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1.  Smoking and Major Depressive Disorder in Chinese Women 
PLoS ONE  2014;9(9):e106287.
Objective
To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.
Methods
We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.
Results
Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.
Conclusions
Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.
doi:10.1371/journal.pone.0106287
PMCID: PMC4152240  PMID: 25180682
2.  Age at onset of major depressive disorder in Han Chinese women: Relationship with clinical features and family history☆ 
Journal of Affective Disorders  2011;135(1-3):89-94.
Background
Individuals with early-onset depression may be a clinically distinct group with particular symptom patterns, illness course, comorbidity and family history. This question has not been previously investigated in a Han Chinese population.
Methods
We examined the clinical features of 1970 Han Chinese women with DSM-IV major depressive disorder (MDD) between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models was used to determine the association between age at onset (AAO) with continuous, binary and discrete characteristic clinical features of MDD.
Results
Earlier AAO was associated with more suicidal ideation and attempts and higher neuroticism, but fewer sleep, appetite and weight changes. Patients with an earlier AAO were more likely to suffer a chronic course (longer illness duration, more MDD episodes and longer index episode), increased rates of MDD in their parents and a lower likelihood of marriage. They tend to have higher comorbidity with anxiety disorders (general anxiety disorder, social phobia and agoraphobia) and dysthymia.
Conclusions
Early AAO in MDD may be an index of a more severe, highly comorbid and familial disorder. Our findings indicate that the features of MDD in China are similar to those reported elsewhere in the world.
doi:10.1016/j.jad.2011.06.056
PMCID: PMC3210897  PMID: 21782247
Major depressive disorder; Age at onset; Symptom; Comorbidity
3.  Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women 
PLoS ONE  2014;9(1):e86674.
Background
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years.
Principal findings
We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders.
Conclusions
In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.
doi:10.1371/journal.pone.0086674
PMCID: PMC3909008  PMID: 24497966
4.  A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia☆ 
Journal of Affective Disorders  2011;135(1-3):106-110.
Background
The relationship between major depressive disorder (MDD) and dysthymia, a form of chronic depression, is complex. The two conditions are highly comorbid and it is unclear whether they are two separate disease entities. We investigated the extent to which patients with dysthymia superimposed on major depression can be distinguished from those with recurrent MDD.
Methods
We examined the clinical features in 1970 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and dysthymia and between dysthymia and disorders comorbid with major depression.
Results
The 354 cases with dysthymia had more severe MDD than those without, with more episodes of MDD and greater co-morbidity for anxiety disorders. Patients with dysthymia had higher neuroticism scores and were more likely to have a family history of MDD. They were also more likely to have suffered serious life events.
Limitations
Results were obtained in a clinically ascertained sample of Chinese women and may not generalize to community-acquired samples or to other populations. It is not possible to determine whether the associations represent causal relationships.
Conclusions
The additional diagnosis of dysthymia in Chinese women with recurrent MDD defines a meaningful and potentially important subtype. We conclude that in some circumstances it is possible to distinguish double depression from recurrent MDD.
doi:10.1016/j.jad.2011.06.051
PMCID: PMC3221043  PMID: 21824660
Major depressive disorder; Dysthymia; Symptom; Comorbidity
5.  Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression 
Psychological Medicine  2011;42(6):1239-1248.
Background
Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders.
Method
A total of 1970 female Chinese MDD patients with or without seven co-morbid anxiety disorders [including generalized anxiety disorder (GAD), panic disorder, and five phobia subtypes] were ascertained in the CONVERGE study. Generalized linear models were used to model association between co-morbid anxiety disorders and various MDD features.
Results
The lifetime prevalence rate for any type of co-morbid anxiety disorder is 60.2%. Panic and social phobia significantly predict an increased family history of MDD. GAD and animal phobia predict an earlier onset of MDD and a higher number of MDD episodes, respectively. Panic and GAD predict a higher number of DSM-IV diagnostic criteria. GAD and blood-injury phobia are both significantly associated with suicidal attempt with opposite effects. All seven co-morbid anxiety disorders predict higher neuroticism.
Conclusions
Patterns of co-morbidity between MDD and anxiety are consistent with findings from the US and European studies; the seven co-morbid anxiety disorders are heterogeneous when tested for association with various MDD features.
doi:10.1017/S003329171100273X
PMCID: PMC3339636  PMID: 22126712
Co-morbid anxiety disorders; major depression
6.  Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010 
PLoS Medicine  2013;10(11):e1001547.
In this paper, Ferrari and colleagues analyzed the burden of depressive disorders in GBD 2010 and identified depressive disorders as a leading cause of burden. The authors present severity proportions; burden by country, region, age, sex, and year; as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Please see later in the article for the Editors' Summary
Background
Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Methods and Findings
Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders.
Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and dysthymia for 1.4% (0.9%–2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and dysthymia for 0.5% (0.3%–0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs.
Conclusions
GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depressive disorders are common mental disorders that occur in people of all ages across all world regions. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—can make people feel that life is no longer worth living. People affected by depression lose interest in the activities they used to enjoy and can also be affected by physical symptoms such as disturbed sleep. Major depressive disorder (MDD, also known as clinical depression) is an episodic disorder with a chronic (long-term) outcome and increased risk of death. It involves at least one major depressive episode in which the affected individual experiences a depressed mood almost all day, every day for at least 2 weeks. Dysthymia is a milder, chronic form of depression that lasts for at least 2 years. People with dysthymia are often described as constantly unhappy. Both these subtypes of depression (and others such as that experienced in bipolar disorder) can be treated with antidepressant drugs and with talking therapies.
