Schizophrenia Research 152 (2014) 164–169
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Predictors of cognition in first episode psychosis Danyael Lutgens, Martin Lepage, Srividya Iyer, Ashok Malla ⁎ Department of Psychiatry, McGill University, Montreal, Quebec, Canada Prevention and Early Intervention Program for the Psychoses, Douglas Mental Health University Institute, Montreal, Quebec, Canada
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Article history: Received 9 August 2013 Received in revised form 29 October 2013 Accepted 30 October 2013 Available online 25 November 2013 Keywords: First episode psychosis Cognitive functioning Duration of untreated psychosis Duration of untreated illness Pre-morbid functioning Socioeconomic status
a b s t r a c t Purpose: Cognitive deficits are common in the first episode of psychosis (FEP) and may begin much earlier. While some evidence suggests that the decline in cognition occurs over the untreated symptomatic period, including the prodromal phase, others point to these deficits being present even earlier. We aimed to investigate the differential effect of untreated symptomatic and pre-morbid phases on cognition in a large sample of FEP. Methods: Two hundred and sixty eight FEP patients, admitted into a specialized early intervention service, were administered neuro-cognitive tests. The Circumstances of Onset and Relapse Schedule (CORS) was administered for measurement of duration of untreated psychosis (DUP), the duration of untreated illness (DUI) and demographic factors. The Pre-morbid Adjustment Scale (PAS) was used to measure different domains of pre-morbid adjustment. Seventy three healthy controls were also recruited for neuro-cognitive comparison. Results: We observed no effect of DUP and a minimal effect of DUI on cognitive functioning in FEP. Instead, the early educational pre-morbid adjustment domain was most strongly associated with cognition and predicted both global cognitive and verbal memory outcome in FEP. Conclusion: Our results suggest that symptoms associated with the symptomatic phase of a FEP do not influence cognitive functioning in FEP. Instead, cognitive deficits in FEP may predate illness onset and may indicate susceptibility to such illness. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Cognitive deficits are regarded as a fundamental feature of schizophrenia and related psychotic disorders (Milev et al., 2005). Compared to healthy controls, greatest impairments are reported in the domains of memory, attention, and executive function (Dickinson et al., 2004; Mesholam-Gately et al., 2009; Holmen, 2010) and are linked to functional outcomes including independent living, occupational status, social relationships, and overall community behavior (Green and King, 1996; Green et al., 2000; Leeson et al., 2009). As current treatments of these deficits are limited, they often persist throughout the course of illness (Harvey and Penn, 2010). Cognitive deficits are present at the time of presentation of treatment of the first episode of psychosis (FEP) (Mesholam-Gately et al., 2009) and to a lesser extent, prior to any psychotic symptoms, in both the pre-morbid as well as prodromal phases of illness (MacCabe, 2008; Woodberry et al., 2008; Fusar-Poli et al., 2012). These deficits tend to remain stable from FEP to later stages of the illness with some possible decline in the later stages due to normal aging and medication effects (Zipursky et al., 2012). A recent meta-analysis reported medium deficits (ES = − 0.54) in the high risk stage (HR), likely representing ⁎ Corresponding author at: Prevention and Early Intervention Program for Psychoses (PEPP-Montreal), Douglas Mental Health University Institute, 6875 Boulevard Lasalle, Montreal, QC H4H 1R3, Canada. Tel.: +1 514 761 6131x2391; fax: +1 514 888 4458. E-mail address: [email protected] (A. Malla). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.10.044
the late prodromal phase, compared with larger deficits in FEP (ES = − 0.91) that remained relatively unchanged in the chronic phase (ES = −0.96) (Mesholam-Gately et al., 2009). While the meta-analysis of cognition in the HR phase attempted to delineate the pre-morbid (asymptomatic) from the prodromal phase of illness by separating results of cognitive tests conducted during childhood from those in adolescence (Mesholam-Gately et al., 2009), this division is challenged by the inclusion of studies that did not specify participant age or used overlapping age ranges. Their conclusion of no deterioration in cognition between childhood and adolescence (MeshalomGately et al., 2009) is in contradiction to several studies reporting an increase in deficits over this transitional period (Watt and Lubensky., 1976; Jones et al., 1994; Bilder et al., 2006; Seidman et al., 2010; MacCabe et al., 2013). What remains unclear is the extent to which the severity of cognitive deficits reported at the time of treatment of a FEP is accounted for by a decline that accompanies the onset of non-psychotic (prodromal phase) and/or psychotic symptoms or by cognitive deterioration that predates the onset of any symptoms, in early childhood or the early adolescence pre-morbid period. This may have some practical significance as any deterioration that accompanies onset of symptoms may be subject to intervention through early identification and interventions during the prodromal (such as, high risk mental states) and/or through early treatment of psychotic symptoms (Perkins et al., 2005). The link between the duration of untreated psychosis (DUP) and outcome is hypothesized to be mediated through a toxic effect on
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brain function (Wyatt, 1991), the latter likely to be represented by cognitive functions should hence reflect an association between duration of untreated psychotic symptoms and cognition. Similarly, the duration of untreated illness (DUI), which incorporates the prodromal as well as the untreated psychotic phase, may have a detrimental effect on long-term cognition but one that begins several years earlier with the start of non-specific symptoms such as depression and anxiety (McGlashan and Johannessen, 1996). While both hypotheses of the effect of DUP and DUI on cognition suggest the impact of either nonpsychotic or psychotic symptoms on cognition, measures of pre-morbid adjustment, before the onset of any symptoms, imply a possible role for early neuro-developmental processes (MacCabe and Murray, 2004; Demjaha et al., 2012), early environmental stressors (Wicks et al., 2005) and individual factors such as sex and substance abuse status (Rund et al., 2004). Among the studies investigating the effect of either DUP or DUI on cognitive functioning in psychosis, six have reported longer DUP to be associated with increased cognitive dysfunction (Scully et al., 1997; Amminger et al., 2002; Joyce et al., 2005; Lappin et al., 2007; Primavera et al., 2012; Chang et al., 2012) while an equal number report no effect (Norman et al., 2001; Ho et al., 2003; Addington et al., 2003; Rund et al., 2007; Barnes et al., 2008; Goldberg et al., 2009). None of the three studies that examined the effect of DUI on cognition found a relationship between the two (Scully et al., 1997; Hoff et al., 2000; Keshavan et al., 2003), although not all used DUI as a primary independent measure. A recent meta-analysis (Bora and Murray, in press) found no deterioration in cognition between baseline and various lengths of follow-up (between 6 months and 5 years) for both those at Ultra High Risk (UHR) and those with an FEP suggesting that the extent of cognitive deficits seen in psychosis occur much earlier, prior to even the prodromal phase (Bora and Murray, in press). Studies that have investigated the association between pre-morbid adjustment and cognition have found either specific (e.g. Silverstein et al., 2002; Larsen et al., 2004; Addington and Addington, 2005; Chang et al., 2013) or general cognitive deficits (Rabinowitz et al., 2006). Another recent study reported the degree of poverty of pre-morbid adjustment to be related to the severity, as opposed to the type, of cognitive deficits in FEP (BechardEvans et al., 2010). These discrepancies of the impact of symptomatic stages versus childhood and early adolescence factors on cognitive function in psychosis derived from multiple samples might be resolved by comparing the putative influence of these stages on cognitive functioning within the same group of FEP individuals. Therefore, our objective was to investigate cognitive deficits in the pre-morbid, prodromal, and untreated psychotic phases of illness and their potentially differential effect on cognitive functioning in a large sample of FEP through measures of pre-morbid adjustment, DUI, and DUP, while controlling for additional variables such as sex and substance abuse status that are known to influence cognitive functions. Given the equivocal results of previous research investigating the impact on cognition of the pre-morbid, prodromal, or untreated phases of the psychotic illness, no a-priori hypothesis is presented. 2. Methods 2.1. Overview In this study, we have used two measures, DUP and DUI, to investigate the association between cognition and duration of different symptoms. DUP is a measure of the duration of psychotic symptoms from their onset until the time of antipsychotic treatment. DUI is defined as the period between the onset of any signs or symptoms to the time that antipsychotics are initiated following FEP. Measures of pre-morbid adjustment are used to assess social and educational functioning before any signs or symptoms of psychosis have occurred. Further putative predictor variables of cognitive functioning in FEP include: age of onset of psychosis (Fusar-Poli et al., 2012), sex (Fusar-
