Nicolas Hoertel
email: nico.hoertel@yahoo.fr

Claire Jaffré

Rachel Pascal De Raykeer

Kibby Mcmahon

Sarah Barrière

Yvonne Blumenstock

Christophe Portefaix

Delphine Raucher-Chéné

Céline Béra-Potelle

Christine Cuervo-Lombard

Astrid Chevance

Christophe Guerin-Langlois

Cédric Lemogne

Guillaume Airagnes

Hugo Peyre

Arthur Kaladjian

Frédéric Limosin

Gilles Amar

Ovidiu Andréi

Denis Arbault

Georges Archambault

Pascaline Aucouturier

Gilles Aurifeuille

Hervé Bardou

Michèle Bareil-Guérin

Pierre Barrau

Claudine Barrouillet

Emilie Baup

Nadine Bazin

Jalel Béatrice Beaufils

Ben Ayed

Michel Benoit

Kader Benyacoub

Thérèse Bichet

Françoise Blanadet

Olivier Blanc

Julien Blanc-Comiti

Didier Boussiron

Anne-Marie Bouysse

Alain Brochard

Olivier Brochart

Bastien Bucheron

Marion Cabot

Vincent Camus

Jean-Marc Chabannes

Véronique Charlot

Thomas Charpeaud

Gilles Chatellier

Cateline Clad-Mor

Colette Combes

Maricela Comisu

Sylvain Cordier

François Costi

Jean-Paul Courcelles

Mercedes Creixell

Henry Cuche

Anis Dammak

Da David

Jean-Bernard Rin

Hélène Denis

Anne Denizot

Eric Deperthuis

Smail Diers

Didier Dirami

Pierre Donneau

Caroline Dreano

Eric Dubertret

Didier Duprat

Christian Duthoit

Philippe Fernandez

Nelly Fonfrede

Yann Freitas

Philippe Frigout

Jacques Gasnier

Fabien Gauillard

Fabien Getten

Fabien Gierski

Raphaël Godart

Gourevitch

Grassin Aude

Juliette Delyle

Hélène Gremion

Véronique Gres

Christian Griner

Olivier Guggiari

Hamadi Guillin

Emmanuel Hadaoui

Cécile Haffen

Sadeq Hanon

Cyril Haouzir

Anne Hazif-Thomas

Bérengère Heron

Isabelle Hubsch

Dominique Jalenques

Jean-François Januel

Oussama Karnycheff

Marie-Odile Kebir

Christine Krebs

Marion Lajugie

Pierre Leboyer

Michel Legrand

Vincent Lejoyeux

Evelyne Lemaire

Diane Leroy

Antoine Levy-Chavagnat

Chantal Leydier

Pierre-Michel Liling

Philippe Llorca

Patrice Loeffel

Stéphane Lucas Louville

Nicolas Navarro

Mohamed Mages

Odile Mahi

Aude Maillet

Catherine Manetti

Pascal Martelli

Marc Martin

Isabelle Masson

Joelle Maurs-Ferrer

Sylvain Mauvieux

Emmanuelle Mazmanian

Lila Mechin

Mostéfa Mekaoui

Agnès Meniai

Amine Metton

Maria Mihoubi

Geneviève Miron

Valérie Niro Mora

Philippe Adès

Cécile Nubukpo

Stéphanie Omnes

Pierre Papin

Christine Paris

Jérôme Passerieux

Sylvie Pellerin

Annie Perron

François Petit

Dominique Petitjean

Andrei Pringuey

Hassan Radtchenko

Anne Rahiou

Lionel Rauzy

Michel Reinheimer

Margaux Renard

Charles-Edouard René

Paul Rengade

Didier Reynaud

Christelle Robin

Aurélie Rodrigues

Fabien Rollet

Bernard Rondepierre

Sarah Rousselot

Ghassen Rubingher

Jean- Pierre Saba

Jean-Claude Salvarelli

Corinne Samuelian

Franck Scemama-Ammar

Jean-Pierre Schurhoff

Daniel Schuster

Béatrice Sechter

Tiphaine Segalas

Anne-Sophie Seguret

Amina Seigneurie

Frédéric Semmak

Sophie Slama

Mohamed Taisne

Jean-Louis Taleb

Dominique Terra

Eric Thefenne

Rémi Tran

Marie-Noëlle Tourtauchaux

Pierre Vacheron

Valérie Vandel

Emmanuel Vanhoucke

Hélène Venet

Anne Verdoux

Gilles Viala

Murielle Vidon

Jean-Luc Vitre

Carole Vurpas

Michel Wagermez

Liova Walter

Xavier Zendjidjian Yon

Subsyndromal and syndromal depressive symptoms among older adults with schizophrenia spectrum disorder: Prevalence and associated factors in a multicenter study

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Background: Few studies have examined the prevalence and correlates of subsyndromal and syndromal depressive symptoms (SSSD) among older adults with schizophrenia spectrum disorder. In this report, we examined the prevalence of SSSD and their associations with sociodemographic characteristics, clinical characteristics of schizophrenia, comorbidity, psychotropic medications, quality of life, functioning and mental health care utilization in a large, multicenter sample of older adults with schizophrenia spectrum disorder. Methods: Data from the Cohort of individuals with Schizophrenia Aged 55 years or more (CSA) were used to examine the prevalence of SSSD, defined using the Center of Epidemiologic Studies Depression (CESD) scale. Clinical characteristics associated with SSSD were explored. Results: Among 343 older adults with schizophrenia spectrum disorder, 78.1% had either subsyndromal (30.6%) or syndromal (47.5%) depressive symptoms. SSSD were independently associated with positive and negative symptoms, lower quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity. There were no significant associations of SSSD with other sociodemographic characteristics and psychotropic medications, or with general medical conditions. We found no significant differences in the proportion of participants who were treated with antidepressants between those with syndromal depressive symptoms and those without depression (22.1% vs. 20.0%, p = 0.89). SSSD were not associated with higher mental health care utilization. Limitations: Data were cross-sectional and depression was not evaluated with a semi-structured interview. Conclusion: SSSD may be highly prevalent and under-assessed and/or undertreated among older adults with schizophrenia spectrum disorder. Our findings should alert clinicians about the need to assess systematically and regularly depression in this vulnerable population.

