Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presenting with first episode psychosis

SCHRES-07361; No of Pages 6 Schizophrenia Research xxx (2017) xxx–xxx

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Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presenting with first episode psychosis Jing Dai a, Xiangdong Du b, Guangzhong Yin b, Yingyang Zhang b, Haishen Xia c, Xiaosi Li c, Rylan Cassidy d, Qingchun Tong d, Dachun Chen e, Antonio Lucio Teixeira f, Yingjun Zheng g, Yuping Ning g, Jair C. Soares f, Man-Xi He a,⁎, Xiang Yang Zhang g,⁎⁎ a

The Fourth People's Hospital of Chengdu, Chengdu Mental Health Center, Chengdu, China Suzhou Psychiatric Hospital, The Affiliated Guangji Hospital of Soochow University, Jiangsu, China c Hefei Fourth People's Hospital, Anhui Mental Health Center, Hefei, China d Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA e Psychiatry Research Center, Beijing HuiLongGuan Hospital, Peking University, Beijing, China f Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA g The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China b

a r t i c l e

i n f o

Article history: Received 19 February 2017 Received in revised form 17 June 2017 Accepted 18 June 2017 Available online xxxx Keywords: Schizophrenia Depression Prevalence Psychopathology Association

a b s t r a c t Depressive symptoms are common in first episode schizophrenia. However, the prevalence and its associations of comorbid depressive symptoms with clinical variables are less well characterized in Chinese Han patients with schizophrenia. In this cross-sectional study, we recruited 240 first-episode and drug naïve (FEDN) inpatients with schizophrenia. All patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD-17) to measure depressive symptoms, and also on the Positive and Negative Syndrome Scale (PANSS) for psychopathology. Our results showed that 131 patients had a total score of 8 or more points on HAMD-17, making the prevalence of comorbid depressive symptoms 54.6%. Fewer women (48.1%, 62 of 129) than men (62.2%, 69 of 111) had comorbid depressive symptoms. Compared to those patients without depressive symptoms, those with depressive symptoms showed higher PANSS total, general psychopathology, cognitive factor and negative symptom scores (all p b 0.05). Further stepwise multiple logistic regression analysis indicated that the PANSS general psychopathology, the PANSS total score and gender (all p b 0.05) remained significantly associated with depressive symptoms. In addition, correlation analysis showed significant correlations between HAMD total score and the following parameters: the PANSS general psychopathology, total score, and cognitive factor (Bonferroni corrected p's b 0.05). Our results suggest that depressive symptoms occur with high prevalence in FEND schizophrenia in a Chinese Han population, and show association with general psychopathology, as well as with cognitive impairment. © 2017 Published by Elsevier B.V.

1. Introduction Depressive symptoms frequently occur in all stages of schizophrenia and appear to be a manifestation of the schizophrenia symptom spectrum in most patients (Buckley et al., 2009; Romm et al., 2010;

⁎ Correspondence to: M-X. He, The Fourth People's Hospital of Chengdu, 8 Huli West 1st Alley, YingMenKou Road, Chengdu 610036, China. ⁎⁎ Correspondence to: X. Y. Zhang, Guangzhou Huiai Hospital, 36 Mingxin Road, Liwan District, Guangzhou 510370, China. E-mail addresses: [email protected] (M.-X. He), [email protected] (X.Y. Zhang).

Chiappelli et al., 2014). Depending on how depressive symptoms are defined, their prevalence in schizophrenia varies markedly (Hou et al., 2016). For example, a previous review paper of 36 studies showed that the depression rate in patients with schizophrenia varied between 6% and 65%, with a modal rate of approximately 25% (Siris and Bench, 2003). A recent study showed that the prevalence rate of clinical depression in chronic patients with schizophrenia was 31% (Majadas et al., 2012). This variance may be attributed to the definition of depression, the time interval under observation, the phase of the illness (Siris and Bench, 2003), and the evaluation tool used for depression identification (Lako et al., 2012). For instance, a previous study found that the frequency of depression was higher in the acute phase than in stable

http://dx.doi.org/10.1016/j.schres.2017.06.029 0920-9964/© 2017 Published by Elsevier B.V.

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029

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J. Dai et al. / Schizophrenia Research xxx (2017) xxx–xxx

