- Email: [email protected]
Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes
Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes Ching-Hua Lin a,b, Chun-Jen Huang b,c, Shi-Kai Liu d,e,n a
Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan Department of Psychiatry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Psychiatry, Kaohsiung Medical University Hospital, Taiwan d Centre for Addiction and Mental Health, Toronto, ON, Canada e Department of Psychiatry, University of Toronto, Toronto, ON, Canada b
art ic l e i nf o
a b s t r a c t
Article history: Received 19 July 2015 Received in revised form 1 November 2015 Accepted 7 November 2015
To determine whether the presence of melancholic features in hospitalized patients with major depressive disorder (MDD) was associated with specific clinical characteristics and treatment outcomes, supporting melancholic depression as a distinct subtype within MDD. 126 acutely ill inpatients with MDD were enrolled in an open, 6-week trial with fixed-dose fluoxetine 20 mg daily. Symptom severity was assessed regularly, using the 17-item Hamilton Depression Rating Scale (HAMD-17) and Clinical Global Impression of Severity (CGI-S). Melancholic features were defined according to the DSM-IV criteria. Clinical variables were compared between patients with and without melancholic features. Generalized estimating equations method was used to explore the differences in HAMD-17 and CGI-S scores between the 2 groups over time. Clinical response was defined as having a 50% or greater reduction in HAMD-17 scores. 96 (76.2%) of the 126 patients with at least one post-baseline assessment met the criteria for melancholic depression. Melancholic depression differed from non-melancholic depression in clinical characteristics and predicted a better response to fluoxetine treatment. The differentiation between melancholic and non-melancholic depression within MDD hence is clinically significant and valid. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melancholic Fluoxetine Major depressive disorder Generalized estimating equations
1. Introduction Major depressive disorder (MDD) is a heterogeneous condition. Identifying subtypes of MDD with differential responses to treatments would be clinically valuable for personalized treatment (Uher et al., 2011). Melancholic depression has been proposed as a clinical subtype of MDD with non-reactivity of mood and/or observable psychomotor disturbance as its core features (Parker et al., 1994). According to either DSM-IV (APA, 1994b) or DSM-5 (APA, 2013) criteria, the principal diagnostic feature is a loss of pleasure in all, or almost all, activities or a lack of reactivity to usually pleasurable stimuli. Additional symptoms include distinct quality of depressed mood, a depressed mood that is worse in the morning, early-morning awakening, marked psychomotor agitation or retardation, excessive guilt, and significant anorexia or weight loss. n Corresponding author at: Department of Psychiatry, University of Toronto, 1001 Queen Street West, Toronto, ON, Canada, M6J 1H4. E-mail address: [email protected] (S.-K. Liu).
Melancholic depression is commonly observed in severely ill patients with MDD (Parker et al., 2010) and a high percentage of inpatients with MDD present with symptoms of melancholia (Guelfi et al., 1995). Compared to non-melancholic depression, melancholic depression has been demonstrated to respond poorly to placebos, psychotherapies and social interventions (Parker, 2007), hence is considered to be more “biologically rooted” and responds well to “biological” treatments such as antidepressants and electroconvulsive therapy (ECT) (Peselow et al., 1992; Perry, 1996; Parker, 2007). Furthermore, patients with melancholic depression may respond to treatment more rapidly than those without (Parker et al., 1992). Such distinctive psychopathology, biological underpinning and treatment outcome seems to differentiate melancholic depression from non-melancholic depression (Shorter, 2007) and provide the basis of new diagnostic criteria for melancholia as a distinct disease entity (Fink et al., 2007a; Parker, 2007). Past treatment outcomes of melancholic depression with fluoxetine or other selective serotonin reuptake inhibitors (SSRIs), compared with non-melancholic depression, have been variable: either better (Heiligenstein et al., 1994), comparable (Joyce et al.,
http://dx.doi.org/10.1016/j.psychres.2015.11.009 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
2002; Mallinckrodt et al., 2005) or poorer (Parker et al., 1999; McGrath et al., 2008a; Gili et al., 2012). In the present study, we intended to test the hypothesis that, as defined by distinct clinical features, melancholic depression can be externally validated by differences in demographic characteristics, clinical course and antidepressant treatment responses, compared to depressed patients without melancholic features. Therefore, the first objective of this study was to determine whether the presence of melancholic vs. non-melancholic features at baseline was associated with specific demographic and clinical course characteristics in Han Chinese inpatients with MDD. The second objective was to explore whether there were differences in treatment outcome between patient with melancholic and non-melancholic depression when treated with fixed-dose fluoxetine.
2. Methods 2.1. Subjects This study was a post-hoc analysis of our previous study on treatment response to fixed-dose fluoxetine in inpatients with MDD. Subjects were recruited from Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan. Participants were considered eligible if they met the following criteria: newly hospitalized for treatment of MDD (diagnosed by using the Structured Clinical Interview for DSM-IV (SCID) (APA, 1994a)); scored at least 18 on the 17-item Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960) and at least 4 on the Clinical Global Impression of Severity (CGI-S) (Guy, 1976); age between 18 and 70 years old; physically healthy (physical examination, neurological examination, and past history) with all laboratory parameters within normal limits (blood routine, urine routine, electrolytes, liver function, renal function, lipid profiles, thyroid function, chest x-ray, electroencephalograph, and electrocardiography); and hospitalized for the entire study. Subjects were excluded on the following criteria: psychotic depression; bipolar I or II disorder; schizophrenia or any other psychotic disorder; any co-morbid diagnosis of substance abuse or dependence (including alcohol) within the past 6 months; pregnancy or lactation; mental disorders due to organic factors; severe cognitive impairment; initiating or ending formal psychotherapy within 6 weeks prior to enrollment; receiving formal psychotherapy during the trial period; treatment-resistant depression (defined as a lack of response to 2 or more adequate courses of antidepressant treatment); a history of poor response to fluoxetine (20 mg/day for Z4 weeks) or intolerance to fluoxetine; and a history of ECT. The study protocol was approved by Kai-Syuan Psychiatric Hospital's institutional review board and conducted in accordance with Good Clinical Practice procedures and the current revision of the Declaration of Helsinki. Written informed consent was obtained from the participants after a full explanation of the study's goals and procedures. This study was registered on Clinicaltrials. gov (Identifier number: NCT01075529). 2.2. Procedures and assessments After a washout period of at least 72 h, patients received openlabel fluoxetine treatment at a fixed dose of 20 mg daily (Beasley et al., 2000) for 6 weeks. During the course of treatment, anxiolytic and/or sedative-hypnotic medications can be used for brief periods (i.e., at most 2 weeks), based on psychiatrists' judgment. No other psychotropic agents were allowed at bedtime for insomnia. Drug adherence was monitored and ensured by psychiatric nurses. Patients were first classified as melancholic or non-melancholic, according to the presence of prominent melancholic features as defined by DSM-IV criteria. The severity of overall