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Poli et al., 2012), substance use (Potvin et al., 2008; Yücel et al., 2012), socio-economic status (Bertrand et al., 2007), and education level (Norman et al., 2001). 2.2. Treatment setting This study is part of a larger longitudinal study of FEP in a specialized early intervention service, the Prevention and Early Intervention Program for Psychosis (PEPP — Montreal, Quebec). This program provides comprehensive phase specific treatment including antipsychotic medication, assertive case management, family intervention and other forms of psychosocial therapy. It is the only FEP program serving this catchment area. This study was approved by the institutional research ethics board. 2.3. Participants All patients consecutively admitted to PEPP between 2003 and 2009 were eligible for participation if they were between the ages of 16–30; from the local catchment area; with a diagnosis of non-affective or affective psychotic disorder; who had not received antipsychotic medication for more than 1 month; and whose IQ was over 70, as assessed by the Wechsler Abbreviated Scale of Intelligence (WAIS-III) (Wechsler, 1997). Healthy controls (n = 73), matched on age and gender, were recruited through local newspaper advertisements. Eligibility criteria included no current or previous history of: any Axis I disorders; any neurological diseases, head trauma causing loss of consciousness; and a 1st degree family member with schizophrenia or related schizophrenia spectrum psychosis. All subjects signed informed consent for their participation. Those under the age of 18 were also required to have their parent or guardian's signed consent. 2.4. Clinical variables As part of PEPP protocol, the Structured Clinical Interview for DSM-IV (SCID; First et al., 1995) was used to establish a baseline diagnosis and current substance use status (yes or no). Interviews for diagnosis and symptom evaluations were carried out by trained staff who had achieved and maintained a high degree of inter-rater reliability. Final diagnosis was arrived at through consensus by two senior psychiatrists (AM & RJ) at baseline and at follow-up 1 year later. All patients were assessed for age at onset of psychosis, sex, and highest level of education achieved. Data on DUP and DUI were collected using the Circumstances of Onset and Relapse Schedule (CORS) (Malla et al., 2006), a structured interview instrument for use with patients and families that includes some sections from the Interview for the Retrospective Assessment of Onset of Schizophrenia _ IRAOS (Hafner et al., 1992). Inter-rater reliability for DUP and DUI was relatively high (ICC varying from 0.86 to 0.98). The Hollingshead two-factor index of social position (Hollingshead, 1965) based on a five point Likert scale was used to calculate the highest level of occupational and educational achievement for each of the patient's parents. A higher score on this scale represents lower SES. Due to greater consistency of data available, only the SES of the father was included. 2.5. Pre-morbid adjustment The Pre-morbid Adjustment Scale (PAS; Cannon-Spoor et al., 1982) was used to assess social and educational pre-morbid functioning across four age ranges: childhood (up to age 11), early adolescence (12– 15 years), late adolescence (16–18 years), and adulthood (≤19 years). Only ratings for childhood and early adolescence were included to avoid any overlap with prodromal symptoms that generally occur
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during late adolescence. Information was collected from the patient and significant family members on distinct items regarding sociability and withdrawal, peer relationships, scholastic performance and school adaptation. Scores from each section of the PAS are anchored between 0 and 1, with 0 representing the best possible adjustment and 1 the worst.
known to influence cognition such as, gender and age of onset. All data were assessed for multi-colinearity and residual plots were examined.
3. Results 3.1. Demographic data (Table 1)
2.6. Neuro-psychological assessment Following the recommendations set out by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) group (Nuechterlein et al., 2004), 6 domains of cognition were tested: verbal learning and memory (Logical Memory I Immediate Recall Raw Score; Logical Memory II Delay Recall Raw Score; Logical Memory II Recognition Raw Score; Wechsler Memory Scale — Third Edition, WMS-III) (Wechsler, 1997a); attention (d2 Test of Attention; concentration performance score) (Brinkenkamp and Zillmer, 1998); working memory (Spatial Span subtests of the WMS-III and the Digit Span subtest of the Wechsler Adult Intelligence Scale — Third Edition; WAIS III) (Wechsler, 1997b); reasoning and problem solving (Trail Making Test B; Completion Time) (Reitan, 1994) and (WAIS 3 Block Design Raw Score); visual memory (WMS 3 Visual Reproduction I Raw Score; WMS3 Visual Reproduction II Recall Raw Score) (Wechsler, 1997a); and speed of processing (Trail Making Test A; Completion Time) (Reitan, 1994). Testing was completed once clinical stability was achieved (i.e. not in the acute state), typically within 3 months after starting treatment. 2.7. Statistical analysis To compute z-scores, cognitive subtests were averaged to calculate each domain for each subject and standardized by subtracting the mean and dividing the difference by the standard deviation of the respective domain in the control group. To reflect overall cognitive performance, a composite score was created by averaging scores across all tests. This ‘global cognition’ variable was likewise transformed using the mean and standard deviation of the control group's global composite score (Bodnar et al., 2008). Shapiro–Wilks test of normality revealed that problem solving, processing speed, verbal memory and visual memory domains were non-normally distributed; (p b 0.05). However, given the sample size (n = 269), and all W statistics N 0.900, the criteria for normality for the cognitive domains was assumed to have been met, as parametric analysis has been shown to be robust when data is near normal. The distribution of values on DUP and DUI was skewed and hence were transformed using a logarithmic and a square root transformation, respectively. To assess differences between patient and controls, two sample t-tests on cognitive domains were conducted using a Bonferroni correction. In total there were seven comparisons, so the alpha value of 0.05 was adjusted to 0.007 in tests for significance. Those cognitive domains, global cognition and verbal memory, that represented the greatest mean difference between patients and controls were used as the primary measures of cognition for all analyses in order to avoid multiple testing. For the patient sample, Pearson correlation coefficients were calculated to examine the association of DUI, DUP, PAS (education and social dimensions during childhood and early adolescence) and other putative predictors (listed above) with verbal memory and global domains of cognition. The association of global cognition and working memory with each of the dichotomous variables, gender and substance abuse, was calculated with a point–biserial correlation. To evaluate the effect of predictor variables on cognition, hierarchical regressions were conducted using the variables that were at least moderately correlated (r N 0.2) and then entered into a regression model along with variables
Three hundred and eighty eight patients were eligible to participate. Of these, two hundred and sixty nine patients (70%) with data on at least one cognitive domain were included. The median DUP and DUI were 16 and 187 weeks, respectively. Patients scored significantly lower than healthy controls across all domains of cognition (all ts − 9.73 to − 19.05, all ps b .001). The greatest mean difference was observed in the global cognitive measure (M = − 1.48, SD = 1.36) followed by verbal memory domain (M = − 1.40, SD = 1.20) (Fig. 1). Thus, these two domains were used as primary measures of cognition for subsequent analyses in order to avoid multiple testing.