Why Was This Study Done?
Depressive disorders were a leading cause of disease burden in the 1990 and 2000 Global Burden of Disease (GBD) studies, collaborative scientific efforts that quantify the health loss attributable to diseases and injuries in terms of disability adjusted life years (DALYs; one DALY represents the loss of a healthy year of life). DALYs are calculated by adding together the years of life lived with a disability (YLD, a measure that includes a disability weight factor reflecting disease severity) and the years of life lost because of disorder-specific premature death. The GBD initiative aims to provide data that can be used to improve public-health policy. Thus, knowing that depressive disorders are a leading cause of disease burden worldwide has helped to prioritize depressive disorders in global public-health agendas. Here, the researchers analyze the burden of MDD and dysthymia in GBD 2010 by country, region, age, and sex, and calculate the burden of suicide and ischemic heart disease attributable to depressive disorders (depression is a risk factor for suicide and ischemic heart disease). GBD 2010 is broader in scope than previous GBD studies and quantifies the direct burden of 291 diseases and injuries and the burden attributable to 67 risk factors across 187 countries.
What Did the Researchers Do and Find?
The researchers collected data on the prevalence, incidence, remission rates, and duration of MDD and dysthymia and on the excess deaths caused by these disorders from published articles. They pooled these data using a statistical method called Bayesian meta-regression and calculated YLDs for MDD and dysthymia using disability weights collected in population surveys. MDD accounted for 8.2% of global YLDs in 2010, making it the second leading cause of YLDs. Dysthymia accounted for 1.4% of global YLDs. MDD and dysthymia were also leading causes of DALYs, accounting for 2.5% and 0.5% of global DALYs, respectively. The regional variation in the burden was greater for MDD than for dysthymia, the burden of depressive disorders was higher in women than men, the largest proportion of YLDs from depressive disorders occurred among adults of working age, and the global burden of depressive disorders increased by 37.5% between 1990 and 2010 because of population growth and ageing. Finally, MDD explained an additional 16 million DALYs and 4 million DALYs when it was considered as a risk factor for suicide and ischemic heart disease, respectively. This “attributable” burden increased the overall burden of depressive disorders to 3.8% of global DALYs.
What Do These Findings Mean?
These findings update and extend the information available from GBD 1990 and 2000 on the global burden of depressive disorders. They confirm that depressive disorders are a leading direct cause of the global disease burden and show that MDD also contributes to the burden allocated to suicide and ischemic heart disease. The estimates of the global burden of depressive disorders reported in GBD 2010 are likely to be more accurate than those in previous GBD studies but are limited by factors such as the sparseness of data on depressive disorders from developing countries and the validity of the disability weights used to calculate YLDs. Even so, these findings reinforce the importance of treating depressive disorders as a public-health priority and of implementing cost-effective interventions to reduce their ubiquitous burden.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001547.
The US National Institute of Mental Health provides information on all aspects of depression
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
MedlinePlus provides links to other resources about depression (in English and Spanish)
The World Health Organization provides information on depression and on the global burden of disease (in several languages)
Information about the Global Burden of Disease initiative is available
beyondblue provides many resources on depression
The Queensland Centre for Mental Health Research provides information on epidemiology and the global burden of disease specifically for mental disorders
doi:10.1371/journal.pmed.1001547
PMCID: PMC3818162  PMID: 24223526
7.  Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder 
Journal of Affective Disorders  2012;136(3):983-987.
Background
Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women.
Methods
A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression.
Results
Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia.
Limitations
Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations.
Conclusions
Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar.
doi:10.1016/j.jad.2011.06.047
PMCID: PMC3315022  PMID: 21824665
Postpartum depression; Major depressive disorder; Neuroticism; Anxiety disorder
8.  Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression 
PLoS ONE  2013;8(12):e83490.
Background
Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.
Results
We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia.
Conclusions
There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.
doi:10.1371/journal.pone.0083490
PMCID: PMC3873934  PMID: 24386213
9.  An exploratory factor analysis of nutritional biomarkers associated with major depression in pregnancy 
Public health nutrition  2011;15(6):1078-1086.
Objective
Major depressive disorder (MDD) during pregnancy increases the risk of adverse maternal and infant outcomes. Maternal nutritional status may be a modifiable risk factor for antenatal depression. We evaluated the association between patterns in mid-pregnancy nutritional biomarkers and MDD.
Design
Prospective cohort study
Setting
Pittsburgh, Pennsylvania, USA
Subjects
Women who enrolled at ≤20 weeks gestation had a diagnosis of MDD made with the Structured Clinical Interview for DSM-IV at 20-, 30-, and 36-week study visits. A total of 135 women contributed 345 person-visits. Non-fasting blood drawn at enrollment was assayed for red cell essential fatty acids, plasma folate, homocysteine, and ascorbic acid; serum 25-hydroxyvitamin D, retinol, vitamin E, carotenoids, ferritin, and soluble transferrin receptors. Nutritional biomarkers were entered into principal components analysis.