patients (Mulholland and Cooper, 2000). Moreover, the highest rates of depression were found in the studies that estimated the accumulated prevalence from 3 to 5 years (Siris and Bench, 2003). A few longitudinal studies found that 25%–40% of patients with schizophrenia remained depressed at baseline and follow-up, 35%– 45% were non-depressed at both baseline and follow-up, 10%–17% became depressed over time, and 13%–19% transitioned to non-depression over time (Sands and Harrow, 1999; Conley et al., 2007; Lako et al., 2012). The most recent longitudinal study examining depression in older adults with schizophrenia after mean 54-month follow-up found that persistent depression occurred in about two-fifths of persons, 30% remain persistently non-depressed, and one-fourth may fluctuate between depression and non-depression (Cohen and Ryu, 2015). These findings suggest a core group of depressed (roughly one-third) and non-depressed (one-third to two-fifths) individuals, with the remainder fluctuating between these two states (Cohen and Ryu, 2015). Depressive symptoms are often associated with other symptom dimensions, particularly negative symptoms (Muller et al., 2006). Depression primarily affects daily activities and social functions (Tan and Rossell, 2016). For example, it has been found that co-morbid depression in schizophrenia is associated with general reduced functioning, worse employment status, poor quality of life, a greater risk of relapse or hospitalization, and an increased risk of suicide (Akinsulore et al., 2014; Abramowitz et al., 2014; Dan et al., 2011). The presence of depressive symptoms in patients with schizophrenia has been associated with overall worse outcomes (Narvaez et al., 2008), and also with an imminent onset of a psychotic relapse (Cohen and Ryu, 2015). Antipsychotics induce a remission of both psychotic symptoms and depressive symptoms; however, the efficacy of adding antidepressants for dual therapy of psychosis and depression is equivocal (Siris et al., 2001; Addington et al., 2002a, 2002b). This indicates that this core group of depressed individuals may represent a specific subtype of schizophrenia in which there is an interrelationship between the depressive symptoms of schizophrenia and the psychosis itself. Although it is well established that schizophrenia is often accompanied by depressive symptoms, few studies have examined comorbid depressive symptoms in the first episode and drug naïve (FEDN) patients with schizophrenia. The study of first-episode psychosis (FEP) is particularly advantageous in understanding the prevalence and the symptom patterns of depressive symptoms in schizophrenia in part because of the opportunity to minimize confounding factors such as illness duration, long-term medication effects, and the psychiatric and medical comorbidities that are associated with chronic schizophrenia. Moreover, most of the previous studies regarding the comorbid depressive symptoms in schizophrenia were carried out in Western countries. Only one study investigated the prevalence and correlates of comorbid moderate–severe depressive symptoms and their association with quality of life (QOL) in Chinese chronic schizophrenia patients, showing that depressive symptoms (defined as a total score of 9 or above on the MADRS) were present in 54.1% of patients. Moreover, comorbid depression was significantly associated with lower mental QOL (Hou et al., 2016). The aims of the present study were therefore to investigate the prevalence, socio-demographic correlates, and clinical correlates of comorbid depressive symptoms among FEND patients with schizophrenia in a Chinese Han population. We hypothesized that: (1) the rates of comorbid depressive symptoms will be high in FEDN patients, ranging approximately 30%; (2) The predictors described above will significantly correlate with depressive symptoms in FEDN patients. 2. Methods 2.1. Subjects All patients were inpatients in Beijing Hui-Long-Guan hospital, one of the largest psychiatric hospitals in China, with about 1400 beds specializing in the treatment of all kinds of mental disorders, and with

about 500 daily outpatient visits. It is a public psychiatric hospital owned by the Beijing city, located 30 km from central Beijing and serves a catchment area population of 25 million people. 240 FEND patients (male/female = 111/129; age range 16– 45 years) were recruited from consecutive admissions to the inpatient unit of the hospital after 27 patients were excluded due to documented medical abnormalities (n = 7), substance dependence other than tobacco (n = 5), comorbid other psychiatric disorders (n = 6), and refusal to participate in the study/inability to provide consent (n = 9). All patients met the following criteria: (1) an acute episode at study intake that met the criteria of the fourth edition of the Diagnostic and Statistical Manual (DSM-IV) for schizophrenia; (2) maximum symptom duration of 60 months; (3) no prior treatment with antipsychotic medication; (4) between 16 and 45 years of age; (5) ethnic Han Chinese; (6) current psychotic symptoms of moderate severity or greater measured with the Clinical Global Impression Scale (CGI) ≥ 4; (7) provided written informed consent and able to take part in clinical assessment. Diagnoses were made for each patient at baseline and at a 3–6 month follow-up by two experienced psychiatrists trained to use the Chinese version of the Structured Clinical Interview for DSM-IV (SCID; Phillips et al., 2007). The schizophrenia clinical subtypes identified were: paranoid, 64 (53.3%), undifferentiated, 44 (36.7%); disorganized 10 (8.3%); others 2 (1.7%). The patients had a mean age of 28.9 ± 9.7 years, and a mean duration of illness of 23.6 ± 19.8 months. A complete medical history and physical examination were obtained from all patients with schizophrenia. Patients with severe physical diseases were excluded. Neither the depressed or non-depressed patients suffered from alcohol or illegal drug abuse/dependence. Psychiatric disorders were ruled out among healthy controls by a psychiatric evaluation. The Institutional Review Board (IRB) at Beijing HuiLongGuan hospital approved this study and each subject gave written informed consent for participating after the study had been fully explained.

2.2. Demographic characteristics Research staff administered a detailed questionnaire that asked for general information, socio-demographic characteristics, smoking behavior, and medical and psychological conditions. Additional information was collected from available medical records and collateral data sources (from family and/or treating clinician).

2.3. Clinical measures Four psychiatrists who were blind to the clinical status assessed the patient's psychopathology with the PANSS (Kay et al., 1987; He and Zhang, 2000) and depressive symptoms with the Hamilton Depression Rating Scale (HAMD) (Hamilton, 1960; Zhang, 1993). To ensure consistency and reliability of ratings across the study, these four psychiatrists, who had worked at least 5 years in clinical practice, simultaneously attended a training session in using the PANSS and the HAMD before the start of the study. After training, they maintained an inter-rater correlation coefficient of 0.82 for the PANSS total score and 0.85 for HAMD total score. We employed HAMD for a comprehensive measure of depressive symptoms. The scoring is based on the first 17 items. Eight items are scored on a 5-point scale, ranging from 0 (not present) to 4 (severe). Nine items are scored from 0 (none) to 2 (symptom-specific severity descriptor). Patients were classified into two groups using HAMD rating cut-offs: ≤ 7 = not depressed (NDP) and ≥ 8 = depressed (DP) (Park et al., 2016). Then moderate to severe depressive symptoms were defined as a total score of 14 or above on the HAMD-17 (Liu et al., 2014).

