Leukemia & Lymphoma, December 2014; 55(12): 2835–2841 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.893309

ORIGINAL ARTICLE: CLINICAL

Prevalence and risk factors for depression in newly diagnosed patients with POEMS syndrome Lu Zhang, Yin-Lei Zhou, Wei Zhang, Ming-Hui Duan, Xin-Xin Cao, Dao-Bin Zhou & Jian Li Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

(minor criteria) [6,7]. Because patients with POEMS syndrome often have various kinds of incapacitating symptoms [6], as well as multiple incorrect diagnoses (e.g. hypothyroidism and Guillain–Barré syndrome [8]), it is very likely that some of the patients might have coexisting depression. Thus, examining the prevalence and risk profiles associated with depression in patients with POEMS syndrome might help to promote their well-being. However, the prevalence, risk factors and the possible impact of depression in patients with POEMS syndrome have not been addressed, possibly due to the rarity of this disease. Depression is not only associated with exacerbation and promotion of symptoms associated with chronic diseases [2–4] but also known to be related to a variety of undesirable risks, such as impairment in functional status, diminished quality of life, poor adherence to medical treatment, risky behaviors (drug and alcohol abuse [1,9,10]) and even death [11,12]. Thus, we conducted a study to assess the prevalence and risk profiles for depression in patients with POEMS syndrome.

Abstract This prospective study delineated the prevalence and risk factors for clinical depression in patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes). Using a PHQ-9 (Patient Health Questionnaire scale-9, which evaluates the severity of depressive symptoms) score cut-off ⱖ 10, the prevalence of pretreatment depression was 38.0%. Based on multivariate logistic regression, higher ONLS (Overall Neuropathy Limitation Scale, which assesses the severity of neuropathy) upper limb scores (hazard ratio [HR] 1.75; 95% confidence interval [CI] 1.09–2.81; p ⴝ 0.02) and ascites (HR 4.30; 95% CI 1.03–17.9; p ⴝ 0.04) were significant and independent predictors for depression. The incidence of post-treatment depression was 1.53% by the end of follow-up, while no patients received antidepressants. A preliminary logistic regression suggested depression to be a risk factor for early death (within 3 months after diagnosis) (HR 9.77; 95% CI, 1.08–88.9; p ⴝ 0.04). Keywords: POEMS syndrome, depression, PHQ-9

Introduction

Patients and methods

Depression is a common and disabling medical condition which frequently coexists with chronic illnesses [1]. There is accumulating evidence that chronic diseases raise the risk of depression, and conversely, depression appears to exacerbate and promote symptoms associated with chronic illness [2–4]. These relationships have also been discussed and demonstrated between depression and hematologic diseases [2,5]. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) is a chronic hematologic disorder characterized by the presence of a monocolonal plasma-cell proliferative disorder, peripheral neuropathy (major criteria) and one or more of the following features: bone lesion, Castleman disease (giant or angiofollicular lymph node hyperplasia), organomegaly, endocrinopathy, edema, skin changes and papilledema

Patients This study was designed as a prospective observational study which enrolled 72 consecutive patients with newly diagnosed POEMS syndrome who were referred to Peking Union Medical College Hospital between June 2011 and May 2013. All patients fulfilled the diagnostic criteria proposed by Dispenzieri et al. [6] in which two major criteria (polyneuropathy and monoclonal plasma proliferative disorder) and at least one of seven minor criteria (bone lesion, Castleman disease, organomegaly, edema, endocrinopathy, skin changes and papilledema) must be met. Exclusion criteria were the following: (1) major comorbidity or language barrier compromising questionnaire completion; (2) a known history of psychosis, bipolar disorder and severe cognitive impairment; and (3) an inability to

Correspondence: Jian Li, MD, Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Tel: ⫹ 86-10-69155549. Fax: ⫹ 86-10-69158292. E-mail: [email protected] Received 29 December 2013; revised 31 January 2014; accepted 31 January 2014