Results
Three factors emerged: Factor 1, Essential Fatty Acids; Factor 2, Micronutrients; and Factor 3, Carotenoids. MDD was prevalent in 21.5% of women. In longitudinal multivariable logistic models, there was no association between the Essential Fatty Acid or Micronutrient patterns and MDD either before or after adjustment for employment, education, or prepregnancy BMI. In unadjusted analysis, women with Carotenoid factor scores in the middle and upper tertiles were 60% less likely than women in the bottom tertile to have MDD during pregnancy, but after adjustment for confounders, the associations were no longer statistically significant.
Conclusions
While meaningful patterns were derived using nutritional biomarkers, significant associations with MDD were not observed in multivariable adjusted analyses. Larger, more diverse samples are needed to understand nutrition-depression relationships during pregnancy.
doi:10.1017/S1368980011002904
PMCID: PMC3309065  PMID: 22152590
diet patterns; biomarkers; pregnancy; depression
10.  Association of the MAOA promoter uVNTR polymorphism with suicide attempts in patients with major depressive disorder 
BMC Medical Genetics  2011;12:74.
Background
The MAOA uVNTR polymorphism has been documented to affect the MAOA gene at the transcriptional level and is associated with aggressive impulsive behaviors, depression associated with suicide (depressed suicide), and major depressive disorder (MDD). We hypothesized that the uVNTR polymorphism confers vulnerability to MDD, suicide or both. The aim of this study was to explore the association between the MAOA uVNTR and depressed suicide, using multiple controls.
Methods
Four different groups were included: 432 community controls, 385 patients with MDD who had not attempted suicide, 96 community subjects without mental disorders who had attempted suicide, and 109 patients with MDD who had attempted suicide. The MAOA uVNTR polymorphism was genotyped by a PCR technique. The symptom profiles and personal characteristics in each group were also compared.
Results
The MAOA 4R allele was more frequent in males with MDD than in male community controls (χ2 = 4.182, p = 0.041). Logistic regression analysis showed that, among the depressed subjects, those younger in age, more neurotic or who smoked had an increased risk of suicide (β = -0.04, p = 0.002; β = 0.15, p = 0.017; β = 0.79, p = 0.031, respectively). Moreover, among those who had attempted suicide, those younger in age, with more paternal overprotection, and more somatic symptoms were more likely to be in the MDD group than in the community group (β = -0.11, p < 0.001; β = 0.15, p = 0.026; β = 1.11, p < 0.001). Structural equation modeling (SEM) showed that nongenetic factors, such as age, paternal overprotection, and somatic symptoms, were associated with MDD, whereas depressed suicide were associated with severity of depression, personality traits, age, marital status, and inversely associated with anxiety symptoms. However, depression did not affect suicidal behavior in the community group.
Conclusion
The MAOA 4R allele is associated with enhanced vulnerability to suicide in depressed males, but not in community subjects. The MAOA 4R allele affects vulnerability to suicide through the mediating factor of depressive symptoms. Further large-scale studies are needed to verify the psychopathology of the relationships among MAOA uVNTR polymorphism, symptom profiles, and suicidal behavior.
doi:10.1186/1471-2350-12-74
PMCID: PMC3127823  PMID: 21605465
MAOA u-VNTR Polymorphisms; Suicide Attempts; Major Depressive Disorder
11.  Psychiatric comorbidities in patients with major depressive disorder 
Background
Psychiatric comorbidities are common in major depressive disorder (MDD). They may worsen outcome and cause economic burden. The primary objective was to examine the prevalence of psychiatric comorbidities in MDD. The secondary objectives were to compare the presence of comorbidities between currently active and past MDD, and between patients with and without suicidal risk.
Methods
This was a cross-sectional study. A total of 250 patients with lifetime MDD and age ≥18 years were enrolled. The Mini International Neuropsychiatric Interview (MINI), Thai version, was used to confirm MDD diagnosis and classify comorbidities. MDD diagnosis was confirmed in 190, and 60 patients were excluded due to diagnosis of bipolar disorder.
Results
Of the 190 MDD patients, 25.8% had current MDD and 74.2% had past MDD. Eighty percent were women. The mean age at enrollment was 50 years, and at MDD onset was 41 years. Most patients were married (53.2%), employed (54.8%), and had ≥12 years of education (66.9%). There were 67 patients (35.3%) with one or more psychiatric comorbidities. Comorbidities included dysthymia (19.5%), any anxiety disorders (21.1%) (panic disorder [6.8%], agoraphobia [5.8%], social phobia [3.7%], obsessive–compulsive disorder [OCD] [4.7%], generalized anxiety disorder [5.3%], and post-traumatic stress disorder [4.2%]), alcohol dependence (0.5%), psychotic disorder (1.6%), antisocial personality (1.1%), and eating disorders (0%). Compared with past MDD, the current MDD group had significantly higher OCD (P<0.001), psychotic disorder (P=0.048), past panic disorder (P=0.017), and suicidal risk (P<0.001). Suicidal risk was found in 32.1% of patients. Patients with suicidal risk had more comorbid anxiety disorder of any type (P=0.019) and psychotic disorder (P=0.032).
