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The association between cognitive deficits and depressive symptoms in at-risk mental state: A comparison with first-episode psychosis

Schizophrenia Research, 1-3, 162, pages 67 - 73

Abstract

Cognitive deficits and a high prevalence of depressive symptoms have been reported in at-risk mental state (ARMS) for psychosis, but the relationships between these variables remain unclear. The Brief Assessment of Cognition in Schizophrenia (BACS) was administered to 50 individuals with ARMS, 50 with first-episode psychosis (FEP), and 30 healthy controls (HC). Clinical symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) and the Beck Depression Inventory-2nd edition (BDI-II). Composite z-scores in BACS were compared between the three groups. Pearson correlations between composite z-scores on the BACS and indices of clinical symptoms were compared in the ARMS and FEP groups. The mean composite z-scores on the BACS for the ARMS (− 2.82) and FEP (− 2.85) groups were significantly lower than the HC group (P < 0.001); no differences between the ARMS and FEP groups emerged (P = 0.995). Cognitive deficits and depressive symptoms were significantly correlated in the ARMS group (PANSS depression:r = − 0.36,P = 0.010; BDI-II:r = − 0.34,P = 0.02), while the correlation between cognitive deficits and negative symptoms was significant in the FEP group (r = − 0.46,P = 0.001) and approached significance in the ARMS group (r = − 0.25,P = 0.08). The correlation between cognitive deficits and depressive symptoms significantly differed between the ARMS and FEP groups (PANSS depression:Z = 2.50,P = 0.012; BDI-II:Z = 1.96,P = 0.0499). Thus, a relationship between cognitive deficits and depression appears to be specific to ARMS compared to FEP.

Keywords: Cognitive function, Psychopathology, Depressive symptoms, First-episode psychosis, At-risk mental state, Ultra-high risk.

1. Introduction

Cognitive impairment has been known to be present in individuals with at-risk mental state (ARMS) for psychosis ( Fusar-Poli et al., 2012a ). Specifically, significant neurocognitive deficits in ARMS have been recorded in general intelligence, attention, executive function, verbal fluency, working memory, verbal memory, and visual memory, but not processing speed domains.

However, high clinical heterogeneity is inherent in the ARMS population, with only a subgroup of this population transitioning to psychosis ( Fusar-Poli et al., 2013a ). Therefore, Fusar-Poli et al. (2012b) suggested that some attenuated psychotic symptoms exhibited by ARMS participants may reflect the emergence of an underlying “core” psychotic process, while some symptoms may be “clinical noise” or epiphenomena associated with a non-psychotic clinical condition; and some symptoms may be normal variations among the general population.

The research is mixed regarding the magnitude of cognitive disturbance in ARMS participants, with some reports of significant differences compared to controls and others reporting no differences (Brewer et al, 2006 and Fusar-Poli et al, 2012a). Moreover, the profile of neurocognitive impairments has varied across studies. These findings suggest that heterogeneity in ARMS participants is observed in both psychopathology and cognition.

Cognitive impairment in individuals with ARMS has largely been investigated in comparison to patients with schizophrenia ( Brewer et al., 2006 ), and some studies report relationships between cognitive deficits and positive ( Frommann et al., 2011 ) and/or negative symptoms (Frommann et al, 2011 and Meyer et al, 2014). Others report no association with positive (Niendam et al, 2006 and Meyer et al, 2014) or negative symptoms ( Niendam et al., 2006 ). Moreover, little attention has focused on the relationship between cognitive deficits and processes other than psychotic or negative symptoms in ARMS.

