Official journal of the Pacific Rim College of Psychiatrists
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Asia-Pacific Psychiatry ISSN 1758-5864
ORIGINAL ARTICLE
Which somatic symptoms are associated with an unfavorable course in Chinese patients with major depressive disorder? Diego Novick1 MD, William S. Montgomery2 B.Pharm, Jaume Aguado3 MS, Xiaomei Peng4 PhD, Roberto Brugnoli5 MD & Josep Maria Haro3 MD PhD 1 Eli Lilly and Company, Windlesham, Surrey, UK 2 Eli Lilly Australia Pty Ltd, Sydney, NSW, Australia 3 Parc Sanitari Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain 4 Eli Lilly and Company, Indianapolis, IN, USA 5 Università di Roma “Sapienza”, Rome, Italy
Keywords Chinese, depression, outcome, pain, somatic symptom Correspondence Diego Novick MD, Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. Tel: +44 1276 483832 Fax: +44 1276 483192 Email: [email protected] Received 8 May 2014 Accepted 21 April 2015 DOI:10.1111/appy.12189
Abstract Introduction: This was an analysis of the impact of somatic symptoms on the severity and course of depression in Chinese patients treated for an acute episode of major depressive disorder (MDD). Methods: Data were extracted from a 3-month prospective observational study which enrolled 909 patients with MDD in psychiatric care settings; this analysis focused on the Chinese patients (n = 300). Depression severity was assessed using the Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD-17); somatic symptoms were assessed using the patient-rated 28-item Somatic Symptom Inventory (SSI). Cluster analysis using baseline SSI scores grouped patients into three clusters with no/mild, moderate, or severe somatic symptoms. Four SSI factors (pain, autonomic symptoms, energy, and central nervous system) were defined, and regression analyses identified which factors were associated with remission at 3 months. Results: More than 70% of the patients had moderate or severe somatic symptoms. Baseline depression severity (HAMD-17 and CGI-S scores) was associated with more severe somatic symptoms. Remission rates differed between clusters of patients: 84.1%, 72.0%, and 55.3% for no/mild, moderate, and severe somatic symptoms, respectively (P = 0.0034). Pain symptoms were the somatic symptoms more strongly associated with lower remission rates at 3 months. Discussion: Somatic symptoms are associated with greater clinical severity and lower remission rates. Among somatic symptoms, pain symptoms have the greatest prognostic value and should be taken into account when treating patients with depression.
Introduction Depression and somatic symptoms often present together, potentially leading to lack of recognition of one of the conditions by both patients and clinicians (Rijavec and Grubic, 2012). Patients with major depressive disorder (MDD) often present only with somatic or painful symptoms in primary care, which can mean that their depressed mood is not recognized, while psychiatrists may concentrate on psychological
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
symptoms and pay less attention to somatic symptoms (Rijavec and Grubic, 2012). Depression-related somatic symptoms are a heterogeneous group that includes both non-painful (e.g. changes in appetite, sleep and libido, lack of energy, dizziness, palpitations, and dyspnea) and painful symptoms (e.g. headache, backache, musculoskeletal aches, gastrointestinal pain, and vague, poorly localized pain) (Corruble and Guelfi, 2000; Bair et al., 2003, 2004; Muñoz et al., 2005; Tylee and Gandhi, 2005;
427
Pain symptoms and course of depression
Kapfhammer, 2006). The recognition and management of somatic symptoms in MDD is clinically relevant, as these symptoms are an important predictor of both short and longer term outcomes. The presence of pain, for example, not only predicts a longer time to remission (Karp et al., 2005), but may also compromise the overall remission rate (Bair et al., 2004; Burt, 2004; Greco et al., 2004), and increase the risk of relapse (Paykel et al., 1995; Burt, 2004). Somatic symptoms in MDD also have economic ramifications, as the presence of multiple somatic symptoms in patients with MDD has been associated with increased depression severity and subsequent increased health care resource utilization (Garcia-Campayo et al., 2008). It has been suggested that ethnicity may influence the somatic and psychiatric presentation of depression (Berganza et al., 2001). Asian patients, for example, are more likely to report somatic symptoms than emotional/mood symptoms (Simon et al., 1999; Parker et al., 2001a,b; Ji and Zhang, 2002). The impact of somatic symptoms on both the severity and course of depression was explored using data from patients in Asia with MDD who participated in a 3-month prospective observational study (Novick et al., 2013). As the Chinese are the world’s largest ethnic group (representing 22% of the global population) (Parker et al., 2001b), a better understanding of depression in this group has the potential to impact a large number of individuals. We present a post hoc analysis of the Chinese cohort from this study, with the aim of improving the understanding of the impact of somatic symptoms on the severity and course of depression. As somatic symptoms are a heterogeneous group, we also explored whether specific somatic symptoms had a greater impact than others on the course of depression.