Conclusion
Several comorbidities were associated with MDD. Patients with active MDD had higher comorbid OCD, psychotic disorder, past panic disorder, and suicidal risk. Patients with suicide risk had higher comorbid anxiety and psychotic disorders.
doi:10.2147/NDT.S72026
PMCID: PMC4235207  PMID: 25419132
suicidal risk; active major depressive disorder; anxiety disorder; psychotic disorder
12.  Decreased suicidal ideation in depressed patients with or without comorbid posttraumatic stress disorder treated with selective serotonin reuptake inhibitors: an open study 
Psychiatry Research  2012;196(2-3):261-266.
Comorbidity of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is associated with higher morbidity including suicidal ideation and behavior. Selective serotonin reuptake inhibitors (SSRIs) are a known treatment for PTSD, MDD and comorbid PTSD and MDD. Since the patients with comorbid MDD and PTSD (PTSD-MDD) are sicker, we hypothesize a poorer response to treatment compared to patients with MDD only. Ninety-six MDD patients were included in the study: 76 with MDD only and 20 with PTSD-MDD. Demographic and clinical parameters at baseline were assessed. We examined clinical parameters before and after 3 months of open SSRI treatment in subjects with PTSD-MDD and compared this group to individuals with MDD only. At baseline, PTSD-MDD patients had higher Hamilton Depression Rating Scale and Buss-Durkee Hostility Scale scores compared with MDD only subjects. There was a significant decrease in scores on the Hamilton Depression Rating Scale, Beck Depression Inventory, Beck Hopelessness Scale, and Beck Scale for Suicidal Ideation after three months of treatment with SSRIs in both groups. The magnitude of improvement in Beck Scale for Suicidal Ideation scores was greater in the PTSD-MDD group compared to the MDD only subjects. Symptoms of depression including suicidal ideation improved in MDD patients with or without comorbid PTSD after 3 months of treatment with SSRIs but improvement in suicidal ideation was greater in the PTSD-MDD group. Our finding has not supported the hypothesis that a response to treatment is poorer in the PTSD-MDD group which may indicate that sicker patients benefit more from treatment.
doi:10.1016/j.psychres.2011.11.010
PMCID: PMC3361617  PMID: 22397913
posttraumatic stress disorder; major depressive disorder; suicidal ideation; selective serotonin reuptake inhibitors
13.  Does Age at Onset of First Major Depressive Episode Indicate the Subtype of Major Depressive Disorder?: The Clinical Research Center for Depression Study 
Yonsei Medical Journal  2014;55(6):1712-1720.
Purpose
The purpose of this study was to evaluate the effects of age at onset of the first major depressive episode on the clinical features of individuals with major depressive disorder (MDD) in a large cohort of Korean depressed patients.
Materials and Methods
We recruited 419 MDD patients of age over 18 years from the Clinical Research Center for Depression study in South Korea. At the start of the study, the onset age of the first major depressive episode was self-reported by the subjects. The subjects were divided into four age-at-onset subgroups: childhood and adolescent onset (ages <18), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late onset (ages 60+). Using analysis of covariance (ANCOVA) and ordinal logistic regression analysis with adjusting the effect of age, the relationships between clinical features and age at onset of MDD were evaluated.
Results
There was an apparent, but inconsistent correlation between clinical features and age at onset. Earlier onset MDD was significantly associated with higher proportion of female gender [adjusted odds ratio (AOR)=0.570, p=0.022], more previous suicide attempts (AOR=0.635, p=0.038), greater number of previous depressive episodes (F=3.475, p=0.016) and higher scores on the brief psychiatric rating scale (F=3.254, p=0.022), its negative symptom subscale (F=6.082, p<0.0001), and the alcohol use disorder identification test (F=7.061, p<0.0001).
Conclusion
Early age at onset may increase the likelihood of distinguishable MDD subtype, and age at onset of the first major depressive episode is a promising clinical indicator for the clinical presentation, course, and outcome of MDD.
doi:10.3349/ymj.2014.55.6.1712
PMCID: PMC4205714  PMID: 25323911
Major depressive disorder; age at onset; clinical indicator; subtype
14.  Depression and Eating Disorders: Treatment and Course 
Journal of affective disorders  2010;130(3):470-477.
Background
We examined the course of major depressive disorder (MDD) and predictors of MDD recovery and relapse in a longitudinal sample of women with eating disorders (ED).
Methods
246 Boston area women with DSM-IV anorexia nervosa-restricting (ANR; n=51), AN-binge/purge (ANBP; n=85), and bulimia nervosa (BN; n=110) were recruited between 1987-1991 and interviewed using the Eating Disorders Longitudinal Interval Follow-up Evaluation (LIFE-EAT-II) every 6-12 months for up to 12 years. 100 participants had MDD at study intake and 45 developed MDD during the study. Psychological functioning and treatment were assessed.
Results
Times to MDD onset (1 week – 4.3 years), recovery (8 weeks – 8.7 years), and relapse (1 week – 5.2 years) varied. 70% recovered from MDD, but 65% subsequently relapsed. ANR patients were significantly less likely to recover from MDD than ANBP patients (p=0.029). Better psychological functioning and history of MDD were associated with higher chance of MDD recovery. Higher baseline depressive severity and full recovery from ED were associated with greater likelihood of MDD relapse; increased weight loss was somewhat protective. Adequate antidepressant treatment was given to 72% of patients with MDD and generally continued after MDD recovery. Time on antidepressants did not predict MDD recovery (p=0.27) or relapse (p=0.26).
Limitations
Small ED diagnostic subgroups; lack of non-ED control group.