ARMS can be comorbid with depression. In previous research ( Fusar-Poli et al., 2012b ), 40% of ARMS participants had a depressive disorder, and a comorbid diagnosis was associated with impaired global functioning. Additionally, significant cognitive disturbances have been reported, and correlations between those deficits and depression have been shown in young adults with major depressive disorder (Egeland et al, 2003, Lee et al, 2012, Merriam et al, 1999, and Trivedi and Greer, 2014). These findings suggest the possibility that cognitive deficits observed in ARMS participants can be associated with participants' depressive symptoms. Moreover, affective dysregulation has an assumed association with reality distortion and the formation of psychotic experiences ( van Rossum et al., 2011 ). It also appears that only one study has investigated the association between cognition and depression in ARMS, and no association was found ( Frommann et al., 2011 ). Therefore, it seems important to clarify the relationship between cognitive deficits and depressive symptoms in ARMS participants.

In the current study, we compared cognitive performance in ARMS and first-episode psychosis (FEP); we also examined if cognitive deficits were associated with clinical symptoms. We hypothesized that cognitive deficits and depressive symptoms would be correlated in ARMS participants, while negative symptoms associated with biological processes in schizophrenia (Baare et al, 1999, Sanfilipo et al, 2000, and Roth et al, 2004) would be correlated with FEP participants' cognitive deficits.

2. Methods

2.1. Participants

Participants included 50 individuals with ARMS, 50 patients with FEP, and 30 healthy control (HC) participants who were Japanese-speaking and between 14 and 35 years of age. The exclusion criteria were as follows: (i) serious risk of suicide or violence due to a personality disorder, (ii) current substance dependence, (iii) intellectual disability (IQ < 70), or (iv) neurological disorder, head injury, or any other significant medical conditions associated with psychiatric symptoms.

Participants in the ARMS and FEP groups were recruited from the Sendai At-Risk Mental State and First Episode (SAFE) clinic at Tohoku University Hospital, which is a specialized clinic for early psychosis (Mizuno et al, 2009 and Katsura et al, 2014). They were referred to the SAFE clinic by health providers or self-referral. Trained psychiatrists and psychologists assessed them with the clinical and cognitive measures described below.

Participants who met the criteria for ARMS or FEP were evaluated during a baseline examination for future comparative studies examining the clinical follow-up of patients. The data reported herein are baseline data from the ARMS or FEP participants who consented to participation.

The ARMS group was assessed using the Japanese version of the Comprehensive Assessment of At-Risk Mental States (CAARMS-J; Miyakoshi et al., 2009 ), and diagnosis was confirmed by the clinical team. Participants had no history of DSM-IV psychotic disorders and met one or more of the following criteria for ARMS developed by the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia ( Yung et al., 2004 ). This procedure has been widely used as standard criteria of ARMS ( Fusar-Poli et al., 2012c ) and includes the following: (i) attenuated psychotic symptoms (APS), (ii) brief limited intermittent psychotic symptoms (BLIPS; a psychotic episode that resolves within 1 week), and (iii) state and trait risk factors (e.g., a recent decline in functioning, plus either a first-degree relative with psychosis or a schizotypal personality disorder). The distribution of the fulfilled criteria in the ARMS group and their comorbid diagnoses for DSM-IV Axis I are summarized in Table 2 . Nine of the ARMS participants made a transition during the follow-up period and were included in the analyses. The mean duration of follow-up was 39.4 months (SD = 18.1, median 40.3).

Table 1 Demographic data.

  ARMS (n = 50) FEP (n = 50) HC (n = 30) Statistic value P
Number of males (%) 18 (36.0) 15 (30.0) 13 (43.3) Exact test 0.49
Age in years at testing, M (SD) 20.1 (4.3) 23.2 (5.9) 21.3 (1.0) F = 5.83 0.004
Years of education, M (SD) 12.0 (2.1) 12.7 (2.1) 14.4 (0.8) H = 27.2 < 0.001
Premorbid IQ, M (SD) 100.1 (10.5) 99.2 (7.9) 111.9 (6.6) a F = 22.0 < 0.001

a Data missing for 1 participant.

ARMS: At-Risk Mental State; FEP: First-Episode Psychosis; HC: Healthy Control; premorbid IQ was measured by the Japanese version of the National Adult Reading Test (JART).

Table 2 Distribution of DSM-IV axis I diagnosis and fulfilled ARMS criteria.