depressive symptoms was assessed at baseline, weeks 1, 2, 3, 4 and 6 by board-certified psychiatrists using the HAMD-17 (scores ranged from 0 to 52) and CGI-S. The intra-class correlation coefficient (ICC) of reliability was 0.95 between the raters. The adverse events were assessed by the Utvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) (Lingjaerde et al., 1987), with scores ranging from 0 (none) to 3 (severe), at baseline and at weeks 1, 2, 3, 4, and 6. A score of 1, 2, or 3 on any UKU item that first occurred or worsened during treatment was defined as an adverse event (Daly et al., 2011). 2.3. Statistical analysis In the first step, patients with melancholic depression and nonmelancholic depression at baseline were compared in terms of sex, marital status, age, age at onset, number of previous episodes, educational level (years), baseline HAMD-17 score, and baseline CGI-S score. Age at onset was defined as age at the first major depressive episode. Pearson χ2 test or Fisher's exact test was used to compare categorical variables and independent t-test was used for continuous variables. In the second step, generalized estimating equations (GEE) method with the first-order autoregressive working correlation structure (Zeger and Liang, 1986) was applied to explore the differences in HAMD-17 and CGI-S scores between groups at weeks 1, 2, 3, 4, and 6 via the group (i.e., melancholic vs. non-melancholic) time interaction analysis with adjustment for sex, age, age at onset, and the severity of baseline depression (i.e., HAMD17 or CGI-S scores at week 0). To reflect the degree of clinical changes, in addition to the absolute changes in HAMD-17 and CGIS scores, clinical response was defined as a reduction of HAMD-17 scores larger than 50% from baseline to the endpoint. Statistical significance was defined as a p-value o 0.05. All data were processed by SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
3. Results 3.1. Characteristics of subjects A total of 131 acutely ill inpatients with MDD agreed to participate in this 6-week fluoxetine trial. Details of the patient sample have been described elsewhere (Lin et al., 2011). Of the 131 participants, 126 (96.2%) had at least one post-baseline assessment and were included in the final analyses. Of these 126 patients, 30 (23.8%) were male and 96 (76.2%) were female, mean age was 45.37 11.0 years, and mean age at onset was 38.9 711.8 years. The mean HAMD-17 score of 31.3 76.5 at baseline reflected a fairly severely depressed population (Table 1). Overall, 96 (76.2%) participants met the criteria of melancholia subtype as defined by DSM-V. The melancholic and non-melancholic groups differed significantly in terms of age, age at onset, baseline HAMD-17, and baseline CGI-S score, whereas there were no statistically significant differences in sex, marital status, number of previous episodes, and educational level between the 2 groups (Table 1). Table 2 shows the anxiolytic/sedative-hypnotic medications use during the clinical trial period. During this period, 89.7% (113/126) of patients exposed to anxiolytic/sedative-hypnotic medications. 3.2. Treatment outcomes between the 2 groups The melancholic group had significantly higher clinical response rate (61.5%) than the non-melancholic group (36.7%) (p ¼0.017) at the end of the study.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Table 1 Comparison of baseline demographic and clinical characteristics with MDD patients with and without melancholic features. Variables
Sex Male Female Married Yes No
Age Age at onset Number of previous episodes Educational level (yrs) Baseline HAMD-17d score Baseline CGI-Se score
Melancholic (n ¼ 96)
Total (n¼ 126)
Non-melancholic (n¼ 30)
Analysis
n
%
n
%
n
%
p
30 96
23.8 76.2
27 69
28.1 71.9
3 27
10.0 90.0
0.05a
64 62
50.8 49.2
53 43
55.2 44.8
11 19
36.7 63.3
Mean
SD
Mean
SD
Mean
SD
p
45.3 38.9 2.4 11.0 31.3 6.2
11.0 11.8 1.9 3.6 6.5 0.7
47.0 41.0 2.4 11.2 32.0 6.3
10.4 11.3 2.0 3.6 6.7 0.7
39.8 32.3 2.6 10.3 29.2 6.0
11.1 11.2 1.7 3.5 5.7 0.7
0.001c o 0.001c 0.56c 0.23c 0.04c 0.03c
0.08b
Bold, statistically significant. a
Fisher's exact test. Pearson's χ2 test. c Independent t-test. d HAMD-17¼ 17-item Hamilton Rating Scale for Depression. e CGI-S ¼ Clinical Global Impression of Severity. b
Table 2 The anxiolytic/sedative-hypnotic medications use during the clinical trial period. Anxiolytics/sedative-hypnotics medications
Case number
bromazepam brotizolam clonazepam estazolam flurazepam lorazepam
2 25 16 54 15 1
The results of the GEE analyses of the HAMD-17 and CGI-S scores across time indicated that symptom severity significantly declined with time after fluoxetine treatment for both melancholic and nonmelancholic groups (Table 3). Notably, the melancholic group experienced a significantly greater reduction in HAMD-17 scores than the non-melancholic group, which started at weeks 2 (estimate¼ 3.70, p¼ 0.014), and persisted through week 3 (estimate¼ 4.12, p¼0.013), 4 (estimate¼ 5.33, po0.001), and 6 (estimate¼ 6.00, po0.001). Similarly, the decrease in CGI-S score was more significant in patients with melancholia than that in those with non-melancholia at weeks 2 (estimate¼ 0.40, p¼0.042), 3 (estimate¼ 0.55, p¼0.009), 4 (estimate¼ 0.68, p¼0.004), and 6 (estimate¼0.25, p¼0.010). The differences in the trend of symptom change (HAMD-17 scores) were illustrated in Fig. 1. There was no significant difference (p ¼0.33) in the number of adverse events reported during the trial period between the melancholic group (4.0 72.8) and non-melancholic group (4.77 4.9) (data not shown in the Table).
4. Discussion In the current 6-week fixed-dose fluoxetine treatment trial not sponsored by pharmaceutical company, acutely ill, severely depressed patients with MDD were repeatedly assessed for clinical symptoms of depression. The medical adherence was ensured and the care followed a standardized protocol in a controlled therapeutic milieu. The outcomes were analyzed as intra-subject changes across multiple time points with adjustment for within-
subject dependence effects by using GEE (Melander et al., 2003). The results indicated that MDD patients with melancholic features did show distinct clinical characteristics and treatment response, compared with those without melancholic features. These also extended the findings that melancholia is a separate depressive sub-type and warrants the prioritizing of antidepressant medication from western groups (Peselow et al., 1992; Fink et al., 2007a; Parker, 2007) to Han Chinese group. In this current study, the percentage of patients with melancholic features was relatively high (76.2%), comparable to those reported in inpatient (76.0%) (Stage et al., 1998), outpatient (67.1%) (Mallinckrodt et al., 2005) and mixed in- and out-patient settings (81.5%) (Sun et al., 2012). This is no surprise as melancholic features were reported in 20–80% of patients with MDD (Taylor and Fink, 2006) and melancholic depression is considered a more severe form of MDD (McGrath et al., 2008b); hospitalization is only warranted in patients with severe symptoms, as reflected in the higher baseline HAMD-17 and CGI-S scores in patients with melancholic features than those non-melancholic patients. Overall, the findings supported the notion that the DSM-IV definition of MDD with melancholic features is associated with higher baseline scores on depression rating scales and describes a more severe form of depression (McGrath et al., 2008b). In the current study, patients with melancholic features were more likely to be older, with a later age at onset of depression and more severe depressive symptoms at baseline, compared to patients with non-melancholic features. Importantly, patients with melancholic features had early treatment response and better treatment outcome after fixed-dose fluoxetine treatment at 6 weeks as measured by either HAMD-17 or CGI-S. Such findings replicate previous findings that melancholic depression is associated with older age (Zimmerman et al., 1989; Parker et al., 1998; Hyett et al., 2008), later age at onset (Parker et al., 2001a; Hyett et al., 2008), greater severity of illness at baseline (Zimmerman et al., 1986; Rush and Weissenburger, 1994; Parker et al., 1996, 2001a; Brodaty et al., 1997; Taylor and Fink, 2006; Hyett et al., 2008), and better response to pharmacotherapy (Zimmerman et al., 1989), hence supporting melancholic depression as a clinical subtype with distinct neurobiological underpinnings from nonmelancholic depression (Joyce et al., 2002). The age at onset of
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
Table 3 GEE analysis of HAMD-17 and CGI-S between melancholic and non-melancholic groups at each visit.a Scale HAMD-17 Week 0 Week 1 Week 2 Week 3 Week 4 Week 6 Group Time group Week 1 group Week 2 group Week 3 group Week 4 group Week 6 group CGI-S Week 0 Week 1 Week 2 Week 3 Week 4 Week 6 Group Time group Week 1 group Week 2 group Week 3 group Week 4 group Week 6 group
Melancholic Mean 7 SD (n)
Nonmelancholic Mean 7 SD (n)
32.0 76.7 21.7 7 8.1 17.6 7 8.1 16.2 78.4 14.6 78.2 13.1 78.0
29.2 75.7 20.2 78.4 18.7 78.3 17.4 79.7 17.5 78.9 16.2 78.8
6.3 70.7 5.3 7 1.0 4.6 7 1.3 4.17 1.3 3.9 7 1.3 3.5 7 1.4
(96) (96) (93) (92) (92) (91)
(96) (96) (93) (92) (92) (91)
6.0 70.7 5.17 1.1 4.7 7 1.2 4.3 7 1.1 4.2 7 1.1 3.8 7 1.1
(30) (30) (27) (25) (24) (21)
(30) (30) (27) (25) (24) (21)
Estimate
Standard error
p
9.07 10.71 11.6 12.0 13.07 0.87
1.18 1.28 1.46 1.22 0.99 0.48
o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.07
1.20 3.70 4.12 5.33 6.00
1.40 1.50 1.67 1.50 1.34
0.39 0.01 0.01 o 0.001 o 0.001
0.93 1.30 1.56 1.73 2.13 0.08
0.14 0.16 0.18 0.20 0.20 0.07
o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.23
0.09 0.40 0.55 0.68 0.63
0.17 0.20 0.21 0.23 0.25
0.59 0.04 0.01 0.004 0.01
Bold, statistically significant. a
Group¼ melancholic vs. non-melancholic.