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obtain informed consent. One patient was excluded due to serious comorbidity compromising questionnaire completion. The remaining cohort of 71 patients was eligible for the study. Each participant completed the baseline evaluation of demographic features, clinical symptoms and signs, POEMS-related features, such as neuropathy, organomegaly, endocrinopathy and skin changes, extravascular volume overload (edema, ascites and pleural effusion), bone lesions, estimated serum creatinine clearance rate (ClCr) and other laboratory results (hemoglobin, platelet count and vascular endothelial growth factor [VEGF] level). In addition, patients were also evaluated with questionnaires of the nine-item Patient Health Questionnaire scale (PHQ-9) [13], to assess the severity of depressive symptoms, and the Overall Neuropathy Limitation Scale (ONLS) [14], to assess the severity of neuropathy and neurologic disability, which has been validated in patients with POEMS [7]. After diagnosis, all patients were treated with different treatment options (e.g. highdose melphalan followed by autologous stem cell transplant [ASCT], melphalan and dexamethasone) according to various socioeconomic and clinical situations [7,15], as well as the discussion of results of risk and benefit between clinicians and patients. Regular follow-up visits were carried out every 3 months after confirmation of the diagnosis; surviving patients received an evaluation of treatment responses, including neurologic responses with ONLS questionnaires, clinical responses of organomegaly and extravascular volume overload, and PHQ-9 questionnaires. At the first follow-up visit, the mortality rate (early death, defined as death within the first 3 months after diagnosis) of patients was documented. An informed consent was signed by every patient, and this study was approved by the Peking Union Medical College Hospital Institutional Review Board, in accordance with the Declaration of Helsinki.

Assessment of depressive symptoms PHQ-9 is a nine-item self-administered instrument to assess depressive symptoms which incorporates the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) classification for major depressive disorder [13]. Each item is scored 0–3, which results in a range of scores between 0 and 27. PHQ-9 scores are interpreted as follows: (1) score ⬍ 5, no depression; (2) score 5–9, mild depression; (3) score 10–14, moderate depression; (4) score 15–19, moderately severe depression; and (5) score 20–27, severe depression. A previous study demonstrated that a PHQ-9 score ⱖ 10 had a sensitivity of 88% and a specificity of 88% for major depression using the mental health professional (MHP) re-interview as the criterion standard [13]. Moreover, the reliability and validity of PHQ-9 in assessing depressive symptoms among Chinese patients has been supported by the literature [16]. In our study, a PHQ-9 score ⱖ 10 was utilized for the diagnosis of clinical depression in patients with POEMS. Further, the validity of this cut-off point has been demonstrated [13] and recommended in other chronic diseases [17].

Statistical analysis Statistical analysis was performed with SPSS statistical software (version 13.0; IBM Corporation, Armonk, NY). All of the possible risk factors for clinical depression (defined as a PHQ-9 ⱖ 10) were first screened with the χ2 test for categorical covariates and Wilcoxon rank-sum test for continuous covariates, aiming for comparisons between patients with and without depression at baseline (p ⬍ 0.05 was considered to be significant). Univariate logistic regression was used to estimate hazard ratios and to determine differences between groups. Variables with a p ⬍ 0.10 in univariate analysis were then entered into the multivariate logistic regression. Factors with a p ⬍ 0.05 were believed to be highly clinically significant and independent predictors for pretreatment depression. Moreover, using the follow-up data, Wilcoxon rank-sum tests were utilized to analyze the difference in scores of questionnaires (PHQ-9, ONLS) in surviving patients. The Wilcoxon rank-sum test and univariate logistic regression were carried out to identify the relationship between depression and early death (defined as death within 3 months after diagnosis). Due to a lack of positive events (death) and limitation of case numbers, multivariate logistic regression was not taken to assess whether or not depression was an independent risk factor for early death.