Introduction

Due to the ageing of the general population in Western countries, the number of people with schizophrenia who are at least 55 years old is rapidly increasing and is expected to reach almost a quarter of the United States population diagnosed with schizophrenia by 2025 [START_REF] Cohen | Focus on geriatric psychiatry: schizophrenia in later life: clinical symptoms and social well-being[END_REF]. Depression is commonly comorbid during the course of schizophrenia. 24% to 48% of older adults with schizophrenia spectrum disorder suffer from syndromal depressive symptoms [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF], and up to 75% of them would suffer from syndromal or subsyndromal depressive symptoms (SSSD) (Cohen et al., 2015). SSSD are associated with the increase in symptoms of schizophrenia [START_REF] Cohen | Studies of the course and outcome of schizophrenia in later life[END_REF][START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF][START_REF] Heila | Suicide and schizophrenia: a nationwide psychological autopsy study on age-and sex-specific clinical characteristics of 92 suicide victims with schizophrenia[END_REF][START_REF] Jin | Association of depressive symptoms with worse functioning in schizophrenia: a study in older outpatients[END_REF][START_REF] Johnson | The significance of depression in the prediction of relapse in chronic schizophrenia[END_REF][START_REF] Roy | Depression in the course of chronic undifferentiated schizophrenia[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF]2007), poorer functional remission (Cohen et al., 2015;[START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Limosin | Schizophrenia and the elderly patient[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF][START_REF] Wetherell | Anxiety symptoms and quality of life in middle-aged and older outpatients with schizophrenia and schizoaffective disorder[END_REF], increased risk of suicide [START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF] and lower quality of life [START_REF] Cohen | A longitudinal analysis of quality of life and associated factors in older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Jin | Association of depressive symptoms with worse functioning in schizophrenia: a study in older outpatients[END_REF][START_REF] Patterson | Health-related quality of life in older patients with schizophrenia and other psychoses: relationships among psychosocial and psychiatric factors[END_REF] among older adults with schizophrenia. Despite the common comorbidity between depression and schizophrenia among older adults and its debilitating consequences, few studies have examined the prevalence of SSSD and their related characteristics among older adults with schizophrenia spectrum disorder (Cohen et al., 2015). Such knowledge would help mental health professionals prevent, detect and manage this often underdiagnosed comorbidity in this population [START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF].

Prior research has yielded conflicting evidence on the role of sociodemographic characteristics, psychiatric and other medical conditions and psychotropic medications in the risk of depression among older adults with schizophrenia. Some studies have identified multiple factors associated with depressive symptoms in this population, such as younger age [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF], psychiatric comorbidity [START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF], general medical comorbidity [START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF], and greater number of psychotropic medications [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF]. On the other hand, other studies did not find a significant impact of these factors, including age [START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF], psychiatric comorbidity [START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF][START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF], general medical comorbidity [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF] and the number and the dose of antipsychotics [START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression[END_REF]. However, this previous research had limited statistical power, as most studies relied on relatively small samples ranging from 60 to 198 older adults with schizophrenia [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression[END_REF]. Additionally, prior studies were conducted in only three sites [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF][START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF][START_REF] Zisook | Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF], limiting the generalizability of their findings. Therefore, research using larger samples of older adults with schizophrenia from multiple sites may provide a better knowledge of clinical factors associated with SSSD and improve their early recognition and treatment in this vulnerable population.

To address this gap in the literature, we used data drawn from a large (n = 353) study conducted at 63 centers in France, the "Cohort of individuals with Schizophrenia Aged 55 years or more" (CSA), and examined the prevalence and potential associations of SSSD with sociodemographic and clinical characteristics, comorbidity, quality of life, functioning, psychotropic medications and mental health care utilization.

Methods

Sample

Data were drawn from the CSA study, a cohort of 353 inpatients (34.1%) or outpatients (65.9%) aged 55 years or more with schizophrenia spectrum disorder, which included people with an International Classification of Diseases, Tenth edition (ICD-10) diagnosis of schizophrenia (82.4%) or schizoaffective disorder (17.6%). Participants were recruited between February 2010 and June 2013 from French state hospital psychiatric departments that covered 63 mutually independent catchment areas [START_REF] Raucher-Chéné | Mental healthcare in older adults with schizophrenia: results from 118 French public psychiatric departments[END_REF]. Exclusion criteria included having limited French proficiency, being not affiliated to the social security system, meeting ICD-10 criteria for any pervasive developmental disorder or major neurocognitive disorder, and having any neurological disorder affecting the central nervous system or any serious, life threatening medical or surgical condition that requires immediate treatment. Each participant was interviewed face-to-face by his/her treating psychiatrist, who collected all clinical data. The research protocol, including informed consent procedures, was conducted in accordance with the Declaration of Helsinki ethical guidelines, and received full ethical review and approval from the local research ethics committee, the Advisory Committee on Information Processing in Material Research in the Field of Health and the National Board on Computerized Information and Freedoms.

Measures

Assessment of schizophrenia spectrum disorder

Diagnoses of schizophrenia and schizoaffective disorder were assessed face-to-face by psychiatrists using ICD-10 criteria. Age at onset of first psychotic symptoms was retrospectively investigated and categorized as non-late-onset (i.e. before 40 years), late-onset (i.e. between 40 and 60 years) and very-late onset (i.e. after 60 years) according to prior recommendation [START_REF] Howard | Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group[END_REF], and the duration of the disorder was estimated.

Assessment of subsyndromal and syndromal depressive symptoms (SSSD)

SSSD over the past week were self-reported by participants using the Center of Epidemiologic Studies Depression scale (CES-D) [START_REF] Radloff | The CES-D scale: a self-report depression scale for research in the general population[END_REF] and categorized as follows: (1) no depression (CES-D ≤ 7), (2) subsyndromal depression (CES-D = 8-15) and (3) syndromal depression (CES-D ≥ 16) [START_REF] Camacho | Association of subsyndromal and depressive symptoms with inflammatory markers among different ethnic groups: the multi-ethnic study of atherosclerosis (MESA)[END_REF]. Respondents were asked to indicate on a scale from 0 (rarely or none of the time) to 3 (most of the time) how often they experience 20 symptoms related to depression (e.g., I felt everything I did was an effort). This questionnaire has been designed for use in community studies (Airagnes et al., 2016b;[START_REF] Matta | Diet and physical activity in the association between depression and metabolic syndrome: constances study[END_REF][START_REF] Radloff | The CES-D scale: a self-report depression scale for research in the general population[END_REF][START_REF] Roy | Depression in the course of chronic undifferentiated schizophrenia[END_REF] and validated in adult samples of all ages with psychiatric disorders [START_REF] Irwin | Screening for depression in the older adult: criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D)[END_REF][START_REF] Shafer | Meta-analysis of the factor structures of four depression questionnaires: beck, CES-D, Hamilton, and Zung[END_REF], including adults with schizophrenia spectrum disorder [START_REF] Herniman | The psychometric validity of the Center for Epidemiological Studies -Depression Scale (CES-D) in first episode schizophrenia spectrum[END_REF]. In our study, internal consistency reliability of the CES-D scale was acceptable, with Cronbach's alpha=0.72.

Sociodemographic characteristics

Sociodemographic characteristics included gender, age, education, marital status, parenthood and urbanicity (defined as living in an area comprising more than 1000 inhabitants per km 2 ).