Conclusions
The course of MDD in EDs is protracted; MDD recovery may depend on ED type. Antidepressants did not impact likelihood of MDD recovery, nor protect against relapse, which may impact on treatment strategies for comorbid MDD and EDs.
doi:10.1016/j.jad.2010.10.043
PMCID: PMC3085695  PMID: 21109307
Major Depressive Disorder; Eating Disorders; Anorexia Nervosa; Bulimia Nervosa; Antidepressants
15.  Anxiety and depressive disorders are associated with delusional-like experiences: a replication study based on a National Survey of Mental Health and Wellbeing 
BMJ Open  2012;2(3):e001001.
Objectives
There is growing evidence that delusional-like experiences (DLE) are associated with common mental disorders. In particular, a National Mental Health Survey conducted in Australia during 2007 reported an association between DLE and both anxiety disorder and major depressive disorder (MDD). However, the previous study did not examine this association with respect to subtypes of anxiety disorder nor with severity of MDD. The aim of this study was to examine the associations between DLE and both anxiety disorder and MDD in more detail based on an independent population sample.
Design
Cross-sectional study.
Setting
Subjects were drawn from the Australian Survey of Mental Health and Wellbeing 1997 using a stratified multistage area sampling of persons living in private dwellings in all States and Territories of Australia.
Participants
Approximately 13 600 private dwellings were initially selected with one person aged 18 years or older from each dwelling invited to participate. In total, 10 641 individuals participated in the survey.
Primary and secondary outcome measures
The Composite International Diagnostic Interview was used to identify individuals with DLE and Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM IV) lifetime diagnoses of anxiety disorders and MDD. The influence of various anxiety disorders and MDD on DLE was assessed with logistic regression.
Results
Having a lifetime diagnosis of either any anxiety disorder or MDD was significantly associated with the endorsement of DLE. The association was found for each of the main anxiety disorders when examined separately. There was a dose–response relationship between increasing severity of MDD and higher odds of DLE endorsement.
Conclusions
DLE are associated with a wide range of anxiety disorders and are more prevalent in those with MDD. Understanding the relationship between DLE, anxiety disorders and depression may provide insights into shared pathways that underpin both psychotic disorders and common mental disorders.
Article summary
Article focus
The study was undertaken in order (1) to examine the association between DLE and (a) broadly defined anxiety disorders and (b) MDDs; (2) to explore the association between DLE and a range of specific anxiety disorders and (3) to examine if severity of MDD influenced the risk of endorsement of DLE.
Key message
Having a lifetime diagnosis of either any anxiety disorder or MDDs was significantly associated with the endorsement of DLE.
The association was found for each of the main anxiety disorders when examined separately.
There was a dose–response relationship between increasing severity of MDD and higher odds of DLE endorsement.
Strengths and limitations of this study
The data were drawn from the nationally representative sample from the Australia general population.
Cross-sectional study.
doi:10.1136/bmjopen-2012-001001
PMCID: PMC3367143  PMID: 22649176
16.  Psychosocial Features Associated with Lifetime Comorbidity of Major Depression and Anxiety Disorders Among a Community Sample of Mid-Life Women: The SWAN Mental Health Study 
Depression and anxiety  2012;29(12):1050-1057.
Background
In clinical samples, comorbidity between depressive and anxiety disorders is associated with greater symptom severity and elevated suicide risk. Less is known, however, regarding the long-term psychosocial impact that a lifetime history of both MDD and one or more anxiety disorders has in community samples. This report evaluates clinical, psychological, social, and stress-related characteristics associated with a lifetime history of MDD and anxiety.
Methods
Data from 915 women aged 42–52 who were recruited as part of the the Study of Women's Health Across the Nation Mental Health Study were used to examine clinical and psychosocial features across groups of women with a SCID-diagnosed lifetime history of MDD alone, anxiety alone, both MDD and anxiety, or neither MDD nor anxiety.
Results
As compared with women with a history of either MDD or anxiety alone, women with a comorbid history were more likely to report recurrent MDD, multiple and more severe lifetime anxiety disorders, greater depressive and anxiety symptoms, diminished social support, and more past-year distressing life events. Exploratory analyses indicated that women with a comorbid history also report more childhood abuse/neglect and diminished self-esteem, as compared with women with a history of either disorder alone.
Conclusions
Midlife women with a comorbid history that includes both MDD and anxiety disorders report diminished social support, more symptomatic distress, and a more severe and recurrent psychiatric history. Future research is needed to clarify the biological and psychosocial risk factors associated with this comorobid profile, and to develop targeted interventions for this at-risk group.
doi:10.1002/da.21990
PMCID: PMC3592574  PMID: 22930404
major depressive disorder; anxiety disorders; comorbidity; child abuse; social support; stress, psychological
17.  Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women☆ 
Journal of Affective Disorders  2011;135(1-3):95-99.
Background
In European and US studies, patients with major depressive disorder (MDD) report more stressful life events (SLEs) than controls, but this relationship has rarely been studied in Chinese populations.
Methods
Sixteen lifetime SLEs were assessed at interview in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MDD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Results
60% of controls and 72% of cases reported at least one lifetime SLE. Fourteen of the sixteen SLEs occurred significantly more frequently in those with MDD (median odds ratio of 1.6). The three SLEs most strongly associated with risk for MDD (OR > 3.0) preceded the onset of MDD the majority of the time: rape (82%), physical abuse (100%) and serious neglect (99%).