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029

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2.4. Statistical analysis Demographic and clinical variables of the depression and non-depression groups were compared using analysis of variance (ANOVA) for continuous variables and chi-squared test for categorical variables. Where there was a significance in ANOVA, the effect of gender were tested by adding it to the analysis model as covariate. The prevalence of comorbid depressive symptoms was analyzed by Pearson's chisquared test. Odds ratios (OR) derived from logistic regression analyses compared depression and non-depression among the patients with schizophrenia after correcting for the related variables. Correlations among demographic and clinical variables were examined by Pearson correlation coefficients. Bonferroni corrections were applied to each test to adjust for multiple testing. A binary logistic regression analysis was conducted to assess which factors were most strongly associated with comorbid depressive symptoms. In addition, stepwise multiple regression analysis was performed to investigate the relationships between HAMD total score and psychotic symptoms shown on PANSS and clinical variables. All statistical analyses were performed in SPSS version 15.0. Continuous data were presented as mean ± SD and categorical data as number with factor/number without factor. All p values were 2 tailed at the significance level of b 0.05. 3. Results Table 1 compares the socio-demographic and clinical characteristics of patients with comorbid depressive symptoms to those without. Since some patients did not fully complete the questionnaire or clinical measures, numbers vary slightly in different categories. As presented in Table 1, 131 (54.6%) of 240 patients met the criteria for comorbid depressive symptoms and 109 (45.4%) did not. Fewer women (48.1%, 62 of 129) than men (62.2%, 69 of 111) suffered from depressive symptoms (χ2 = 4.28, df = 1, p = 0.039). This difference remained significant after using logistic regression to adjust for the characteristics including age, education and body mass index (BMI) (χ2 = 4.12, p = 0.042; adjusted odds ratio = 0.576; 95% confidence interval, 0.338–0.981). There was no a significant difference in any other demographic variables including age, education, body mass index (BMI), smoking and FTND between those with and without comorbid depressive symptoms (all p N 0.05). In addition, 52 (21.7%) of 240 patients met the criteria for moderate/severe depressive symptoms. Mean scores on the PANSS were: positive subscore, 25.5 ± 6.6; negative subscale, 19.3 ± 7.8; general psychopathology subscale, 41.0 ± 11.8 and total PANSS score, 85.8 ± 19.9.2.3. The ‘cognitive factor’ was Table 1 Demographic and clinical characteristics between the FEDN schizophrenia patients with and without depression. Characteristics

Depression (n = 131)

Non-depression (n = 109)

F/x2

Df

p-Value

Males/females Age (years) Education (years) Smoker/non-smoker Age at onset (years) Marriage Single Married Divorced BMI (kg/m2) PANSS Positive score Negative score General score Total score Cognitive factor

69/62 29.3 ± 10.5 12.2 ± 3.1 23/77 26.2 ± 9.3

42/67 27.3 ± 9.2 12.6 ± 4.0 12/69 26.1 ± 9.3

4.28 0.30 0.79 1.92 0.002 1.38

1 1238 1237 1 1234 2

0.039 0.58 0.38 0.17 0.97 0.50

88 37 6 22.1 ± 3.9

70 30 9 21.8 ± 3.8

0.28

1236 0.60

26.3 ± 6.9 21.0 ± 8.6 45.3 ± 11.8 92.6 ± 20.4 8.6 ± 3.9

24.9 ± 6.0 18.4 ± 6.8 36.0 ± 7.2 79.3 ± 14.2 7.1 ± 3.4

2.55 6.74 51.78 33.12 9.35

1238 1238 1238 1238 1238

0.11 b0.01 b0.001 b0.001 0.002

Note: PANSS = Positive and Negative Syndrome Scale; BMI = body mass index. The significance of bold emphases in the table is p b 0.05.

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derived from several elements of the total PANSS, as described in previous report (Rodriguez-Jimenez et al., 2013). The PANSS general psychopathology subscore, total score (both p b 0.001), cognitive factor (p = 0.002) and negative symptom subscores (p b 0.01) were significantly higher in patients with than those without comorbid depressive symptoms. After the Bonferroni correction (α = 0.05 / 5 = 0.01), all these results remained significant (all p b 0.01). After controlling for gender, all these differences remained significant (all p b 0.05; Table 1). In logistic regression analysis for associations with comorbid depressive symptoms, the PANSS general psychopathology (Wald x2 = 29.3, df = 1, p b 0.001), the PANSS total score (Wald x2 = 23.7 df = 1, p b 0.001) and gender (x2 = 4.1, df = 1, p = 0.042) remained significant (Table 2). In addition, correlation analysis showed significant correlations between HAMD total score and the following parameters, the PANSS general psychopathology (r = 0.61, df = 240, p b 0.001), PANSS total score (r = 0.46, df = 240, p b 0.001), PANSS cognitive factor (r = 0.20, df = 240, p = 0.002), negative symptom (r = 0.18, df = 240, p = 0.005) and gender (r = −0.18, df = 240, p = 0.006) (Table 3). However, after the Bonferroni correction (α = 0.05/10 = 0.005), only the significant associations between HAMD total score and the PANSS general psychopathology, the PANSS total score, the cognitive factor and negative symptom passed the Bonferroni corrections (all p b 0.005). Multiple regression showed significant associations between HAMD total score and the PANSS general psychopathology or the PANSS total score (both p b 0.01). 4. Discussion To our best knowledge, this is the first study to examine the prevalence, socio-demographic and clinical characteristics of comorbid depressive symptoms in the FEDN patients with schizophrenia in a Chinese Han population. We found that a slight majority of FEDN patients were depressed, and the significant clinical correlates of depressive symptoms in this population were gender, negative, psychopathological and cognitive symptoms. In our present study, the prevalence of comorbid depressive symptoms at 54.6% and moderate/severe depressive symptoms at 21.7% in FEDN patients with schizophrenia closely corresponds with a recent report finding 54.1% and 17.7%, respectively, in Chinese chronic patients with schizophrenia evaluated in the primary care setting (Hou et al., 2016). However, a previous study found a lower prevalence (40.6%) of comorbid depressive symptoms when using a cut-off point of 6 or above on the Calgary Depression Scale for Schizophrenia (CDSS) in Chinese chronic schizophrenia outpatients (Liu and Zhou, 2009). These results suggest that the rate of comorbid depressive symptoms in schizophrenia may be different even in the same ethnic population due to the differences in sensitivity and specificity of the measure of depression, the different stages of disease progression (acute, early, or chronic) and different illness courses. Our schizophrenia inpatients displayed more severe psychopathology - including depressive symptoms - than those treated in primary care, which may explain the depression prevalence estimates (Hou et al., 2016). The prevalence of comorbid depressive symptoms in our sample of 54.1% is within the range (6%–65%) of existing worldwide prevalence Table 2 Predictors generated by Multivariate Logistic Regression with depression as dependent variable. Coefficients