ARMS (n = 50) FEP (n = 50)
Diagnosis for DSM-IV axis I
Mood disorder 38% Schizophrenia 60%
 Major depressive disorder 16% Schizophreniform disorder 8%
 Depressive disorder NOS 16% Brief psychotic disorder 4%
 Bipolar II disorder 2% Delusional disorder 2%
 Mood disorder NOS 4% Bipolar disorder with  
Anxiety disorder 60% Psychotic features 4%
Somatoform disorder 8% Psychotic disorder NOS 22%
Dissociative disorder 4%    
Eating disorder 4%    
Adjustment disorder 4%    
Pervasive developmental disorder NOS 4%    
No axis I diagnosis 2%    
 
Fulfilled ARMS criteria
APS 80%  
BLIPS 2%  
State and trait factors 2%  
APS plus state and trait factors 14%  
APS plus BLIPS 2%  

ARMS: At-Risk Mental State; FEP: First-Episode Psychosis; NOS: Not Otherwise Specified; APS: attenuated psychotic symptoms; BLIPS: brief limited intermittent psychotic symptoms.

Participants included in the FEP group met the CAARMS-J criteria for psychosis and had a Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987 ) score of 4 or more on the items for delusion, hallucinatory behavior, grandiosity, suspiciousness, or unusual thought content for more than 1 week. Although participants were experiencing their first episode and had not fully remitted at the time of the neuropsychological examination, they were all sufficiently stable to undergo neuropsychological examination. The distribution of baseline diagnosis in the FEP group is summarized in Table 2 .

The HC participants were recruited from a local university. All participants reported that they had never been diagnosed with a psychiatric disorder.

The study was conducted with the authorization of the Ethics Committee of Tohoku University Graduate School of Medicine and Tohoku University Hospital. Written informed consent was obtained from participants 18 years of age or older and from the parents of participants under 18, with written assent from the participants.

2.2. Measures

2.2.1. Clinical assessments

Psychopathology (positive symptoms, negative symptoms, depression, and anxiety) was assessed with the PANSS. Subjective severity of depression was assessed with the Beck Depression Inventory-2nd edition (BDI-II, Beck et al., 1996 ). Global functioning was assessed with the Global Assessment of Functioning (GAF, American Psychiatric Association, 1994 ). Social functioning was assessed with the Japanese version of the Social Functioning Scale (SFS, Birchwood et al., 1990 ; the Japanese version of SFS, Nemoto et al., 2008 ). Estimated premorbid IQ was assessed using the Japanese version of the National Adult Reading Test (NART, Nelson, 1982 ; JART, Matsuoka et al., 2006 ).

2.2.2. Cognitive assessments

The Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS) was used in the current study ( Kaneda et al., 2007 ). The BACS ( Keefe et al., 2004 ) consists of six subtests of verbal memory, working memory, motor speed, verbal fluency, attention/processing speed, and executive function. All study participants were administered the BACS and raw subtest scores were standardized by creating z-scores. The HC group's means and standard deviations were set to 0 and 1 respectively ( Keefe et al., 2004 ). A composite z-score was calculated by averaging the z-scores from all six subtests and then dividing them by the standard deviation in the HC groups; higher scores reflected higher cognitive performance.

2.3. Statistical analysis

One-way ANOVAs were used to compare the ARMS, FEP, and HC groups for the demographic variables (i.e., age at testing, years of education, estimated premorbid IQ) and BACS scores. Tukey post-hoc tests were used to determine specific group differences.

T-tests were performed to compare the ARMS and FEP groups on PANSS, BDI-II, GAF, and SFS scores, and dose of medicated antipsychotics. Fisher's exact tests were performed to compare the ratio of gender in the three groups, and psychotropic medication in the ARMS and FEP groups. Pearson correlations were calculated to examine the relationships between the indices of cognition and symptomatology in the ARMS and FEP groups. Additionally, we compared correlation coefficients between the two groups using a test for the equality of correlation coefficients.