Assessment of psychiatric symptoms, alcohol and nicotine consumption and suicide attempts

We used the 18-item version of the Brief Psychiatric Rating Scale (BPRS) [START_REF] Overall | The brief psychiatric rating scale[END_REF][START_REF] Leucht | Clinical implications of Brief Psychiatric Rating Scale scores[END_REF], a widely used instrument for assessing psychiatric symptoms in individuals with schizophrenia spectrum disorder. Each symptom is rated from 1 (absence) to 7 (severe). We examined the total score and the 5 subscale scores [START_REF] Shafer | Meta-analysis of the brief psychiatric rating scale factor structure[END_REF]: 1) Affect (anxiety, guilt, depression, somatic); 2) Positive Symptoms (thought content, conceptual disorganization, hallucinatory behavior, grandiosity); 3) Negative Symptoms (blunted affect, emotional withdrawal, motor retardation); 4) Resistance (hostility, uncooperativeness, suspiciousness); and 5) Activation (excitement, tension, mannerisms-posturing). In our study, internal consistency reliability of the BPRS scale was good, with Cronbach's alpha=0.85.

Current smoking status was recorded. At-risk alcohol consumption was evaluated using the CAGE questionnaire [START_REF] Ewing | Detecting alcoholism. The CAGE questionnaire[END_REF][START_REF] Kitchens | Does this patient have an alcohol problem?[END_REF]. All participants were also asked whether they ever attempted suicide and whether they attempted suicide during the year preceding the interview.

Psychotropic medications

All psychotropic medications prescribed at the time of the interview were recorded, and in particular antipsychotics, antidepressants, benzodiazepines and anticholinergic antiparkinsonian drugs.

Mental health care utilization

The lifetime number of hospitalizations in a psychiatric department was recorded at the time of the interview.

Medical conditions

The number of comorbid non-psychiatric medical conditions (e.g., cardiovascular disorder, cancer) was recorded for all participants at the time of the interview. Blood pressure and body mass index (BMI) were measured in all participants. Individuals whose systolic blood pressure was >140 mm Hg or diastolic blood pressure >90 mm Hg were considered as having high blood pressure. Based on the recommendation of a recent meta-analysis [START_REF] Winter | BMI and allcause mortality in older adults: a meta-analysis[END_REF] on the association between BMI and all-cause mortality risk in older adults, we categorized BMI as follows: underweight (<23 kg/m 2 ), healthy weight (23-30 kg/m 2 ) and overweight (>30 kg/m 2 ).

Investigators were asked whether the participant had a blood test or an electrocardiogram in the past year, and whether the participant consulted a general practitioner or was hospitalized in a non-psychiatric medical department in the past year.

Overall functioning and cognitive functioning

The Global Assessment of Functioning (GAF) scale [START_REF] Endicott | The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance[END_REF] was used for evaluating the overall social, occupational, and psychological functioning of participants. Scale scores range from 0 to 100 with higher scores signifying better functioning. Prior studies support the reliability and convergent validity of the GAF scale scores in populations with psychiatric disorders [START_REF] Jones | A brief mental health outcome scale-reliability and validity of the Global Assessment of Functioning (GAF)[END_REF]. The Mini-Mental State Examination (MMSE) [START_REF] Folstein | Mini-mental state". A practical method for grading the cognitive state of patients for the clinician[END_REF] was used for evaluating global cognitive impairment. In our study, internal consistency reliability of the GAF and MMSE scores was good (Cronbach's alpha=0.87 and 0.93, respectively).

Quality of life

We used the Quality of Life Scale (QLS) [START_REF] Heinrichs | The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome[END_REF], an instrument widely used to assess quality of life in clinical studies of schizophrenia [START_REF] Lehman | Measures of quality of life among persons with severe and persistent mental disorders[END_REF]. The QLS has 21 items rated on a 7-point scale from 0 to 6 with descriptive anchors; higher scores reflect higher quality of life [START_REF] Heinrichs | The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome[END_REF]. In our study, internal consistency reliability of the QLS was excellent (Cronbach's alpha=0.91).

Missing data

The mean percentage of missing data in the study was 1.2%. Missing data were imputed using Markov chain Monte Carlo (MCMC) methods [START_REF] Schafer | Analysis of Incomplete Multivariate Data[END_REF]. All significant results remained significant in sensitivity analyses excluding respondents with missing data.

Statistical analyses

Percentages and means ( ± SD) were estimated to provide descriptive information on sociodemographic and clinical characteristics, psychiatric and other medical comorbidity, quality of life and overall functioning, psychotropic medications and mental health care utilization in older adults with schizophrenia spectrum disorder according to the presence of depressive symptoms. Subsyndromal and syndromal depressive symptoms (SSSD) were considered a 3-class categorical variable (i.e., no depression (CES-D score≤7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D ≥ 16)). This categorical variable of SSSD was used as the outcome variable and the rest of the variables were used as predictors. Multinomial logistic regression analyses were used to study the univariate associations between SSSD and its potential predictors. Given our relatively large sample, statistical significance was evaluated using a two-sided design with alpha risk set a priori at 0.01 to reduce the risk of type I error due to multiple testing. Next, in order to determine whether variables that are significant in univariate analyses and possibly correlated with each other do have independent associations with SSSD, we performed a multivariable multinomial logistic regression analysis that included all variables showing a significant association in univariate analyses (except the BPRS "affect" subscale whom items are substantially associated with the CES-D score (eTable 11)). For all logistic regression models, we examined potential collinearity problem by performing collinearity diagnostics produced by linear regressions with the option tolerance and variance inflation factor [START_REF] Midi | Collinearity diagnostics of binary logistic regression model[END_REF]. To have enough statistical power in the multivariable analysis, statistical significance was evaluated using a two-sided design with alpha risk set a priori at 0.05. Statistical analyses were performed using PASW Statistics 18 software (IBM Corp., Armonk, NY, USA, released 2009).

Supplementary analyses

We conducted the same analyses described above, distinguishing between inpatients and outpatients. These supplementary analyses allowed us to evaluate whether there are differences in the prevalence of SSSD between inpatients and outpatients. They also allowed us to examine whether the pattern of associations observed in the full sample holds across these two subpopulations.

Results

Prevalence of depressive symptoms

Among the 353 older participants with schizophrenia or schizoaffective disorder, 10 (2.8%) were excluded from our analyses because data on depression were missing. Out of the 343 remaining participants, 75 (21.9%) had no depression, 105 (30.6%) subsyndromal depressive symptoms, 163 (47.5%) depressive symptoms and 268 (78.1%) either subsyndromal or syndromal depressive symptoms (SSSD).

Depressive symptoms and sociodemographic and clinical characteristics

Among older participants with schizophrenia spectrum disorder, SSSD were significantly and positively associated with BPRS total score and scores of the 5 subscales of the BPRS (i.e., affect, positive symptoms, negative symptoms, activation and resistance), non-late-onset psychosis and urbanicity (Table 1).