3.2. Global cognition (Table 2) Neither DUP nor DUI satisfied our criterion (r = 0.2) for an adequate strength of association with global cognition (Table 2) in the context of multiple comparisons. Global cognition was significantly negatively correlated with father's SES and positively correlated with patient's level of education. Patient sex, age of onset, and substance abuse status were not significantly correlated with the global measure of cognition (Table 2). While the PAS total score was not significantly correlated with global cognition, early adolescent and childhood educational adjustment scores were correlated moderately and modestly, respectively, with global cognition (Table 3).
Table 1 Patient demographics (n = 269), control demographics (n = 73). Variable
Patients (n = 269) Mean/median (SD)
Age at onset
M = 22 years, (SD = 3.94) M = 23 years, (SD = 3.86) Md = 16, (M = 56, SD = 114.09) Md = 187, (M = 287.96, SD = 271.79) 65.7% (n = 154)
Age at testing DUP (in weeks) DUI (in weeks)
Sex (male) Primary diagnosis Schizophrenia — paranoid Schizoaffective Schizophrenia — undifferentiated Bipolar with psychotic features Major depression with psychotic features Psychosis NOS All other Co-morbid substance use (yes) Antipsychotic medication (yes) SAPS positive symptoms (global) SANS negative symptoms (global)
Controls (n = 73) Mean/median (SD)
M = 25 years, (SD = 3.27)
65.2% (n = 45)
27% (n = 97) 10% (n = 36) 12.5% (n = 45) 9.5% (n = 35) 11.7% (n = 42) 9.8% (n = 38) 17.7% (n = 53) 57.7% (n = 154) 93.1% (n = 201) M = 3.33, (SD = 3.33) M = 9.29, (SD = 4.31)
Sample sizes (n) may not add up to 269/73 due to missing observations. DUP: Duration of Untreated Psychosis. DUI: Duration of Untreated Illness. SSD: Schizophrenia Spectrum Disorder. SAPS: Scale for the Assessment of Positive Symptoms. SANS: Scale for the Assessment of Negative Symptoms. PAS: Pre-morbid Adjustment Scale.
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Table 3 Pearson's correlation coefficients for the association of cognition with the components of PAS. PAS component
Global cognition r, n, p
Verbal memory r, n, p
Childhood education Early adolescent education Childhood social Early adolescent social
−.271⁎⁎, n = 222, p b 0.001 −.394⁎⁎, n = 220, p b 0.001 −.184, n = 222, p = .006 −.278⁎⁎, n = 220, p b 0.001 .081, n = 225, p = .225 −.007, n = 223, p = 919
.004, n = 223, p = .225 −.037, n = 221, p = .586
⁎⁎ p b 0.001.
Fig. 1. Standardized cognitive performance of patients (n = 269) relative to controls (n = 73).
only being female (F(1,159) = 13.43, p ≤ .001) and SES (F(1,157) = 21.62, p ≤ .001) were significant and explained additional unique variance (8% and 6%, respectively) in verbal memory outcome (Table 4).
4. Discussion 3.3. Verbal memory (Table 2) Neither DUP nor DUI satisfied our criterion for a significant correlation with verbal memory (Table 2). Verbal memory was positively correlated with being female and education level achieved, and negatively correlated with father's SES; and not correlated with substance abuse and age at onset of psychosis. PAS total score was negatively correlated with verbal memory. This association of PAS with verbal memory was derived primarily from both the childhood and early adolescence educational components of PAS. Social adjustment indicators were not significantly associated with verbal memory (Table 2). 3.4. Models for predictors of cognition (Table 3) All variables we used as predictors showed relative independence of br = .5, and therefore we concluded there was no significant colinearity. The hierarchical model that explained the most variance (15%) in global cognition included PAS childhood education, SES, and education level F(3,159) = 10.656, p b 0.001. However, only PAS (Childhood Education) (F(1,161) = 18.827, p b .001) and SES (F(1,161) = 18.827, p b .001) contributed unique variance to global cognitive outcome (10% and 4%, respectively) (Table 4). A hierarchical regression was similarly conducted to assess the contribution of each predictor to verbal memory. The childhood and early adolescence educational domains of PAS were significantly correlated (r = .653, n = 254, p b .001). As the childhood educational domain was found to be a better predictor of verbal memory than the childhood early adolescence domain, only the former was retained for our model. The full model that contained sex, PAS childhood education, SES, and education level achieved was significant, F(4,156) = 17.08, p b .001, and explained 29% of variance in verbal memory. PAS childhood education contributed the greatest amount of variance explained (15%) and was significant F(1,158) = 27.70, p ≤ .001. In addition,
Table 2 Pearson's correlation coefficients for the association between cognition and putative predictors including DUP, DUI, and PAS. Factor
Global cognition r, n, p
Verbal memory r, n, p
DUP DUI Sex Age of onset PAS Total Substance abuse SES Education level
.046, n = 263, p = .458 .171, n = 262, p = .006 .092, n = 269, p = .132 −.025, n = 264, p = .690 −.124, n = 170, p = .106 .008, n = 258, p = .075 −.266⁎⁎, n = 184, p b 0.001 .304⁎⁎, n = 261, p b 0.001
.004, n = 260, p = .952 .143, n = 259, p = .021 .281⁎⁎, n = 266, p b 0.001 .022, n = 261, p = .721 −.272⁎⁎, n = 168, p b 0.001 −.175, n = 255, p = .068 −.305⁎⁎, n = 181, p b 0.001 .363⁎⁎, n = 258, p b 0.001
⁎⁎ p b 0.001.