Statistical analyses were conducted using the statistical package SPSS for Windows (version 17.0). Testing was two-tailed at a 5% significance level.

3. Results

3.1. Demographic data

Table 1 summarizes the demographic data. Age at testing differed significantly among the three groups, and the FEP group was significantly older than the ARMS group (P = 0.004). More females than males were included in each group, which was due to the high proportion of female clients in the SAFE clinic. Moreover, the groups differed significantly in years of education and premorbid IQ. The HC group had a higher mean education level and estimated premorbid IQ compared with the ARMS and FEP groups.

3.2. Clinical variables and medication status

Clinical characteristics and medication status in the ARMS and FEP groups are summarized in Table 3 . The ARMS participants had significantly more depressive symptoms. In contrast, the FEP samples had significantly more positive and negative symptoms. Moreover, the GAF score in the FEP group was significantly lower than in the ARMS group, whereas no significant difference in the SFS total score was found between the two groups.

Table 3 Clinical variables and medication status.

  ARMS (n = 50) FEP (n = 50) Statistic value P
Clinical variables
PANSS positive, M (SD) 13.1 (3.3) 18.1 (5.4) t = − 5.61 < 0.001
PANSS negative, M (SD) 13.0 (5.0) 16.9 (7.0) t = − 3.25 0.002
PANSS depression, M (SD) 3.4 (0.9) 2.7 (1.2) t = 3.04 0.003
BDI-II, M (SD) 30.2 (12.3) 23.5 (13.4) t = 2.61 0.01
GAF, M (SD) 47.3 (7.3) 38.9 (9.8) t = 4.82 < 0.001
SFS total, M (SD) 106.5 (21.2) a 109.0 (24.4) b t = − 0.54 0.59
 
Medications
Antipsychotics, n (%) 13 (26.0%) 44 (88.0%) Exact test < 0.001
Atypical antipsychotics, n (%) 12 (24.0%) 42 (84.0%) Exact test < 0.001
Mean dose (CP eq.) (mg) (SD) range (mg) c 223.2 (104.9)

75–475

(n = 13)
346.7 (227.0)

75–976

(n = 44)
t = − 2.75 0.009
Antidepressants, n (%) 13 (26.0%) 2 (4.0%) Exact test 0.004
Benzodiazepines, n (%) 25 (50.0%) 30 (60.0%) Exact test 0.42
Mood stabilizers, n (%) 5 (10.0%) 5 (10.0%) Exact test 1.00
Anticholinergics, n (%) 5 (10.0%) 8 (16.0%) Exact test 0.55

a Data missing for 3 participants.

b Data missing for 5 participants.

c Not including data for those who did not receive antipsychotics.

ARMS: At-Risk Mental State; FEP: First-Episode Psychosis; PANSS: Positive and Negative Syndrome Scale; BDI-II: Beck Depression Inventory-2nd edition; GAF: Global Assessment of Functioning; SFS: Social Functioning Scale; CP: chlorpromazine; SD: standard deviation

Thirteen participants (26%) in the ARMS group were medicated with antipsychotics at testing; this proportion was lower than in the FEP group (44 participants, 88%) but similar to proportions observed in other previous studies (Cannon et al, 2008, Ruhrmann et al, 2010, and Fusar-Poli et al, 2013a). Most of the participants in the ARMS and FEP groups were prescribed atypical antipsychotics, with the mean daily dose for those in the ARMS group (n = 13) significantly lower than the dose in the FEP group (n = 44). However, the rate of antidepressant medication in the ARMS group was significantly higher than in the FEP group. There were no significant differences in other medications.