Depressive symptoms and psychotropic medications

SSSD were significantly associated with benzodiazepine use (Table 2). The proportion of participants with schizophrenia spectrum disorder receiving an antidepressant did not differ statistically across the 3 groups: 20.0% in those with no depression, 20.0% in those with subsyndromal depression and 22.1% in older adults with syndromal depression (p = 0.89). There were no significant associations of depressive symptoms with the number of antipsychotics, antipsychotic type (i.e., typical or atypical), or its formulation (oral vs. long-acting injectable formulation).

Depressive symptoms and general medical conditions

Among older adults with schizophrenia spectrum disorder, we did not find any significant associations between SSSD and physical health features (i.e., BMI, high blood pressure, smoking and at-risk drinking), past-year physical health monitoring (i.e., rates of consultation with a general practitioner and hospitalization in a non-psychiatric department, and proportions of participants who had an electrocardiogram and a blood test in the past year), and the number of general medical conditions (Table 3).

Depressive symptoms and quality of life and overall functioning

The mean MMSE and GAF total scores were significantly lower in participants with SSSD than in those without depressive symptoms. The mean QLS total score of participants with depressive symptoms was significantly lower than participants without depressive symptoms (49.0 vs. 65.6; p<0.001). History of suicide attempts within the past year was more frequent in participants with depressive symptoms than in their counterparts without depressive symptoms (3.1% vs. 0.0%). There were no significant associations of SSSD with lifetime history of suicide attempts or mental health utilization (Table 4). The CES-D variable was categorized as no depression (CES-D score ≤ 7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D score ≥ 16).

Estimates in bold are statistically significant (two-sided p-value < 0.01). Abbreviations: CESD=Center of Epidemiologic Studies Depression scale; OR=odds ratio; CI=confidence interval; na=not applicable; SD=standard deviation. a Urbanicity was defined as living in an area comprising more than 1000 inhabitants per km 2 . £ Odds ratios were obtained using logistic regression models with 'no depression' as reference category.

⁎ p<0.05; ⁎⁎ p<0.01; ⁎⁎⁎ p<0.001.

Depressive symptoms and associated factors

Results from the multivariable multinomial logistic regression analysis with all variables that had a significant association in univariate analyses revealed that positive and negative symptoms, low quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity were significantly and independently associated with SSSD among older adults with schizophrenia spectrum disorder (Table 5).

Supplementary statistical analyses

Among the 117 inpatients, 24 (20.5%) did not have depressive symptoms, 30 (25.6%) had subsyndromal depressive symptoms, 63 (53.8%) syndromal depressive symptoms and 93 (79.5%) either subsyndromal or syndromal depressive symptoms. Among the 226 outpatients, these rates were respectively 22.6% (N = 51), 33.2% (N = 75), 44.2% (N = 100) and 77.4% (N = 175). There were no significant differences in the prevalence of SSSD between these two subpopulations (p = 0.213). Among outpatients, we found that SSSD were independently associated with lower quality of life, negative symptoms, resistance and non-late-onset psychosis (eTables 1 to 5), while they were independently associated with higher BPRS total score and lower quality of life among inpatients (eTables 6 to 10).

In all multivariable logistic regressions, the variance inflation factor and tolerance values of each predictor variable were respectively lower than 2.5 and higher than 0.2, supporting that multicollinearity was not a concern in our analyses [START_REF] Midi | Collinearity diagnostics of binary logistic regression model[END_REF]) (eTable 12).

Discussion

In a large, multicenter sample of older adults with schizophrenia spectrum disorder, we found that 78.1% of older adults had either subsyndromal (30.6%) or syndromal (47.5%) depressive symptoms (SSSD). SSSD were independently associated with positive and negative symptoms, lower quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity, although the magnitudes of these associations were modest. Furthermore, our findings suggest potential differences between inpatients and outpatients in these associations. There were no significant differences in antidepressant prescription rates between participants with and without SSSD. Finally, SSSD were not significantly associated with other sociodemographic characteristics and other types of psychotropic medications, general medical conditions, and mental health care utilization.

SSSD were highly prevalent among older adults with schizophrenia spectrum disorder in our study. We found that 78.1% of participants had either subsyndromal (30.6%) or syndromal (47.5%) depressive symptoms (SSSD), which is in line with prior studies indicating that 24% to 48% of older with schizophrenia spectrum disorder suffer from syndromal depression [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF] and that up to 75% suffer from subsyndromal or syndromal depression (Cohen et al., 2015). Taking together, these findings support that most older adults with schizophrenia present substantial depressive symptoms.

We found that SSSD among older adults with schizophrenia were independently associated with an increased likelihood of endorsing positive and negative symptoms, lower quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity. In a large, multicenter sample, we confirmed earlier findings that depressive symptoms may be associated with an increase in positive and negative symptoms [START_REF] Cohen | Studies of the course and outcome of schizophrenia in later life[END_REF][START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF][START_REF] Heila | Suicide and schizophrenia: a nationwide psychological autopsy study on age-and sex-specific clinical characteristics of 92 suicide victims with schizophrenia[END_REF][START_REF] Jin | Association of depressive symptoms with worse functioning in schizophrenia: a study in older outpatients[END_REF][START_REF] Johnson | The significance of depression in the prediction of relapse in chronic schizophrenia[END_REF][START_REF] Roy | Depression in the course of chronic undifferentiated schizophrenia[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF] and lower quality of life [START_REF] Cohen | A longitudinal analysis of quality of life and associated factors in older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Jin | Association of depressive symptoms with worse functioning in schizophrenia: a study in older outpatients[END_REF][START_REF] Patterson | Health-related quality of life in older patients with schizophrenia and other psychoses: relationships among psychosocial and psychiatric factors[END_REF] among older adults with schizophrenia spectrum disorder. To our knowledge, this is the first study to demonstrate significant associations between SSSD and benzodiazepine use, non-late onset schizophrenia and urbanicity within a sample of older adults with schizophrenia spectrum disorder. Although benzodiazepine use in older patients is associated with many debilitating side effects that might increase the risk of depression (Airagnes et al., 2016a), this association may mainly reflect a therapeutic strategy that many providers use for older patients with more severe or co-morbid disorders. The association of urbanicity with SSSD in our study is consistent with the well-established effect of urbanicity on risks of schizophrenia and affective disorders in the general population [START_REF] Eckert | Urbanization and health in developing countries: a systematic review[END_REF][START_REF] Vassos | Meta-analysis of the association of urbanicity with schizophrenia[END_REF]. We also found a higher prevalence of SSSD in individuals with an onset of schizophrenia spectrum disorder before 40 years of age than in those with an age at onset between 40 and 60 years. This difference was not explained by a significant difference in the proportion of The CES-D variable was categorized as no depression (CES-D score ≤ 7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D score ≥ 16).