Our primary objective was to determine whether cognitive deficits in FEP are associated with the symptomatic phase of the illness or predate the onset of any symptoms. Our results show that length of untreated psychotic symptoms was not associated with cognition and that the entire length of any symptoms, including the prodromal period, was at best weakly correlated with cognition in FEP. In both our models of global cognition and verbal memory in FEP, early educational adjustment (PAS) proved to be the strongest predictor, although each of the following – patient's sex, paternal SES and level of education achieved at the time of presentation – also contributed uniquely. Our findings on the role of DUP and DUI in relation to cognition confirm results from several previous studies (Scully et al., 1997; Hoff et al., 2000; Norman et al., 2001; Addington et al., 2003; Ho et al., 2003; Keshavan et al., 2003; Rund et al., 2007; Barnes et al., 2008; Goldberg et al., 2009; Malla et al., 2011) and add weight to the evidence that neither specific psychotic (DUP) nor non-specific symptoms (DUI) have a negative effect on cognitive function (Wyatt, 1991). The finding of PAS childhood education, which represents educational adjustment before the age of 11, being most strongly associated with cognitive functioning in FEP, suggests that the level of cognitive functions seen at the time of presentation of FEP for treatment are associated with indices that reflect the pre-symptomatic state. Educational adjustment during childhood or early adolescence is likely to be a proxy measure of cognitive abilities at the time. A total lack of association of cognition in FEP with any other aspect of pre-morbid adjustment (e.g. social adjustment) during these early periods further confirms that the status of cognitive functioning in FEP is related to long-term cognitive abilities. Our results correspond to previous findings of cognitive deficits in childhood as a signal of later psychosis (Seidman et al., 2006; Woodberry et al., 2008; MacCabe et al., 2013); and of pre-morbid adjustment as a determinant of cognitive functioning in FEP (Rund et al., 2004; Norman et al., 2005; Béchard-Evans et al., 2010).
Table 4 Hierarchical regression for predictors of global cognition and verbal memory. Effects
B
β
T
Global cognition PAS childhood −1.78 −0.23 −2.86 SES −0.21 −0.19 −2.47 Education 0.08 0.14 1.62 Model is significant: [F(3, 159) = 10.656, p b 0.001] Verbal memory Gender 0.63 0.24 3.43 PAS childhood −1.99 −0.28 −3.06 SES −0.24 −0.24 −3.29 Education 0.06 0.19 1.57 Model is significant: [F(5,153) = 13.015, p b 0.001]
p
R2
0.01 0.02 0.11
0.11 0.15 0.17
0.001 0.003 0.001 0.119
0.08 0.23 0.29 0.30
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We found that educational pre-morbid adjustment but not the prodromal symptomatic phase was associated with the extent of cognitive deficits in FEP. Although Woodberry et al. (2008) found relative stability in cognitive deficits from the pre-morbid period until the onset of psychosis, they were not able to separate the pre-morbid from the prodromal phase. This was due to the cross-sectional nature of the studies they reviewed and by measuring cognition at age ranges that likely overlapped with prodromal symptoms. Our data are based on measures that reflect variables during different phases prior to onset of psychosis, including childhood and early adolescence asymptomatic phases. While Mesholam-Gately et al. (2009) reported milder cognitive deficits in the pre-morbid stage as compared to those in FEP, they were not able to determine whether cognitive decline had occurred prior to or following the onset of symptoms. Our findings may help clarify these ambiguities and add support to results of the most recent meta-analysis by Bora and Murray (in press), suggesting a neuro-developmental view of cognitive deficits. In their analysis of only longitudinal studies, they concluded that rather than a stark decline in functioning across stages of psychosis, those who go on to develop a FEP may not acquire the same cognitive abilities in childhood as do controls, thus limiting their cognitive progress (Bora and Murray, in press). Our results also show that additional stable characteristics, emergent in early childhood, may predict level of cognition in FEP. For example, our finding of better cognitive functioning in females is consistent with previous research on overall cognitive performance in FEP (Norman et al., 2001). We also found that paternal SES predicted both global cognition and verbal memory in FEP. The negative association between SES in childhood and cognitive performance in adulthood has been shown in two large longitudinal cohort studies (Turrell et al., 2002; Luo and Waite, 2005). These studies also found significant associations between low SES in childhood, low educational attainment, and poorer cognitive functioning in adulthood (Turrell et al., 2002; Luo and Waite, 2005). In contrast to early putative predictors, factors representing later development, age of onset, substance use status, and educational attainment were not associated with cognitive functioning. Our findings regarding age of onset are in contrast to the systematic review by Rajii et al (2009). This discrepancy may reflect our young sample (ages 16– 30) and differences in the definition of FEP. Substance use was not correlated with cognition in our sample. This lack of association may reflect a tendency towards patients mostly using cannabis in our sample. While a meta-analysis published recently found that FEP patients who used cannabis displayed better cognition (Yücel et al., 2012), polysubstance abuse has been found to have the opposite effect (Potvin et al., 2008). Overall, our regression models only explained between 15 and 30% of the variation in cognitive functioning on global and verbal memory domains, respectively. This suggests that there are other unmeasured variables that account for a great portion of the variance in cognitive outcomes. We made use of conservative criteria to limit the selection of explanatory variables. For example, DUI did not meet our criteria of at least a modest correlation at r = 0.2. This may have contributed to the low explanatory performance of our models, especially if cognitive performance is truly affected by many factors. Our explanatory variables, such as DUP and DUI are challenging to measure and our findings may underestimate their influence. However, thorough patient interviews and clinical consensus suggests our measures of treatment delay are robust. Among the strengths of our study are the use of a catchment area based previously untreated and relatively large and well characterized sample, lack of any competitive service suggesting that all treated incidence cases are treated in the SEI service from which this sample is derived and the fact that a large proportion of patients consented to participate in all evaluations. To conclude, our results suggest that the length of both untreated psychotic and nonpsychotic symptoms do not affect cognitive performance. Instead, cognitive deficits in psychosis may predate illness onset, including the
prodromal phase and are likely to be part of what constitutes later susceptibility to such illness. Role of funding source The first author, Danyael Lutgens, is funded through a graduate scholarship as part of a CIHR grant to the senior author (Dr. Malla). The latter is funded by the Canada Research Chairs program. Contributors All authors have made substantial contributions to the conception, design and analysis of this study. Each has reviewed this article and has also approved this paper for submission. Conflict of interest All authors of this manuscript (Danyael Lutgens, Dr. Ashok Malla, Dr. Martin Lepage, Dr. Srividya Iyer) have no conflicts of interest to report. Acknowledgments The authors gratefully acknowledge the contribution of patients and community participants as well as Nicole Pawliuk, Gerald Jordan, and Michael Bodnar for their help with data acquisition and analysis.
