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1.  Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys 
To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD).
Nationally or regionally representative epidemiological interviews were administered to 74,045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI).
45.7% of respondents with lifetime MDD (32.0–46.5% inter-quartile range [IQR] across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8–54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9–47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset of their first anxiety disorder than their MDD, while 13.5% reported an earlier age-of-onset of MDD and the remaining 18.5% reported the same age-of-onset of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4% vs. 46.0%; χ21=187.0, p<.001) and suicide ideation (19.5% vs. 8.9%; χ21=71.6, p<.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high income countries (68.8% vs. 45.4%; χ21=108.8, p<.001) than low/middle income countries (30.3% vs. 20.6%; χ21=11.7, p<.001).
Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6–74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers versus causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.
PMCID: PMC5129607  PMID: 25720357
anxious depression; comorbidity; epidemiology
2.  The effects of comorbidity in defining major depression subtypes associated with long-term course and severity 
Psychological medicine  2014;44(15):3289-3302.
Although variation in long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods. However, it is not known whether these distinctions can be refined by added information about comorbid conditions. The current report presents results on this question.
Data come from 8,261 respondents with lifetime DSM-IV MDD in the WHO World Mental Health (WMH) Surveys. Outcomes include four retrospectively-reported measures of persistence-severity of course (years in episode; years in chronic episodes, hospitalization for MDD; disability due to MDD). Machine learning methods (regression tree analysis; lasso, ridge, and elastic net penalized regression) followed by k-means cluster analysis were used to augment previously-detected subtypes with information about prior comorbidity to predict these outcomes.
Predicted values were strongly correlated across outcomes. Cluster analysis of predicted values found 3 clusters with consistently high, intermediate, or low values. The high-risk cluster (32.4% of cases) accounted for 56.6–72.9% of high persistence, high chronicity, hospitalization, and disability. This high-risk cluster had both higher sensitivity and likelihood-ratio positive (relative proportions of cases in the high-risk cluster versus other clusters having the adverse outcomes) than in a parallel analysis that excluded measures of comorbidity as predictors.
Although results using the retrospective data reported here suggest that useful MDD subtyping distinctions can be made with machine learning and clustering across multiple indicators of illness persistence-severity, replication is need with prospective data to confirm this preliminary conclusion.
PMCID: PMC4180779  PMID: 25066141
Comorbidity; data mining; depression subtypes; depression symptom profiles; elastic net; machine learning; predictive modeling; risk assessment
3.  Major depressive disorder subtypes to predict long-term course 
Depression and anxiety  2014;31(9):765-777.
Variation in course of major depressive disorder (MDD) is not strongly predicted by existing subtype distinctions. A new subtyping approach is considered here.
Two data mining techniques, ensemble recursive partitioning and Lasso generalized linear models (GLMs) followed by k-means cluster analysis, are used to search for subtypes based on index episode symptoms predicting subsequent MDD course in the World Mental Health (WMH) Surveys. The WMH surveys are community surveys in 16 countries. Lifetime DSM-IV MDD was reported by 8,261 respondents. Retrospectively reported outcomes included measures of persistence (number of years with an episode; number of with an episode lasting most of the year) and severity (hospitalization for MDD; disability due to MDD).
Recursive partitioning found significant clusters defined by the conjunctions of early onset, suicidality, and anxiety (irritability, panic, nervousness-worry-anxiety) during the index episode. GLMs found additional associations involving a number of individual symptoms. Predicted values of the four outcomes were strongly correlated. Cluster analysis of these predicted values found three clusters having consistently high, intermediate, or low predicted scores across all outcomes. The high-risk cluster (30.0% of respondents) accounted for 52.9-69.7% of high persistence and severity and was most strongly predicted by index episode severe dysphoria, suicidality, anxiety, and early onset. A total symptom count, in comparison, was not a significant predictor.
Despite being based on retrospective reports, results suggest that useful MDD subtyping distinctions can be made using data mining methods. Further studies are needed to test and expand these results with prospective data.
PMCID: PMC5125445  PMID: 24425049
Epidemiology; Depression; Anxiety/Anxiety Disorders; Suicide/Self Harm; Panic Attacks
Depression and Anxiety  2013;30(6):506-514.
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.
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.
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.
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.
PMCID: PMC3738937  PMID: 23288653
anxiety disorders; depressive disorders; depression; postpartum; comorbidity; diagnosis; prospective studies; epidemiology
5.  Depressive Symptoms Predict Major Depressive Disorder after 15 Years among Whites but Not Blacks 
Black–White differences are shown in psychosocial and medical correlates of depressive symptoms and major depressive disorder (MDD). The current longitudinal study compared Blacks and Whites for the association between baseline depressive symptoms and subsequent risk of MDD after 15 years.