Estimates in bold are statistically significant (two-sided p-value < 0.01). Abbreviations: OR=odds ratio; CI=confidence interval; SD=standard deviation; na=not applicable. a Body mass index was defined as body weight (in kg) divided by the square of height (in m). Obesity and malnutrition were defined as having a body mass index >30 kg/m2 and <23 kg/m2, respectively.

b High blood pressure was defined as having a systolic blood pressure >140 mm Hg or a diastolic blood pressure > 90 mm Hg.

c At-risk drinking was defined as having a CAGE test score ≥2.

£ Odds ratios were obtained using logistic regression models with 'no depression' as reference category. *p<0.05; **p<0.01; ***p<0.001.

Table 4

Associations of subsyndromal or syndromal depressive symptoms (SSSD) with functioning, quality of life, suicide attempts and mental health care utilization in older adults with schizophrenia (n = 343). individuals with schizoaffective disorder between these 2 groups (16.9% vs. 23.0%, respectively, p = 0.51). Although the duration of schizophrenia spectrum disorder was not significantly associated with SSSD, this difference in the prevalence of SSSD may result from a longer exposition to schizophrenia spectrum disorder and its negative functional consequences or might reflect a true clinical difference, which might support the view that late-onset schizophrenia spectrum disorder could be a distinct subtype of schizophrenia [START_REF] Howard | Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group[END_REF][START_REF] Maglione | Late-onset schizophrenia: do recent studies support categorizing LOS as a subtype of schizophrenia?[END_REF]. However, this finding was only significant when considering the full sample of inpatients and outpatients, suggesting the need of other studies to confirm this result. Although we did not find any significant difference in the prevalence of SSSD between inpatients and outpatients, there were substantial differences in the associations between depressive symptoms and psychiatric symptoms, quality of life, and age at onset of psychosis between these two groups. Among outpatients, SSSD were independently associated with negative symptoms, resistance, lower quality of life and non-late-onset psychosis. On the other hand, SSSD were independently associated with higher psychiatric symptoms, assessed with the BPRS total score, and lower quality of life among inpatients. These differences should be interpreted with caution given the relatively low proportion of inpatients in our study (N = 117), which may have limited the statistical power. However, our results support that SSSD are associated with an increased likelihood of endorsing symptoms of schizophrenia and may play an important role in the quality of life of older adults with schizophrenia spectrum disorder. These findings suggest that treating depression in this population may have a broad range of benefits such as reducing the suffering of these patients, decreasing the burden of suicide and improving their quality of life [START_REF] Hoertel | A comprehensive model of predictors of suicide attempt in depressed individuals and effect of treatment-seeking behavior: results from a national 3-year prospective study[END_REF](Hoertel et al., , 2015a;;[START_REF] Kasckow | Treatment of subsyndromal depressive symptoms in middle-aged and older adults with schizophrenia: effect on functioning[END_REF][START_REF] Pascal De Raykeer | Effects of psychiatric disorders on suicide attempt: similarities and differences between older and younger adults in a National Cohort Study[END_REF][START_REF] Sheline | Cognitive function in late life depression: relationships to depression severity, cerebrovascular risk factors and processing speed[END_REF][START_REF] Vulser | Depression, Cognitive Functions, and Impaired Functioning in Middle-Aged Adults From the CONSTANCES Cohort[END_REF][START_REF] Zisook | Citalopram augmentation for subsyndromal symptoms of depression in middle-aged and older outpatients with schizophrenia and schizoaffective disorder: a randomized controlled trial[END_REF].

We found no significant differences in antidepressant prescription rates between participants with and without SSSD. We found that 22.1% of participants with syndromal depressive symptoms were prescribed an antidepressant medication. This proportion is similar to what has been observed in a nationally representative sample of individuals with schizophrenia who have had office visits with outpatient physicians (20.2% to 28.2%) [START_REF] Olfson | Antidepressant prescribing practices of outpatient psychiatrists[END_REF] and lower than those reported by earlier studies in depressed older adults with schizophrenia (30% to 43%) [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF]. These findings point to a potential gap between guidelines [START_REF] Alexopoulos | Pharmacotherapy for late-life depression[END_REF]Alexopoulos et al., 2001;Hasan et al., 2017;[START_REF] Lehman | Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition[END_REF][START_REF] Rajji | Use of antidepressants in late-life depression[END_REF] and the actual antidepressant prescribing practices for this population. Expert guidelines indicate that antidepressants may be useful in adjunction to antipsychotics, psychotherapeutic and psychosocial interventions among people with schizophrenia when the depressive symptoms meet syndromal criteria for major depressive episode or are sufficiently severe to cause significant distress or interfere with functioning, along with a close monitoring of psychotic symptoms, suicidality, drug-drug interactions and ECG. In addition, a recent systematic review and meta-analysis concluded that antidepressants may be effective for the treatment of depression in schizophrenia, although the evidence is mixed and conclusions are limited by the small number of low-or moderate-quality studies [START_REF] Gregory | Treatment of depression in schizophrenia: systematic review and meta-analysis[END_REF]. Further, only two studies to our knowledge [START_REF] Kasckow | Citalopram augmentation of antipsychotic treatment in older schizophrenia patients[END_REF][START_REF] Zisook | Citalopram augmentation for subsyndromal symptoms of depression in middle-aged and older outpatients with schizophrenia and schizoaffective disorder: a randomized controlled trial[END_REF] have examined the efficiency of antidepressants specifically among depressed older adults with schizophrenia and have suggested their potential usefulness in this population. Taking together, our results underscore the need to disseminate guidelines more effectively for improving the diagnosis and the treatment of depression among older adults with schizophrenia (Hasan et al., 2017;[START_REF] Lehman | Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition[END_REF].

Finally, we found no significant associations of SSSD with the number of antipsychotics or their type (typical or atypical). This finding is in line with previous research [START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Depressive symptom patterns in patients with chronic schizophrenia and subsyndromal depression[END_REF] and suggests that antipsychotic monotherapy may not increase the risk of depression among older patients with schizophrenia as previous findings have suggested in younger patients (Hasan et al., 2017;[START_REF] Lehman | Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition[END_REF]. Although many psychosocial factors, environmental factors and general medical conditions have been implicated as risk factors for depression in clinical and community samples [START_REF] Beekman | Major and minor depression in later life: a study of prevalence and risk factors[END_REF][START_REF] Hasin | Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions[END_REF]Hoertel et al., 2015b[START_REF] Hoertel | Why does the lifetime prevalence of major depressive disorder in the elderly appear to be lower than in younger adults? Results from a national representative sample[END_REF][START_REF] Kendler | The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism[END_REF][START_REF] Kessler | The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R)[END_REF][START_REF] Manetti | Comorbidity of late-life depression in the United States: a population-based study[END_REF][START_REF] Schuster | Personality disorders in older adults: findings from the National Epidemiologic Survey on Alcohol and Related Conditions[END_REF], we found no significant associations of depression with sociodemographic characteristics, except urbanicity, and general medical conditions among older adults with schizophrenia. These results are in line with prior research that did not find significant differences in sociodemographic characteristics [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Cohen | Depression among aging persons with schizophrenia who live in the community[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF][START_REF] Zisook | Depressive symptoms in schizophrenia[END_REF][START_REF] Zisook | Subsyndromal depressive symptoms in middle-aged and older persons with schizophrenia[END_REF] and in number of physical illnesses [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF] between depressed and non-depressed older adults with schizophrenia. Taken together, these results suggest the need to regularly and systematically assess for depression among all older adults with schizophrenia spectrum disorder. The CES-D variable was categorized as no depression (CES-D score ≤ 7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D score ≥ 16).