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Predictors of cognition in first episode psychosis Danyael Lutgens, Martin Lepage, Srividya Iyer, Ashok Malla ⁎ Department of Psychiatry, McGill University, Montreal, Quebec, Canada Prevention and Early Intervention Program for the Psychoses, Douglas Mental Health University Institute, Montreal, Quebec, Canada
a r t i c l e
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Article history: Received 9 August 2013 Received in revised form 29 October 2013 Accepted 30 October 2013 Available online 25 November 2013 Keywords: First episode psychosis Cognitive functioning Duration of untreated psychosis Duration of untreated illness Pre-morbid functioning Socioeconomic status
a b s t r a c t Purpose: Cognitive deficits are common in the first episode of psychosis (FEP) and may begin much earlier. While some evidence suggests that the decline in cognition occurs over the untreated symptomatic period, including the prodromal phase, others point to these deficits being present even earlier. We aimed to investigate the differential effect of untreated symptomatic and pre-morbid phases on cognition in a large sample of FEP. Methods: Two hundred and sixty eight FEP patients, admitted into a specialized early intervention service, were administered neuro-cognitive tests. The Circumstances of Onset and Relapse Schedule (CORS) was administered for measurement of duration of untreated psychosis (DUP), the duration of untreated illness (DUI) and demographic factors. The Pre-morbid Adjustment Scale (PAS) was used to measure different domains of pre-morbid adjustment. Seventy three healthy controls were also recruited for neuro-cognitive comparison. Results: We observed no effect of DUP and a minimal effect of DUI on cognitive functioning in FEP. Instead, the early educational pre-morbid adjustment domain was most strongly associated with cognition and predicted both global cognitive and verbal memory outcome in FEP. Conclusion: Our results suggest that symptoms associated with the symptomatic phase of a FEP do not influence cognitive functioning in FEP. Instead, cognitive deficits in FEP may predate illness onset and may indicate susceptibility to such illness. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Cognitive deficits are regarded as a fundamental feature of schizophrenia and related psychotic disorders (Milev et al., 2005). Compared to healthy controls, greatest impairments are reported in the domains of memory, attention, and executive function (Dickinson et al., 2004; Mesholam-Gately et al., 2009; Holmen, 2010) and are linked to functional outcomes including independent living, occupational status, social relationships, and overall community behavior (Green and King, 1996; Green et al., 2000; Leeson et al., 2009). As current treatments of these deficits are limited, they often persist throughout the course of illness (Harvey and Penn, 2010). Cognitive deficits are present at the time of presentation of treatment of the first episode of psychosis (FEP) (Mesholam-Gately et al., 2009) and to a lesser extent, prior to any psychotic symptoms, in both the pre-morbid as well as prodromal phases of illness (MacCabe, 2008; Woodberry et al., 2008; Fusar-Poli et al., 2012). These deficits tend to remain stable from FEP to later stages of the illness with some possible decline in the later stages due to normal aging and medication effects (Zipursky et al., 2012). A recent meta-analysis reported medium deficits (ES = − 0.54) in the high risk stage (HR), likely representing ⁎ Corresponding author at: Prevention and Early Intervention Program for Psychoses (PEPP-Montreal), Douglas Mental Health University Institute, 6875 Boulevard Lasalle, Montreal, QC H4H 1R3, Canada. Tel.: +1 514 761 6131x2391; fax: +1 514 888 4458. E-mail address: [email protected] (A. Malla). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.10.044
the late prodromal phase, compared with larger deficits in FEP (ES = − 0.91) that remained relatively unchanged in the chronic phase (ES = −0.96) (Mesholam-Gately et al., 2009). While the meta-analysis of cognition in the HR phase attempted to delineate the pre-morbid (asymptomatic) from the prodromal phase of illness by separating results of cognitive tests conducted during childhood from those in adolescence (Mesholam-Gately et al., 2009), this division is challenged by the inclusion of studies that did not specify participant age or used overlapping age ranges. Their conclusion of no deterioration in cognition between childhood and adolescence (MeshalomGately et al., 2009) is in contradiction to several studies reporting an increase in deficits over this transitional period (Watt and Lubensky., 1976; Jones et al., 1994; Bilder et al., 2006; Seidman et al., 2010; MacCabe et al., 2013). What remains unclear is the extent to which the severity of cognitive deficits reported at the time of treatment of a FEP is accounted for by a decline that accompanies the onset of non-psychotic (prodromal phase) and/or psychotic symptoms or by cognitive deterioration that predates the onset of any symptoms, in early childhood or the early adolescence pre-morbid period. This may have some practical significance as any deterioration that accompanies onset of symptoms may be subject to intervention through early identification and interventions during the prodromal (such as, high risk mental states) and/or through early treatment of psychotic symptoms (Perkins et al., 2005). The link between the duration of untreated psychosis (DUP) and outcome is hypothesized to be mediated through a toxic effect on
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brain function (Wyatt, 1991), the latter likely to be represented by cognitive functions should hence reflect an association between duration of untreated psychotic symptoms and cognition. Similarly, the duration of untreated illness (DUI), which incorporates the prodromal as well as the untreated psychotic phase, may have a detrimental effect on long-term cognition but one that begins several years earlier with the start of non-specific symptoms such as depression and anxiety (McGlashan and Johannessen, 1996). While both hypotheses of the effect of DUP and DUI on cognition suggest the impact of either nonpsychotic or psychotic symptoms on cognition, measures of pre-morbid adjustment, before the onset of any symptoms, imply a possible role for early neuro-developmental processes (MacCabe and Murray, 2004; Demjaha et al., 2012), early environmental stressors (Wicks et al., 2005) and individual factors such as sex and substance abuse status (Rund et al., 2004). Among the studies investigating the effect of either DUP or DUI on cognitive functioning in psychosis, six have reported longer DUP to be associated with increased cognitive dysfunction (Scully et al., 1997; Amminger et al., 2002; Joyce et al., 2005; Lappin et al., 2007; Primavera et al., 2012; Chang et al., 2012) while an equal number report no effect (Norman et al., 2001; Ho et al., 2003; Addington et al., 2003; Rund et al., 2007; Barnes et al., 2008; Goldberg et al., 2009). None of the three studies that examined the effect of DUI on cognition found a relationship between the two (Scully et al., 1997; Hoff et al., 2000; Keshavan et al., 2003), although not all used DUI as a primary independent measure. A recent meta-analysis (Bora and Murray, in press) found no deterioration in cognition between baseline and various lengths of follow-up (between 6 months and 5 years) for both those at Ultra High Risk (UHR) and those with an FEP suggesting that the extent of cognitive deficits seen in psychosis occur much earlier, prior to even the prodromal phase (Bora and Murray, in press). Studies that have investigated the association between pre-morbid adjustment and cognition have found either specific (e.g. Silverstein et al., 2002; Larsen et al., 2004; Addington and Addington, 2005; Chang et al., 2013) or general cognitive deficits (Rabinowitz et al., 2006). Another recent study reported the degree of poverty of pre-morbid adjustment to be related to the severity, as opposed to the type, of cognitive deficits in FEP (BechardEvans et al., 2010). These discrepancies of the impact of symptomatic stages versus childhood and early adolescence factors on cognitive function in psychosis derived from multiple samples might be resolved by comparing the putative influence of these stages on cognitive functioning within the same group of FEP individuals. Therefore, our objective was to investigate cognitive deficits in the pre-morbid, prodromal, and untreated psychotic phases of illness and their potentially differential effect on cognitive functioning in a large sample of FEP through measures of pre-morbid adjustment, DUI, and DUP, while controlling for additional variables such as sex and substance abuse status that are known to influence cognitive functions. Given the equivocal results of previous research investigating the impact on cognition of the pre-morbid, prodromal, or untreated phases of the psychotic illness, no a-priori hypothesis is presented. 2. Methods 2.1. Overview In this study, we have used two measures, DUP and DUI, to investigate the association between cognition and duration of different symptoms. DUP is a measure of the duration of psychotic symptoms from their onset until the time of antipsychotic treatment. DUI is defined as the period between the onset of any signs or symptoms to the time that antipsychotics are initiated following FEP. Measures of pre-morbid adjustment are used to assess social and educational functioning before any signs or symptoms of psychosis have occurred. Further putative predictor variables of cognitive functioning in FEP include: age of onset of psychosis (Fusar-Poli et al., 2012), sex (Fusar-