Std. error

Wald

p value

B (Constant) G subscale PANSS Gender

−2.92 0.141 0.044 −0.059

1.05 0.026 0.009 0.029

7.71 29.3 23.7 4.1

0.005 0.000 0.000 0.042

95.0% confidence interval for EXP(B) Exp(B)

Lower

Upper

1.15 1.05 0.94

1.09 1.03 0.89

1.21 1.06 1.00

Note: PANSS = Positive and Negative Syndrome Scale; G = general psychopathology.

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029

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Table 3 Inter-correlations between HAMD and gender, PANSS total and its subscales in FEDN patients with schizophrenia. Variables

HAMD Gender PANSS total

G subscale

Cognitive factor

N subscale

HAMD Gender PANSS total G subscale Cognitive factor N subscale

1 0.006 0.000 0.000 0.002

−0.18 1 0.002 0.001 0.001

0.46 −0.20 1 0.000 0.000

0.61 −0.22 0.91 1 0.000

0.20 −0.21 0.66 0.50 1

0.18 −0.18 0.63 0.37 0.58

0.005

0.005

0.000

0.000

0.000

1

Note: HAMD = Hamilton Depression Rating Scale, PANSS = Positive and Negative Syndrome Scale; G = general psychopathology; N = negative symptom. In the right side of the diagonal elements of correlation matrix, correlations coefficients between the possible pairs of variables are shown. In the left side of the diagonal elements, the p-values corresponding to the significance levels of correlation coefficients are shown.

estimates, but much higher than the average rate of 25%–31% in chronic patients with schizophrenia (Siris and Bench, 2003; Majadas et al., 2012). One may reasonably attribute this high prevalence to the typically severe psychopathology found in first-episode patients along with lack of treatment (Upthegrove et al., 2010, 2014). A recent Australian study showed a depression prevalence of 29.30% in first-episode patients with schizophrenia (Herniman et al., 2017). Thus, there may also be cultural and/or genetic component underlying differences in population prevalence of depression. Increasing evidence shows substantial genetic overlap between schizophrenia and major depressive disorder (Cheah et al., 2015; Chen et al., 2016). For example, the presence of the single nucleotide polymorphism (SNP) rs1344706 of the zinc finger-coding gene ZNF804A increases susceptibility to developing schizophrenia as well as major depressive disorder (Ou et al., 2016). Further, the NMDA receptor subunit gene GRIN1, the hippocampal stress modulating glycoprotein gene GPM6A, and chromosomal regions 4q28.3 and 20q11.21 were associated with depression comorbidity in patients with schizophrenia (Georgi et al., 2007; Boks et al., 2008). A recent study showed that the nitric oxide synthase 1 adaptor protein gene (NOS1AP) variants were associated with various forms of depression in schizophrenia (Cheah et al., 2015). The variation in the frequency of these alleles likely varies from population to population, thus providing a mechanism by which depression and schizophrenia comorbidity rates may also vary between studies which typically look at a population drawn from a single city or within a single country. We found significant gender difference in the prevalence of comorbid depressive symptoms in schizophrenia, showing a higher rate in males compared to females (62.2% vs. 48.1%). Numerous studies have showed gender differences in age of onset, symptom severity, treatment response, course of illness, and outcome in schizophrenia with men typically earlier, more severe, worse response, and worse outcome (Grossman et al., 2008; Zhang et al., 2012). A previous study has demonstrated that female subjects exhibit a higher prevalence of depression than male subjects in a large representative, population-based samples of adults (n = 89,037) in 18 countries, a consistent pattern across culture (Bromet et al., 2011). The gender difference in prevalence and clinical correlates of depression have not been specifically studied in patients with schizophrenia probably due to the limited sample size in former studies. A previous study did not find consistent gender differences with respect to the level of depression severity in schizophrenia (Addington et al., 1998). Also, another study did not find significant gender differences with respect to global illness severity (CGI, PANSS total score), positive, negative and depressive symptoms assessed by the Calgary Depression Rating Scale for Schizophrenia (CDSS) in patients during hospitalization for an acute exacerbation (Müller, 2007). Conversely, a recent study reported gender difference in depressive symptoms in patients of multiplex (MS) and simplex schizophrenia families (SS), showing that SS females had significantly higher