Estimates in bold are statistically significant (two-sided p-value < 0.05).

Abbreviations: AOR=adjusted odds ratio; CI=confidence interval; GAF=Global Assessment of functioning; QLS=Quality of Life Scale; na=not applicable. £ Odds ratios were obtained using logistic regression models with 'no depression' as reference category and were adjusted for all other variables (df=11). *p<0.05; **p<0.01; ***p<0.001.

Our study has several limitations. First, depression was only measured with a self-report scale and not with a semi-structured interview. Although other rating scales such as the Calgary Depression Rating Scale [START_REF] Addington | Specificity of the Calgary Depression Scale for schizophrenics[END_REF] are validated to measure depression among individuals with schizophrenia, we chose to use the CES-D scale to favor comparability of our results with recent studies examining SSSD among older adults with schizophrenia spectrum disorder [START_REF] Cohen | A longitudinal study of the outcome and associated factors of subsyndromal and syndromal depression in community-dwelling older adults with schizophrenia spectrum disorder[END_REF][START_REF] Diwan | Depression in older adults with schizophrenia spectrum disorders: prevalence and associated factors[END_REF][START_REF] Meesters | Prevalence and correlates of depressive symptoms in a catchment-area based cohort of older community-living schizophrenia patients[END_REF]. In addition, a prior study [START_REF] Doorack | Co-occurring SAD symptomatology and schizophrenia at high latitude: a pilot study[END_REF] found that the CES-D scale correlated highly (r = 0.91) with the Calgary Depression Rating Scale for Schizophrenia, suggesting that the CES-D scale may be as valid as this scale to screen for depressive symptoms among older adults with schizophrenia. Second, due to the cross-sectional design of this study, evidence of associations do not necessarily imply causal relationships (Le [START_REF] Strat | Correlation is no causation: gymnasium proliferation and the risk of obesity[END_REF]. Third, because each participant was interviewed by only one psychiatrist and participants were recruited from a large number of centers (n = 63) in our study, we were unable to evaluate potential error variance in rating measurements. Fourth, the lack of a control group limits the interpretation of prevalence and risk factors of SSSD in our study. Finally, the recruiting psychiatric departments were only public-sector departments, which would possibly limit the generalizability of our findings to other types of institutions.

Conclusion

In a large, multicenter sample of older adults with schizophrenia spectrum disorder, we found that 78.1% of older adults had either subsyndromal (30.6%) or syndromal (47.5%) depressive symptoms (SSSD). SSSD were independently associated with positive and negative symptoms, lower quality of life, non-late-onset psychosis, benzodiazepine use and urbanicity. We found that 22.1% of patients with schizophrenia spectrum disorder and syndromal depression were treated with antidepressant medication, similar to the proportion of participants without depressive symptoms treated with antidepressants (i.e., 20.0%). Furthermore, SSSD were not associated with higher mental health care utilization, suggesting that depression may be under-assessed and/or undertreated in this population. Finally, there were no significant associations of depression with sociodemographic characteristics, except urbanicity, general medical conditions, mental health care utilization and psychotropic medications except benzodiazepines. Our findings should inform clinicians about the need to systematically and regularly assess depression in all older individuals with schizophrenia.

Table 1

 1 Associations of subsyndromal or syndromal depressive symptoms (SSSD) with sociodemographic and clinical characteristics of schizophrenia in older adults with schizophrenia spectrum disorder (n = 343).

		No depression	Subsyndromal	Syndromal	Syndromal or	Subsyndromal	Syndromal	Syndromal or
		(n = 75)	depression	depression	subsyndromal	depression versus No	depression versus No	subsyndromal
			(n = 105)	(n = 163)	depression	depression	depression	depression versus No
					(n = 268)			depression
		%	%	%	%	OR [95% CI] £	OR [95% CI] £	OR [95% CI] £
	Sociodemographic
	characteristics
	Gender
	Men	52.0	46.7	49.1	48.1	1.00	1.00	1.00
	Women	48.0	53.3	50.9	51.9	1.24 [0.68-2.24]	1.12 [0.65-1.94]	1.17 [0.70-1.95]
	Education
	Less than high school 69.9	66.7	71.2	69.4	0.87 [0.39-1.94]	1.30 [0.60-2.84]	1.09 [0.54-2.24]
	High school	13.7	15.2	16.0	15.7	1.01 [0.35-2.95]	1.49 [0.54-4.11]	1.26 [0.49-3.24]
	College or higher	16.4	18.1	12.9	14.9	1.00	1.00	1.00
	Marital status
	Widowed	8.0	12.4	8.6	10.1	2.03 [0.71-5.80]	1.18 [0.43-3.27]	1.48 [0.58-3.81]
	Married or as if	12.0	15.2	17.2	16.4	1.67 [0.67-4.15]	1.57 [0.69-3.61]	1.61 [0.73-3.54]
	married
	Divorced or	18.7	25.7	18.4	21.3	1.81 [0.85-3.87]	1.08 [0.52-2.24]	1.34 [0.68-2.62]
	separated
	Never married	61.3	46.7	55.8	52.2	1.00	1.00	1.00
	Parenthood	37.3	45.7	40.5	42.5	1.41 [0.77-2.59]	1.14 [0.65-2.01]	1.24 [0.73-2.10]
	Urbanicity a	66.7	69.2	84.9	78.7	1.13 [0.60-2.12]	2.81 [1.47-5.37] ⁎⁎	1.85 [1.05-3.25]*
	Age
	55-64	44.0	31.4	49.7	42.5	0.67 [0.26-1.70]	0.79 [0.35-1.80]	0.75 [0.34-1.65]
	65-74	42.7	54.3	31.3	40.3	1.19 [0.48-2.95]	0.51 [0.22-1.19]	0.73 [0.33-1.62]
	75+	13.3	14.3	19.0	17.2	1.00	1.00	1.00
	Inpatient/outpatient
	status
	Inpatient	32.0	28.6	38.9	34.8	1.00	1.00	1.00
	Outpatient	68.0	71.4	61.1	65.2	1.18 [0.62-2.24]	0.74 [0.41-1.32]	0.65 [0.51-1.52]
	Characteristics of
	schizophrenia
	Age-at-onset
	Non-late-onset	69.9	80.8	84.0	82.7	1.00	1.00	1.00
	(<40y)
	Late-onset (40-60y)	27.4	18.3	12.8	15.0	0.58 [0.28-1.18]	0.39 [0.19-0.78] ⁎⁎	0.46 [0.25-0.86]*
	Very late-onset	2.7	1.0	3.2	2.3	na	na	na
	(>60y)
		Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	OR [95% CI] £	OR [95% CI] £	OR [95% CI] £
	BPRS total score	32.3 (9.5)	39.8 (14.0)	49.8 (14.1)	45.9 (14.8)	1.06 [1.03-1.10] ⁎⁎⁎ 1.12 [1.09-1.15] ⁎⁎⁎ 1.09 [1.06-1.12]***
	Affect	7.1 (3.2)	9.2 (3.6)	12.7 (4.1)	11.3 (4.3)	1.22 [1