3.3. Cognitive profiles

The results of the BACS are summarized in Table 4 . The composite z-scores on the BACS were − 2.82 (SD = 1.88) in the ARMS group and − 2.85 (SD = 1.43) in the FEP group. A significant difference in the BACS composite z-scores was observed among the ARMS, FEP, and HC groups (F = 39.23,df = 2, 127,P < 0.001). Follow-up Tukey's tests indicated that the ARMS and FEP groups significantly differed from the HC group (Ps < 0.001), while no differences between the ARMS and FEP groups were evident (P = 0.995). Moreover, these differences remained significant when age at examination, years of education, dose of antipsychotics, and JART score were controlled. Similarly, on all six subtests, significant differences were found among the three groups. The scores of five of the six subtests (verbal memory, working memory, verbal fluency, attention and processing speed, and executive function) in the ARMS and FEP groups were significantly lower than those of the HC group; no significant differences were found between the ARMS and FEP groups. The score of the motor speed test in the ARMS group was significantly lower than the score in the HC group; no significant differences were found between the ARMS and FEP groups or between the FEP and HC groups.

Table 4 Z-scores on the BACS in each group.

  ARMS FEP HC F P Multiple comparison
BACS subtest Mean (SD) 95% CI Mean (SD) 95% CI Mean (SD) 95% CI  
Verbal memory − 2.36 (2.01) − 2.93 to − 1.79 − 2.15 (1.52) − 2.59 to − 1.72 0 (1) − 0.37 to 0.37 22.11 < 0.001 HC > ARMS

HC > FEP
Working memory − 2.13 (1.96) − 2.69 to − 1.58 − 2.39 (1.20) − 2.73 to − 2.05 0 (1) − 0.37 to 0.37 26.41 < 0.001 HC > ARMS

HC > FEP
Motor speed − 0.82 (1.11) − 1.14 to − 0.51 − 0.37 (1.16) − 0.70 to − 0.04 0 (1) − 0.37 to 0.37 5.42 0.005 HC > ARMS
Verbal fluency − 1.26 (1.19) − 1.60 to − 0.93 − 1.30 (0.96) − 1.57 to − 1.02 0 (1) − 0.37 to 0.37 16.68 < 0.001 HC > ARMS

HC > FEP
Attention and processing speed − 1.32 (1.19) − 1.65 to − 0.98 − 1.58 (0.92) − 1.84 to − 1.32 0 (1) − 0.37 to 0.37 22.76 < 0.001 HC > ARMS

HC > FEP
Executive function − 1.02 (1.43) − 1.42 to − 0.61 − 1.22 (1.49) − 1.64 to − 0.79 0 (1) − 0.37 to 0.37 7.93 0.001 HC > ARMS

HC > FEP
Composite score − 2.82 (1.88) − 3.36 to − 2.29 − 2.85 (1.43) − 3.26 to − 2.45 0 (1) − 0.37 to 0.37 39.23 < 0.001 HC > ARMS

HC > FEP

ARMS: At-Risk Mental State; FEP: First-Episode Psychosis; HC: Healthy Control; BACS: Brief Assessment of Cognition in Schizophrenia; CI: Confidence Interval; the BACS subtest and composite scores are shown as z-scores normalized by the mean and standard deviation of healthy control participants; Post-hoc multiple comparisons were performed using Tukey's test.

3.4. Correlations between cognitive profiles and clinical symptoms

The correlations between the cognitive profiles and clinical variables, as well as a comparison of correlation coefficients between the ARMS and FEP groups are summarized in Table 5 . Depressive symptoms (BDI-II or PANSS depression scores) were significantly related to BACS composite z-scores in the ARMS group; however, no significant correlations were observed in the FEP group. The correlation coefficients between cognitive function and depressive symptoms were significantly different between the two groups. The correlation of PANSS negative scores with the BACS composite z-score was significant in the FEP group, whereas in the ARMS group, the correlation only approached significance. The correlation coefficient between cognitive function and negative symptoms did not differ between the two groups. The BACS composite z-scores and the PANSS positive scores were not correlated in both groups, and the correlation coefficients did not differ between the two groups. Importantly, these results remained significant when partial correlation analysis was conducted with age at examination, years of education, antipsychotic medication, and estimated premorbid IQ controlled.

Table 5 Correlations between the scores of the BACS composite z-score and the clinical variables and comparison of correlation coefficients between the ARMS and FEP groups.