Fig. 1. The HAMD-17 scores in the melancholic and non-melancholic groups at each visit.
major depressive episode in melancholic group in current study (41.0 yrs) approached to those in the studies by Parker et al. (1994) (38 yrs) and by Gili et al. (2012) (39.9 yrs), and was older than that in general population (30.4 yr) (Hasin et al., 2005). Aging has been proposed to be a significant factor affecting the presence of melancholic features in depression (Thase and Friedman, 1999). The ratio of melancholic depression vs. non-melancholic depression has been demonstrated to increase with age, presumably reflecting the older age at onset of melancholic depression (Parker et al., 1996). Also, disturbance in psychomotor activity, a core melancholic feature, becomes more apparent in those with melancholic depression as they become older, which might reflect the progressive decrease with age in the levels of neurotransmitters considered significant in the pathophysiology of
depression (Leventhal and Rehm, 2005). Indeed, some of these characteristics (e.g., apathy, lethargy and cognitive slowing) are closely associated with melancholic depression and older age and later onset depression has been demonstrated to be related to different neurobiological and risk factors than early onset depression (Amsterdam, 1998). In the current study, the results of GEE analysis indicated that melancholic depression showed greater improvement in HAMD17 or CGI-S scores than non-melancholic depression, beginning at the 2nd week of fluoxetine treatment. Furthermore, the strictly defined clinical response rate (a reduction of 50% or more of the HAMD-17 score from baseline to endpoint) was significantly higher in the melancholic group (61.5%) than in the non-melancholic group (36.7%) (p ¼0.017). Although, without a placebocontrolled group, the impacts of placebo effects in current study could not be estimated, the differences in the degree of symptom improvement and clinical response rate are not likely solely attributable to placebo effects for the following reasons: first, the response rate in the melancholic group (61.5%) is too high to be accountable by the typical placebo effects, i.e., around 30%, as estimated from past clinical placebo-controlled antidepressant trials (Walsh et al., 2002); second, it has been demonstrated that patients with more severe depression are less subject to placebo effect (Khan et al., 2002)—the differences in clinical response would have been larger if placebo effects were taken into account. Hospitalization itself can be a significant non-pharmacological therapeutic factor contributing to clinical improvement in MDD, with differential impacts on antidepressant treatment response in melancholic vs. non-melancholic depressions in current study. In previous placebo-controlled antidepressant trials, the magnitude of the drug-placebo difference was smaller when less severe cases were included, indicating more significant placebo effects. In contrast, studies using stricter criteria and more severe patients could better reflect the genuine drug-placebo difference by reducing placebo effects (Khan and Schwartz, 2005; Khan and Brown,
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2015). In current study, both melancholic and non-melancholic groups were severely depressed and were comparable in terms of severity of depressive symptoms; it is unlikely that discrepant clinical severity resulted in discrepant impact of hospitalization as a non-pharmacological therapeutic factor on clinical response. Furthermore, since melancholia is considered to have distinct biological underpinnings (Parker and Paterson, 2014), its clinical response to antidepressant is less likely a result of non-pharmacological interventions. In this regard, if hospitalization, as a nonpharmacological therapeutic factor, is at work in current study, it will be more manifest in the non-melancholic group, resulting in underestimation of the real differences in antidepressant response between the two groups in current study. Overall, although the impact of hospitalization is difficult to estimate, it is reasonable to assume that between-group difference in clinical response in current study was not significantly biased due to the differential impacts of hospitalization. The treatment outcome in the current melancholic group is noteworthy, considering the low dosage of fluoxetine treatment, the fast onset of clinical response and the high treatment response rate. In this sense, melancholic features are important prognostic signs that warrant careful clinical attention in predicting the antidepressant treatment outcome. As mentioned above, inconsistent treatment outcomes of melancholic depression with fluoxetine or other SSRIs, compared with non-melancholic depression, may come from different diagnostic criteria (Duggan et al., 1991; Parker et al., 1999, 2001b; Joyce et al., 2002) and variability in trial duration, outcome measures (e.g., patients' judgments, clinician-rating scales, or self-reporting questionnaires) (Parker et al., 1999; Leventhal and Rehm, 2005), methodology (e.g., retrospective or prospective study), race/ethnicity (Xiang et al., 2012) and treatment setting (e.g., inpatient or outpatient) (Joyce et al., 2002). Due to the limitation in study design, how these methodological issues affected the current outcome could not be addressed. Nevertheless, in the real life clinical practice scenario, the outcome of melancholic depression is can be better, as higher dosage of antidepressant and longer observation period are allowed. Some limitations in this study are worth noting. First, use of a single site with a relatively small sample size, especially the small numbers in the non-melancholic group (n¼ 30), limited the generalizability of our results. Second, the study period of 6 weeks is relatively short when considering the total duration of depression. However, it is relatively long and sufficient for inpatient trials to detect initial antidepressant responses. Long-term follow-up after hospitalization would allow further elucidation whether the differences persist beyond the study period. Third, as an open-label study, the clinical ratings might be biased and await future doubleblind study to confirm the findings. Moreover, without a control group, the differential placebo effects on the two groups could not be determined. However, as the setting and treatment protocol are more close to everyday clinical practice setting (Nierenberg et al., 1995), and as such, the results may be more generalizable to clinical settings. Fourth, this post-hoc analysis was not designed, a priori, to compare melancholic depression with non-melancholic depression. This could have reduced the power to detect some clinical differences between the 2 groups (Fink et al., 2007b). Fifth, anxiolytic/sedative-hypnotic medications may lower the HAMD-17 score during the trial period, often resulting in an improvement. Thus, some initial improvement may be due to the sedating effects of anxiolytics/hypnotics rather than to the antidepressants (Roose and Nobler, 2001). However, no significant difference (p ¼ 0.95) in the rates of anxiolytics/hypnotics use existed between melancholic group (86/96 ¼89.6%) and non-melancholic group (27/30 ¼90.0%). The impact on outcome between two groups should be comparable. Finally, only a single antidepressant agent (i.e., fluoxetine)
5
was used; therefore, it is unclear whether the finding can be generalized to other antidepressants. In conclusion, the findings from current study indicated that melancholic features in patients with MDD were associated with specific demographic, disease course indices and differential treatment responses, supporting the concept of melancholic depression as a subtype of MDD. Future research strategies to substantiate such findings include randomized, placebo-controlled trials involving other antidepressants, larger inpatient or outpatient groups from multi-centers, and extension of study duration beyond 6 weeks to ascertain longer term treatment responses.
Acknowledgments This study was funded by the Kai-Syuan Psychiatric Hospital (KSPH-2007-16) and the Ministry of Science and Technology, Taiwan (MOST-103-2314-B-280-001-MY3). All authors declare that they have no conflicts of interest. The authors thank Professor YueCune Chang for the contribution of GEE model.
References Amsterdam, J.D., 1998. Selective serotonin reuptake inhibitor efficacy in severe and melancholic depression. J. Psychopharmacol. Suppl. 12, S99–S111. APA, 1994a. American Psychiatric Association: Structured Clinical Interview for DSM-IV. American Psychiatric Press, Washington, DC. APA, 1994b. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th ed. American Psychiatric Association, Washington, D.C.. APA, 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Fifth ed. Beasley Jr., C.M., Nilsson, M.E., Koke, S.C., Gonzales, J.S., 2000. Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose. J. Clin. Psychiatry 61, 722–728. Brodaty, H., Luscombe, G., Parker, G., Wilhelm, K., Hickie, I., Austin, M.P., Mitchell, P., 1997. Increased rate of psychosis and psychomotor change in depression with age. Psychol. Med. 27, 1205–1213. Daly, E.J., Trivedi, M.H., Fava, M., Shelton, R., Wisniewski, S.R., Morris, D.W., Stegman, D., Preskorn, S.H., Rush, A.J., 2011. The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study. J. Clin. Psychopharmacol. 31, 31–38. Duggan, C.F., Lee, A.S., Murray, R.M., 1991. Do different subtypes of hospitalized depressives have different long-term outcomes? Arch. Gen. Psychiatry 48, 308–312. Fink, M., Bolwig, T.G., Parker, G., Shorter, E., 2007a. Melancholia: restoration in psychiatric classification recommended. Acta Psychiatr. Scand. 115, 89–92. Fink, M., Rush, A.J., Knapp, R., Rasmussen, K., Mueller, M., Rummans, T.A., O'Connor, K., Husain, M., Biggs, M., Bailine, S., Kellner, C.H., Consortium for Research in, E. C.T.S.G., 2007b. DSM melancholic features are unreliable predictors of ECT response: a CORE publication. J. ECT 23, 139–146. Gili, M., Roca, M., Armengol, S., Asensio, D., Garcia-Campayo, J., Parker, G., 2012. Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions. PloS One 7, e48200. Guelfi, J.D., White, C., Hackett, D., Guichoux, J.Y., Magni, G., 1995. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J. Clin. Psychiatry 56, 450–458. Guy, W., 1976. ECDEU Assessment manual for psychopharmacology. DHEW Publication 76338, Washington DC. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Hasin, D.S., Goodwin, R.D., Stinson, F.S., Grant, B.F., 2005. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch. Gen. Psychiatry 62, 1097–1106. Heiligenstein, J.H., Tollefson, G.D., Faries, D.E., 1994. Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo. J. Affect. Disord. 30, 163–173. Hyett, M.P., Parker, G.B., Proudfoot, J., Fletcher, K., 2008. Examining age effects on prototypic melancholic symptoms as a strategy for refining definition of melancholia. J. Affect. Disord. 109, 193–197. Joyce, P.R., Mulder, R.T., Luty, S.E., McKenzie, J.M., Sullivan, P.F., Abbott, R.M., Stevens, I.F., 2002. Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response. Aust. N. Z. J. Psychiatry 36, 376–383. Khan, A., Brown, W.A., 2015. Antidepressants versus placebo in major depression: an overview. World Psychiatry 14, 294–300. Khan, A., Leventhal, R.M., Khan, S.R., Brown, W.A., 2002. Severity of depression and