Results Patient characteristics Seventy-one consecutive patients were enrolled in the study; 23 patients were female and 48 were male. The median age at diagnosis was 47 years (range, 24–74 years), with a median delay in diagnosis (time interval between first symptom and final diagnosis) of 13 months (range, 1–252 months). The treatment options included ASCT (n ⫽ 44, 62.0%), melphalan and dexamethasone (MDex; n ⫽ 17, 23.9%), melphalan and prednisolone (MP; n ⫽ 1, 1.4%), bortezomib and dexamethasone (BDex; n ⫽ 2, 2.8%), lenalidomide and dexamethasone (LDex; n ⫽ 6, 8.5%) and untreated (n ⫽ 1, 1.4%). The median follow-up time was 12 months (range, 3–24 months). By the end of the follow-up evaluation six patients had died, all within the first 3 months after diagnosis, which fulfilled the criteria for early death. Thus, the early-death mortality rate was 8.5% (n ⫽ 6). Five patients died from disease progression (four died from renal failure and one died from heart failure) and one patient died from treatment-related (transplant) acute cholecystitis. Of note, the “untreated” patient died before initiation of therapy targeting POEMS syndrome.

Prevalence of pretreatment depression The median PHQ-9 score at baseline was 6 (range, 0–27) with a distribution of scores as follows: ⬍ 5, n ⫽ 21 (29.6%); 5–9, n ⫽ 23 (32.4%); 10–14, n ⫽ 11 (15.5%); 15–19, n ⫽ 14 (19.7%); and 20–27, n ⫽ 2 (2.8%). With a PHQ-9 score cut-off ⱖ 10, the prevalence of clinical depression in this set of patients with POEMS was 38.0% (n ⫽ 27). None of the patients were taking antidepressants.

Depression in POEMS syndrome

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Table I. Comparison of risk factor distributions between patients with and without depression. With depression General characteristics Demographic Age, years, median (range) Gender, male, no. City dweller, no. Previous treatment, no. Delay in diagnosis, months, median (range) Accuracy in first diagnosis, no. Symptoms and signs Weakness, no. Weight loss, no. Fever, no. Diarrhea, no. Dyspnea, no. Polyneuropathy Motor, no. Sensor, no. ONLS upper limb ONLS lower limb ONLS total CSF pressure, mmH2O, median (range) CSF protein, g/L, median (range)* Organomegaly Lymphadenopathy, no. Castleman disease, no. Hepatomegaly, no. Splenomegaly, no. Endocrinopathy Diabetes, no. Hypothyroidism, no. Skin changes Hyperpigmentation, no. Hemangioma, no. Hypertrichosis, no. Thickening, no. Extravascular overload Edema, no. Acites, no. Pleural effusion, no. Pericardial effusion, no. Other Cerebral infarction, no. Cerebral hemorrhage, no. Bone lesions, no. Laboratory tests and findings Hemoglobin, g/L, median (range) Plt, ⫻ 109/L, median (range) ClCr ⬍ 60 mL/min, no. Papilledema, no. PAH, no. VEGF, pg/mL, median (range)†

Value

Without depression No.

Value

No.

27 27 27 27 27

47.5 (24.0–74.0) 29 23 27 12.5 (1.0–164.0)

44 44 44 44 44

0.29 0.70 0.21 0.89 0.85

5

27

13

44

0.30

20 22 4 1 4

27 27 27 27 27

31 33 2 3 6

44 44 44 44 44

0.74 0.53 0.13 0.58 0.89

47.0 (27.0–72.0) 18 10 17 13.0 (1.5–252.0)

p-Value

27 27 2.0 (0.0–4.0) 3.0 (0.0–6.0) 5.0 (0.0–10.0) 180.0 (105.0–330.0)

27 27 27 27 27 25

43 44 1.0 (0.0–4.0) 2.0 (0.0–7.0) 4.0 (0.0–11.0) 200.0 (130.0–330.0)

44 44 44 44 44 43

0.43 NA 0.03 0.29 0.07 0.60

1.30 (0.11–2.93)