Limitations
Our results may apply to females only. SLEs were rated retrospectively and are subject to biases in recollection. We did not assess contextual information for each life event.
Conclusions
More severe SLEs are more strongly associated with MDD. These results support the involvement of psychosocial adversity in the etiology of MDD in China.
doi:10.1016/j.jad.2011.06.054
PMCID: PMC3210899  PMID: 21821294
Major depressive disorder; Stressful life event; Social adversity; Symptom
18.  Course of Major Depressive Disorder and Labor Market Outcome Disruption 
Background
Major depressive disorder (MDD) has been found to be negatively associated with labor market outcomes. However, MDD has many different courses that are chronic or persistent, relapsing and remitting, or limited to a single lifetime episode. Such heterogeneity has been ignored in most past analyses.
Aims of the Study
We examine the impact of heterogeneity in course of MDD on labor market outcomes.
Methods
Wave I (2001-2002) respondents of the National Epidemiological Survey on Alcohol and Related Conditions - a nationally representative panel survey - were interviewed on average 3 years later (2004-2005). We categorized changes in MDD before and after wave I and before wave II into six courses: incident, recent remission, persistent remission, relapse, persistent depression, and no history of MDD. Odds ratios (ORs) and marginal effects of MDD transitions in multivariable multinomial regressions of labor market outcomes (being out of the labor force, being unemployed, working part-time, and working full-time - the reference outcome) are reported.
Results
Men and women who exhibited persistent remission (2 to 3 years) were equally likely to be in the labor force, employed, and working full-time, compared to those with no history of MDD (reference group). For men, recently remitted MDD (<1 year), compared to the reference group, increased the likelihood of being unemployed (3.2% higher probability of being unemployed conditional on being in the labor force; OR = 1.97, 95% confidence interval [CI] = 1.13-3.44) and working part-time (5.8% higher probability of working part-time conditional on being employed; OR = 1.75, 95% CI = 1.10-2.80). For women, no statistically significant effect for recent remission was found. The negative effects of incident onset, relapse, and persistence of MDD were found on some labor market outcomes for men and, to a lesser extent, for women.
Discussion
Clinical treatment for depression should be coordinated and/or integrated with work-related interventions that help individuals who are recovering from depression to maintain their jobs. Such coordination will add to the value of clinical treatment for depression.
Implications for Health Policies
The impact of MDD on labor market outcomes varies by course of illness. Past studies may have underestimated lost earnings due to mental illness because they did not distinguish between recent and persistent remission and thus did not account for lost earnings due to recent remission.
Implications for Further Research
Further research is needed to understand why there are differential impacts for men and women and to make causal inferences on the relationships between MDD and labor market outcomes.
PMCID: PMC3292040  PMID: 21051796
19.  POSTPARTUM GAD IS A RISK FACTOR FOR POSTPARTUM MDD: THE COURSE AND LONGITUDINAL RELATIONSHIPS OF POSTPARTUM GAD AND MDD 
Depression and Anxiety  2013;30(6):506-514.
Background
The objective was to examine the course and longitudinal associations of generalized anxiety disorder (GAD) and major depressive disorder (MDD) in mothers over the postpartum 2 years.
Method
Using a prospective naturalistic design, 296 mothers recruited from a large community pool were assessed for GAD and MDD at 3, 6, 10, 14, and 24 months postpartum. Structured clinical interviews were used for diagnoses, and symptoms were assessed using self-report questionnaires. Logistic regression analyses were used to examine diagnostic stability and longitudinal relations, and latent variable modeling was employed to examine change in symptoms.
Results
MDD without co-occurring GAD, GAD without co-occurring MDD, and co-occurring GAD and MDD, displayed significant stability during the postpartum period. Whereas MDD did not predict subsequent GAD, GAD predicted subsequent MDD (in the form of GAD + MDD). Those with GAD + MDD at 3 months postpartum were significantly less likely to be diagnosis free during the follow-up period than those in other diagnostic categories. At the symptom level, symptoms of GAD were more trait-like than those of depression.
Conclusions
Postpartum GAD and MDD are relatively stable conditions, and GAD is a risk factor for MDD but not vice versa. Given the tendency of MDD and GAD to be persistent, especially when comorbid, and the increased risk for MDD in mothers with GAD, as well as the potential negative effects of cumulative exposure to maternal depression and anxiety on child development, the present findings clearly highlight the need for screening and treatment of GAD in addition to MDD during the postpartum period.
doi:10.1002/da.22040
PMCID: PMC3738937  PMID: 23288653
anxiety disorders; depressive disorders; depression; postpartum; comorbidity; diagnosis; prospective studies; epidemiology
20.  The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women 
Journal of Affective Disorders  2011;135(1-3):100-105.
Objective
The personality trait of neuroticism is a risk factor for major depressive disorder (MDD), but this relationship has not been demonstrated in clinical samples from Asia.
Methods
We examined a large-scale clinical study of Chinese Han women with recurrent major depression and community-acquired controls.
Results
Elevated levels of neuroticism increased the risk for lifetime MDD (with an odds ratio of 1.37 per SD), contributed to the comorbidity of MDD with anxiety disorders, and predicted the onset and severity of MDD. Our findings largely replicate those obtained in clinical populations in Europe and US but differ in two ways: we did not find a relationship between melancholia and neuroticism; we found lower mean scores for neuroticism (3.6 in our community control sample).