Data were obtained from the Americans’ Changing Lives (ACL) Study that included 3,361 individuals (2,205 Whites and 1,156 Blacks) from 1986 to 2001. Baseline depressive symptoms measured using an 11-item Center for Epidemiological Studies-Depression (CES-D) in 1986 were predictors. The outcome of 12-month MDD was measured using the Composite International Diagnostic Interview (CIDI) in 2001. Covariates such as baseline socio-demographics (SES), financial difficulty, chronic medical conditions (CMC), and self-rated health (SRH) were measured in 1986. Logistic regression models were used to evaluate the association between baseline CES-D score and CIDI-based MDD after 15 years net of demographics, SES, CMC, and SRH. The models were applied in the pooled sample, as well as in Blacks and Whites. Data on reliability and factor structure of CES-D based on ethnicity were also reported.
In the pooled sample, we found an interaction between race and baseline depressive symptoms, suggesting a stronger effect of baseline depressive symptoms on the subsequent risk of MDD for Whites compared with that of Blacks. Such an interaction was significant net of socioeconomic and health status. Based on our ethnic-specific models, among Whites but not Blacks, baseline CES-D score was predictive of the subsequent risk of MDD after 15 years, net of SES and health at baseline. Black–White differences in the predictive role of CES-D scores on MDD could not be attributed to the ethnic differences in the reliability of the CES-D, which was even higher for Blacks compared with those of Whites. Loadings of the CES-D positive affect items were reverse among Blacks compared to Whites.
Black–White differences exist in the association between baseline depressive symptoms and subsequent risk of MDD >15 years. Ethnic differences in the longitudinal link between baseline CES-D and subsequent risk of MDD may explain some of the Black–White differences in social, psychological, and medical correlates of depressive symptoms and depression. Future research is still needed to compare Blacks and Whites for factor structure of the CES-D.
PMCID: PMC4756109  PMID: 26925396
ethnic groups; African Americans; depressive symptoms; depression; validity; reliability
6.  Neuroticism Predicts Subsequent Risk of Major Depression for Whites but Not Blacks 
Behavioral Sciences  2017;7(4):64.
Cultural and ethnic differences in psychosocial and medical correlates of negative affect are well documented. This study aimed to compare blacks and whites for the predictive role of baseline neuroticism (N) on subsequent risk of major depressive episodes (MDD) 25 years later. Data came from the Americans’ Changing Lives (ACL) Study, 1986–2011. We used data on 1219 individuals (847 whites and 372 blacks) who had data on baseline N in 1986 and future MDD in 2011. The main predictor of interest was baseline N, measured using three items in 1986. The main outcome was 12 months MDD measured using the Composite International Diagnostic Interview (CIDI) at 2011. Covariates included baseline demographics (age and gender), socioeconomics (education and income), depressive symptoms [Center for Epidemiologic Studies Depression Scale (CES-D)], stress, health behaviors (smoking and driking), and physical health [chronic medical conditions, obesity, and self-rated health (SRH)] measured in 1986. Logistic regressions were used to test the predictive role of baseline N on subsequent risk of MDD 25 years later, net of covariates. The models were estimated in the pooled sample, as well as blacks and whites. In the pooled sample, baseline N predicted subsequent risk of MDD 25 years later (OR = 2.23, 95%CI = 1.14–4.34), net of covariates. We also found a marginally significant interaction between race and baseline N on subsequent risk of MDD (OR = 0.37, 95% CI = 0.12–1.12), suggesting a stronger effect for whites compared to blacks. In race-specific models, among whites (OR = 2.55; 95% CI = 1.22–5.32) but not blacks (OR = 0.90; 95% CI = 0.24–3.39), baseline N predicted subsequent risk of MDD. Black-white differences in socioeconomics and physical health could not explain the racial differences in the link between N and MDD. Blacks and whites differ in the salience of baseline N as a psychological determinant of MDD risk over a long period of time. This finding supports the cultural moderation hypothesis and is in line with other previously reported black–white differences in social, psychological, and medical correlates of negative affect and depression.
PMCID: PMC5746673  PMID: 28934128
ethnic groups; African Americans; whites; neuroticism; depression
7.  Prevalence and Predictors of Major Depressive Disorder for Fertility Treatment Patients and their Partners 
Fertility and sterility  2015;103(5):1332-1339.
Structured Abstract
To examine the prevalence and predictors of major depressive disorder (MDD) for women and their partners during the course of fertility treatment.
Prospective cohort study over an 18-month period. Participants completed interviews and questionnaires at baseline and at 4, 10, and 18 months follow-up.
Five community and academic fertility practices.
174 women and 144 of their male partners who did not have a successful child-related outcome during the timeframe of the study.
No interventions administered.
Main Outcome Measures
MDD was assessed using the Composite International Diagnostic Interview (CIDI) Major Depression module, a structured diagnostic interview. Additional variables were assessed with self-report questionnaire measures.