25

1.16 (0.30–2.64)

43

0.51

14 3 15 21

27 27 27 27

23 6 23 30

44 44 44 44

0.97 0.76 0.79 0.38

4 24

27 27

10 26

44 44

0.42 0.01

25 15 16 19

27 27 27 27

39 25 22 24

44 44 44 44

0.59 0.92 0.45 0.19

25 21 15 20

27 27 27 27

35 17 13 28

44 44 44 44

0.14 ⬍ 0.01 0.03 0.36

4 0 14

27 27 27

3 1 28

44 44 44

0.27 0.43 0.33

129.0 (91.0–163.0) 281.0 (80.0–621.0) 7 20 7 3629.5 (187.0–10928.0)

27

143.0 (87.0–179.0)

44

0.04

27 27 27 27 26

311.0 (39.0–609.0) 6 29 6 3020.0 (142.0–8138.0)

44 44 44 44 41

0.92 0.19 0.47 0.19 0.23

ONLS, Overall Neuropathy Limitation Scale; CSF, cerebrospinal fluid; Plt, platelets; ClCr, creatinine clearance; PAH, pulmonary artery hypertension; VEGF, vascular endothelial growth factor; NA, not applicable. *Three patients did not have lumbar puncture due to difficulty in access and comorbidity compromising this invasive procedure. †Four patients did not have VEGF level tested due to inadequate sample preparation.

Risk profiles for pretreatment depression The clinical features of patients are listed in Table I along with risk factor distributions between patients with and without clinical depression (before treatment for the underlying POEMS syndrome). Compared to patients without depression, patients with clinical depression had higher ONLS upper limb scores (median ⫽ 2.0 vs. 1.0, p ⫽ 0.03) and lower hemoglobin levels (median ⫽ 129.0 vs. 143.0 g/L,

p ⫽ 0.04). Patients with depression also had higher incidences of hypothyroidism (24/27 vs. 26/44, p ⫽ 0.01), ascites (21/27 vs. 17/44, p ⬍ 0.01) and pleural effusion (15/27 vs. 17/44, p ⫽ 0.03). Based on univariate logistic regression (Table II), five risk factors were shown to be significant predictors of pretreatment depression in patients with POEMS. Higher ONLS upper limb scores (hazard ratio [HR] ⫽ 1.59; 95% confidence

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L. Zhang et al. Table II. Risk factors for depression in patients with POEMS (using logistic regression). Univariate analysis Risk factors Demographic Age, years Gender, male City dweller Previous treatment Delay in diagnosis, months Accuracy in first diagnosis Symptoms and signs Weakness Weight loss Fever Diarrhea Dyspnea Polyneuropathy Motor Sensor ONLS upper limb ONLS lower limb ONLS total CSF pressure, mmH2O CSF protein, g/L Organomegaly Lymphadenopathy Castleman disease Hepatomegaly Splenomegaly Endocrinopathy Diabetes Hypothyroidism Skin changes Hyperpigmentation Hemangioma Hypertrichosis Thickening Extravascular overload Edema Ascites Pleural effusion Pericardial effusion Other Cerebral infarction Cerebral hemorrhage Bone lesions Lab tests and findings Hemoglobin, g/L Plt, ⫻ 109/L CCrl ⬍ 60 mL/min Papilledema PAH VEGF, pg/mL

HR (95% CI)

p-Value

0.99 (0.94–1.04) 0.81 (0.29–2.29) 0.54 (0.20–1.43) 1.07 (0.40–2.88) 1.01 (0.99–1.02) 0.54 (0.17–1.74)

0.620 0.700 0.210 0.890 0.340 0.300

1.20 (0.41–3.52) 1.47 (0.45–4.81) 3.65 (0.62–21.48) 0.53 (0.05–5.33) 1.10 (0.28–4.32)