  ARMS FEP Test for the equality of correlation coefficients
  Pearson's r P Pearson's r P Z P
PANSS
Positive − 0.13 0.38 − 0.23 0.11 0.52 0.61
Negative − 0.25 0.08 − 0.46 0.001 lowastlowast 1.15 0.25
Depression − 0.36 0.010 lowastlowast 0.14 0.35 2.50 0.012 lowast
BDI-II − 0.34 0.02 lowast 0.05 0.75 1.96 0.0499 lowast

lowast P < 0.05.

lowastlowast P < 0.01.

ARMS: At-Risk Mental State; FEP: First-Episode Psychosis; PANSS: Positive and Negative Syndrome Scale; BDI-II: Beck Depression Inventory-2nd edition; asterisks indicate significantP-values.

3.5. Additional analyses for the profiles of converters to psychosis

Baseline BACS scores did not differ for those participants who converted to psychosis and those who did not convert during follow-ups (− 1.96 vs. − 3.01,t = − 1.55,df = 48,P = 0.13). In addition, there were no significant correlations between the cognitive profiles and clinical variables in the converters.

4. Discussion

Cognitive performance in both the ARMS and FEP groups was significantly lower than in the HC group, while no difference between the ARMS and FEP groups emerged. In addition, cognitive deficits were correlated with depressive symptoms in the ARMS group, and with negative symptoms in the FEP group and approached significance in the ARMS group.

The neurocognitive performance in both the ARMS and FEP groups was significantly lower than in the HC group; no significant differences were observed between the ARMS and FEP groups. These findings were confirmed in five of six subdomains; in the motor speed subdomain, there was a difference between the ARMS and HC groups, while there was no difference between the FEP and HC groups. Our finding replicates findings of disturbed motor function in those with ARMS (Niendam et al, 2006, Carrión et al, 2011, Frommann et al, 2011, and Ziermans et al, 2014) but not in those with FEP (Mohamed et al, 1999, Addington et al, 2003, Brickman et al, 2004, and Addington and Addington, 2008). The reason why no significant difference was found in motor speed between the FEP and HC groups in the current study is unclear; however, previous research investigating motor skill in patients with FEP seems relatively sparse, and the effect sizes in terms of impairment in this subdomain seem diverse among the studies ( Aas et al., 2014 ). Therefore, more research is needed.

The current findings indicated that the cognitive deficits in the ARMS participants were comparable to those in the FEP participants. This is inconsistent with previous studies in which ARMS participants exhibited cognitive deficits between the levels of FEP and healthy participants (Keefe et al, 2006, Eastvold et al, 2007, Jahshan et al, 2010, and Kim et al, 2011). The severe cognitive deficits exhibited in the ARMS participants may be partially explained by the correlation analysis interpreted below.

In the ARMS participants, moderate-to-severe depressive symptoms were observed and were correlated with neurocognitive deficits. This is consistent with research indicating that cognitive performance in those with major depressive disorder is significantly deteriorated when compared to healthy controls, and that cognitive deficits in depressed patients are significantly correlated with the severity of their depressive symptoms (Egeland et al, 2003, Lee et al, 2012, McDermott and Ebmeier, 2009, and Merriam et al, 1999).

While cognitive performance in ARMS and FEP has been previously compared (Keefe et al, 2006, Eastvold et al, 2007, Simon et al, 2007, Simon et al, 2012, Ozgurdal et al, 2009, Jahshan et al, 2010, Kim et al, 2011, and Üçok et al, 2013), the severity of depressive symptoms in ARMS and FEP participants has not been reported. In addition, few studies have examined the relationship between depressive symptoms and cognitive deficits in ARMS participants. Indeed, a single study reported that depressive symptoms in ARMS were not correlated with cognitive functioning ( Frommann et al., 2011 ). Although differences in measurement make it difficult to compare the magnitude of depressive symptoms in the current sample to previous samples, the ARMS group demonstrated severe depressive symptoms, which may have affected the correlation between cognitive deficits and depressive symptoms reported herein.