depression symptoms than SS males, while MS male and female groups did not have any differences in term of depression (Martín-Reyes et al., 2011). In our current study, we found lower depressive symptoms in female than in male FEND patients, which was opposite to our expected direction. This finding is inconsistent with those studies showing higher prevalence of depression in female than male subjects in general population (Bromet et al., 2011) or greater depression symptoms in female than male SS patients with schizophrenia (Martín-Reyes et al., 2011). The mechanisms responsible for these discrepant findings are still unknown. We hypothesize that the phase of the schizophrenia illness may play a role, since our patients were first-episode and drug naïve and had severe symptoms and thus likely are different from chronic patients or non-schizophrenic population. A further finding of our present study was that comorbid depressive symptoms were positively associated with negative and general psychopathological symptoms in schizophrenia. Previous studies have explored the relationship between depression and psychosis especially negative symptoms in schizophrenia, with mixed results. A recent study showed a moderate positive correlation of depressive symptoms (as assessed by CDSS total score) and negative symptoms (via the Scale for the Assessment of Negative Symptoms (SANS)), and a low correlation with the PANSS negative symptom subscale in 90 outpatients with chronically stable schizophrenia (Majadas et al., 2012). In contrast, a previous study reported depression and anxiety scores were associated with PANSS positive symptom scores but not negative symptom scores (Emsley et al., 1999). Yet another recent study found that the total CDSS score showed a low negative correlation with the total SANS score, in particular with its avolition subscale, in 240 patients with schizophrenia with predominantly negative symptoms (Rabany et al., 2011). A recent longitudinal study focused primarily on the interrelationship between depressive and negative or positive symptoms in the long-term course of schizophrenia showed a positive association between the SANS subsyndrome-anhedonia and depressive symptoms which remained stable over a period of 5 years; the association between abulia and depression grew increasingly pronounced over the illness course (An der Heiden et al., 2016). A possible synthesis of these discordant findings is that the relationship between depressive and positive or negative schizophrenic symptoms depends in large part upon the phase of illness and medication; but the exact association of depression with psychotic symptoms in schizophrenia warrants further investigation. In addition, since depressive and negative symptoms are more difficult to distinguish from one another in patients with schizophrenia, and both are heterogeneous in their nature, we cannot attribute causality to this simple quantitative association. Using a longitudinal study design, further evaluations of FEND patients and their subsequent depressive and schizophrenic symptomatology would clarify their interrelationship. We also found a significantly positive correlation of depressive symptom with the PANSS cognitive factor. Many studies have shown significant deficits in cognitive performance in schizophrenia across several domains, including learning, memory, attention, executive functioning and cognitive processing speed (Bora et al., 2010; D'Antonio and Serper, 2012; Fioravanti et al., 2012; Schaefer et al., 2013; Lennertz et al., 2016). This has also been demonstrated by numerous studies evaluating worsening MDD correlating with worse cognitive function (Snyder, 2013). Modest cognitive deficits are still apparent in euthymic periods of patients with MDD (Bora et al., 2013). A few previous studies have explored the association between depressive symptoms and cognitive deficits in schizophrenic patients. For instance, Möser et al. (2006) reported that part of the neuropsychological impairment, especially attention and memory disturbances, seen in schizophrenia is linked with symptoms of depression. In a series of studies, Brébion et al. found that acute inpatients who were depressed performed worse on measures of effortful but not automatic memory, and worse on measures of global verbal memory efficiency, compared to their nondepressed counterparts (Brébion et al., 2001, 2009). Thus, our results are

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029

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consistent with some of the literature examining cognition in depression alone and in schizophrenia comorbid with depressive symptoms. However, other studies found no relationship between depressive symptoms and any measure of neuropsychological functioning, including memory, attention, executive functioning and processing speed in schizophrenia (Gladsjo et al., 2004; Bowie et al., 2006; Tanaka et al., 2012). A recent study demonstrated that depressive symptoms did not have a significant relationship either with objective measures of neurocognition and functional capacity or with clinician ratings of everyday functioning in a large sample of schizophrenia outpatients (Harvey et al., 2016). These results contradict our own, and as yet an explanation remains to be found. It is possible that, again, FEDN patients may have far worse cognitive scores than the chronic schizophrenia baseline due to worse symptomatology overall. The real relationship between depressive symptom and cognitive function in schizophrenia warrants further investigation using longitudinal design. Our current study shows the clinical importance of depressive symptom as a symptom domain in FEDN patients with schizophrenia, suggesting the importance of monitoring and treating depressive pathology in the management and treatment of these FEND patients (Herniman et al., 2017). However, data on therapeutic interventions for depressive pathology in FEND patients is rare (Cotton et al., 2010). Although pharmacotherapy has been indicated as a potential treatment a recent meta-analysis suggests small, beneficial effects of adjunctive antidepressants. Moreover, this augmentation may be accomplished with a low risk of exacerbation of psychosis and adverse effects (Helfer et al., 2016). Additionally, cognitive behavioral therapy (CBT) has been shown beneficial efficacy for depression, but no CBT studies have specifically targeted depressive pathology in schizophrenia patients (Upthegrove et al., 2016). Therefore, future clinical trials using the double-blind, randomized design will be needed to investigate the efficacy of pharmacotherapy or/and CBT interventions in ameliorating depressive pathology in FEND patients with schizophrenia. Several limitations to the present study should be noted. First, although the SCID for DSM-IV was used for the diagnosis of schizophrenia, depressive disorder diagnoses was not established, which could have been useful for our current study. Moreover, a comprehensive assessment of depressive pathology should have also encompassed a diagnostic interview. Second, with regard to our subject sample, the participants in this study were recruited from an acute inpatient psychiatry unit. Thus they had more severe psychiatric symptoms and the results in our current study may not apply to stable chronic patients, or outpatients with mild or moderate severity of symptoms. Third, the patients were recruited from the inpatients only in one hospital in Beijing in this survey. Therefore, the findings could not be generalized to other settings and outpatients. Fourth, we did not use a specific cognitive test in the present study; instead, we employed the five-factor model of the PANSS and derived the cognitive score from this model. The use of this method has not achieved broad consensus and its limitations need to be fully explored before directly comparing it to other neurocognitive function tests. Moreover, this cognitive factor is a general measure of cognition and could not test specific domains. The association of depressive symptoms and cognitive performance in our present study should be confirmed using specific cognitive evaluation in future investigations to validate our study's findings. In summary, our results show the prevalence of comorbid depressive symptoms of 54.6% in FEDN patients with schizophrenia, suggesting that depressive symptoms are common in the acute early phase of schizophrenia in the Chinese Han population. Thus, this finding has important implications for clinical care in that recognition and treatment of depressive symptomatology may enable better outcomes in FEDN patients with schizophrenia (Upthegrove et al., 2016). Moreover, we found a significantly higher rate of comorbid depressive symptoms in male compared to female patients (62.2% vs. 48.1%), suggesting gender difference in the depressive symptom rate in schizophrenia. Moreover, depressive symptom shown on HAM-D was found to be positively