0.740 0.530 0.150 0.590 0.890

NA NA 1.59 (1.045–2.432) 1.10 (0.85–1.43) 1.16 (0.96–1.39) 1.00 (0.99–1.01) 1.14 (0.52–2.50)

0.030 0.470 0.130 0.810 0.750

0.98 (0.38–2.57) 0.79 (0.18–3.47) 1.14 (0.44–3.00) 1.63 (0.54–4.94)

0.970 0.760 0.790 0.390

0.59 (0.17–2.12) 5.54 (1.45–21.20)

0.420 0.012

1.60 (0.29–8.91) 0.95 (0.36–2.50) 1.46 (0.55–3.83) 1.98 (0.72–5.47)

0.590 0.920 0.448 0.190

3.21 (0.64–16.18) 5.56 (1.87–16.56) 2.98 (1.099–8.09) 1.63 (0.57–4.70)

0.157 0.002 0.032 0.364

2.38 (0.49–11.56) NA 0.62 (0.23–1.63)

0.280 0.330

0.98 (0.96–0.99) 1.00 (0.99–1.00) 2.22 (0.66–7.49) 1.48 (0.51–4.28) 2.22 (0.66–7.49) 1.00 (1.00–1.00)

0.038 0.870 0.200 0.471 0.200 0.270

Multivariate analysis HR (95% CI)

p-Value

1.75 (1.09–2.81)

0.02

3.94 (0.88–17.68)

0.07

4.3 (1.03–17.9) 1.04 (0.27–3.95)

0.04 0.96

0.99 (0.96–1.02)

0.49

POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; ONLS, Overall Neuropathy Limitation Scale; CSF, cerebrospinal fluid; Plt, platelets; ClCr, creatinine clearance; PAH, pulmonary artery hypertension; VEGF, vascular endothelial growth factor; HR, hazard ratio; CI, confidence interval.

interval [CI], 1.05–2.43; p ⫽ 0.03), hypothyroidism (HR ⫽ 5.54; 95% CI, 1.45–21.20; p ⫽ 0.01), ascites (HR ⫽ 5.56; 95% CI 1.87–16.56, p ⬍ 0.01), pleural effusion (HR ⫽ 2.98; 95% CI, 1.10–8.09; p ⫽ 0.03) and lower hemoglobin level (HR ⫽ 0.98; 95% CI, 0.96–0.99; p ⫽ 0.04) were associated with pretreatment clinical depression. After incorporation of variables with a p ⬍ 0.10 in univariate analysis, multivariate logistic regression revealed that higher ONLS upper limb scores (HR ⫽ 1.75; 95% CI, 1.09–2.81; p ⫽ 0.02) and ascites (HR ⫽ 4.30; 95% CI, 1.03– 17.9; p ⫽ 0.04) were clinically significant and independent predictors for clinical depression in patients with POEMS (Table II).

Responses after treatment There were 65 survivors at the last follow-up visit. Of the surviving patients, the incidences of ascites, edema, hepatomegaly and splenomegaly decreased from 49.2%, 83.1%, 52.3% and 72.3% to 0, 18.5%, 3.1% and 12.3%, respectively, indicating good clinical responses. The median ONLS score also decreased significantly from 4.0 to 2.0 (p ⬍ 0.001), suggesting a good neurologic response (Table III). Although no antidepressants were administered to our patients, after treatment of the underlying disease, the median PHQ-9 score decreased from 6.0 to 0.0 (p ⬍ 0.001), revealing improvement in the depressive symptoms (Table III). With the exception of the patients who had died, all of the patients who had a

Depression in POEMS syndrome Table III. Improvement after treatment (in 65 survivors). Variable PHQ-9 ONLS upper limb ONLS lower limb ONLS total

Before treatment, median (range)

After treatment, median (range)

p-Value

6.0 (0–27.0) 2.0 (0–4.0)

0.0 (0.0–26.0) 0.0 (0.0–5.0)

⬍ 0.001 ⬍ 0.001

2.0 (0–7.0)

2.0 (0.0–7.0)

⬍ 0.001

4.0 (0–11.0)

2.0 (0.0–11.0)

⬍ 0.001

PHQ-9, Patient Health Questionnaire scale-9; ONLS, Overall Neuropathy Limitation Scale.