.10-1.34] ⁎⁎⁎ 1.52 [1.37-1.68] ⁎⁎⁎ 1.36 [1.24-1.49] ⁎⁎⁎

	Positive symptoms	7.2 (3.7)	8.3 (4.5)	10.4 (5.2)	9.6 (5.1)	1.08 [0.99-1.17]	1.19 [1.10-1.28] ⁎⁎⁎ 1.15 [1.07-1.23] ⁎⁎⁎
	Negative symptoms 6.7 (3.5)	8.5 (4.1)	10.0 (4.0)	9.4 (4.1)	1.

14 [1.05-1.24] ⁎⁎ 1.26 [1.16-1.36] ⁎⁎⁎ 1.21 [1.12-1.30] ⁎⁎⁎

	Activation	5.6 (2.7)	6.7 (3.2)	7.4 (3.5)	7.1 (3.4)	1.14 [1.03-1.26]*	1.

21 [1.09-1.33] ⁎⁎⁎ 1.18 [1.07-1.29] ⁎⁎⁎

	Resistance	4.5 (2.1)	5.6 (3.4)	7.3 (3.9)	6.7 (3.8)	1.

19 [1.05-1.34] ⁎⁎ 1.36 [1.21-1.53] ⁎⁎⁎ 1.29 [1.15-1.44] ⁎⁎⁎ Duration of disorder

	36.2 (13.5)	37.3 (10.9)	38.2 (14.2)	37.9 (13.0)	1.01 [0.98-1.03]	1.01 [0.99-1.03]	1.01 [0.99-1.03]

Table 2

 2 Associations of subsyndromal or syndromal depressive symptoms (SSSD) with psychotropic medications in older adults

with schizophrenia (n = 343).

		No	Subsyndromal	Syndromal	Syndromal or	Subsyndromal	Syndromal	Syndromal or
		depression	depression	depression	subsyndromal	depression versus	depression versus	subsyndromal
		(n = 75)	(n = 105)	(n = 163)	depression	No depression	No depression	depression versus
					(n = 268)			No depression
		%	%	%	%	OR [95% CI] £	OR [95% CI] £	OR [95% CI] £
	Psychotropic medications
	Number of antipsychotics prescribed
	0	8.0	6.7	8.6	7.8	1.02 [0.28-3.77]	0.82 [0.26-2.54]	0.88 [0.30-2.58]
	1	73.3	78.1	66.9	71.3	1.31 [0.59-2.89]	0.69 [0.35-1.38]	0.87 [0.45-1.68]
	2+	18.7	15.2	24.5	20.9	1.00	1.00	1.00
	Atypical antipsychotics	50.7	63.8	61.3	62.3	1.72 [0.94-3.14]	1.55 [0.89-2.68]	1.61 [0.96-2.70]
	Typical antipsychotics	49.3	41.0	47.2	44.8	0.71 [0.39-1.29]	0.92 [0.53-1.59]	0.83 [0.50-1.39]
	Antipsychotic under long-acting	31.1	36.5	29.6	32.3	1.28 [0.68-2.41]	0.93 [0.51-1.70]	1.06 [0.61-1.85]
	injectable (LAI) formulation
	Antidepressants	20.0	20.0	22.1	21.3	1.00 [0.48-2.10]	1.13 [0.58-2.23]	1.08 [0.57-2.04]
	Benzodiazepines	18.7	29.5	35.6	33.2	1.83 [0.89-3.74]	2.41	2.17 [1.15-4.08]*
							[1.21-4.67] ⁎⁎
	Anticholinergic antiparkinsonian	32.0	27.6	38.0	34.0	0.81 [0.43-1.55]	1.30 [0.73-2.33]	1.09 [0.63-1.89]
	drugs
	The CES-D variable was categorized as no depression (CES-D score ≤ 7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D score ≥
	16).
	Estimates in bold are statistically significant (two-sided p-value < 0.01).
	Abbreviations: OR=odds ratio; CI=confidence interval; na=not applicable.

£ Odds ratios were obtained using logistic regression models with 'no depression' as reference category.

Table 3

 3 Associations of subsyndromal or syndromal depressive symptoms (SSSD) with physical

health features and monitoring and medical conditions in older participants with schizophrenia (n = 343).

	Syndromal or subsyndromal	depression versus No depression	OR [95% CI] £	0.93 [0.48-1.79]		0.96 [0.58-1.61]	0.55 [0.27-1.10]	0.78 [0.43-1.42]				1.28 [0.65-2.54]	1.26 [0.69-2.32]	1.00	0.62 [0.34-1.13]	0.95 [0.54-1.68]	na	OR [95% CI] £	1.14 [0.96-1.35]
	Syndromal depression	versus No depression	OR [95% CI] £	1.06 [0.52-2.15]		0.92 [0.53-1.60]	0.48 [0.23-1.00]	0.72 [0.44-1.74]				1.55 [0.74-3.22]	1.39 [0.72-2.69]	1.00	0.63 [0.33-1.18]	0.95 [0.52-1.73]	na	OR [95% CI] £	1.17 [0.98-1.40]
	Subsyndromal depression	versus No depression	OR [95% CI] £	0.78 [0.37-1.62]		1.02 [0.57-1.85]	0.69 [0.31-1.53]	0.87 [0.44-1.74]				0.96 [0.43-2.12]	1.10 [0.55-2.21]	1.00	0.61 [0.31-1.21]	0.96 [0.50-1.85]	na	OR [95% CI] £	1.09 [0.89-1.32]
	Syndromal or subsyndromal	depression (n = 268)	%	80.2		47.0	76.1	20.9				27.8	44.7	27.4	67.9	28.4	1.5	Mean (SD)	2.2 (1.6)
	Syndromal	depression (n = 163)	%	82.2		46.0	73.6	19.6				30.4	44.7	24.8	68.1	28.2	2.5	Mean (SD)	2.3 (1.7)
	Subsyndromal depression	(n = 105)	%	77.1		48.6	80.0	22.9				23.8	44.8	31.4	67.6	28.6	0.0	Mean (SD)	2.1 (1.6)
	No depression	(n = 75)	%	81.3		48.0	85.3	25.3				25.7	41.9	32.4	77.3	29.3	0.0	Mean (SD)	1.9 (1.4)
			Past-year physical health monitoring	At least one consultation with a	general practitioner	At least one electrocardiogram	At least one blood test	Hospitalization in a non-psychiatric	department	Physical health features	BMI a	Obesity	Normal weight	Malnutrition	High blood pressure b	Current smokers	At-risk drinking c	Medical conditions	Number of medical conditions

  were obtained using logistic regression models with 'no depression' as reference category.