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Poli et al., 2012), substance use (Potvin et al., 2008; Yücel et al., 2012), socio-economic status (Bertrand et al., 2007), and education level (Norman et al., 2001). 2.2. Treatment setting This study is part of a larger longitudinal study of FEP in a specialized early intervention service, the Prevention and Early Intervention Program for Psychosis (PEPP — Montreal, Quebec). This program provides comprehensive phase specific treatment including antipsychotic medication, assertive case management, family intervention and other forms of psychosocial therapy. It is the only FEP program serving this catchment area. This study was approved by the institutional research ethics board. 2.3. Participants All patients consecutively admitted to PEPP between 2003 and 2009 were eligible for participation if they were between the ages of 16–30; from the local catchment area; with a diagnosis of non-affective or affective psychotic disorder; who had not received antipsychotic medication for more than 1 month; and whose IQ was over 70, as assessed by the Wechsler Abbreviated Scale of Intelligence (WAIS-III) (Wechsler, 1997). Healthy controls (n = 73), matched on age and gender, were recruited through local newspaper advertisements. Eligibility criteria included no current or previous history of: any Axis I disorders; any neurological diseases, head trauma causing loss of consciousness; and a 1st degree family member with schizophrenia or related schizophrenia spectrum psychosis. All subjects signed informed consent for their participation. Those under the age of 18 were also required to have their parent or guardian's signed consent. 2.4. Clinical variables As part of PEPP protocol, the Structured Clinical Interview for DSM-IV (SCID; First et al., 1995) was used to establish a baseline diagnosis and current substance use status (yes or no). Interviews for diagnosis and symptom evaluations were carried out by trained staff who had achieved and maintained a high degree of inter-rater reliability. Final diagnosis was arrived at through consensus by two senior psychiatrists (AM & RJ) at baseline and at follow-up 1 year later. All patients were assessed for age at onset of psychosis, sex, and highest level of education achieved. Data on DUP and DUI were collected using the Circumstances of Onset and Relapse Schedule (CORS) (Malla et al., 2006), a structured interview instrument for use with patients and families that includes some sections from the Interview for the Retrospective Assessment of Onset of Schizophrenia _ IRAOS (Hafner et al., 1992). Inter-rater reliability for DUP and DUI was relatively high (ICC varying from 0.86 to 0.98). The Hollingshead two-factor index of social position (Hollingshead, 1965) based on a five point Likert scale was used to calculate the highest level of occupational and educational achievement for each of the patient's parents. A higher score on this scale represents lower SES. Due to greater consistency of data available, only the SES of the father was included. 2.5. Pre-morbid adjustment The Pre-morbid Adjustment Scale (PAS; Cannon-Spoor et al., 1982) was used to assess social and educational pre-morbid functioning across four age ranges: childhood (up to age 11), early adolescence (12– 15 years), late adolescence (16–18 years), and adulthood (≤19 years). Only ratings for childhood and early adolescence were included to avoid any overlap with prodromal symptoms that generally occur
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during late adolescence. Information was collected from the patient and significant family members on distinct items regarding sociability and withdrawal, peer relationships, scholastic performance and school adaptation. Scores from each section of the PAS are anchored between 0 and 1, with 0 representing the best possible adjustment and 1 the worst.
known to influence cognition such as, gender and age of onset. All data were assessed for multi-colinearity and residual plots were examined.
3. Results 3.1. Demographic data (Table 1)
2.6. Neuro-psychological assessment Following the recommendations set out by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) group (Nuechterlein et al., 2004), 6 domains of cognition were tested: verbal learning and memory (Logical Memory I Immediate Recall Raw Score; Logical Memory II Delay Recall Raw Score; Logical Memory II Recognition Raw Score; Wechsler Memory Scale — Third Edition, WMS-III) (Wechsler, 1997a); attention (d2 Test of Attention; concentration performance score) (Brinkenkamp and Zillmer, 1998); working memory (Spatial Span subtests of the WMS-III and the Digit Span subtest of the Wechsler Adult Intelligence Scale — Third Edition; WAIS III) (Wechsler, 1997b); reasoning and problem solving (Trail Making Test B; Completion Time) (Reitan, 1994) and (WAIS 3 Block Design Raw Score); visual memory (WMS 3 Visual Reproduction I Raw Score; WMS3 Visual Reproduction II Recall Raw Score) (Wechsler, 1997a); and speed of processing (Trail Making Test A; Completion Time) (Reitan, 1994). Testing was completed once clinical stability was achieved (i.e. not in the acute state), typically within 3 months after starting treatment. 2.7. Statistical analysis To compute z-scores, cognitive subtests were averaged to calculate each domain for each subject and standardized by subtracting the mean and dividing the difference by the standard deviation of the respective domain in the control group. To reflect overall cognitive performance, a composite score was created by averaging scores across all tests. This ‘global cognition’ variable was likewise transformed using the mean and standard deviation of the control group's global composite score (Bodnar et al., 2008). Shapiro–Wilks test of normality revealed that problem solving, processing speed, verbal memory and visual memory domains were non-normally distributed; (p b 0.05). However, given the sample size (n = 269), and all W statistics N 0.900, the criteria for normality for the cognitive domains was assumed to have been met, as parametric analysis has been shown to be robust when data is near normal. The distribution of values on DUP and DUI was skewed and hence were transformed using a logarithmic and a square root transformation, respectively. To assess differences between patient and controls, two sample t-tests on cognitive domains were conducted using a Bonferroni correction. In total there were seven comparisons, so the alpha value of 0.05 was adjusted to 0.007 in tests for significance. Those cognitive domains, global cognition and verbal memory, that represented the greatest mean difference between patients and controls were used as the primary measures of cognition for all analyses in order to avoid multiple testing. For the patient sample, Pearson correlation coefficients were calculated to examine the association of DUI, DUP, PAS (education and social dimensions during childhood and early adolescence) and other putative predictors (listed above) with verbal memory and global domains of cognition. The association of global cognition and working memory with each of the dichotomous variables, gender and substance abuse, was calculated with a point–biserial correlation. To evaluate the effect of predictor variables on cognition, hierarchical regressions were conducted using the variables that were at least moderately correlated (r N 0.2) and then entered into a regression model along with variables
Three hundred and eighty eight patients were eligible to participate. Of these, two hundred and sixty nine patients (70%) with data on at least one cognitive domain were included. The median DUP and DUI were 16 and 187 weeks, respectively. Patients scored significantly lower than healthy controls across all domains of cognition (all ts − 9.73 to − 19.05, all ps b .001). The greatest mean difference was observed in the global cognitive measure (M = − 1.48, SD = 1.36) followed by verbal memory domain (M = − 1.40, SD = 1.20) (Fig. 1). Thus, these two domains were used as primary measures of cognition for subsequent analyses in order to avoid multiple testing.