39.1% of the women and 15.3% of the men met the criteria for MDD during the 18-month course of the study. A binary logistic covariate-adjusted model including showed that, for both women and men, past MDD was a significant predictor of MDD during treatment. Past MDD further predicted significant risk for MDD during treatment after controlling for other well-established risk factors (i.e., baseline levels of depression, anxiety, and partner support).
MDD was highly prevalent for fertility treatment patients and their partners. Past MDD predicted risk for MDD during treatment, and it contributed to MDD risk over and above other commonly-assessed risk factors. This suggests patients and their partners would benefit from being routinely assessed for a history of MDD prior to the start of treatment in order to best direct psychosocial support and interventions to those most in need.
PMCID: PMC4417384  PMID: 25796319
fertility treatment; depression
8.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
9.  Predictors of First Lifetime Onset of Major Depressive Disorder in Young Adulthood 
The first onset of major depressive disorder (MDD) most frequently occurs in young adulthood. However, few studies have examined predictors of first lifetime MDD during this high-risk period. The present study examined a broad range of demographic, clinical, and psychosocial variables as prospective predictors of first onset of MDD in a large community sample of young adults (N = 502) from the Oregon Adolescent Depression Project. Between ages 19-31, 35.3% of the sample had a first lifetime MDD episode. Female gender, familial loading of mood disorders, history of childhood sexual abuse, prior history of anxiety disorder, poor self-reported physical health, and subthreshold depressive symptoms significantly predicted MDD onset. In a multivariate model, female gender, familial loading of mood disorders, and subthreshold depression each contributed unique variance in predicting first lifetime MDD. This model had a moderate-to-large effect in predicting MDD onset. Gender did not moderate the other predictors, and the magnitude of the effects did not diminish over the course of the follow-up. These findings indicate that a number of risk factors significantly predict first lifetime MDD in young adulthood, and that simple multivariate risk models may be useful for identifying individuals at high risk for MDD.
PMCID: PMC3570686  PMID: 22889243
major depressive disorder; onset; risk; young adulthood
Depression and anxiety  2013;30(4):395-406.
Although irritability is a core symptom of DSM-IV major depressive disorder (MDD) for youth but not adults, clinical studies find comparable rates of irritability between nonbipolar depressed adults and youth. Including irritability as a core symptom of adult MDD would allow detection of depression-equivalent syndromes with primary irritability hypothesized to be more common among males than females. We carried out a preliminary examination of this issue using cross-national community-based survey data from 21 countries in the World Mental Health (WMH) Surveys (n = 110,729).
The assessment of MDD in the WHO Composite International Diagnostic Interview includes one question about persistent irritability. We examined two expansions of the definition of MDD involving this question: (1) cases with dysphoria and/or anhedonia and exactly four of nine Criterion A symptoms plus irritability; and (2) cases with two or more weeks of irritability plus four or more other Criterion A MDD symptoms in the absence of dysphoria or anhedonia.
Adding irritability as a tenth Criterion A symptom increased lifetime prevalence by 0.4% (from 11.2 to 11.6%). Adding episodes of persistent irritability increased prevalence by an additional 0.2%. Proportional prevalence increases were significantly higher, but nonetheless small, among males compared to females. Rates of severe role impairment were significantly lower among respondents with this irritable depression who did not meet conventional DSM-IV criteria than those with DSM-IV MDD.
Although limited by the superficial assessment in this single question on irritability, results do not support expanding adult MDD criteria to include irritable mood.
PMCID: PMC4117370  PMID: 23364997
epidemiology; depression; mood disorders; assessment/diagnosis; measurement/psychometrics; irritability; major depression; nosology; world mental health (WMH) surveys
11.  Do anxiety symptoms predict major depressive disorder in midlife women? The Study of Women’s Health Across the Nation (SWAN) Mental Health Study (MHS) 
Psychological medicine  2014;44(12):2593-2602.
In women, anxiety symptoms are common and increase during midlife, but little is known about whether these symptoms predict onsets of major depressive disorder (MDD) episodes. We examined whether anxiety symptoms are associated with subsequent episodes of MDD in midlife African-American and Caucasian women, and whether they confer a different risk for first versus recurrent MDD episodes.
A longitudinal analysis was conducted using 12 years of data from the Study of Women’s Health Across the Nation (SWAN) Mental Health Study (MHS). The baseline sample comprised 425 Caucasian (n=278) and African American (n=147) community-dwelling women, aged 46.1±2.5 years. Anxiety symptoms measured annually using a self-report questionnaire were examined in relation to MDD episodes in the subsequent year, assessed with the SCID. Multivariable models were estimated with random effects logistic regression.
Higher anxiety symptoms scores were associated with a significantly higher adjusted odds of developing an episode of MDD at the subsequent annual visit [odds ratio (OR) 1.47, p=0.01], specifically for a recurrent episode (OR 1.49, p=0.03) but non-significant for a first episode (OR 1.32, p=0.27). There were no significant racial effects in the association between anxiety symptoms and subsequent MDD episodes.