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
6
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J. Clin. Psychopharmacol. 22, 40–45. Khan, A., Schwartz, K., 2005. Study designs and outcomes in antidepressant clinical trials. Essent. Psychopharmacol. 6, 221–226. Leventhal, A.M., Rehm, L.P., 2005. The empirical status of melancholia: implications for psychology. Clin. Psychol. Rev. 25, 25–44. Lin, C.H., Lane, H.Y., Chen, C.C., Juo, S.H., Yen, C.F., 2011. Early prediction of fluoxetine response for Han Chinese inpatients with major depressive disorder. J. Clin. Psychopharmacol. 31, 187–193. Lingjaerde, O., Ahlfors, U.G., Bech, P., Dencker, S.J., Elgen, K., 1987. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr. Scand. Suppl. 334, S1–S100. Mallinckrodt, C.H., Watkin, J.G., Liu, C., Wohlreich, M.M., Raskin, J., 2005. Duloxetine in the treatment of Major Depressive Disorder: a comparison of efficacy in patients with and without melancholic features. BMC Psychiatry 5, 1. McGrath, P.J., Khan, A.Y., Trivedi, M.H., Stewart, J.W., Morris, D.W., Wisniewski, S.R., Miyahara, S., Nierenberg, A.A., Fava, M., Rush, A.J., 2008a. Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. J. Clin. Psychiatry 69, 1847–1855. McGrath, P.J., Khan, A.Y., Trivedi, M.H., Stewart, J.W., Morris, D.W., Wisniewski, S.R., Miyahara, S., Nierenberg, A.A., Fava, M., Rush, A.J., 2008b. Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. J. Clin Psychiatry 69, 1847–1855. Melander, H., Ahlqvist-Rastad, J., Meijer, G., Beermann, B., 2003. Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 326, 1171–1173. Nierenberg, A.A., McLean, N.E., Alpert, J.E., Worthington, J.J., Rosenbaum, J.F., Fava, M., 1995. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am. J. Psychiatry 152, 1500–1503. Parker, G., 2007. Defining melancholia: the primacy of psychomotor disturbance. Acta Psychiatr. Scand. Suppl., 21–30. Parker, G., Fink, M., Shorter, E., Taylor, M.A., Akiskal, H., Berrios, G., Bolwig, T., Brown, W.A., Carroll, B., Healy, D., Klein, D.F., Koukopoulos, A., Michels, R., Paris, J., Rubin, R.T., Spitzer, R., Swartz, C., 2010. Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am. J. Psychiatry 167, 745–747. Parker, G., Hadzi-Pavlovic, D., Brodaty, H., Boyce, P., Mitchell, P., Wilhelm, K., Hickie, I., 1992. Predicting the course of melancholic and nonmelancholic depression. A naturalistic comparison study. J. Nerv. Ment. Dis. 180, 693–702. Parker, G., Hadzi-Pavlovic, D., Eyers, K., 1996. Melancholia: a disorder of movement and mood: a phenomenological and neurobiological review. Cambridge University Press, Cambridge. Parker, G., Hadzi-Pavlovic, D., Wilhelm, K., Hickie, I., Brodaty, H., Boyce, P., Mitchell, P., Eyers, K., 1994. Defining melancholia: properties of a refined sign-based measure. Br. J. Psychiatry 164, 316–326. Parker, G., Mitchell, P., Wilhelm, K., Menkes, D., Snowdon, J., Schweitzer, I., Grounds, D., Skerritt, P., Roy, K., Hadzi-Pavlovic, D., 1999. Are the newer antidepressant drugs as effective as established physical treatments? Results from an Australasian clinical panel review. Aust. N. Z. J. Psychiatry 33, 874–881. Parker, G., Paterson, A., 2014. Melancholia: definition and management. Curr. Opin. Psychiatry 27, 1–6. Parker, G., Roussos, J., Austin, M.P., Hadzi-Pavlovic, D., Wilhelm, K., Mitchell, P., 1998. Disordered personality style: higher rates in non-melancholic compared
to melancholic depression. J. Affect. Disord. 47, 131–140. Parker, G., Roy, K., Hadzi-Pavlovic, D., Wilhelm, K., Mitchell, P., 2001a. The differential impact of age on the phenomenology of melancholia. Psychol. Med. 31, 1231–1236. Parker, G., Roy, K., Wilhelm, K., Mitchell, P., 2001b. Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J. Clin. Psychiatry 62, 117–125. Perry, P.J., 1996. Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J. Affect. Disord. 39, 1–6. Peselow, E.D., Sanfilipo, M.P., Difiglia, C., Fieve, R.R., 1992. Melancholic/endogenous depression and response to somatic treatment and placebo. Am. J. Psychiatry 149, 1324–1334. Roose, S.P., Nobler, M., 2001. ECT and onset of action. J. Clin. Psychiatry 62 (Suppl 4), S24–S26. Rush, A.J., Weissenburger, J.E., 1994. Melancholic symptom features and DSM-IV. Am. J. Psychiatry 151, 489–498. Shorter, E., 2007. The doctrine of the two depressions in historical perspective. Acta Psychiatr. Scand. Suppl., 5–13. Stage, K.B., Bech, P., Gram, L.F., Kragh-Sorensen, P., Rosenberg, C., Ohrberg, S., 1998. Are in-patient depressives more often of the melancholic subtype? Danish University Antidepressant Group. Acta Psychiatr. Scand. 98, 432–436. Sun, N., Li, Y., Cai, Y., Chen, J., Shen, Y., Sun, J., Zhang, Z., Zhang, J., Wang, L., Guo, L., Yang, L., Qiang, L., Yang, Y., Wang, G., Du, B., Xia, J., Rong, H., Gan, Z., Hu, B., Pan, J., Li, C., Sun, S., Han, W., Xiao, X., Dai, L., Jin, G., Zhang, Y., Sun, L., Chen, Y., Zhao, H., Dang, Y., Shi, S., Kendler, K.S., Flint, J., Zhang, K., 2012. A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women. Depress. Anxiety 29, 4–9. Taylor, M.A., Fink, M., 2006. Melancholia: the Diagnosis, Pathophysiology, and Treatment of Depressive Illness. Cambridge University Press, Cambridge. Thase, M.E., Friedman, E.S., 1999. Is psychotherapy an effective treatment for melancholia and other severe depressive states? J. Affect. Disord. 54, 1–19. Uher, R., Dernovsek, M.Z., Mors, O., Hauser, J., Souery, D., Zobel, A., Maier, W., Henigsberg, N., Kalember, P., Rietschel, M., Placentino, A., Mendlewicz, J., Aitchison, K.J., McGuffin, P., Farmer, A., 2011. Melancholic, atypical and anxious depression subtypes and outcome of treatment with escitalopram and nortriptyline. J. Affect. Disord. 132, 112–120. Walsh, B.T., Seidman, S.N., Sysko, R., Gould, M., 2002. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287, 1840–1847. Xiang, Y.T., Wang, G., Hu, C., Guo, T., Ungvari, G.S., Kilbourne, A.M., Lai, K.Y., Si, T.M., Zheng, Q.W., Chen, D.F., Fang, Y.R., Lu, Z., Yang, H.C., Hu, J., Chen, Z.Y., Huang, Y., Sun, J., Wang, X.P., Li, H.C., Zhang, J.B., Chiu, H.F., 2012. Demographic and clinical features and prescribing patterns of psychotropic medications in patients with the melancholic subtype of major depressive disorder in China. PloS One 7, e39840. Zeger, S.L., Liang, K.Y., 1986. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121–130. Zimmerman, M., Black, D.W., Coryell, W., 1989. Diagnostic criteria for melancholia. The comparative validity of DSM-III and DSM-III-R. Arch. Gen. Psychiatry 46, 361–368. Zimmerman, M., Coryell, W., Pfohl, B., Stangl, D., 1986. The validity of four definitions of endogenous depression. II. Clinical, demographic, familial, and psychosocial correlates. Arch. Gen. Psychiatry 43, 234–244.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes Ching-Hua Lin a,b, Chun-Jen Huang b,c, Shi-Kai Liu d,e,n a
Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan Department of Psychiatry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Psychiatry, Kaohsiung Medical University Hospital, Taiwan d Centre for Addiction and Mental Health, Toronto, ON, Canada e Department of Psychiatry, University of Toronto, Toronto, ON, Canada b
art ic l e i nf o
a b s t r a c t
Article history: Received 19 July 2015 Received in revised form 1 November 2015 Accepted 7 November 2015
To determine whether the presence of melancholic features in hospitalized patients with major depressive disorder (MDD) was associated with specific clinical characteristics and treatment outcomes, supporting melancholic depression as a distinct subtype within MDD. 126 acutely ill inpatients with MDD were enrolled in an open, 6-week trial with fixed-dose fluoxetine 20 mg daily. Symptom severity was assessed regularly, using the 17-item Hamilton Depression Rating Scale (HAMD-17) and Clinical Global Impression of Severity (CGI-S). Melancholic features were defined according to the DSM-IV criteria. Clinical variables were compared between patients with and without melancholic features. Generalized estimating equations method was used to explore the differences in HAMD-17 and CGI-S scores between the 2 groups over time. Clinical response was defined as having a 50% or greater reduction in HAMD-17 scores. 96 (76.2%) of the 126 patients with at least one post-baseline assessment met the criteria for melancholic depression. Melancholic depression differed from non-melancholic depression in clinical characteristics and predicted a better response to fluoxetine treatment. The differentiation between melancholic and non-melancholic depression within MDD hence is clinically significant and valid. & 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Melancholic Fluoxetine Major depressive disorder Generalized estimating equations
1. Introduction Major depressive disorder (MDD) is a heterogeneous condition. Identifying subtypes of MDD with differential responses to treatments would be clinically valuable for personalized treatment (Uher et al., 2011). Melancholic depression has been proposed as a clinical subtype of MDD with non-reactivity of mood and/or observable psychomotor disturbance as its core features (Parker et al., 1994). According to either DSM-IV (APA, 1994b) or DSM-5 (APA, 2013) criteria, the principal diagnostic feature is a loss of pleasure in all, or almost all, activities or a lack of reactivity to usually pleasurable stimuli. Additional symptoms include distinct quality of depressed mood, a depressed mood that is worse in the morning, early-morning awakening, marked psychomotor agitation or retardation, excessive guilt, and significant anorexia or weight loss. n Corresponding author at: Department of Psychiatry, University of Toronto, 1001 Queen Street West, Toronto, ON, Canada, M6J 1H4. E-mail address: [email protected] (S.-K. Liu).