PHQ-9 score ⱖ 10 experienced a drop in the score to ⬍ 10. Compared to an incidence of depression of 38.0% before treatment, there was only one patient with clinical depression (PHQ-9 score ⫽ 26) at the last follow-up visit (post-treatment incidence of depression ⫽ 1.53%), who had mild depressive symptoms (PHQ score ⫽ 6) before treatment. This patient also suffered from refractory disease, which did not respond to treatment with worsening symptoms and ONLS scores.

Association between depression and early death The baseline PHQ-9 scores were significantly lower in survivors (n ⫽ 65; median ⫽ 6.0 vs. 14.0; p ⫽ 0.04) compared to non-survivors (n ⫽ 6). Moreover, with a PHQ-9 score cutoff ⱖ 10, the incidence of pretreatment clinical depression was significantly lower (22/65 vs. 5/6, p ⫽ 0.02) in survivors. Based on univariate logistic regression, pretreatment clinical depression was shown to be significantly associated with early death (HR ⫽ 9.77; 95% CI, 1.08–88.9; p ⫽ 0.04).

Discussion This is the first study to address the prevalence and risk profiles for depression in patients with POEMS syndrome. The prevalence of clinical depression in patients newly diagnosed with POEMS syndrome screened in our study was 38.0%, which is similar to patients with chronic diseases (33%) [18], malignant diseases (8–24%) [19] or other hematologic diseases, such as hemophilia (18% using a PHQ-9 cut-off ⱖ 10 [2]). Thus, patients with POEMS syndrome appear to be at a higher risk for clinical depression, especially in comparison with a much lower prevalence of depression (1.6%) in mainland China [20]. Two significant and independent risk factors (ONLS upper limb score and presence of ascites) are associated with an increasing risk of clinical depression in patients with POEMS syndrome. The ONLS is a measure for the severity of neuropathy and neurologic disability which has been recommended in various peripheral neuropathies [14], including POEMS syndrome [7]. The ONLS has an upper (range, 0–5) and a lower limb section (range, 0–7), with a total score ranging from 0 to 12. The association between the severity of peripheral neuropathies and depression has been well elucidated, mainly in patients with diabetes [21,22]. Neuropathy is thought to be a risk factor for depressive symptoms. Thus, higher ONLS scores indicate more severe neuropathies, which could be associated with depressive symptoms in our cohort of patients with POEMS syndrome. The discrepancy between the upper and lower limb sections (NB the upper