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associated with the PANSS negative, general psychopathology and cognitive factor subscales. Our results suggest instinct interrelationships between depressive symptom and negative or psychopathological symptoms in first-episode patients with schizophrenia. Although we cannot attribute causality to a simple quantitative association, it appears that depressive and negative or psychopathological symptoms may share similar phenomenological features or biological bases. More interestingly, we found a significantly positive correlation of depressive symptom with the PANSS cognitive factor, suggesting that the greater depressive symptom was associated with the worse cognitive performance in FEDN patients with schizophrenia. Longitudinal research will more definitively establish whether depression is an early factor for the cognitive decline in patients with schizophrenia in their early course of the illness. Taken together, understanding the depressive symptoms in early stage of schizophrenia and their relationships with clinical symptoms and cognitive deficits would provide important implications for therapeutic interventions and functioning. Contributors Jing Dai, Man-Xi He and Xiang Yang Zhang were responsible for study design, statistical analysis, manuscript preparation and writing the protocol and the paper. Dachun Chen, Xiangdong Du, Guangzhong Yin, Haishen Xia and Xiaosi Li were responsible for clinical data collection. Rylan Cassidy, Qingchun Tong, Antonio L. Teixeira, Yingjun Zhen, Yuping Ning, Yingyang Zhang and Jair C. Soares were involved in evolving the ideas and editing the manuscript. All authors have contributed to and have approved the final manuscript. Funding source Funding for this study was provided by grants from the National Natural Science Foundation of China (81371477), the Beijing Municipal Natural Science Foundation (7132063) and the NARSAD Independent Investigator Grant (20314). Conflict of interest The authors have no conflicts to disclose. Acknowledgement The authors would like to thank Mei Hong Xiu, Wu Fang Zhang, Song Chen, Zhi Ren Wang, Bao Hua Zhang, and Gui Gang Yang for all of their hard work and significant contributions toward the study.

References Abramowitz, A.C., Ginger, E.J., Gollan, J.K., Smith, M.J., 2014. Empathy, depressive symptoms, and social functioning among individuals with schizophrenia. Psychiatry Res. 216 (3), 325–332. Addington, D., Addington, J., Patten, S., 1998. Depression in people with first-episode schizophrenia. Br. J. Psychiatry 172, 90–92. Addington, D., Addington, J., Patten, S., Remington, G., Moamai, J., Labelle, A., Beauclair, L., 2002a. Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia. J. Clin. Psychopharmacol. 22 (1), 20–25. Addington, D.D., Azorin, J.M., Falloon, I.R., Gerlach, J., Hirsch, S.R., Siris, S.G., 2002b. Clinical issues related to depression in schizophrenia: an international survey of psychiatrists. Acta Psychiatr. Scand. 105 (3), 189–195. Akinsulore, A., Aloba, O.O., Mapayi, B.M., Oloniniyi, I.O., Fatoye, F.O., Makanjuola, R.O., 2014. Relationship between depressive symptoms and quality of life in Nigerian patients with schizophrenia. Soc. Psychiatry Psychiatr. Epidemiol. 49 (8), 1191–1198. An der Heiden, W., Leber, A., Häfner, H., 2016. Negative symptoms and their association with depressive symptoms in the long-term course of schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 266 (5), 387–396. Boks, M.P.M., Hoogendoorn, M., Jungerius, B.J., Bakker, S.C., Sommer, I.E., Sinke, R.J., Ophoff, R.A., Kahn, R.S., 2008. Do mood symptoms subdivide the schizophrenia phenotype? Association of the GMP6A gene with a depression subgroup. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 707–711. Bora, E., Yücel, M., Pantelis, C, 2010. Cognitive impairment in affective psychoses: a metaanalysis. Schizophr. Bull. 36 (1), 112–125. Bora, E., Harrison, B.J., Yücel, M., Pantelis, C., 2013. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol. Med. 43 (10), 2017–2026. Bowie, C.R., Reichenberg, A., Patterson, T.L., Heaton, R.K., Harvey, P.D., 2006. Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. Am. J. Psychiatry 163 (3), 418–425. Brébion, G., Gorman, J.M., Malaspina, D., Sharif, Z., Amador, X., 2001. Clinical and cognitive factors associated with verbal memory task performance in patients with schizophrenia. Am. J. Psychiatry 158 (5), 758–764. Brébion, G., Bressan, R.A., Pilowsky, L.S., David, A.S., 2009. Depression, avolition, and attention disorders in patients with schizophrenia: associations with verbal memory efficiency. J. Neuropsychiatr. Clin. Neurosci. 21 (2), 206–215. Bromet, E., Andrade, L.H., Hwang, I., Sampson, N.A., Alonso, J., de Girolamo, G., de Graaf, R., Demyttenaere, K., Hu, C., Iwata, N., Karam, A.N., Kaur, J., Kostyuchenko, S., Lépine, J.P.,

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029

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J. Dai et al. / Schizophrenia Research xxx (2017) xxx–xxx