Melancholic depression is commonly observed in severely ill patients with MDD (Parker et al., 2010) and a high percentage of inpatients with MDD present with symptoms of melancholia (Guelfi et al., 1995). Compared to non-melancholic depression, melancholic depression has been demonstrated to respond poorly to placebos, psychotherapies and social interventions (Parker, 2007), hence is considered to be more “biologically rooted” and responds well to “biological” treatments such as antidepressants and electroconvulsive therapy (ECT) (Peselow et al., 1992; Perry, 1996; Parker, 2007). Furthermore, patients with melancholic depression may respond to treatment more rapidly than those without (Parker et al., 1992). Such distinctive psychopathology, biological underpinning and treatment outcome seems to differentiate melancholic depression from non-melancholic depression (Shorter, 2007) and provide the basis of new diagnostic criteria for melancholia as a distinct disease entity (Fink et al., 2007a; Parker, 2007). Past treatment outcomes of melancholic depression with fluoxetine or other selective serotonin reuptake inhibitors (SSRIs), compared with non-melancholic depression, have been variable: either better (Heiligenstein et al., 1994), comparable (Joyce et al.,
http://dx.doi.org/10.1016/j.psychres.2015.11.009 0165-1781/& 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
2002; Mallinckrodt et al., 2005) or poorer (Parker et al., 1999; McGrath et al., 2008a; Gili et al., 2012). In the present study, we intended to test the hypothesis that, as defined by distinct clinical features, melancholic depression can be externally validated by differences in demographic characteristics, clinical course and antidepressant treatment responses, compared to depressed patients without melancholic features. Therefore, the first objective of this study was to determine whether the presence of melancholic vs. non-melancholic features at baseline was associated with specific demographic and clinical course characteristics in Han Chinese inpatients with MDD. The second objective was to explore whether there were differences in treatment outcome between patient with melancholic and non-melancholic depression when treated with fixed-dose fluoxetine.
2. Methods 2.1. Subjects This study was a post-hoc analysis of our previous study on treatment response to fixed-dose fluoxetine in inpatients with MDD. Subjects were recruited from Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan. Participants were considered eligible if they met the following criteria: newly hospitalized for treatment of MDD (diagnosed by using the Structured Clinical Interview for DSM-IV (SCID) (APA, 1994a)); scored at least 18 on the 17-item Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960) and at least 4 on the Clinical Global Impression of Severity (CGI-S) (Guy, 1976); age between 18 and 70 years old; physically healthy (physical examination, neurological examination, and past history) with all laboratory parameters within normal limits (blood routine, urine routine, electrolytes, liver function, renal function, lipid profiles, thyroid function, chest x-ray, electroencephalograph, and electrocardiography); and hospitalized for the entire study. Subjects were excluded on the following criteria: psychotic depression; bipolar I or II disorder; schizophrenia or any other psychotic disorder; any co-morbid diagnosis of substance abuse or dependence (including alcohol) within the past 6 months; pregnancy or lactation; mental disorders due to organic factors; severe cognitive impairment; initiating or ending formal psychotherapy within 6 weeks prior to enrollment; receiving formal psychotherapy during the trial period; treatment-resistant depression (defined as a lack of response to 2 or more adequate courses of antidepressant treatment); a history of poor response to fluoxetine (20 mg/day for Z4 weeks) or intolerance to fluoxetine; and a history of ECT. The study protocol was approved by Kai-Syuan Psychiatric Hospital's institutional review board and conducted in accordance with Good Clinical Practice procedures and the current revision of the Declaration of Helsinki. Written informed consent was obtained from the participants after a full explanation of the study's goals and procedures. This study was registered on Clinicaltrials. gov (Identifier number: NCT01075529). 2.2. Procedures and assessments After a washout period of at least 72 h, patients received openlabel fluoxetine treatment at a fixed dose of 20 mg daily (Beasley et al., 2000) for 6 weeks. During the course of treatment, anxiolytic and/or sedative-hypnotic medications can be used for brief periods (i.e., at most 2 weeks), based on psychiatrists' judgment. No other psychotropic agents were allowed at bedtime for insomnia. Drug adherence was monitored and ensured by psychiatric nurses. Patients were first classified as melancholic or non-melancholic, according to the presence of prominent melancholic features as defined by DSM-IV criteria. The severity of overall
depressive symptoms was assessed at baseline, weeks 1, 2, 3, 4 and 6 by board-certified psychiatrists using the HAMD-17 (scores ranged from 0 to 52) and CGI-S. The intra-class correlation coefficient (ICC) of reliability was 0.95 between the raters. The adverse events were assessed by the Utvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) (Lingjaerde et al., 1987), with scores ranging from 0 (none) to 3 (severe), at baseline and at weeks 1, 2, 3, 4, and 6. A score of 1, 2, or 3 on any UKU item that first occurred or worsened during treatment was defined as an adverse event (Daly et al., 2011). 2.3. Statistical analysis In the first step, patients with melancholic depression and nonmelancholic depression at baseline were compared in terms of sex, marital status, age, age at onset, number of previous episodes, educational level (years), baseline HAMD-17 score, and baseline CGI-S score. Age at onset was defined as age at the first major depressive episode. Pearson χ2 test or Fisher's exact test was used to compare categorical variables and independent t-test was used for continuous variables. In the second step, generalized estimating equations (GEE) method with the first-order autoregressive working correlation structure (Zeger and Liang, 1986) was applied to explore the differences in HAMD-17 and CGI-S scores between groups at weeks 1, 2, 3, 4, and 6 via the group (i.e., melancholic vs. non-melancholic) time interaction analysis with adjustment for sex, age, age at onset, and the severity of baseline depression (i.e., HAMD17 or CGI-S scores at week 0). To reflect the degree of clinical changes, in addition to the absolute changes in HAMD-17 and CGIS scores, clinical response was defined as a reduction of HAMD-17 scores larger than 50% from baseline to the endpoint. Statistical significance was defined as a p-value o 0.05. All data were processed by SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).