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limb score is a risk factor, while the lower limb score is not a risk factor) might be explained as follows: upper limbs perform more delicate functions, and once disabled, might impose more influence on mental activities; nerve damage in the upper limbs without involvement of the lower limbs may also cause depression [23]; and although not statistically significant, our study also revealed a slightly higher ONLS lower limb score in patients with depression (median ⫽ 3.0 vs. 2.0). The difference might be more evident if the sample size is enlarged. In addition to the ONLS upper limb score, the presence of ascites in POEMS syndrome is another independent risk factor for depression. Ascites is a common symptom in patients with POEMS syndrome. As a component of extravascular volume overload, ascites in POEMS syndrome could be long-term, massive, unexplained and refractory [6,24], which might cause physical and psychological burdens and subsequently lead to depressive symptoms. Depression has been shown to be a risk factor for death in patients with chronic diseases, such as coronary artery disease [11] and cancer [12]. This relationship does not weaken over time, and the prognostic impact of initial depression affects short- and long-term mortality [11,12]. In our study the preliminary results suggest that depression is related to early death (within 3 months after diagnosis). Due to a lack of positive events (death) and the limited number of cases, multivariate regression was not performed, and it was not clear whether the relationship between depression and mortality was independent. Unlike coronary artery disease and cancer, POEMS syndrome is a very rare disease. It is really difficult to recruit a sufficient number of patients to analyze the association between depression and mortality. We hope to collect more data and better elucidate this relationship in the future. Some of our patients were not treated with antidepressants, either before treatment for the underlying diseases or after initiation of various kinds of therapeutic options. There is no evidence or consensus regarding the benefit of treating patients with POEMS syndrome and depressive symptoms with antidepressants. Moreover, whether or not patients without psychiatric conditions should be treated with antidepressants is controversial [25]. According to the results of our observational study, we postulate that antidepressants might not be necessary in patients with POEMS syndrome, because the depressive symptoms parallel the clinical severity of the underlying disease and are likely to resolve after initiation of treatment for POEMS syndrome (with the improvement of other symptoms). However, for those patients who have persistent depressive symptoms or newly developed depression after treatment for POEMS syndrome, additional data are needed to determine whether antidepressants are beneficial. The underlying pathophysiology of POEMS syndrome has been postulated to be related to chronic overproduction of proinflammatory and other cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), IL-6 [26] and VEGF [27]. Further, some of these cytokines have been correlated with the occurrence of clinical depression [28,29]. Based on these findings, we measured the serum VEGF levels in our

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patients and tried to delineate the relationship between pretreatment VEGF concentration and depression. However, the VEGF level was not found to be a risk factor for clinical depression in this set of patients (p ⫽ 0.27, Table II). This finding seems to be acceptable considering the fact that there are conflicting data regarding VEGF levels in depressed patients [29]: some investigators find VEGF levels to be elevated in depressed patients, while others suggest that VEGF levels are decreased in these patients. Thus, the relationship between VEGF levels and the incidence of depression in patients with POEMS syndrome requires further clarification. Despite the prominent use of steroids (dexamethasone and prednisolone) among treatment regimens for POEMS, there was no evidence in our cohort for any rise in depressive symptoms as treatment unfolded. This phenomenon seems worthy of discussion, as exogenous corticosteroids have been associated with clinical depression [30]: the post-treatment prevalence of depression was very low (1.53%) in our cohort of patients, which made it difficult to analyze the effects of different treatment options (whether to use steroids or not) on the prevalence of depression. However, the only one patient who experienced post-treatment depression indeed received MDex, which contains steroids. Thus, it might be possible that a higher post-treatment prevalence of depression would be observed in steroid-treated patients if our patient population could be expanded. Another phenomenon observed in our study was that patients who had pretreatment depression experienced a dramatic decrease in the incidence of depression despite the use of steroids. This finding could be explained as follows: a prior study found that in patients exposed to exogenous corticosteroids, the prevalence of depression was 11.1% [30]; in our cohort of untreated patients with POEMS syndrome, the prevalence of depression was much higher (38.0%). This might suggest that, compared to the use of corticosteroids, the untreated underlying disease might impose a larger influence on the occurrence of depression in our patients.

Conclusions Clinical depression is a common manifestation of POEMS syndrome. The ONLS upper limb score, which reflects the severity of peripheral neuropathies, and the presence of ascites are two significant and independent risk factors for clinical depression before the initiation of treatment for POEMS. The depressive symptoms in most patients resolve after treatment for the underlying diseases without the utilization of antidepressants. Depression might be a risk factor for early death in patients with POEMS syndrome.

Acknowledgements The authors thank all the patients who participated in this study. The study was funded by Capital Health Research and Development of Special (No. 2011-4001-03), Beijing Municipal Science & Technology Commission (No. Z111107058811019), Peking Union Medical College New Star (2011, for J.L.) and the National Public Health Grand Research Foundation (No. 201202017).

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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Prevalence and risk factors for depression in newly diagnosed patients with POEMS syndrome.

This prospective study delineated the prevalence and risk factors for clinical depression in patients with POEMS syndrome (polyneuropathy, organomegal...
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