Methods Study design and population Data for this post hoc analysis were from a prospective, observational study that assessed the frequency of somatic symptoms in East Asian patients treated for an acute episode of a MDD in the psychiatric care setting (Ang et al., 2009). Patients from 40 study sites across six East Asian countries and regions participated: China (Mainland), Hong Kong, South Korea, Malaysia, Singapore, and Taiwan. Recruitment was from June 14, 2006 to February 15, 2007, with individual patients followed for 3 months. The overall study
428
D. Novick et al.
enrolled 909 patients; this analysis focused on the Chinese patients (n = 300). Inpatients and outpatients, ≥18 years of age, who presented with a new or first episode of MDD according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (American Psychiatric Association, 2000) or International Classification of Diseases, 10th Revision (World Health Organization, 2007), were eligible for study entry. Additional inclusion criteria were: a Clinical Global Impressions of Severity scale (CGI-S) (Guy, 1976) score ≥4 (moderately ill or worse) at study entry; at least 2 months free of depression symptoms before the onset of the current episode; and consent to participate. Patients were excluded if their current depressive episode had persisted for more than 6 months; if they had a previous or current diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, or dementia; if they were experiencing chronic treatment-resistant pain or inflammatory pain related to a medical condition; or if they were simultaneously participating in another study of a treatment or drug. All patients who satisfied the entry criteria were enrolled up to the sample size allocated. No further selection or stratification was involved. All treatment decisions were based solely on the health care provider’s usual practice for MDD care, independently of participation in the study. Adverse events were reported to the health authorities according to each country’s local rules, regulations, and legislation. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonization good clinical practice guidelines. The study was approved and reviewed by the institutional or ethical review board of at least one site in each participating country or region. Written informed consent was obtained from all patients or their legal representative prior to enrolment. Measures Demographic and clinical data (including course of MDD and comorbidities) were collected at the baseline visit. Depression severity was assessed at baseline and 3 months using the physician-rated CGI-S and the 17-item Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960). Remission was defined as a HAMD-17 total score of ≤7 at study endpoint. Somatic symptoms were assessed using the 28-item modified
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
D. Novick et al.
Somatic Symptom Inventory (SSI) (Kroenke et al., 1994), which is a patient self-report scale that assesses the extent to which symptoms have bothered the patient over the previous week on a scale of 1 (“not at all”) to 5 (“a great deal”). The total score was calculated by adding all items. For patients who were employed in the 3 months before study entry and/or during the study, the impact of depression-related illness on work productivity (e.g. hours worked and days absent) was evaluated through a questionnaire. Patient perception of quality of life and health status was assessed using the EuroQOL Questionnaire-5 Dimensions. For patients who were hospitalized, the number of admissions and length of hospital stay were collected. Data on treatment patterns (including antidepressants and other prescribed medications and treatments for MDD and pain) were collected at baseline and during the study. The baseline characteristics of patients with and without painful physical symptoms (PPS+ defined as a mean score ≥2 on the seven pain-related items of the SSI) have been reported previously (Lee et al., 2009), as have the changes in disease severity, treatment patterns, and quality of life over the 3-month observation period (Ang et al., 2009). All the instruments were translated into simplified Chinese using standard procedures. Training and assessment (rating of a videotaped patient interview) were performed to ensure consistency between investigators with respect to HAMD-17 ratings. A maximum variation of +3 or −3 from the prespecified HAMD-17 total score was considered acceptable, and 60% agreement with the 17 individual items was required. Investigators with scores outside the acceptable range were retrained until an adequate level of consistency with other raters was achieved. Statistical analysis Of the 909 patients enrolled in the study, 300 were from China and had complete baseline SSI data. A hierarchical cluster analysis that employed Ward’s minimum-variance method was used to define distinct groups of patients based on the 28 SSI items at baseline. Clusters were created using all the information available and the clustering procedure was applied to the standardized data. The number of clusters was based on the proportion of variation in the data captured by the clusters. A canonical variables plot was used to assist in the estimation of the clusters. Patient characteristics by somatic symptoms cluster were described and statistical differences between clusters were tested using Chi-square or analysis of variance tests as appropriate.