3. Results 3.1. Characteristics of subjects A total of 131 acutely ill inpatients with MDD agreed to participate in this 6-week fluoxetine trial. Details of the patient sample have been described elsewhere (Lin et al., 2011). Of the 131 participants, 126 (96.2%) had at least one post-baseline assessment and were included in the final analyses. Of these 126 patients, 30 (23.8%) were male and 96 (76.2%) were female, mean age was 45.37 11.0 years, and mean age at onset was 38.9 711.8 years. The mean HAMD-17 score of 31.3 76.5 at baseline reflected a fairly severely depressed population (Table 1). Overall, 96 (76.2%) participants met the criteria of melancholia subtype as defined by DSM-V. The melancholic and non-melancholic groups differed significantly in terms of age, age at onset, baseline HAMD-17, and baseline CGI-S score, whereas there were no statistically significant differences in sex, marital status, number of previous episodes, and educational level between the 2 groups (Table 1). Table 2 shows the anxiolytic/sedative-hypnotic medications use during the clinical trial period. During this period, 89.7% (113/126) of patients exposed to anxiolytic/sedative-hypnotic medications. 3.2. Treatment outcomes between the 2 groups The melancholic group had significantly higher clinical response rate (61.5%) than the non-melancholic group (36.7%) (p ¼0.017) at the end of the study.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Table 1 Comparison of baseline demographic and clinical characteristics with MDD patients with and without melancholic features. Variables
Sex Male Female Married Yes No
Age Age at onset Number of previous episodes Educational level (yrs) Baseline HAMD-17d score Baseline CGI-Se score
Melancholic (n ¼ 96)
Total (n¼ 126)
Non-melancholic (n¼ 30)
Analysis
n
%
n
%
n
%
p
30 96
23.8 76.2
27 69
28.1 71.9
3 27
10.0 90.0
0.05a
64 62
50.8 49.2
53 43
55.2 44.8
11 19
36.7 63.3
Mean
SD
Mean
SD
Mean
SD
p
45.3 38.9 2.4 11.0 31.3 6.2
11.0 11.8 1.9 3.6 6.5 0.7
47.0 41.0 2.4 11.2 32.0 6.3
10.4 11.3 2.0 3.6 6.7 0.7
39.8 32.3 2.6 10.3 29.2 6.0
11.1 11.2 1.7 3.5 5.7 0.7
0.001c o 0.001c 0.56c 0.23c 0.04c 0.03c
0.08b
Bold, statistically significant. a
Fisher's exact test. Pearson's χ2 test. c Independent t-test. d HAMD-17¼ 17-item Hamilton Rating Scale for Depression. e CGI-S ¼ Clinical Global Impression of Severity. b
Table 2 The anxiolytic/sedative-hypnotic medications use during the clinical trial period. Anxiolytics/sedative-hypnotics medications
Case number
bromazepam brotizolam clonazepam estazolam flurazepam lorazepam
2 25 16 54 15 1
The results of the GEE analyses of the HAMD-17 and CGI-S scores across time indicated that symptom severity significantly declined with time after fluoxetine treatment for both melancholic and nonmelancholic groups (Table 3). Notably, the melancholic group experienced a significantly greater reduction in HAMD-17 scores than the non-melancholic group, which started at weeks 2 (estimate¼ 3.70, p¼ 0.014), and persisted through week 3 (estimate¼ 4.12, p¼0.013), 4 (estimate¼ 5.33, po0.001), and 6 (estimate¼ 6.00, po0.001). Similarly, the decrease in CGI-S score was more significant in patients with melancholia than that in those with non-melancholia at weeks 2 (estimate¼ 0.40, p¼0.042), 3 (estimate¼ 0.55, p¼0.009), 4 (estimate¼ 0.68, p¼0.004), and 6 (estimate¼0.25, p¼0.010). The differences in the trend of symptom change (HAMD-17 scores) were illustrated in Fig. 1. There was no significant difference (p ¼0.33) in the number of adverse events reported during the trial period between the melancholic group (4.0 72.8) and non-melancholic group (4.77 4.9) (data not shown in the Table).
4. Discussion In the current 6-week fixed-dose fluoxetine treatment trial not sponsored by pharmaceutical company, acutely ill, severely depressed patients with MDD were repeatedly assessed for clinical symptoms of depression. The medical adherence was ensured and the care followed a standardized protocol in a controlled therapeutic milieu. The outcomes were analyzed as intra-subject changes across multiple time points with adjustment for within-
subject dependence effects by using GEE (Melander et al., 2003). The results indicated that MDD patients with melancholic features did show distinct clinical characteristics and treatment response, compared with those without melancholic features. These also extended the findings that melancholia is a separate depressive sub-type and warrants the prioritizing of antidepressant medication from western groups (Peselow et al., 1992; Fink et al., 2007a; Parker, 2007) to Han Chinese group. In this current study, the percentage of patients with melancholic features was relatively high (76.2%), comparable to those reported in inpatient (76.0%) (Stage et al., 1998), outpatient (67.1%) (Mallinckrodt et al., 2005) and mixed in- and out-patient settings (81.5%) (Sun et al., 2012). This is no surprise as melancholic features were reported in 20–80% of patients with MDD (Taylor and Fink, 2006) and melancholic depression is considered a more severe form of MDD (McGrath et al., 2008b); hospitalization is only warranted in patients with severe symptoms, as reflected in the higher baseline HAMD-17 and CGI-S scores in patients with melancholic features than those non-melancholic patients. Overall, the findings supported the notion that the DSM-IV definition of MDD with melancholic features is associated with higher baseline scores on depression rating scales and describes a more severe form of depression (McGrath et al., 2008b). In the current study, patients with melancholic features were more likely to be older, with a later age at onset of depression and more severe depressive symptoms at baseline, compared to patients with non-melancholic features. Importantly, patients with melancholic features had early treatment response and better treatment outcome after fixed-dose fluoxetine treatment at 6 weeks as measured by either HAMD-17 or CGI-S. Such findings replicate previous findings that melancholic depression is associated with older age (Zimmerman et al., 1989; Parker et al., 1998; Hyett et al., 2008), later age at onset (Parker et al., 2001a; Hyett et al., 2008), greater severity of illness at baseline (Zimmerman et al., 1986; Rush and Weissenburger, 1994; Parker et al., 1996, 2001a; Brodaty et al., 1997; Taylor and Fink, 2006; Hyett et al., 2008), and better response to pharmacotherapy (Zimmerman et al., 1989), hence supporting melancholic depression as a clinical subtype with distinct neurobiological underpinnings from nonmelancholic depression (Joyce et al., 2002). The age at onset of
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
Table 3 GEE analysis of HAMD-17 and CGI-S between melancholic and non-melancholic groups at each visit.a Scale HAMD-17 Week 0 Week 1 Week 2 Week 3 Week 4 Week 6 Group Time group Week 1 group Week 2 group Week 3 group Week 4 group Week 6 group CGI-S Week 0 Week 1 Week 2 Week 3 Week 4 Week 6 Group Time group Week 1 group Week 2 group Week 3 group Week 4 group Week 6 group
Melancholic Mean 7 SD (n)
Nonmelancholic Mean 7 SD (n)
32.0 76.7 21.7 7 8.1 17.6 7 8.1 16.2 78.4 14.6 78.2 13.1 78.0
29.2 75.7 20.2 78.4 18.7 78.3 17.4 79.7 17.5 78.9 16.2 78.8
6.3 70.7 5.3 7 1.0 4.6 7 1.3 4.17 1.3 3.9 7 1.3 3.5 7 1.4
(96) (96) (93) (92) (92) (91)
(96) (96) (93) (92) (92) (91)
6.0 70.7 5.17 1.1 4.7 7 1.2 4.3 7 1.1 4.2 7 1.1 3.8 7 1.1
(30) (30) (27) (25) (24) (21)
(30) (30) (27) (25) (24) (21)
Estimate
Standard error
p
9.07 10.71 11.6 12.0 13.07 0.87
1.18 1.28 1.46 1.22 0.99 0.48
o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.07
1.20 3.70 4.12 5.33 6.00
1.40 1.50 1.67 1.50 1.34
0.39 0.01 0.01 o 0.001 o 0.001
0.93 1.30 1.56 1.73 2.13 0.08
0.14 0.16 0.18 0.20 0.20 0.07
o 0.001 o 0.001 o 0.001 o 0.001 o 0.001 0.23
0.09 0.40 0.55 0.68 0.63
0.17 0.20 0.21 0.23 0.25
0.59 0.04 0.01 0.004 0.01
Bold, statistically significant. a
Group¼ melancholic vs. non-melancholic.