Levinson, D., Matschinger, H., Mora, M.E., Browne, M.O., Posada-Villa, J., Viana, M.C., Williams, D.R., Kessler, R.C., 2011. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 9 (1), 90. Buckley, P.F., Miller, B.J., Lehrer, D.S., Castle, D.J., 2009. Psychiatric comorbidities and schizophrenia. Schizophr. Bull. 35 (2), 383–402. Cheah, S.Y., Lawford, B.R., Young, R.M., Morris, C.P., Voisey, J., 2015. Association of NOS1AP variants and depression phenotypes in schizophrenia. J. Affect. Disord. 188, 263–269. Chen, J., Khan, R.A., Wang, M., He, K., Wang, Q., Li, Z., Li, W., Wen, Z., Song, Z., Shen, J., Xu, Y., Shi, Y., 2016. Association between the variability of ABCA13 gene and the risk of major depressive disorder and schizophrenia in Han Chinese population. World J. Biol. Psychiatry 1–15 (Epub ahead of print). Chiappelli, J., Kochunov, P., DeRiso, K., Thangavelu, K., Sampath, H., Muellerklein, F., Nugent, K.L., Postolache, T.T., Carpenter Jr., W.T., Hong, L.E., 2014. Testing trait depression as a potential clinical domain in schizophrenia. Schizophr. Res. 159 (1), 243–248. Cohen, C.I., Ryu, H.H., 2015. A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder. Am. J. Geriatr. Psychiatry 23 (9), 925–933. Conley, R.R., Ascher-Svanum, H., Zhu, B., Faries, D.E., Kinon, B.J., 2007. The burden of depressive symptoms in the long-term treatment of patients with schizophrenia. Schizophr. Res. 90, 186–197. Cotton, S.M., Gleeson, J.F., Alvarez-Jimenez, M., McGorry, P.D., 2010. Quality of life in patients who have remitted from their first episode of psychosis. Schizophr. Res. 121 (1–3), 259–265. Dan, A., Kumar, S., Avasthi, A., Grover, S., 2011. A comparative study on quality of life of patients of schizophrenia with and without depression. Psychiatry Res. 189 (2), 185–189. D'Antonio, E., Serper, M.R., 2012. Depression and cognitive deficits in geriatric schizophrenia. Schizophr. Res. 134 (1), 65–69. Emsley, R.A., Oosthuizen, P.P., Joubert, A.F., Roberts, M.C., Stein, D.J., 1999. Depressive and anxiety symptoms in patients with schizophrenia and schizophreniform disorder. J. Clin. Psychiatry 60, 747–751. Fioravanti, M., Bianchi, V., Cinti, M.E., 2012. Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence. BMC Psychiatry 12, 64. Georgi, A., Jamra, R.A., Klein, K., Villela, A.W., Schumacher, J., Becker, T., Paul, T., Schmael, C., Höfels, S., Klopp, N., Illig, T., Propping, P., Cichon, S., Nöthen, M.M., Schulze, T.G., Rietschel, M., 2007. Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample. Psychiatr. Genet. 17, 308–310. Gladsjo, J.A., LA, McAdams, Palmer, B.W., Moore, D.J., Jeste, D.V., Heaton, R.K., 2004. A sixfactor model of cognition in schizophrenia and related psychotic disorders: relationships with clinical symptoms and functional capacity. Schizophr. Bull. 30 (4), 739–754. Grossman, L.S., Harrow, M., Rosen, C., Faull, R., Strauss, G.P., 2008. Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery. Compr. Psychiatry 49 (6), 523–529. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Harvey, P.D., Twamley, E.W., Pinkham, A.E., Depp, C.A., Patterson, T.L., 2016. Depression in schizophrenia: associations with cognition, functional capacity, everyday functioning, and self-assessment. Schizophr. Bull. (pii: sbw103, Epub ahead of print). He, Y.L., Zhang, M.Z., 2000. The Chinese norm and factor analysis of PANSS. Chin. J. Clin. Psych. 8, 65–69. Helfer, B., Samara, M.T., Huhn, M., Klupp, E., Leucht, C., Zhu, Y., Engel, R.R., Leucht, S., 2016. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am. J. Psychiatry 173 (9), 876–886. Herniman, S.E., Allott, K.A., Killackey, E., Hester, R., Cotton, S.M., 2017. The effect of comorbid depression on facial and prosody emotion recognition in first-episode schizophrenia spectrum. J. Affect. Disord. 208, 223–229. Hou, C.L., Ma, X.R., Cai, M.Y., Li, Y., Zang, Y., Jia, F.J., Lin, Y.Q., Chiu, H.F., Ungvari, G.S., Hall, B.J., Zhong, B.L., Cao, X.L., Xiang, Y.T., 2016. Comorbid moderate-severe depressive symptoms and their association with quality of life in Chinese patients with schizophrenia treated in primary care. Community Ment. Health J. 52 (8), 921–926. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Lako, I.M., Bruggeman, R., Knegtering, H., Wiersma, D., Schoevers, R.A., Slooff, C.J., Taxis, K., 2012. A systematic review of instruments to measure depressive symptoms in patients with schizophrenia. J. Affect. Disord. 140 (1), 38–47. Lennertz, L., An der Heiden, W., Kronacher, R., Schulze-Rauschenbach, S., Maier, W., Häfner, H., Wagner, M., 2016. Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort. Eur. Arch. Psychiatry Clin. Neurosci. 266 (5), 423–431. Liu, L.Q., Zhou, P., 2009. Depressive symptoms in patients with chronic schizophrenia (in Chinese). J. Clin. Psychiatry 19, 34–36. Liu, J., Xiang, Y.T., Lei, H., Wang, Q., Wang, G., Ungvari, G.S., Morris, D.W., Zhu, X.Z., Lai, K.Y., Zhong, B.L., Wong, S.Y., Zhang, L., Zhang, Q., Zou, Y.C., Xiao, L., Zhao, Q., Li, Y., Wu, J., Zhang, G.F., Chiu, H.F., 2014. Guidance on the conversion of the Chinese versions of