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
Pain symptoms and course of depression
Factors of the SSI were defined based on an exploratory factor analysis and expert opinion. Four factors were defined from the 28 SSI items: factor 1 – pain (muscle soreness, pains abdomen, pains lower back, pains heart/chest, headaches, joints pains, neck pain); factor 2 – autonomic symptoms (nausea/ vomiting, muscles twitching/jumping, constipation, trouble catching breath, hot/cold spells, indigestion, upset/acid stomach, numbness, tingling, burning parts of body, lump in throat, heart pounding, cold hands and feet); factor 3 – energy (feeling faint/dizzy, fatigued, weak, tired, fullness in head/nose, feeling in worse physical health than friends, feeling weak in parts of body, not feeling well most of time in past years, heavy arms and legs); and factor 4 – central nervous system (CNS) (vision trouble, ring/buzz in ears, difficulty keeping balance walking, hearing not as good as it used to be). Confirmatory factor analysis (CFA) was used to test the adequacy of the hypothesized factor structure. This is a confirmatory technique in that the model is specified based on theory, empirical research, or both; it postulates the relationship pattern a priori and then tests the hypothesis statistically. The fit of the CFA was assessed based on the root mean square error of approximation (RMSEA) and the comparative fit index (CFI). The RMSEA measures the fit of the model to the covariance matrix. As a guideline, RMSEA values
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Asia-Pacific Psychiatry ISSN 1758-5864
ORIGINAL ARTICLE
Which somatic symptoms are associated with an unfavorable course in Chinese patients with major depressive disorder? Diego Novick1 MD, William S. Montgomery2 B.Pharm, Jaume Aguado3 MS, Xiaomei Peng4 PhD, Roberto Brugnoli5 MD & Josep Maria Haro3 MD PhD 1 Eli Lilly and Company, Windlesham, Surrey, UK 2 Eli Lilly Australia Pty Ltd, Sydney, NSW, Australia 3 Parc Sanitari Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain 4 Eli Lilly and Company, Indianapolis, IN, USA 5 Università di Roma “Sapienza”, Rome, Italy
Keywords Chinese, depression, outcome, pain, somatic symptom Correspondence Diego Novick MD, Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. Tel: +44 1276 483832 Fax: +44 1276 483192 Email: [email protected] Received 8 May 2014 Accepted 21 April 2015 DOI:10.1111/appy.12189
Abstract Introduction: This was an analysis of the impact of somatic symptoms on the severity and course of depression in Chinese patients treated for an acute episode of major depressive disorder (MDD). Methods: Data were extracted from a 3-month prospective observational study which enrolled 909 patients with MDD in psychiatric care settings; this analysis focused on the Chinese patients (n = 300). Depression severity was assessed using the Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD-17); somatic symptoms were assessed using the patient-rated 28-item Somatic Symptom Inventory (SSI). Cluster analysis using baseline SSI scores grouped patients into three clusters with no/mild, moderate, or severe somatic symptoms. Four SSI factors (pain, autonomic symptoms, energy, and central nervous system) were defined, and regression analyses identified which factors were associated with remission at 3 months. Results: More than 70% of the patients had moderate or severe somatic symptoms. Baseline depression severity (HAMD-17 and CGI-S scores) was associated with more severe somatic symptoms. Remission rates differed between clusters of patients: 84.1%, 72.0%, and 55.3% for no/mild, moderate, and severe somatic symptoms, respectively (P = 0.0034). Pain symptoms were the somatic symptoms more strongly associated with lower remission rates at 3 months. Discussion: Somatic symptoms are associated with greater clinical severity and lower remission rates. Among somatic symptoms, pain symptoms have the greatest prognostic value and should be taken into account when treating patients with depression.