Fig. 1. The HAMD-17 scores in the melancholic and non-melancholic groups at each visit.
major depressive episode in melancholic group in current study (41.0 yrs) approached to those in the studies by Parker et al. (1994) (38 yrs) and by Gili et al. (2012) (39.9 yrs), and was older than that in general population (30.4 yr) (Hasin et al., 2005). Aging has been proposed to be a significant factor affecting the presence of melancholic features in depression (Thase and Friedman, 1999). The ratio of melancholic depression vs. non-melancholic depression has been demonstrated to increase with age, presumably reflecting the older age at onset of melancholic depression (Parker et al., 1996). Also, disturbance in psychomotor activity, a core melancholic feature, becomes more apparent in those with melancholic depression as they become older, which might reflect the progressive decrease with age in the levels of neurotransmitters considered significant in the pathophysiology of
depression (Leventhal and Rehm, 2005). Indeed, some of these characteristics (e.g., apathy, lethargy and cognitive slowing) are closely associated with melancholic depression and older age and later onset depression has been demonstrated to be related to different neurobiological and risk factors than early onset depression (Amsterdam, 1998). In the current study, the results of GEE analysis indicated that melancholic depression showed greater improvement in HAMD17 or CGI-S scores than non-melancholic depression, beginning at the 2nd week of fluoxetine treatment. Furthermore, the strictly defined clinical response rate (a reduction of 50% or more of the HAMD-17 score from baseline to endpoint) was significantly higher in the melancholic group (61.5%) than in the non-melancholic group (36.7%) (p ¼0.017). Although, without a placebocontrolled group, the impacts of placebo effects in current study could not be estimated, the differences in the degree of symptom improvement and clinical response rate are not likely solely attributable to placebo effects for the following reasons: first, the response rate in the melancholic group (61.5%) is too high to be accountable by the typical placebo effects, i.e., around 30%, as estimated from past clinical placebo-controlled antidepressant trials (Walsh et al., 2002); second, it has been demonstrated that patients with more severe depression are less subject to placebo effect (Khan et al., 2002)—the differences in clinical response would have been larger if placebo effects were taken into account. Hospitalization itself can be a significant non-pharmacological therapeutic factor contributing to clinical improvement in MDD, with differential impacts on antidepressant treatment response in melancholic vs. non-melancholic depressions in current study. In previous placebo-controlled antidepressant trials, the magnitude of the drug-placebo difference was smaller when less severe cases were included, indicating more significant placebo effects. In contrast, studies using stricter criteria and more severe patients could better reflect the genuine drug-placebo difference by reducing placebo effects (Khan and Schwartz, 2005; Khan and Brown,
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2015). In current study, both melancholic and non-melancholic groups were severely depressed and were comparable in terms of severity of depressive symptoms; it is unlikely that discrepant clinical severity resulted in discrepant impact of hospitalization as a non-pharmacological therapeutic factor on clinical response. Furthermore, since melancholia is considered to have distinct biological underpinnings (Parker and Paterson, 2014), its clinical response to antidepressant is less likely a result of non-pharmacological interventions. In this regard, if hospitalization, as a nonpharmacological therapeutic factor, is at work in current study, it will be more manifest in the non-melancholic group, resulting in underestimation of the real differences in antidepressant response between the two groups in current study. Overall, although the impact of hospitalization is difficult to estimate, it is reasonable to assume that between-group difference in clinical response in current study was not significantly biased due to the differential impacts of hospitalization. The treatment outcome in the current melancholic group is noteworthy, considering the low dosage of fluoxetine treatment, the fast onset of clinical response and the high treatment response rate. In this sense, melancholic features are important prognostic signs that warrant careful clinical attention in predicting the antidepressant treatment outcome. As mentioned above, inconsistent treatment outcomes of melancholic depression with fluoxetine or other SSRIs, compared with non-melancholic depression, may come from different diagnostic criteria (Duggan et al., 1991; Parker et al., 1999, 2001b; Joyce et al., 2002) and variability in trial duration, outcome measures (e.g., patients' judgments, clinician-rating scales, or self-reporting questionnaires) (Parker et al., 1999; Leventhal and Rehm, 2005), methodology (e.g., retrospective or prospective study), race/ethnicity (Xiang et al., 2012) and treatment setting (e.g., inpatient or outpatient) (Joyce et al., 2002). Due to the limitation in study design, how these methodological issues affected the current outcome could not be addressed. Nevertheless, in the real life clinical practice scenario, the outcome of melancholic depression is can be better, as higher dosage of antidepressant and longer observation period are allowed. Some limitations in this study are worth noting. First, use of a single site with a relatively small sample size, especially the small numbers in the non-melancholic group (n¼ 30), limited the generalizability of our results. Second, the study period of 6 weeks is relatively short when considering the total duration of depression. However, it is relatively long and sufficient for inpatient trials to detect initial antidepressant responses. Long-term follow-up after hospitalization would allow further elucidation whether the differences persist beyond the study period. Third, as an open-label study, the clinical ratings might be biased and await future doubleblind study to confirm the findings. Moreover, without a control group, the differential placebo effects on the two groups could not be determined. However, as the setting and treatment protocol are more close to everyday clinical practice setting (Nierenberg et al., 1995), and as such, the results may be more generalizable to clinical settings. Fourth, this post-hoc analysis was not designed, a priori, to compare melancholic depression with non-melancholic depression. This could have reduced the power to detect some clinical differences between the 2 groups (Fink et al., 2007b). Fifth, anxiolytic/sedative-hypnotic medications may lower the HAMD-17 score during the trial period, often resulting in an improvement. Thus, some initial improvement may be due to the sedating effects of anxiolytics/hypnotics rather than to the antidepressants (Roose and Nobler, 2001). However, no significant difference (p ¼ 0.95) in the rates of anxiolytics/hypnotics use existed between melancholic group (86/96 ¼89.6%) and non-melancholic group (27/30 ¼90.0%). The impact on outcome between two groups should be comparable. Finally, only a single antidepressant agent (i.e., fluoxetine)
5
was used; therefore, it is unclear whether the finding can be generalized to other antidepressants. In conclusion, the findings from current study indicated that melancholic features in patients with MDD were associated with specific demographic, disease course indices and differential treatment responses, supporting the concept of melancholic depression as a subtype of MDD. Future research strategies to substantiate such findings include randomized, placebo-controlled trials involving other antidepressants, larger inpatient or outpatient groups from multi-centers, and extension of study duration beyond 6 weeks to ascertain longer term treatment responses.
Acknowledgments This study was funded by the Kai-Syuan Psychiatric Hospital (KSPH-2007-16) and the Ministry of Science and Technology, Taiwan (MOST-103-2314-B-280-001-MY3). All authors declare that they have no conflicts of interest. The authors thank Professor YueCune Chang for the contribution of GEE model.