the quick inventory of depressive symptomatology-self-report (C-QIDS-SR) and the Montgomery-Asberg Scale (C-MADRS) in Chinese patients with major depression. J. Affect. Disord. 152, 530–533. Majadas, S., Olivares, J., Galan, J., Diez, T., 2012. Prevalence of depression and its relationship with other clinical characteristics in a sample of patients with stable schizophrenia. Compr. Psychiatry 53, 145–151. Martín-Reyes, M., Mendoza, R., Domínguez, M., Caballero, A., Bravo, T.M., Díaz, T., Gerra, S., Ibáñez, A., Linares, A.R., 2011. Depressive symptoms evaluated by the Calgary Depression Scale for Schizophrenia (CDSS): genetic vulnerability and sex effects. Psychiatry Res. 189 (1), 55–61. Möser, C., Krieg, J.C., Zihl, J., Lautenbacher, S., 2006. Attention and memory deficits in schizophrenia: the role of symptoms of depression. Cogn. Behav. Neurol. 19 (3), 150–156. Mulholland, C., Cooper, S., 2000. The symptom of depression in schizophrenia and its management. Adv. Psychiatr. Treat. 6, 169–177. Müller, M.J., 2007. Gender-specific associations of depression with positive and negative symptoms in acute schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 31, 1095–1100. Muller, M.J., Muller, K.M., Fellgiebel, A., 2006. Detection of depression in acute schizophrenia: sensitivity and specificity of 2 standard observer rating scales. Can. J. Psychiatr. 51 (6), 387–392. Narvaez, J.M., Twamley, E.W., McKibbin, C.L., Heaton, R.K., Patterson, T.L., 2008. Subjective and objective quality of life in schizophrenia. Schizophr. Res. 98, 201–208. Ou, J., Li, M., Xiao, X., 2016. The schizophrenia susceptibility gene ZNF804A confers risk of major mood disorders. World J. Biol. Psychiatry 1–17 (Epub ahead of print). Park, S.C., Kim, J.M., Jun, T.Y., Lee, M.S., Kim, J.B., Yim, H.W., Park, Y.C., 2016. How many different symptom combinations fulfil the diagnostic criteria for major depressive disorder? Results from the CRESCEND study. Nord. J. Psychiatry 1–6 (Epub ahead of print). Phillips, M.R., Shen, Q., Liu, X., Pritzker, S., Streiner, D., Conner, K., Yang, G., 2007. Assessing depressive symptoms in persons who die of suicide in mainland China. J. Affect. Disord. 98 (1–2), 73–82. Rabany, L., Weiser, M., Werbeloff, N., Levkovitz, Y., 2011. Assessment of negative symptoms and depression in schizophrenia: revision of the SANS and how it relates to the PANSS and CDSS. Schizophr. Res. 126 (1–3), 226–230. Rodriguez-Jimenez, R., Bagney, A., Mezquita, L., Martinez-Gras, I., Sanchez-Morla, E.M., Mesa, N., Ibañez, M.I., Diez-Martin, J., Jimenez-Arriero, M.A., Lobo, A., Santos, J.L., Palomo, T., PARG, 2013. Cognition and the five-factor model of the positive and negative syndrome scale in schizophrenia. Schizophr. Res. 143 (1), 77–83. Romm, K.L., Rossberg, J.I., Berg, A.O., Barrett, E.A., Faerden, A., Agartz, I., Andreassen, O.A., Melle, I., 2010. Depression and depressive symptoms in first episode psychosis. J. Nerv. Ment. Dis. 198 (1), 67–71. Sands, J.R., Harrow, M., 1999. Depression during the longitudinal course of schizophrenia. Schizophr. Bull. 25, 157–171. Schaefer, J., Giangrande, E., Weinberger, D.R., Dickinson, D., 2013. The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr. Res. 150 (1), 42–50. Siris, S.G., Bench, C., 2003. Depression and schizophrenia. In: Hirsch, S.R., Weinberger, D.R. (Eds.), Schizophrenia, 2nd edn Blackwell Publishing, Oxford, pp. 142–167. Siris, S.G., Addington, D., Azorin, J.M., Falloon, I.R., Gerlach, J., Hirsch, S.R., 2001. Depression in schizophrenia: recognition and management in the USA. Schizophr. Res. 47, 185–197. Snyder, H.R., 2013. Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol. Bull. 139 (1), 81–132. Tan, E.J., Rossell, S.L., 2016. Comparing how co-morbid depression affects individual domains of functioning and life satisfaction in schizophrenia. Compr. Psychiatry 66, 53–58. Tanaka, T., Tomotake, M., Ueoka, Y., Kaneda, Y., Taniguchi, K., Nakataki, M., Numata, S., Tayoshi, S., Yamauchi, K., Sumitani, S., Ohmori, T., Ueno, S., Ohmori, T., 2012. Clinical correlates associated with cognitive dysfunction in people with schizophrenia. Psychiatry Clin. Neurosci. 66 (6), 491–498. Upthegrove, R., Birchwood, M., Ross, K., Brunett, K., McCollum, R., Jones, L., 2010. The evolution of depression and suicidality in first episode psychosis. Acta Psychiatr. Scand. 122, 211–218. Upthegrove, R., Ross, K., Brunet, K., McCollum, R., Jones, L., 2014. Depression in first episode psychosis: the role of subordination and shame. Psychiatry Res. 217, 177–184. Upthegrove, R., Marwaha, S., Birchwood, M., 2016. Depression and schizophrenia: cause, consequence or trans-diagnostic issue? Schizophr. Bull. (pii: sbw097, Epub ahead of print). Zhang, M.Y., 1993. Handbook of Rating Scales in Psychiatry. Hunan SciTech Publishing, Changsha, China. Zhang, X.Y., Chen, D.C., Xiu, M.H., Yang, F.D., Haile, C.N., Kosten, T.A., Kosten, T.R., 2012. Gender differences in never-medicated first-episode schizophrenia and medicated chronic schizophrenia patients. J. Clin. Psychiatry 73 (7), 1025–1033.

Please cite this article as: Dai, J., et al., Prevalence, demographic and clinical features of comorbid depressive symptoms in drug naïve patients with schizophrenia presentin..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.029