Introduction Depression and somatic symptoms often present together, potentially leading to lack of recognition of one of the conditions by both patients and clinicians (Rijavec and Grubic, 2012). Patients with major depressive disorder (MDD) often present only with somatic or painful symptoms in primary care, which can mean that their depressed mood is not recognized, while psychiatrists may concentrate on psychological
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
symptoms and pay less attention to somatic symptoms (Rijavec and Grubic, 2012). Depression-related somatic symptoms are a heterogeneous group that includes both non-painful (e.g. changes in appetite, sleep and libido, lack of energy, dizziness, palpitations, and dyspnea) and painful symptoms (e.g. headache, backache, musculoskeletal aches, gastrointestinal pain, and vague, poorly localized pain) (Corruble and Guelfi, 2000; Bair et al., 2003, 2004; Muñoz et al., 2005; Tylee and Gandhi, 2005;
427
Pain symptoms and course of depression
Kapfhammer, 2006). The recognition and management of somatic symptoms in MDD is clinically relevant, as these symptoms are an important predictor of both short and longer term outcomes. The presence of pain, for example, not only predicts a longer time to remission (Karp et al., 2005), but may also compromise the overall remission rate (Bair et al., 2004; Burt, 2004; Greco et al., 2004), and increase the risk of relapse (Paykel et al., 1995; Burt, 2004). Somatic symptoms in MDD also have economic ramifications, as the presence of multiple somatic symptoms in patients with MDD has been associated with increased depression severity and subsequent increased health care resource utilization (Garcia-Campayo et al., 2008). It has been suggested that ethnicity may influence the somatic and psychiatric presentation of depression (Berganza et al., 2001). Asian patients, for example, are more likely to report somatic symptoms than emotional/mood symptoms (Simon et al., 1999; Parker et al., 2001a,b; Ji and Zhang, 2002). The impact of somatic symptoms on both the severity and course of depression was explored using data from patients in Asia with MDD who participated in a 3-month prospective observational study (Novick et al., 2013). As the Chinese are the world’s largest ethnic group (representing 22% of the global population) (Parker et al., 2001b), a better understanding of depression in this group has the potential to impact a large number of individuals. We present a post hoc analysis of the Chinese cohort from this study, with the aim of improving the understanding of the impact of somatic symptoms on the severity and course of depression. As somatic symptoms are a heterogeneous group, we also explored whether specific somatic symptoms had a greater impact than others on the course of depression.
Methods Study design and population Data for this post hoc analysis were from a prospective, observational study that assessed the frequency of somatic symptoms in East Asian patients treated for an acute episode of a MDD in the psychiatric care setting (Ang et al., 2009). Patients from 40 study sites across six East Asian countries and regions participated: China (Mainland), Hong Kong, South Korea, Malaysia, Singapore, and Taiwan. Recruitment was from June 14, 2006 to February 15, 2007, with individual patients followed for 3 months. The overall study
428
D. Novick et al.
enrolled 909 patients; this analysis focused on the Chinese patients (n = 300). Inpatients and outpatients, ≥18 years of age, who presented with a new or first episode of MDD according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (American Psychiatric Association, 2000) or International Classification of Diseases, 10th Revision (World Health Organization, 2007), were eligible for study entry. Additional inclusion criteria were: a Clinical Global Impressions of Severity scale (CGI-S) (Guy, 1976) score ≥4 (moderately ill or worse) at study entry; at least 2 months free of depression symptoms before the onset of the current episode; and consent to participate. Patients were excluded if their current depressive episode had persisted for more than 6 months; if they had a previous or current diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, or dementia; if they were experiencing chronic treatment-resistant pain or inflammatory pain related to a medical condition; or if they were simultaneously participating in another study of a treatment or drug. All patients who satisfied the entry criteria were enrolled up to the sample size allocated. No further selection or stratification was involved. All treatment decisions were based solely on the health care provider’s usual practice for MDD care, independently of participation in the study. Adverse events were reported to the health authorities according to each country’s local rules, regulations, and legislation. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonization good clinical practice guidelines. The study was approved and reviewed by the institutional or ethical review board of at least one site in each participating country or region. Written informed consent was obtained from all patients or their legal representative prior to enrolment. Measures Demographic and clinical data (including course of MDD and comorbidities) were collected at the baseline visit. Depression severity was assessed at baseline and 3 months using the physician-rated CGI-S and the 17-item Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960). Remission was defined as a HAMD-17 total score of ≤7 at study endpoint. Somatic symptoms were assessed using the 28-item modified