Anxiety symptoms often precede MDD and may increase the vulnerability of midlife women to depressive episodes, particularly recurrences. Women with anxiety symptoms should be monitored clinically during the ensuing year for the development of an MDD episode.
PMCID: PMC4135380  PMID: 24467997
Anxiety; longitudinal; major depressive disorder; midlife women; race
12.  Prevalence and age-of-onset distributions of DSM IV mental disorders and their severity among school going Omani adolescents and youths: WMH-CIDI findings 
There is a dearth of studies exploring the magnitude of mental disorders amongst adolescents and youths in the Arab world. To our knowledge, this phase 2 survey in Oman is the first nationally representative school-based study to determine the prevalence of DSM-IV mental disorders (lifetime and over the preceding 12 months), their age-of-onset distributions and determine their severity over the past 12 months using the World Mental Health-Composite International Diagnostic Interview, the WMH-CIDI, used for international comparison.
A total of 1,682 (91.61%) students out of 1836 students who formed the phase 2 random sub-sample of a multi-stage, stratified, random sampling design (phase 1), participated in the face-to-face structured interview using the Arabic-version of WMH-CIDI 3.0.
The phase 1 results using the General Health Questionnaire (GHQ-12) and Child Depression Inventory (CDI) showed depressive symptoms to be 17% prevalent in the larger sample of 5409 adolescents and youths. Amongst the phase 2 respondents from this sample, 13.9% had at least one DSM IV diagnostic label. The lifetime prevalence of Major Depressive Disorder (MDD) was 3.0%; Bipolar Mood Disorder (BMD) was 1%, Specific phobia 5.8% and Social phobia 1.6%. The female gender was a strong predictor of a lifetime risk of MDD (OR 3.3, 95% CI 1.7-6.3, p = 0.000); Any Mood Disorders (OR 2.5, 95% CI 1.4-4.3, p = 0.002) and Specific Phobia (OR 1.5, 95% CI 1.0-2.4, p = 0.047). The severity of illness for cases diagnosed with 12 month DSM IV disorders was found to be 80% lower in females (OR 0.2, 95%CI 0.0-0.8). The estimates over the previous 12 month period when compared with the lifetime prevalence showed a 25% to 40% lower prevalence for MDD, Specific phobia, Social phobia, Any Anxiety Disorders (AAD) and Any Mood disorders (AMD) while the rate was 80% lower for Separation Anxiety Disorder/Adult Separation Anxiety (SAD/ASA). Mood disorders were significantly lower in the 14-16 age groups (70% lower) in comparison to the older age groups and AMD showed a linear increase in prevalence across increasing age groups (p = 0.035).
The implications of the present findings are not clear cut, however this study endorses the adult CIDI studies findings that mental disorders do begin earlier in life. The relatively lower prevalence of DSM IV depressive disorders cautions against any conclusive interpretation of the inflated results based on the exclusive study of the depressive symptoms alone in the same sample in the same time period. The female gender proved to be a strong predictor of lifetime risk of MDD, any mood disorder and specific phobia. Under-reporting by males or some other gender-specific factors may have contributed to such a discrepancy. The odds of the severity of illness for cases with 12 month DSM IV disorders were significantly lower in females.
PMCID: PMC2761855  PMID: 19781098
13.  Quantifying the impact of chronic conditions on a diagnosis of major depressive disorder in adults: a cohort study using linked electronic medical records 
BMC Psychiatry  2016;16:114.
Major depressive disorder (MDD) is often comorbid with other chronic mental and physical health conditions. Although the literature widely acknowledges the association of many chronic conditions with the risk of MDD, the relative importance of these conditions on MDD risk in the presence of other conditions is not well investigated. In this study, we aimed to quantify the relative contribution of selected chronic conditions to identify the conditions most influential to MDD risk in adults and identify differences by age.
This study used electronic health record (EHR) data on patients empanelled with primary care at Mayo Clinic in June 2013. A validated EHR-based algorithm was applied to identify newly diagnosed MDD patients between 2000 and 2013. Non-MDD controls were matched 1:1 to MDD cases on birth year (±2 years), sex, and outpatient clinic visits in the same year of MDD case diagnosis. Twenty-four chronic conditions defined by Chronic Conditions Data Warehouse were ascertained in both cases and controls using diagnosis codes within 5 years of index dates (diagnosis dates for cases, and the first clinic visit dates for matched controls). For each age group (45 years or younger, between 46 and 60, and over 60 years), conditional logistic regression models were used to test the association between each condition and subsequent MDD risk, adjusting for educational attainment and obesity. The relative influence of these conditions on the risk of MDD was quantified using gradient boosting machine models.
A total of 11,375 incident MDD cases were identified between 2000 and 2013. Most chronic conditions (except for eye conditions) were associated with risk of MDD, with different association patterns observed depending on age. Among 24 chronic conditions, the greatest relative contribution was observed for diabetes mellitus for subjects aged ≤ 60 years and rheumatoid arthritis/osteoarthritis for those over 60 years.