In contrast, no significant relationship between depressive symptoms and neurocognitive deficits was observed in the FEP group. FEP participants' depressive symptoms were less severe than those in the ARMS group, which may have had less of an effect on cognitive deficits in the FEP group. The relationship between depression severity and cognitive disturbance in psychosis seems more inconsistent than that seen in depressive disorder. A systematic review by Dominguez Mde et al. (2009) demonstrated that depressive dimensions of psychopathology in psychosis were not consistently associated with the neurocognitive measures used. Although the dynamic course and nature of depression in the early phase of psychosis are unclear, there is a possibility that the role and/or cause of depression may differ somewhat at the pre- and post-onset phases of psychosis. As was shown in the current study, ARMS could include more severe depressive symptoms ( Pruessner et al., 2011 ) and be more sensitive to everyday stressors ( Palmier-Claus et al., 2012 ) than FEP, and therefore affective dysregulation may be more prevalent or prominent in ARMS individuals and may compromise cognitive functioning. These characteristics may explain why cognitive–behavioral therapy ( van der Gaag et al., 2013 ) and antidepressants ( Cornblatt, et al., 2007 ) can be effective in this population. In line with this argument, a recent neurodevelopmental model of psychosis posits different neural mechanisms which would be involved at the pre- and post-onset phases of psychosis ( Holtzman et al., 2013 ).

Negative symptoms were significantly correlated with cognitive deficits in the FEP group, which is consistent with previous studies (Bilder et al, 2000, Heydebrand et al, 2004, Rund et al, 2004, and Lindsberg et al, 2009). Negative symptoms and cognitive deficits in psychosis have a strong relationship to pathological alterations in the brain (e.g.,Baare et al, 1999, Sanfilipo et al, 2000, and Roth et al, 2004), and current evidence demonstrates that brain alteration in FEP is more severe than that in ARMS ( Takahashi et al., 2009 ). Therefore, the relationship between negative symptoms and cognitive deficits in the current FEP group may reflect an underlying biological pathology.

We also observed a trend toward an association between cognitive deficits and negative symptoms in ARMS participants. Although previous research in this area is mixed (Niendam et al, 2006, Frommann et al, 2011, and Meyer et al, 2014), neurocognitive deficits in ARMS could impact functioning prior to the onset of psychosis (Niendam et al, 2006, Carrión et al, 2011, and Meyer et al, 2014) and may predict future psychosis ( Bora et al., 2014 ) or poor functioning ( Carrión et al., 2011 ). At the post-onset phase of psychosis, FEP individuals might present pre-existing developmental and/or illness-acquired cognitive dysfunctions, which might be closely related to the “core” psychotic process ( Fusar-Poli et al., 2012a ) and negative symptoms. However, since ARMS is heterogeneous in its presentation, longitudinal course, and putative pathophysiology ( Fusar-Poli et al., 2013c ), and approximately two thirds of those with ARMS do not develop psychosis ( Fusar-Poli, et al., 2012c ), the proportion of individuals who have a “core” psychotic process would be less in individuals with ARMS than in those with FEP. Thus, it could be assumed that this population is composed of both individuals whose cognitive deficits are more related to negative symptoms and those whose cognitive deficits are more related to depressive symptoms. Accordingly, the clinical characteristics of the present ARMS population (relatively mild negative and moderate-to-severe depressive symptoms) may explain the pattern of cognitive function with depressive and negative symptoms.

In terms of the relationship between cognition and depression in psychosis, most of the evidence so far has been obtained from patients with chronic schizophrenia, and evidence is scarce in early psychosis. Therefore, further studies are needed to elucidate the role and cause of depression at the pre- and post-onset phases of psychosis.