	OR [95% CI] £ OR [95% CI] £	Functioning	GAF total score 53.7 (16.9) 49.3 (17.4) 44.8 (14.8) 46.6 (16.0) 0.98 [0.97-1.01] 0.97 [0.95-0.98] ⁎⁎⁎ 0.97 [0.96-0.99] ⁎⁎	MMSE total score 24.4 (4.4) 23.9 (4.8) 22.6 (5.4) 23.1 (5.1) 0.98 [0.92-1.05] 0.93 [0.87-0.98] 0.95 [0.90-0.99]*	Quality of life	QLS total score 65.6 (19.3) 54.9 (20.9) 45.0 (17.5) 49.0 (19.5) 0.98 [0.96-0.99] ⁎⁎ 0.95 [0.93-0.97] ⁎⁎⁎ 0.96 [0.95-0.98] ⁎⁎⁎	Suicide attempts % % % % OR [95% CI] £ OR [95% CI] £ OR [95% CI] £	Lifetime history of suicide attempts 29.3 22.9 30.7 27.6 0.71 [0.36-1.40] 1.07 [0.59-1.94] 0.92 [0.52-1.62]	Past-year history of suicide attempts 0.0 0.0 2.5 1.5 na na na	Mental health utilization	Lifetime number of hospitalizations in	a psychiatric department attempts	0-4 50.7 49.5 41.1 44.4 0.71 [0.32-1.57] 0.47 [0.23-1.00] 0.55 [0.28-1.10]	5-10 32.0 26.7 28.8 28.0 0.61 [0.26-1.44] 0.52 [0.24-1.14] 0.55 [0.26-1.16]	>10 17.3 23.8 30.1 27.6 1.00 1.00 1.00	The CES-D variable was categorized as no depression (CES-D score ≤ 7), subsyndromal depression (CES-D score: 8-15) and syndromal depression (CES-D score ≥ 16).	Estimates in bold are statistically significant (two-sided p-value < 0.01).	Abbreviations: OR=odds ratio; CI=confidence interval; CI=confidence interval; GAF=Global Assessment of functioning; MMSE=Mini Mental State Examination; QLS=Quality of Life Scale; SD=standard deviation;	na=not applicable.	⁎ p<0.05;	⁎⁎ p<0.01;

£

Odds ratios ⁎⁎⁎ p<0.001.

Table 5

 5 Multivariable logistic regression analyses of factors showing significant univariate associations with subsyndromal or syndromal depressive symptoms (SSSD) in older adults with schizophrenia (n = 343).

		Subsyndromal depression versus No	Syndromal depression versus No	Syndromal or subsyndromal depression versus No
		depression	depression	depression
		AOR [95% CI] / p-value £	AOR [95% CI] / p-value £	AOR [95% CI] / p-value £
	Urbanicity	1.55 [0.62-3.87] / 0.344	6.89 [2.28-20.87] / 0.001	2.53 [1.06-6.02] / 0.037
	Age-at-onset of schizophrenia
	Non-late-onset (<40y)	1.00	1.00	1.00
	(40-60y)	0.42 [0.14-1.25] / 0.120	0.25 [0.07-0.85] / 0.027	0.35 [0.13-0.99] / 0.049
	Very late-onset (>60y)	na	na	na
	Positive symptoms	1.02 [0.88-1.17] / 0.835	1.18 [1.02-1.38] / 0.031	1.07 [0.94-1.22] / 0.312
	Negative symptoms	1.14 [0.99-1.30] / 0.071	1.22 [1.05-1.41] / 0.008	1.17 [1.02-1.33] / 0.023
	Activation	1.02 [0.86-1.22] / 0.823	0.86 [0.70-1.05] / 0.129	0.97 [0.82-1.15] / 0.713
	Resistance	1.12 [0.91-1.38] / 0.268	1.17 [0.95-1.45] / 0.141	1.14 [0.94-1.40] / 0.187
	Benzodiazepines	1.59 [0.59-4.30] / 0.358	3.42 [1.19-9.86] / 0.023	2.09 [0.82-5.32] / 0.123
	GAF total score	1.00 [0.97-1.04] / 0.859	1.02 [0.98-1.06] / 0.338	1.01 [0.98-1.04] / 0.592
	QLS total score	0.98 [0.95-1.01] / 0.114	0.96 [0.93-0.98] / 0.002	0.97 [0.95-0.99] / 0.012

Acknowledgments

This study was supported by a grant from the French Ministry of Health and Social Affairs (PHRC 2008-N11-01) (http://solidarites-sante.gouv.fr/). It was promoted by the University of Reims Champagne-Ardenne (http://www.univ-reims.fr/) and the University Paris-Descartes (https://www.univ-paris5.fr/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the Clinical Research Unit of Georges Pompidou European Hospital, and in particular Pr Gilles Chatellier, Mr Yann Frigout and Mrs Pascaline Aucouturier, and the Clinical Research Unit of Robert Debré Hospital, and in particular Mrs Sarah Rubingher, Dr Bérengère Hubsch, Dr Eric Tran, Dr Fabien Gierski and Mr David Da Rin. We warmly thank all the patients and the investigators who made this study possible. Members (i.e. investigators) of the CSA Study group are: Jean Adès, Charles Alezrah, Isabelle

Author contributions statement

NH and FL designed the study. FL obtained the funding. FL, SB, YB, DRC, CBP, CCL supervised patient recruitment. CP, AC and NH undertook data management. NH and RPDR undertook statistical analyses. NH and CJ wrote the first draft of the manuscript. RPDR, KM, SB, YB, CP, DRC, CBP, CCL, AC, CGL, CL, GA, HP, AK and FL critically reviewed the manuscript. All authors contributed to and have approved the final manuscript.

Conflicts of interest

FL has received speaker and consulting fees from AstraZeneca, Janssen, Lundbeck, Otsuka Pharmaceuticals, Roche and Servier outside the submitted work. DRC reports personal fees from Lundbeck and Otsuka, unrelated to the submitted work. CBP reports personal fees from Lundbeck, Otsuka and Janssen, unrelated to the submitted work. CL reports personal fees and non-financial support from Lundbeck, personal fees from Janssen, non-financial support from Otsuka Pharmaceuticals, outside the submitted work. AK reports personal fees from Eutherapie, Lundbeck, Otsuka and Janssen, unrelated to the submitted work. Other authors report no conflicts of interest relevant to the content of this article.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2019.03.007.