Our results suggest that specific chronic conditions such as diabetes mellitus and rheumatoid arthritis/osteoarthritis may have greater influence than others on the risk of MDD.
PMCID: PMC4845377  PMID: 27112538
Major depressive disorder; Depression; Multimorbidity; Comorbidity; Risk factors; Relative influence
14.  Co-morbidity between major depressive disorder and anxiety disorders: shared etiology or direct causation? 
Psychological medicine  2011;41(10):2023-2034.
Major depressive disorder (MDD) and anxiety disorders (ANX) are debilitating and prevalent conditions that often co-occur in adolescence and young adulthood. The leading theoretical models of their co-morbidity include the direct causation model and the shared etiology model. The present study compared these etiological models of MDD–ANX co-morbidity in a large, prospective, non-clinical sample of adolescents tracked through age 30.
Logistic regression was used to examine cross-sectional associations between ANX and MDD at Time 1 (T1). In prospective analyses, Cox proportional hazards models were used to examine T1 predictors of subsequent disorder onset, including risk factors specific to each disorder or common to both disorders. Prospective predictive effect of a lifetime history of one disorder (e.g. MDD) on the subsequent onset of the second disorder (e.g. ANX) was then examined. This step was repeated while controlling for common risk factors.
The findings supported relatively distinct profiles of risk between MDD and ANX depending on order of development. Whereas the shared etiology model best explained co-morbid cases in which MDD preceded ANX, direct causation was supported for co-morbid cases in which ANX preceded MDD.
Consistent with previous research, significant cross-sectional and prospective associations were found between MDD and ANX. The results of the present study suggest that different etiological models may characterize the co-morbidity between MDD and ANX based upon the temporal order of onset. Implications for classification and prevention efforts are discussed.
PMCID: PMC3713851  PMID: 21439108
Anxiety; co-morbidity; depression; etiology
15.  Recurrent Depression, Cardiovascular Disease, and Diabetes among Middle-Aged and Older Adult Women 
Journal of affective disorders  2013;150(3):895-902.
The goal of this study was to investigate the concurrent and prospective relationships between a history of single and recurrent Major Depression Disorder (MDD) and the medical conditions of cardiovascular disease (CVD) and diabetes using a community sample of middle- and older-aged women.
Data from women (n=557 at baseline; mean age=55.7 yrs.) participating in a two-wave longitudinal study (5-year interval) were used to examine associations between single and recurrent MDD, assessed with a structured clinical interview, and three self-report indicators of CVD (heart attack or myocardial infarction, stroke, angina), major CVD risk markers (hypertension, high cholesterol), and diabetes. Analyses were conducted to evaluate hypotheses which proposed that recurrent depression would be significantly associated with the three medical outcomes, but not single episode MDD.
After controlling for a range of important covariates (e.g., BMI, smoking, alcohol use), cross-sectional analyses indicated that recurrent MDD, but not single episode MDD, significantly predicted CVD risk and diabetes. Prospective analyses indicated that recurrent MDD, but not single episode MDD, increased the risk for CVD and diabetes.
The sample was a predominantly white, middle-class sample so generalizability of findings may be limited for minorities and men. Reliance on self-report data may have biased the findings.
These findings suggest the benefits of measuring single versus recurrent MDD when investigating the risk of depression on chronic diseases. Findings also suggest the importance of identifying individuals suffering from recurrent MDD early in their lifespan with the goal of preventing future depressive episodes.
PMCID: PMC3759584  PMID: 23721922
Depression; CVD; Diabetes; Hypertension; Cholesterol
16.  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
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.
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
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
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
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
PMCID: PMC3818162  PMID: 24223526
17.  Poor sleep quality predicts onset of either major depression or subsyndromal depression with irritability during interferon-alpha treatment 
Psychiatry research  2010;177(1-2):240-245.
Major depressive disorder (MDD) often occurs during pegylated IFN-α2 (IFN-α) treatment. Identifying who is at risk for MDD in this population is essential, and epidemiological studies suggest that sleep may be related to depression risk. Controlling for pre-existing depression symptoms, we therefore examined whether sleep quality prior to IFN-α treatment would predict subsequent MDD incidence during IFN-α treatment. Adults with hepatitis C but without current clinical MDD (n=86) were evaluated prior to IFN-α treatment and then prospectively monitored during treatment using self-report measures of sleep quality (PSQI), depression (BDI), and anger and irritability (AIAQ), as well as with Structured Clinical Interviews for DSM-IV Axis I Disorders (SCID-I). During IFN-α treatment, 19% developed MDD, 19% developed subsyndromal depression with irritability, and one developed mania. Controlling for baseline depression symptoms and past history of depression, patients with worse sleep quality (PSQI≥10) prior to treatment had shorter time until developing MDD (Hazard ratio = 10.6; 95% Confidence Interval = 3.4–32.2; log-rank χ2=33.83, P<0.0001) or any severe psychiatric problem (Hazard ratio = 6.2; 95% Confidence Interval=2.9–13.1; log-rank χ2=36.86, P<0.0001). These findings may have important implications for understanding, predicting, and possibly preventing depression, particularly in individuals treated with IFN-α.