Limitations
Our findings do not apply to MDD in community-acquired samples and may be limited to Han Chinese women. It is not possible to determine whether the association between neuroticism and MDD reflects a causal relationship.
Conclusions
Neuroticism acts as a risk factor for MDD in Chinese women, as it does in the West and may particularly predispose to comorbidity with anxiety disorders. Cultural factors may have an important effect on its measurement.
doi:10.1016/j.jad.2011.06.053
PMCID: PMC3220767  PMID: 21824661
Major depressive disorder; Anxiety disorders; Neuroticism
21.  Decreased frontal regulation during pain anticipation in unmedicated subjects with major depressive disorder 
Translational Psychiatry  2013;3(3):e239-.
Major depressive disorder (MDD) is characterized by impaired processing of negative information, possibly due to dysfunction in both, the bottom-up emotional network and top-down modulatory network. By acquiring functional magnetic resonance imaging (fMRI) on a pain-anticipation task, we tested the hypothesis that individuals with MDD would show increased negative biasing that may be associated with reduced frontal connectivity. Thirty-one (15 females) unmedicated young adults with current MDD and 22 (11 females) healthy subjects with no history of MDD were recruited. Groups did not differ significantly in age, race, level of education, marital status or gender distribution. fMRI data were collected during an event-related pain-anticipation paradigm, during which subjects were cued to anticipate painful heat stimuli of high or low intensity. All temperature stimuli were applied to each subject's left forearm. We found that relative to healthy comparison subjects, participants with MDD showed significantly stronger responses to high versus low pain anticipation within right ventral anterior insula (AI), but overlapping response within right dorsal AI, which correlated positively with the depression symptoms severity in the MDD group. Functional connectivity analyses showed increased functional connectivity between dorsal insula and posterior thalamus and decreased functional connectivity between dorsal insula and the right inferior frontal gyrus in the MDD compared with the non-MDD group. Our results demonstrate that unmedicated individuals with current MDD compared with healthy never-depressed subjects show both differential and overlapping response within AI during anticipation of pain. Furthermore, the overlapping insular response is less regulated by frontal brain systems and is more subservient to affective processing regions in the posterior thalamus in MDD. These results support and provide functional validation of the co-occurring enhanced ‘bottom-up' and attenuated ‘top-down' processing of salient, unpleasant emotional information in MDD.
doi:10.1038/tp.2013.15
PMCID: PMC3625914  PMID: 23481626
depression; emotion; fMRI; imaging; insula; modulation
22.  Characteristics of subjects with comorbidity of symptoms of generalized anxiety and major depressive disorders and the corresponding threshold and subthreshold conditions in an Arab general population sample 
Summary
Background
There is controversy about differential meaningfulness between comorbid generalized anxiety disorder (GAD)/ major depressive disorder (MDD), the corresponding “pure” disorders and subthreshold conditions. We compared subjects who met DSM-IVTR criteria of symptoms and functional impairment for comorbid GAD/MDD, versus those with GAD, MDD, subthreshold conditions, and without significant symptoms. The comparison measures were socio-demographics, clinical severity, and quality of life (QOL).
Material/Methods
Participants (N=3155: 55.1% female, aged 16–87 yrs) were a general population sample of Kuwaitis who self-completed DSM-IVTR criteria-based questionnaires and the WHOQOL-BREF in 2006/7. We scrutinized the questionnaires and classified them into categories.
Results
Of the 273 GAD and 210 MDD cases, the prevalence of comorbidity among cases with GAD was 30.8%, and 40% among MDD. Of the 398 subthreshold GAD and 194 subthreshold MDD cases, 58 had subthreshold anxiety/depression comorbidity. Comorbid threshold GAD/MDD cases were significantly older, and more likely to be women, divorced and unemployed, compared with GAD and MDD. In all measures, the threshold GAD/MDD comorbidity was the severest condition. There was a monotonic decrease in QOL with increasing anxiety-depression symptoms. For the predictors of subjective QOL, the GAD/MDD comorbidity group differed markedly from the others.
Conclusions
The high prevalence of comorbidity and subthreshold conditions supports the recommendation to assess them routinely, regardless of the primary reason for consultation. Our findings support a dimensional model with comorbid GAD/MDD at the higher end of a continuum, and differing from the “pure” conditions by a later onset and predictors of subjective wellbeing.
doi:10.12659/MSM.882521
PMCID: PMC3560754  PMID: 22367127
comorbidity; anxiety; depression; subthreshold
23.  POSTTRAUMATIC STRESS DISORDER INCREASES RISK FOR SUICIDE ATTEMPT IN ADULTS WITH RECURRENT MAJOR DEPRESSION 
Depression and anxiety  2013;30(10):940-946.
Background
Genetics of Recurrent Early-Onset Depression study (GenRED II) data were used to examine the relationship between posttraumatic stress disorder (PTSD) and attempted suicide in a population of 1,433 individuals with recurrent early-onset major depressive disorder (MDD). We tested the hypothesis that PTSD resulting from assaultive trauma increases risk for attempted suicide among individuals with recurrent MDD.