References Amsterdam, J.D., 1998. Selective serotonin reuptake inhibitor efficacy in severe and melancholic depression. J. Psychopharmacol. Suppl. 12, S99–S111. APA, 1994a. American Psychiatric Association: Structured Clinical Interview for DSM-IV. American Psychiatric Press, Washington, DC. APA, 1994b. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 4th ed. American Psychiatric Association, Washington, D.C.. APA, 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Fifth ed. Beasley Jr., C.M., Nilsson, M.E., Koke, S.C., Gonzales, J.S., 2000. Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose. J. Clin. Psychiatry 61, 722–728. Brodaty, H., Luscombe, G., Parker, G., Wilhelm, K., Hickie, I., Austin, M.P., Mitchell, P., 1997. Increased rate of psychosis and psychomotor change in depression with age. Psychol. Med. 27, 1205–1213. Daly, E.J., Trivedi, M.H., Fava, M., Shelton, R., Wisniewski, S.R., Morris, D.W., Stegman, D., Preskorn, S.H., Rush, A.J., 2011. The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study. J. Clin. Psychopharmacol. 31, 31–38. Duggan, C.F., Lee, A.S., Murray, R.M., 1991. Do different subtypes of hospitalized depressives have different long-term outcomes? Arch. Gen. Psychiatry 48, 308–312. Fink, M., Bolwig, T.G., Parker, G., Shorter, E., 2007a. Melancholia: restoration in psychiatric classification recommended. Acta Psychiatr. Scand. 115, 89–92. Fink, M., Rush, A.J., Knapp, R., Rasmussen, K., Mueller, M., Rummans, T.A., O'Connor, K., Husain, M., Biggs, M., Bailine, S., Kellner, C.H., Consortium for Research in, E. C.T.S.G., 2007b. DSM melancholic features are unreliable predictors of ECT response: a CORE publication. J. ECT 23, 139–146. Gili, M., Roca, M., Armengol, S., Asensio, D., Garcia-Campayo, J., Parker, G., 2012. Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions. PloS One 7, e48200. Guelfi, J.D., White, C., Hackett, D., Guichoux, J.Y., Magni, G., 1995. Effectiveness of venlafaxine in patients hospitalized for major depression and melancholia. J. Clin. Psychiatry 56, 450–458. Guy, W., 1976. ECDEU Assessment manual for psychopharmacology. DHEW Publication 76338, Washington DC. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Hasin, D.S., Goodwin, R.D., Stinson, F.S., Grant, B.F., 2005. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch. Gen. Psychiatry 62, 1097–1106. Heiligenstein, J.H., Tollefson, G.D., Faries, D.E., 1994. Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo. J. Affect. Disord. 30, 163–173. Hyett, M.P., Parker, G.B., Proudfoot, J., Fletcher, K., 2008. Examining age effects on prototypic melancholic symptoms as a strategy for refining definition of melancholia. J. Affect. Disord. 109, 193–197. Joyce, P.R., Mulder, R.T., Luty, S.E., McKenzie, J.M., Sullivan, P.F., Abbott, R.M., Stevens, I.F., 2002. Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response. Aust. N. Z. J. Psychiatry 36, 376–383. Khan, A., Brown, W.A., 2015. Antidepressants versus placebo in major depression: an overview. World Psychiatry 14, 294–300. Khan, A., Leventhal, R.M., Khan, S.R., Brown, W.A., 2002. Severity of depression and
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i
6
C.-H. Lin et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J. Clin. Psychopharmacol. 22, 40–45. Khan, A., Schwartz, K., 2005. Study designs and outcomes in antidepressant clinical trials. Essent. Psychopharmacol. 6, 221–226. Leventhal, A.M., Rehm, L.P., 2005. The empirical status of melancholia: implications for psychology. Clin. Psychol. Rev. 25, 25–44. Lin, C.H., Lane, H.Y., Chen, C.C., Juo, S.H., Yen, C.F., 2011. Early prediction of fluoxetine response for Han Chinese inpatients with major depressive disorder. J. Clin. Psychopharmacol. 31, 187–193. Lingjaerde, O., Ahlfors, U.G., Bech, P., Dencker, S.J., Elgen, K., 1987. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr. Scand. Suppl. 334, S1–S100. Mallinckrodt, C.H., Watkin, J.G., Liu, C., Wohlreich, M.M., Raskin, J., 2005. Duloxetine in the treatment of Major Depressive Disorder: a comparison of efficacy in patients with and without melancholic features. BMC Psychiatry 5, 1. McGrath, P.J., Khan, A.Y., Trivedi, M.H., Stewart, J.W., Morris, D.W., Wisniewski, S.R., Miyahara, S., Nierenberg, A.A., Fava, M., Rush, A.J., 2008a. Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. J. Clin. Psychiatry 69, 1847–1855. McGrath, P.J., Khan, A.Y., Trivedi, M.H., Stewart, J.W., Morris, D.W., Wisniewski, S.R., Miyahara, S., Nierenberg, A.A., Fava, M., Rush, A.J., 2008b. Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report. J. Clin Psychiatry 69, 1847–1855. Melander, H., Ahlqvist-Rastad, J., Meijer, G., Beermann, B., 2003. Evidence b(i)ased medicine–selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 326, 1171–1173. Nierenberg, A.A., McLean, N.E., Alpert, J.E., Worthington, J.J., Rosenbaum, J.F., Fava, M., 1995. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am. J. Psychiatry 152, 1500–1503. Parker, G., 2007. Defining melancholia: the primacy of psychomotor disturbance. Acta Psychiatr. Scand. Suppl., 21–30. Parker, G., Fink, M., Shorter, E., Taylor, M.A., Akiskal, H., Berrios, G., Bolwig, T., Brown, W.A., Carroll, B., Healy, D., Klein, D.F., Koukopoulos, A., Michels, R., Paris, J., Rubin, R.T., Spitzer, R., Swartz, C., 2010. Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am. J. Psychiatry 167, 745–747. Parker, G., Hadzi-Pavlovic, D., Brodaty, H., Boyce, P., Mitchell, P., Wilhelm, K., Hickie, I., 1992. Predicting the course of melancholic and nonmelancholic depression. A naturalistic comparison study. J. Nerv. Ment. Dis. 180, 693–702. Parker, G., Hadzi-Pavlovic, D., Eyers, K., 1996. Melancholia: a disorder of movement and mood: a phenomenological and neurobiological review. Cambridge University Press, Cambridge. Parker, G., Hadzi-Pavlovic, D., Wilhelm, K., Hickie, I., Brodaty, H., Boyce, P., Mitchell, P., Eyers, K., 1994. Defining melancholia: properties of a refined sign-based measure. Br. J. Psychiatry 164, 316–326. Parker, G., Mitchell, P., Wilhelm, K., Menkes, D., Snowdon, J., Schweitzer, I., Grounds, D., Skerritt, P., Roy, K., Hadzi-Pavlovic, D., 1999. Are the newer antidepressant drugs as effective as established physical treatments? Results from an Australasian clinical panel review. Aust. N. Z. J. Psychiatry 33, 874–881. Parker, G., Paterson, A., 2014. Melancholia: definition and management. Curr. Opin. Psychiatry 27, 1–6. Parker, G., Roussos, J., Austin, M.P., Hadzi-Pavlovic, D., Wilhelm, K., Mitchell, P., 1998. Disordered personality style: higher rates in non-melancholic compared
to melancholic depression. J. Affect. Disord. 47, 131–140. Parker, G., Roy, K., Hadzi-Pavlovic, D., Wilhelm, K., Mitchell, P., 2001a. The differential impact of age on the phenomenology of melancholia. Psychol. Med. 31, 1231–1236. Parker, G., Roy, K., Wilhelm, K., Mitchell, P., 2001b. Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study. J. Clin. Psychiatry 62, 117–125. Perry, P.J., 1996. Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants. J. Affect. Disord. 39, 1–6. Peselow, E.D., Sanfilipo, M.P., Difiglia, C., Fieve, R.R., 1992. Melancholic/endogenous depression and response to somatic treatment and placebo. Am. J. Psychiatry 149, 1324–1334. Roose, S.P., Nobler, M., 2001. ECT and onset of action. J. Clin. Psychiatry 62 (Suppl 4), S24–S26. Rush, A.J., Weissenburger, J.E., 1994. Melancholic symptom features and DSM-IV. Am. J. Psychiatry 151, 489–498. Shorter, E., 2007. The doctrine of the two depressions in historical perspective. Acta Psychiatr. Scand. Suppl., 5–13. Stage, K.B., Bech, P., Gram, L.F., Kragh-Sorensen, P., Rosenberg, C., Ohrberg, S., 1998. Are in-patient depressives more often of the melancholic subtype? Danish University Antidepressant Group. Acta Psychiatr. Scand. 98, 432–436. Sun, N., Li, Y., Cai, Y., Chen, J., Shen, Y., Sun, J., Zhang, Z., Zhang, J., Wang, L., Guo, L., Yang, L., Qiang, L., Yang, Y., Wang, G., Du, B., Xia, J., Rong, H., Gan, Z., Hu, B., Pan, J., Li, C., Sun, S., Han, W., Xiao, X., Dai, L., Jin, G., Zhang, Y., Sun, L., Chen, Y., Zhao, H., Dang, Y., Shi, S., Kendler, K.S., Flint, J., Zhang, K., 2012. A comparison of melancholic and nonmelancholic recurrent major depression in Han Chinese women. Depress. Anxiety 29, 4–9. Taylor, M.A., Fink, M., 2006. Melancholia: the Diagnosis, Pathophysiology, and Treatment of Depressive Illness. Cambridge University Press, Cambridge. Thase, M.E., Friedman, E.S., 1999. Is psychotherapy an effective treatment for melancholia and other severe depressive states? J. Affect. Disord. 54, 1–19. Uher, R., Dernovsek, M.Z., Mors, O., Hauser, J., Souery, D., Zobel, A., Maier, W., Henigsberg, N., Kalember, P., Rietschel, M., Placentino, A., Mendlewicz, J., Aitchison, K.J., McGuffin, P., Farmer, A., 2011. Melancholic, atypical and anxious depression subtypes and outcome of treatment with escitalopram and nortriptyline. J. Affect. Disord. 132, 112–120. Walsh, B.T., Seidman, S.N., Sysko, R., Gould, M., 2002. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287, 1840–1847. Xiang, Y.T., Wang, G., Hu, C., Guo, T., Ungvari, G.S., Kilbourne, A.M., Lai, K.Y., Si, T.M., Zheng, Q.W., Chen, D.F., Fang, Y.R., Lu, Z., Yang, H.C., Hu, J., Chen, Z.Y., Huang, Y., Sun, J., Wang, X.P., Li, H.C., Zhang, J.B., Chiu, H.F., 2012. Demographic and clinical features and prescribing patterns of psychotropic medications in patients with the melancholic subtype of major depressive disorder in China. PloS One 7, e39840. Zeger, S.L., Liang, K.Y., 1986. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121–130. Zimmerman, M., Black, D.W., Coryell, W., 1989. Diagnostic criteria for melancholia. The comparative validity of DSM-III and DSM-III-R. Arch. Gen. Psychiatry 46, 361–368. Zimmerman, M., Coryell, W., Pfohl, B., Stangl, D., 1986. The validity of four definitions of endogenous depression. II. Clinical, demographic, familial, and psychosocial correlates. Arch. Gen. Psychiatry 43, 234–244.
Please cite this article as: Lin, C.-H., et al., Melancholic features in inpatients with major depressive disorder associate with differential clinical characteristics and treatment outcomes. Psychiatry Research (2016), http://dx.doi.org/10.1016/j.psychres.2015.11.009i