PMCID: PMC2861158  PMID: 20381876
Insomnia; Survival Analysis
18.  Single versus Recurrent Depression History: Differentiating risk-factors among current U.S. Smokers 
Drug and alcohol dependence  2010;109(1-3):90-95.
The strong relationship between persistent tobacco use and Major Depressive Disorder (MDD) has motivated clinical trials of specialized treatments targeting smokers with a history of MDD. Meta-analyses suggest positive responses to specialized treatments have been observed consistently among smokers with history of recurrent rather than a single episode of MDD. Approximately 15% of current US smokers have a history of recurrent MDD. Little is known about the risk factors that contribute to persistent smoking and differentiate these at-risk smokers. US.
The National Comorbidity Survey – Replication (NCS-R) included a survey of 1560 smokers participants aged 18 and older in the United States. Lifetime history of MDD was categorized according to chronicity: No History (No MDD), single episode (MDD-S) and recurrent depression (MDD-R). The relationship between the chronicity of MDD, smoking characteristics, cessation history, nicotine dependence, comorbidity with psychiatric disorders, and current functional impairments were examined.
MDD-R smokers reported fewer lifetime cessation efforts, smoked more cigarettes, had higher levels of nicotine dependence, had higher rates of co-morbid psychiatric disorders and greater functional impairment than smokers with No MDD. MDD-S smokers were not consistently distinguished from No MDD smokers on cessation attempts, level of daily smoking, nicotine dependence or functional impairment indices.
The study highlights the importance of chronicity when characterizing depression related risk of persistent smoking behavior. Although, clinical trials suggest MDD-R smokers specifically benefit from specialized behavioral treatments, these services are not widely available and more efforts are needed to engage MDD-R smokers in efficacious treatments. Abstract Word Count: 249
PMCID: PMC2890270  PMID: 20074868
Smoking; Depression; Recurrent Depression; Nicotine Dependence; Item
19.  Testing the Predictive Value of Peripheral Gene Expression for Nonremission Following Citalopram Treatment for Major Depression 
Neuropsychopharmacology  2014;40(3):701-710.
Major depressive disorder (MDD) in general, and anxious-depression in particular, are characterized by poor rates of remission with first-line treatments, contributing to the chronic illness burden suffered by many patients. Prospective research is needed to identify the biomarkers predicting nonremission prior to treatment initiation. We collected blood samples from a discovery cohort of 34 adult MDD patients with co-occurring anxiety and 33 matched, nondepressed controls at baseline and after 12 weeks (of citalopram plus psychotherapy treatment for the depressed cohort). Samples were processed on gene arrays and group differences in gene expression were investigated. Exploratory analyses suggest that at pretreatment baseline, nonremitting patients differ from controls with gene function and transcription factor analyses potentially related to elevated inflammation and immune activation. In a second phase, we applied an unbiased machine learning prediction model and corrected for model-selection bias. Results show that baseline gene expression predicted nonremission with 79.4% corrected accuracy with a 13-gene model. The same gene-only model predicted nonremission after 8 weeks of citalopram treatment with 76% corrected accuracy in an independent validation cohort of 63 MDD patients treated with citalopram at another institution. Together, these results demonstrate the potential, but also the limitations, of baseline peripheral blood-based gene expression to predict nonremission after citalopram treatment. These results not only support their use in future prediction tools but also suggest that increased accuracy may be obtained with the inclusion of additional predictors (eg, genetics and clinical scales).
PMCID: PMC4289958  PMID: 25176167
20.  Using patient self-reports to study heterogeneity of treatment effects in major depressive disorder 
Clinicians need guidance to address the heterogeneity of treatment responses of patients with major depressive disorder (MDD). While prediction schemes based on symptom clustering and biomarkers have so far not yielded results of sufficient strength to inform clinical decision-making, prediction schemes based on big data predictive analytic models might be more practically useful.
We review evidence suggesting that prediction equations based on symptoms and other easily-assessed clinical features found in previous research to predict MDD treatment outcomes might provide a foundation for developing predictive analytic clinical decision support models that could help clinicians select optimal (personalized) MDD treatments. These methods could also be useful in targeting patient subsamples for more expensive biomarker assessments.
