through their effect on remission, but may also have a direct effect (in the case of pre-morbid adjustment). There are also cultural variations in rates of functional recovery, with higher rates reported in some low-middle income countries, such as India (Shrivastava et al. Clin Schizophr Relat Psychoses 2011;5:95-101), which is most likely related to higher rates of remission and greater family involvement.
Last, but not least, clinical trials such as QUALIFY and RELIAM, cited in the article, are able to show differences in levels of functioning either between two treatments (QUALIFY), or across time (RELIAM), but were not designed to explore what mediates that difference. We need to refrain from mixing the concept and measurement of quality of life with functioning. Rating scales, such as the Quality of Life Scale, do not measure quality of life – essentially a subjective experience – but more likely measure social, interpersonal and occupational functioning. Little research has been conducted on the relationship between remission and subjective aspects of recovery and quality of life. We should, therefore, be cautious in interpreting the results of the studies cited as they were not designed to assess personal recovery as an outcome, nor do they establish a causal relationship between type of medication and improvement in functioning. Their effect is most likely related to sustaining remission of positive and, to a lesser extent, negative symptoms, along with a higher level of tolerability. This is in itself an important contribution to the well-being of patients with psychotic disorders.
Dr. Ashok Malla is Professor and Canada Research Chair in Early Psychosis and Early Intervention in Youth Mental Health, Department of Psychiatry, McGill University, Montreal.