Methods
Data on lifetime trauma exposures and clinical symptoms were collected using the Diagnostic Interview for Genetic Studies version 3.0 and best estimate diagnoses of MDD, PTSD, and other DSM-IV Axis I disorders were reported with best estimated age of onset.
Results
The lifetime prevalence of suicide attempt in this sample was 28%. Lifetime PTSD was diagnosed in 205 (14.3%) participants. We used discrete time-survival analyses to take into account timing in the PTSD-suicide attempt relationship while adjusting for demographic variables (gender, race, age, and education level) and comorbid diagnoses prior to trauma exposure. PTSD was an independent predictor of subsequent suicide attempt (HR = 2.5, 95% CI: 1.6, 3.8; P < .0001). Neither assaultive nor nonassaultive trauma without PTSD significantly predicted subsequent suicide attempt after Bonferroni correction. The association between PTSD and subsequent suicide attempt was driven by traumatic events involving assaultive violence (HR = 1.7, 95% CI: 1.3, 2.2; P < .0001).
Conclusions
Among those with recurrent MDD, PTSD appears to be a vulnerability marker of maladaptive responses to traumatic events and an independent risk factor for attempted suicide. Additional studies examining differences between those with and without PTSD on biological measures might shed light on this potential vulnerability
doi:10.1002/da.22160
PMCID: PMC4026925  PMID: 23893768
24.  The Influence of Depressive Symptoms on Suicidal Ideation Among U.S. Vietnam-Era and Afghanistan/Iraq-Era Veterans With Posttraumatic Stress Disorder 
Journal of traumatic stress  2012;25(5):578-582.
Major depressive disorder (MDD) co-occurs frequently with posttraumatic stress disorder (PTSD), and both disorders are linked to suicidal ideation. An emergent literature examines suicidal ideation in U.S. Afghanistan/Iraq-era veterans. Little research, however, has studied the role of PTSD and comorbid MDD on suicidal ideation across service eras. Therefore, this study aimed to examine the impact of depression on suicidal ideation in Afghanistan/Iraq-era and Vietnam-era veterans with PTSD. The sample included 164 Vietnam and 98 Afghanistan/Iraq veterans diagnosed with PTSD at a VA outpatient PTSD Clinic. Using structured interviews, 63% of the Vietnam sample and 45% of the Afghanistan/Iraq sample were diagnosed with comorbid current MDD. Measures included self-report assessments of PTSD and depressive symptoms and the Personality Assessment Inventory. Results of analyses suggested that in veterans of both eras, PTSD, MDD, and their interaction were significantly related to suicidal ideation (PTSD: η2 = .01; MDD: η2 = .10; PTSD × MDD: η2 = .02). For veterans reporting greater depressive symptoms, there was a stronger relationship between PTSD symptoms and suicidal ideation. These results suggest that veterans from both eras display a similar clinical presentation and highlight the need to consider depressive symptoms when assessing veterans with PTSD. Future research should examine suicidal ideation and behaviors as they change over time in these two cohorts.
doi:10.1002/jts.21741
PMCID: PMC3752899  PMID: 23047458
25.  Atypical depression is more common than melancholic in fibromyalgia: an observational cohort study 
Background
It has been postulated that atypical and melancholic depression subtypes exist in depressed fibromyalgia (FM) patients, yet no study has empirically tested this hypothesis. The purpose of this study is to determine whether major depressive disorder (MDD) with atypical features and MDD with melancholic features occurs in a FM sample and to describe their demographic, clinical and diagnostic characteristics.
Methods
An observational cohort study using a descriptive cross-sectional design recruited a convenience sample of 76 outpatients with FM from an academic Rheumatology clinic and a community mental health practice. Diagnoses of FM were confirmed using the 1990 ACR classification guidelines. Diagnoses of MDD and diagnostic subtypes were determined using the DSM-IV-TR criteria. Clinical characteristics were measured using the Fibromyalgia Impact Questionnaire, Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and other standardized instruments. Odds ratios were computed on subtype-specific diagnostic criteria. Correlations assessed associations between subtype diagnoses and diagnostic criteria.
Results
Of the 76 subjects with FM, 11.8% (n = 9) were euthymic, 52.6% (n = 40) met diagnostic criteria for MDD with atypical features and 35.6% (n = 27) for MDD with melancholic features. Groups did not differ on demographic characteristics except for gender (p = 0.01). The non-depressed and atypical groups trended toward having a longer duration of FM symptoms (18.05 yrs. ± 12.83; 20.36 yrs. ± 15.07) compared to the melancholic group (14.11 yrs. ± 8.82; p = 0.09). The two depressed groups experienced greater severity on all clinical features compared to the non-depressed group. The atypical group did not differ clinically from the melancholic group except the latter experienced greater depression severity (p = 0.001). The atypical group demonstrated the highest prevalence and correlations with atypical-specific diagnostic criteria: (e.g., weight gain/ increased appetite: OR = 3.5, p = 0.02), as did the melancholic group for melancholic-specific criteria: (e.g., anhedonia: OR = 20, p < 0.001).
Conclusion
Depressed fibromyalgia patients commonly experience both atypical and melancholic depressive features; however, in this study, atypical depression was 1.5 times more common than melancholic depression. This finding may have significant research and clinical implications.
doi:10.1186/1471-2474-11-120
PMCID: PMC2909161  PMID: 20546614

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