Approximately two dozen baseline variables obtained from medical records or patient reports have been found repeatedly in MDD treatment trials to predict overall treatment outcomes (i.e., intervention versus control) or differential treatment outcomes (i.e., intervention A versus intervention B). Similar evidence has been found in observational studies of MDD persistence-severity. However, no treatment studies have yet attempted to develop treatment outcome equations using the full set of these predictors. Promising preliminary empirical results coupled with recent developments in statistical methodology suggest that models could be developed to provide useful clinical decision support in personalized treatment selection. These tools could also provide a strong foundation to increase statistical power in focused studies of biomarkers and MDD heterogeneity of treatment response in subsequent controlled trials.
Coordinated efforts are needed to develop a protocol for systematically collecting information about established predictors of heterogeneity of MDD treatment response in large observational treatment studies, applying and refining these models in subsequent pragmatic trials, carrying out pooled secondary analyses to extract the maximum amount of information from these coordinated studies, and using this information to focus future discovery efforts in the segment of the patient population in which continued uncertainty about treatment response exists.
PMCID: PMC5125904  PMID: 26810628
Depression; evidence-based psychiatry; research design and methods; treatment allocation; epidemiology
21.  Prognostic Utility of a Self-Reported Depression Questionnaire versus Clinician-Based Assessment on Renal Outcomes 
American journal of nephrology  2016;44(3):234-244.
The prognostic utility of self-administered depression scales in CKD independent of a clinician-based Major Depressive Disorder (MDD) diagnosis is not clearly established, nor the optimal cutoff scores for predicting outcomes. The overlap between symptoms of depression and chronic disease raises the question of whether a cut-off score on a depression scale can be substituted for a time-consuming diagnostic interview to prognosticate risk.
The Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR16) was administered to 266 consecutive outpatients with non-dialysis CKD, followed prospectively for 12 months for an apriori composite outcome of death or dialysis or hospitalization. Association of QIDS-SR16 best cut-off score, determined by receiver/responder operating characteristics curves, with outcomes was investigated using survival analysis. The effect modification of an interview-based clinician MDD diagnosis on this association was ascertained.
There were 126 composite events. A QIDS-SR16 cutoff ≥8 had the best prognostic accuracy, HR =1.77 (1.24–2.53), p =0.002. This cutoff remained significantly associated with outcomes even after controlling for comorbidities, eGFR, hemoglobin and serum albumin, adjusted HR (aHR) =1.80 (1.23–2.62), p =0.002, and performed similarly to a clinician-based MDD diagnosis [aHR =1.72 (1.14, 2.68)]. Adjustment for MDD conferred the association of QIDS-SR16 with outcomes no longer significant.
QIDS-SR16 cutoff ≥8 adds to the prognostic information available to practicing nephrologists during routine clinic visits from comorbidities and laboratory data. This cutoff score performs similarly to a clinician diagnosis of MDD and provides a feasible and time-saving alternative to an interview-based MDD diagnosis for determining prognosis in CKD patients.
PMCID: PMC5033719  PMID: 27592294
Depression; chronic kidney disease; outcomes; survival; hospitalization; prognosis
22.  The prospective association between obesity and major depression in the general population: does single or recurrent episode matter? 
BMC Public Health  2015;15:350.
Obesity and major depressive disorder (MDD) are important public health problems. MDD is a heterogeneous disorder and the direction of its association with obesity remains unclear. Evidence grows that recurrent MDD (MDD-R) differs in etiology and prognosis from single episode MDD (MDD-S), which could affect associations with obesity. However, evidence on this differential effect is lacking. The aim of this study was to examine the direction of the association between obesity and MDD, single or recurrent episode.
A longitudinal study was performed in a cohort of 1094 participants of the PREVEND study, on whom data were collected at baseline and at an average 2-year follow-up. MDD-S and MDD-R were assessed by the Composite International Diagnostic Interview (CIDI 2.1). Obesity was defined as Body Mass Index ≥ 30 kg/m2. Binary logistic regression analyses were conducted to examine whether obesity predicts MDD-S/MDD-R or vice versa, adjusted for potential confounders.
Prospective analyses showed that BMI at baseline was associated with the onset of MDD-R (Odds ratio, OR = 1.32; 95% confidence interval, 95%CI: 1.11; 1.57) during 2-year follow-up, but not with the onset of MDD-S (OR = 0.98; 95%CI: 0.89; 1.07). Obesity at baseline was not associated with the onset of MDD-S during follow-up (OR = 0.75; 95%CI: 0.25; 2.30), but associated with the onset of MDD-R during follow-up (OR = 11.63; 95%CI: 1.05; 128.60). Neither MDD-S nor MDD-R were associated with the development of obesity during 2-year follow-up (OR = 1.67, 95%CI: 0.64; 4.29 and OR = 2.32, 95%CI: 0.82; 6.58, respectively).
Our findings add to the available evidence that obesity might specifically be associated with the onset of multiple episodes of major depression (MDD-R). Although the reverse association was not found, MDD-R tends to be also associated with subsequent development of obesity, but larger studies are needed to fully assess this issue. The heterogeneity of MDD should be considered when examining the effect of obesity on MDD.