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
D. Novick et al.
Somatic Symptom Inventory (SSI) (Kroenke et al., 1994), which is a patient self-report scale that assesses the extent to which symptoms have bothered the patient over the previous week on a scale of 1 (“not at all”) to 5 (“a great deal”). The total score was calculated by adding all items. For patients who were employed in the 3 months before study entry and/or during the study, the impact of depression-related illness on work productivity (e.g. hours worked and days absent) was evaluated through a questionnaire. Patient perception of quality of life and health status was assessed using the EuroQOL Questionnaire-5 Dimensions. For patients who were hospitalized, the number of admissions and length of hospital stay were collected. Data on treatment patterns (including antidepressants and other prescribed medications and treatments for MDD and pain) were collected at baseline and during the study. The baseline characteristics of patients with and without painful physical symptoms (PPS+ defined as a mean score ≥2 on the seven pain-related items of the SSI) have been reported previously (Lee et al., 2009), as have the changes in disease severity, treatment patterns, and quality of life over the 3-month observation period (Ang et al., 2009). All the instruments were translated into simplified Chinese using standard procedures. Training and assessment (rating of a videotaped patient interview) were performed to ensure consistency between investigators with respect to HAMD-17 ratings. A maximum variation of +3 or −3 from the prespecified HAMD-17 total score was considered acceptable, and 60% agreement with the 17 individual items was required. Investigators with scores outside the acceptable range were retrained until an adequate level of consistency with other raters was achieved. Statistical analysis Of the 909 patients enrolled in the study, 300 were from China and had complete baseline SSI data. A hierarchical cluster analysis that employed Ward’s minimum-variance method was used to define distinct groups of patients based on the 28 SSI items at baseline. Clusters were created using all the information available and the clustering procedure was applied to the standardized data. The number of clusters was based on the proportion of variation in the data captured by the clusters. A canonical variables plot was used to assist in the estimation of the clusters. Patient characteristics by somatic symptoms cluster were described and statistical differences between clusters were tested using Chi-square or analysis of variance tests as appropriate.
Asia-Pacific Psychiatry 7 (2015) 427–435 © 2015 Wiley Publishing Asia Pty Ltd
Pain symptoms and course of depression
Factors of the SSI were defined based on an exploratory factor analysis and expert opinion. Four factors were defined from the 28 SSI items: factor 1 – pain (muscle soreness, pains abdomen, pains lower back, pains heart/chest, headaches, joints pains, neck pain); factor 2 – autonomic symptoms (nausea/ vomiting, muscles twitching/jumping, constipation, trouble catching breath, hot/cold spells, indigestion, upset/acid stomach, numbness, tingling, burning parts of body, lump in throat, heart pounding, cold hands and feet); factor 3 – energy (feeling faint/dizzy, fatigued, weak, tired, fullness in head/nose, feeling in worse physical health than friends, feeling weak in parts of body, not feeling well most of time in past years, heavy arms and legs); and factor 4 – central nervous system (CNS) (vision trouble, ring/buzz in ears, difficulty keeping balance walking, hearing not as good as it used to be). Confirmatory factor analysis (CFA) was used to test the adequacy of the hypothesized factor structure. This is a confirmatory technique in that the model is specified based on theory, empirical research, or both; it postulates the relationship pattern a priori and then tests the hypothesis statistically. The fit of the CFA was assessed based on the root mean square error of approximation (RMSEA) and the comparative fit index (CFI). The RMSEA measures the fit of the model to the covariance matrix. As a guideline, RMSEA values