3.2. Global cognition (Table 2) Neither DUP nor DUI satisfied our criterion (r = 0.2) for an adequate strength of association with global cognition (Table 2) in the context of multiple comparisons. Global cognition was significantly negatively correlated with father's SES and positively correlated with patient's level of education. Patient sex, age of onset, and substance abuse status were not significantly correlated with the global measure of cognition (Table 2). While the PAS total score was not significantly correlated with global cognition, early adolescent and childhood educational adjustment scores were correlated moderately and modestly, respectively, with global cognition (Table 3).
Table 1 Patient demographics (n = 269), control demographics (n = 73). Variable
Patients (n = 269) Mean/median (SD)
Age at onset
M = 22 years, (SD = 3.94) M = 23 years, (SD = 3.86) Md = 16, (M = 56, SD = 114.09) Md = 187, (M = 287.96, SD = 271.79) 65.7% (n = 154)
Age at testing DUP (in weeks) DUI (in weeks)
Sex (male) Primary diagnosis Schizophrenia — paranoid Schizoaffective Schizophrenia — undifferentiated Bipolar with psychotic features Major depression with psychotic features Psychosis NOS All other Co-morbid substance use (yes) Antipsychotic medication (yes) SAPS positive symptoms (global) SANS negative symptoms (global)
Controls (n = 73) Mean/median (SD)
M = 25 years, (SD = 3.27)
65.2% (n = 45)
27% (n = 97) 10% (n = 36) 12.5% (n = 45) 9.5% (n = 35) 11.7% (n = 42) 9.8% (n = 38) 17.7% (n = 53) 57.7% (n = 154) 93.1% (n = 201) M = 3.33, (SD = 3.33) M = 9.29, (SD = 4.31)
Sample sizes (n) may not add up to 269/73 due to missing observations. DUP: Duration of Untreated Psychosis. DUI: Duration of Untreated Illness. SSD: Schizophrenia Spectrum Disorder. SAPS: Scale for the Assessment of Positive Symptoms. SANS: Scale for the Assessment of Negative Symptoms. PAS: Pre-morbid Adjustment Scale.
D. Lutgens et al. / Schizophrenia Research 152 (2014) 164–169
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Table 3 Pearson's correlation coefficients for the association of cognition with the components of PAS. PAS component
Global cognition r, n, p
Verbal memory r, n, p
Childhood education Early adolescent education Childhood social Early adolescent social
−.271⁎⁎, n = 222, p b 0.001 −.394⁎⁎, n = 220, p b 0.001 −.184, n = 222, p = .006 −.278⁎⁎, n = 220, p b 0.001 .081, n = 225, p = .225 −.007, n = 223, p = 919
.004, n = 223, p = .225 −.037, n = 221, p = .586
⁎⁎ p b 0.001.
Fig. 1. Standardized cognitive performance of patients (n = 269) relative to controls (n = 73).
only being female (F(1,159) = 13.43, p ≤ .001) and SES (F(1,157) = 21.62, p ≤ .001) were significant and explained additional unique variance (8% and 6%, respectively) in verbal memory outcome (Table 4).
4. Discussion 3.3. Verbal memory (Table 2) Neither DUP nor DUI satisfied our criterion for a significant correlation with verbal memory (Table 2). Verbal memory was positively correlated with being female and education level achieved, and negatively correlated with father's SES; and not correlated with substance abuse and age at onset of psychosis. PAS total score was negatively correlated with verbal memory. This association of PAS with verbal memory was derived primarily from both the childhood and early adolescence educational components of PAS. Social adjustment indicators were not significantly associated with verbal memory (Table 2). 3.4. Models for predictors of cognition (Table 3) All variables we used as predictors showed relative independence of br = .5, and therefore we concluded there was no significant colinearity. The hierarchical model that explained the most variance (15%) in global cognition included PAS childhood education, SES, and education level F(3,159) = 10.656, p b 0.001. However, only PAS (Childhood Education) (F(1,161) = 18.827, p b .001) and SES (F(1,161) = 18.827, p b .001) contributed unique variance to global cognitive outcome (10% and 4%, respectively) (Table 4). A hierarchical regression was similarly conducted to assess the contribution of each predictor to verbal memory. The childhood and early adolescence educational domains of PAS were significantly correlated (r = .653, n = 254, p b .001). As the childhood educational domain was found to be a better predictor of verbal memory than the childhood early adolescence domain, only the former was retained for our model. The full model that contained sex, PAS childhood education, SES, and education level achieved was significant, F(4,156) = 17.08, p b .001, and explained 29% of variance in verbal memory. PAS childhood education contributed the greatest amount of variance explained (15%) and was significant F(1,158) = 27.70, p ≤ .001. In addition,
Table 2 Pearson's correlation coefficients for the association between cognition and putative predictors including DUP, DUI, and PAS. Factor
Global cognition r, n, p
Verbal memory r, n, p
DUP DUI Sex Age of onset PAS Total Substance abuse SES Education level
.046, n = 263, p = .458 .171, n = 262, p = .006 .092, n = 269, p = .132 −.025, n = 264, p = .690 −.124, n = 170, p = .106 .008, n = 258, p = .075 −.266⁎⁎, n = 184, p b 0.001 .304⁎⁎, n = 261, p b 0.001
.004, n = 260, p = .952 .143, n = 259, p = .021 .281⁎⁎, n = 266, p b 0.001 .022, n = 261, p = .721 −.272⁎⁎, n = 168, p b 0.001 −.175, n = 255, p = .068 −.305⁎⁎, n = 181, p b 0.001 .363⁎⁎, n = 258, p b 0.001
⁎⁎ p b 0.001.