Positive symptoms were not correlated with cognitive deficits in ARMS and FEP participants. Few studies have examined the relationship between positive symptoms and cognitive deficits in ARMS participants. One study demonstrated a relationship between positive symptoms and memory disturbance ( Frommann et al., 2011 ), whereas other studies have not (Niendam et al, 2006 and Meyer et al, 2014); the latter was consistent with our results. Similarly, few studies have reported a relationship between positive symptoms and cognitive deficits in FEP participants. The studies that have been conducted in FEP participants are mixed, with some indicating a relationship between positive symptoms and memory disturbance ( Heydebrand et al., 2004 ) or motor speed ( Rund et al., 2004 ), and others failing to demonstrate an association (Bilder et al, 2000 and Lindsberg et al, 2009), which was consistent with our results.

This study had several limitations. First, the small sample size in the present study was due to major logistical constraints. With a moderate effect size (0.30), the statistical power for this study is 0.59, which indicates that the current study was underpowered. Therefore, the results of the present study should be considered to be preliminary, and future multicenter studies are needed, involving more patients with ARMS and FEP, to replicate the present findings.

Second, there was a higher ratio of females in the clinical groups. However, previous findings on cognitive performance in ARMS indicate increases in female performance only at the trend-level ( Fusar-Poli et al., 2012a ), with equivocal findings in schizophrenia or FEP ( Rubin et al., 2008 ).

Third, there was also the possibility of confounding factors caused by the correlational design and possibility of a sampling bias.

Fourth, medications that affect cognitive performance and severity of clinical symptoms may have also influenced the results.

Fifth, since the estimated premorbid IQ in the HC group was higher than that of the general population, the magnitude of the cognitive disturbance in the ARMS and FEP groups may be overestimated. However, the ANCOVA results indicated that these significant differences remained when years of education or JART were controlled, and the pattern of results did not change if we used standardized BACS values from a healthy Japanese sample ( Kaneda, 2013 ).

Finally, the longitudinal courses of ARMS and FEP are heterogeneous; some individuals with FEP fully remit, but others develop chronic psychosis after an acute psychotic episode. Similarly, many individuals with ARMS will not develop FEP. Future work should examine the longitudinal associations between cognitive functioning and clinical symptoms in ARMS and FEP.

Overall, the findings provide clarification for the characteristics of the cognitive deficits in these groups. Specifically, cognitive deficits observed in ARMS may be more heterogeneous than those in FEP. Furthermore, cognition in FEP could be compromised mainly by fundamental biological alterations corresponding to a “core psychotic process” associated with negative symptoms, whereas cognition in ARMS could be associated with two different processes: depression and psychosis. These findings indicate that different pathological processes could lead to cognitive deficits in ARMS and FEP in differing proportions. Specifically, the severity of depressive symptoms in ARMS participants should be examined when evaluating their cognitive deficits. Future criteria regarding ARMS should take into account the heterogeneous nature of the putative pathophysiology of ARMS.

Role of funding source

This research was supported in part by a Grant-in-Aid for Scientific Research (B) 22390219 and a Grant-in-Aid for Young Scientists (B) 23791307 and 25860984 from the Japan Society for the Promotion of Science.

Contributors

NO and KM designed the study and wrote the manuscript. KM and HM contributed to managing the project. NO, KM, MK, CO, TK, and FI recruited and clinically evaluated the participants. NO, MK, and CO managed the data. NO analyzed the data and KM, MK, CO, TK, YH, AS, KI, and FI assisted NO with analysis and interpretation of the data. They also approved the final manuscript.

Conflicts of interest

All authors declare no conflicts of interest for the work presented here.

Acknowledgments

We thank Emi Sunakawa, Tomohiro Uchida, and Rie Koshimichi for their help with the neuropsychological assessments.

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Footnotes

a Department of Psychiatry, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan

b Department of Preventive Psychiatry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan

c Department of Psychiatry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan

d Department of Psychiatry, Tohoku Pharmaceutical University Hospital, 1-12-1 Fukumuro, Miyagino-ku, Sendai, Miyagi, Japan

lowast Corresponding author at: Department of Psychiatry, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. Tel.: + 81 22 717 7262; fax: + 81 22 717 7266.