Functional deficits in attenuated psychosis syndrome and related conditions: Current and future treatment options

The schizophrenia spectrum has been a long-time concept and includes conditions that are related genetically and phenomenologically to schizophrenia, such as schizoaffective disorder, schizotypal personality disorder (SPD), and attenuated psychosis syndrome (APS). The spectrum, now officially recognized within Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), also reflects the genetic and neurobiological relationships between schizophrenia, schizoaffective disorder, and SPD (Clark et al., 2017). APS, although not currently recognized as part of the spectrum within DSM-5 (Tsuang et al., 2013), has been shown to predict conversion to full-scale schizophrenia spectrum disorders (Zuschlag et al., 2016), potentially warranting its inclusion. Often referred to by a variety of terms such as the prodrome, at-risk mental state, or ultra-high-risk, APS is characterized by subthreshold levels of psychosis, negative symptoms, and social, productive, and cognitive deficits (Glenthoj et al., 2016; Lam et al., 2018; Piskulic et al., 2012; Tsuang et al., 2013). Importantly, patients diagnosed with APS do not uniformly either convert to psychosis or recover; rather, many of these individuals go on to develop other conditions, which may include SPD. A central feature of the spectrum, noted since its earliest description, is cognitive impairment; this is seen in schizophrenia and in other conditions of the spectrum including SPD. Impaired cognition is also observed in individuals who eventually develop schizophrenia when they are seen during their premorbid or prodromal periods, and in unaffected first-degree relatives of people with spectrum conditions, including children who are potentially vulnerable (Harvey et al., 1981) and those who have likely already passed the age of highest risk for developing schizophrenia (Keefe et al., 1994). Impairments in the ability to perform everyday functions are a central feature of schizophrenia and, more recently, have been studied in the spectrum. Since the first descriptions of schizophrenia, the pervasive inability to sustain employment, social relationships, and functional independence has been reported (Harvey et al., 2007). Cognitive impairments are central determinants of these aspects of disability (Green, 1996), and in the last 15 years, it has been proposed that the influence of cognitive deficits on disability is largely mediated by their impact on functional capacity (i.e., the ability to perform critical, cognitively demanding functional skills). These include social and vocational skills, and everyday functions, such as medication management and activities of daily living (Harvey et al., 2007). Across the spectrum, a number of studies have linked cognitive impairment, functional capacity, and everyday functioning. Recently, attempts have been made to intervene with spectrum members who do not meet the criteria for schizophrenia by using rehabilitation-focused interventions including cognitive remediation. Such efforts are longstanding in schizophrenia (but are a new development in other spectrum conditions), and the results of meta-analyses support their efficacy (McGurk et al., 2007; Wykes et al., 2011). Interestingly, in the context of relatively poor results for pharmacological interventions aimed at cognition in schizophrenia, there have been several successful interventions using pharmacological approaches in SPD (McClure et al., 2007; McClure et al., 2010; Rosell et al., 2015). This paper reviews cognitive impairments, functional capacity deficits, and impairments in everyday functioning of people in the schizophrenia spectrum who do not meet the criteria for schizophrenia, with a focus on characteristics and recent treatment approaches. This will include both cognitive remediation and pharmacological-focused efforts and will address improvements in cognition and functional capacity using these interventions. 1.1. Specific features of attenuated psychosis syndrome Prodromal features of schizophrenia have been described for many decades and have typically included deterioration in social and functional competence prior to the onset of psychotic symptoms. Furthermore, cognitive functioning appears to change over the lifetime of psychotic symptom development. As noted by Seidman et al. (2016), “there is ample evidence of significant but milder impairments during the premorbid phase, greater deficits during the prodromal or clinical high-risk (CHR) period [of psychosis], culminating in relatively severe deficits in the first episode and chronic phases (Seidman et al., 2016).” Several large-scale studies have focused on cognition in prodromal cases, including the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1) (Seidman et al., 2010) and 2 (NAPLS-2) (Seidman et al., 2016), the Longitudinal Youth at-Risk Study (LYRIKS) in Singapore (Lam et al., 2018), and several other studies conducted in Europe and Australia (Dickson et al., 2018; McDonald et al., 2018; Mollon et al., 2018; Nelson et al., 2018a; Nelson et al., 2018b). Analyses of data from NAPLS-2 revealed that among 609 patients at CHR, 74 (12%) converted to psychosis, 242 (40%) did not convert, and 293 (48%) went on to develop other outcomes (McLaughlin et al., 2016). As of 2018, 10% of patients in the LYRIKS study were converters; of the 90% who did not convert, 54% were found to remit and the other 46% remained impaired over the entire follow-up period (Lam et al., 2018). Longer-term studies with up to 10 years of follow-up suggest that those who are stably impaired at 2 years do not show marked changes toward conversion to psychosis (Klosterkotter et al., 2001; Nelson et al., 2013) or remission of symptoms (Klosterkotter et al., 2001). Thus, a substantial proportion of individuals within NAPLS, and other similar studies, are not converted/recovered and may potentially represent the earliest stages of SPD. Indeed, non-remitting patients with APS have been suggested to demonstrate similar cognitive and functional deficits to those observed in SPD populations (Harvey, 2018). In fact, SPD was used as one of the potential entry criteria for adolescent patients (age < 19) enrolled in NAPLS-2, (Seidman et al., 2016), although not all cases met criteria. From a clinical perspective, APS cases are selected on the basis of the presence of attenuated psychosis, while it is possible to meet criteria for SPD without that level of severity of attenuated psychosis. It has been reported consistently (Cannon et al., 2008; McLaughlin et al., 2016) that the severity of attenuated psychosis at baseline predicts risk for conversion in APS samples, so non-converting non-remitters, cases who meet SPD criteria in the long term, would be expected to manifest lower levels of attenuated psychosis at baseline.