PMCID: PMC4488044  PMID: 25880736
Obesity; Major depression; Single; Recurrent; Association; Longitudinal study
23.  Demographic Correlates of DSM-IV Major Depressive Disorder among Older African Americans, Black Caribbeans, and Non-Hispanic Whites: Results from the National Survey of American Life 
To examine the demographic correlates of lifetime and 12-month prevalence of major depressive disorder (MDD) among older African Americans, Black Caribbeans, and non-Hispanic Whites.
Data are from adults age 55 years and older (n = 1439) recruited to the National Survey of American Life (NSAL; 2001–2003). The DSM-IV World Mental Health Composite International Diagnostic Interview was used to assess 12-month and lifetime MDD. Weighted logistic regression was used to model demographic correlates of MDD.
The population prevalence of lifetime and 12-month MDD were 11.2% and 4.1%, respectively. Bivariate analyses revealed that younger respondents and those with greater disability had a higher prevalence of both lifetime and 12-month MDD compared to those who were older and had lower disability. Multivariable logistic regressions controlling for demographic characteristics revealed that non-Hispanic Whites had the greatest odds of lifetime MDD (OR = 2.27, 95% CI = 1.32, 3.93). Women had significantly greater odds of lifetime MDD compared to men (OR = 2.49, 95% CI = 1.14, 5.41); there were no gender differences in 12-month MDD. Other significant predictors of MDD were marital status and region of residence.
The distribution, correlates, and nature of associations with MDD vary as a function of whether we examined lifetime vs. 12-month MDD. Future work should account for within group differences among older adults with depression. Understanding MDD correlates and the nature of intergroup diversity can inform the identification of particularly vulnerable subgroups as well as appropriate treatment approaches.
PMCID: PMC3418432  PMID: 22038674
depression; Caribbean Blacks; race; ethnicity gender; disability; marital status
24.  The Importance of Irritability as a Symptom of Major Depressive Disorder: Results from the National Comorbidity Survey Replication 
Molecular psychiatry  2009;15(8):856-867.
Irritability is a diagnostic symptom of child-adolescent but not adult major depressive disorder (MDD) in both the DSM-IV and ICD-10 systems. We explore the importance of irritability for sub-typing adult DSM-IV MDD in the National Comorbidity Survey Replication (NCS-R), a national US adult household survey. The WHO Composite International Diagnostic Interview (CIDI) was used to assess prevalence of many DSM-IV disorders in the lifetime and in the year before interview (12-month prevalence). MDD was assessed conventionally (i.e., requiring either persistent sadness or loss of interest), but with irritability included as one of the Criterion A symptoms. We also considered the possibility that irritability might be a diagnostic symptom of adult MDD (i.e., detect cases who had neither sad mood nor loss of interest). Twelve-month MDD symptom severity was assessed with the Quick Inventory of Depressive Symptomatology and role impairment with the Sheehan Disability Scale. After excluding bipolar spectrum disorders, irritability during depressive episodes was reported by roughly half of respondents with lifetime DSM-IV MDD. Irritability in the absence of either sad mood or loss of interest, in comparison, was rare. Irritability in MDD was associated with early age-of-onset, lifetime persistence, comorbidity with anxiety and impulse-control disorders, fatigue and self-reproach during episodes, and disability. Irritability was especially common in MDD among respondents in the age range 18–44 and students. Further investigation is warranted of distinct family aggregation, risk factors, and treatment response. Consideration should also be given to including irritability as a non-diagnostic symptom of adult MDD in DSM-V and ICD-11.
PMCID: PMC3012558  PMID: 19274052
Epidemiology; Irritability; Major Depressive Disorder (MDD); National Comorbidity Survey Replication (NCS-R); adult
25.  Subthreshold Substance Use and the Treatment of Resistant Depression in Adolescents 
Despite the known association between substance use disorders (SUD) and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD.
Youth with MDD who had not improved after an adequate SSRI trial (N = 334) were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial. Analyses examined substance use (via the Drug Use Severity Index) and changes therein in relation to treatment and depressive symptoms. Adolescents meeting SUD criteria via the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version at baseline were excluded.
Substance use was common: 28.1% reported repeated experimentation at baseline. Substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. There was significant improvement in substance-related impairment among adolescents who responded to MDD treatment. Baseline suicidal ideation was higher among subjects who progressed to high substance-related impairment (≥75th percentile) versus those whose substance-related impairment remained low (<75th percentile), and parental depressive symptoms predicted persistence of high substance-related impairment during the study. MDD response was best among adolescents with low 12-week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairment. There were no significant differential effects of specific treatments, pharmacological or CBT, on substance use.
Substance use is common among adolescents with treatment-resistant MDD. Subjects who had persistently low substance-related impairment or who demonstrated reduced substance-related impairment had better MDD treatment response, although the direction of this association is uncertain.
PMCID: PMC2895963  PMID: 19858762
substance use; depression; adolescents; treatment

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