Our primary objective was to determine whether cognitive deficits in FEP are associated with the symptomatic phase of the illness or predate the onset of any symptoms. Our results show that length of untreated psychotic symptoms was not associated with cognition and that the entire length of any symptoms, including the prodromal period, was at best weakly correlated with cognition in FEP. In both our models of global cognition and verbal memory in FEP, early educational adjustment (PAS) proved to be the strongest predictor, although each of the following – patient's sex, paternal SES and level of education achieved at the time of presentation – also contributed uniquely. Our findings on the role of DUP and DUI in relation to cognition confirm results from several previous studies (Scully et al., 1997; Hoff et al., 2000; Norman et al., 2001; Addington et al., 2003; Ho et al., 2003; Keshavan et al., 2003; Rund et al., 2007; Barnes et al., 2008; Goldberg et al., 2009; Malla et al., 2011) and add weight to the evidence that neither specific psychotic (DUP) nor non-specific symptoms (DUI) have a negative effect on cognitive function (Wyatt, 1991). The finding of PAS childhood education, which represents educational adjustment before the age of 11, being most strongly associated with cognitive functioning in FEP, suggests that the level of cognitive functions seen at the time of presentation of FEP for treatment are associated with indices that reflect the pre-symptomatic state. Educational adjustment during childhood or early adolescence is likely to be a proxy measure of cognitive abilities at the time. A total lack of association of cognition in FEP with any other aspect of pre-morbid adjustment (e.g. social adjustment) during these early periods further confirms that the status of cognitive functioning in FEP is related to long-term cognitive abilities. Our results correspond to previous findings of cognitive deficits in childhood as a signal of later psychosis (Seidman et al., 2006; Woodberry et al., 2008; MacCabe et al., 2013); and of pre-morbid adjustment as a determinant of cognitive functioning in FEP (Rund et al., 2004; Norman et al., 2005; Béchard-Evans et al., 2010).
Table 4 Hierarchical regression for predictors of global cognition and verbal memory. Effects
B
β
T
Global cognition PAS childhood −1.78 −0.23 −2.86 SES −0.21 −0.19 −2.47 Education 0.08 0.14 1.62 Model is significant: [F(3, 159) = 10.656, p b 0.001] Verbal memory Gender 0.63 0.24 3.43 PAS childhood −1.99 −0.28 −3.06 SES −0.24 −0.24 −3.29 Education 0.06 0.19 1.57 Model is significant: [F(5,153) = 13.015, p b 0.001]
p
R2
0.01 0.02 0.11
0.11 0.15 0.17
0.001 0.003 0.001 0.119
0.08 0.23 0.29 0.30
168
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We found that educational pre-morbid adjustment but not the prodromal symptomatic phase was associated with the extent of cognitive deficits in FEP. Although Woodberry et al. (2008) found relative stability in cognitive deficits from the pre-morbid period until the onset of psychosis, they were not able to separate the pre-morbid from the prodromal phase. This was due to the cross-sectional nature of the studies they reviewed and by measuring cognition at age ranges that likely overlapped with prodromal symptoms. Our data are based on measures that reflect variables during different phases prior to onset of psychosis, including childhood and early adolescence asymptomatic phases. While Mesholam-Gately et al. (2009) reported milder cognitive deficits in the pre-morbid stage as compared to those in FEP, they were not able to determine whether cognitive decline had occurred prior to or following the onset of symptoms. Our findings may help clarify these ambiguities and add support to results of the most recent meta-analysis by Bora and Murray (in press), suggesting a neuro-developmental view of cognitive deficits. In their analysis of only longitudinal studies, they concluded that rather than a stark decline in functioning across stages of psychosis, those who go on to develop a FEP may not acquire the same cognitive abilities in childhood as do controls, thus limiting their cognitive progress (Bora and Murray, in press). Our results also show that additional stable characteristics, emergent in early childhood, may predict level of cognition in FEP. For example, our finding of better cognitive functioning in females is consistent with previous research on overall cognitive performance in FEP (Norman et al., 2001). We also found that paternal SES predicted both global cognition and verbal memory in FEP. The negative association between SES in childhood and cognitive performance in adulthood has been shown in two large longitudinal cohort studies (Turrell et al., 2002; Luo and Waite, 2005). These studies also found significant associations between low SES in childhood, low educational attainment, and poorer cognitive functioning in adulthood (Turrell et al., 2002; Luo and Waite, 2005). In contrast to early putative predictors, factors representing later development, age of onset, substance use status, and educational attainment were not associated with cognitive functioning. Our findings regarding age of onset are in contrast to the systematic review by Rajii et al (2009). This discrepancy may reflect our young sample (ages 16– 30) and differences in the definition of FEP. Substance use was not correlated with cognition in our sample. This lack of association may reflect a tendency towards patients mostly using cannabis in our sample. While a meta-analysis published recently found that FEP patients who used cannabis displayed better cognition (Yücel et al., 2012), polysubstance abuse has been found to have the opposite effect (Potvin et al., 2008). Overall, our regression models only explained between 15 and 30% of the variation in cognitive functioning on global and verbal memory domains, respectively. This suggests that there are other unmeasured variables that account for a great portion of the variance in cognitive outcomes. We made use of conservative criteria to limit the selection of explanatory variables. For example, DUI did not meet our criteria of at least a modest correlation at r = 0.2. This may have contributed to the low explanatory performance of our models, especially if cognitive performance is truly affected by many factors. Our explanatory variables, such as DUP and DUI are challenging to measure and our findings may underestimate their influence. However, thorough patient interviews and clinical consensus suggests our measures of treatment delay are robust. Among the strengths of our study are the use of a catchment area based previously untreated and relatively large and well characterized sample, lack of any competitive service suggesting that all treated incidence cases are treated in the SEI service from which this sample is derived and the fact that a large proportion of patients consented to participate in all evaluations. To conclude, our results suggest that the length of both untreated psychotic and nonpsychotic symptoms do not affect cognitive performance. Instead, cognitive deficits in psychosis may predate illness onset, including the
prodromal phase and are likely to be part of what constitutes later susceptibility to such illness. Role of funding source The first author, Danyael Lutgens, is funded through a graduate scholarship as part of a CIHR grant to the senior author (Dr. Malla). The latter is funded by the Canada Research Chairs program. Contributors All authors have made substantial contributions to the conception, design and analysis of this study. Each has reviewed this article and has also approved this paper for submission. Conflict of interest All authors of this manuscript (Danyael Lutgens, Dr. Ashok Malla, Dr. Martin Lepage, Dr. Srividya Iyer) have no conflicts of interest to report. Acknowledgments The authors gratefully acknowledge the contribution of patients and community participants as well as Nicole Pawliuk, Gerald Jordan, and Michael Bodnar for their help with data acquisition and analysis.
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