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1.  Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study 
Neuropsychopharmacology  2015;41(2):454-463.
Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5–44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5–8 Hz) and alpha2 (10.5–12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.
doi:10.1038/npp.2015.165
PMCID: PMC5130121  PMID: 26068725
2.  THE PRO-INFLAMMATORY PROFILE OF DEPRESSED PATIENTS IS (PARTLY) RELATED TO OBESITY 
Many people with major depressive disorder (MDD) show evidence of systemic inflammation, including elevations in inflammatory factors, but the cause is unclear. The purpose of this analysis was to determine if obesity might contribute to the pro-inflammatory state in MDD patients. Blood was obtained from 135 MDD patients and 50 controls. Serum was extracted and assayed for interleukin (IL) −1β, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), C-reactive protein (CRP), leptin, and adiponectin using single- or multi-plex human immunoassay kits. The primary analysis contrasted IL-6, TNFα, and CRP between MDD and control groups with body mass index (BMI) as a covariate. The other analytes were compared in an exploratory fashion. IL-6 (but not TNFα or CRP) showed significant differences between MDD and controls even after covarying for BMI. Obese controls and obese MDD groups were significantly higher in IL-6 than both lean groups, but the two obese groups did not differ from each other. In the exploratory analyses, the IL-2 level showed robust and significant differences between MDD and controls even after covarying for BMI. Both lean and obese MDD were higher than lean and obese controls. Adiponectin levels were also lower in the MDD sample than controls. Prior findings of higher IL-6, and CRP in MDD patients may be explained, at least in part, based on obesity. High IL-2, however, was associated with depression and not obesity. The results have significant implications for the understanding of pathophysiology and, potentially treatment of MDD.
doi:10.1016/j.jpsychires.2015.09.001
PMCID: PMC4734093  PMID: 26424427
Depression; inflammation; cytokine; C-reactive protein; leptin; adiponectin
3.  Gender Differences in Somatic Symptoms and Current Suicidal Risk in Outpatients with Major Depressive Disorder 
Psychiatry Investigation  2016;13(6):609-615.
Objective
Although somatic symptoms are common complaints of patients with major depressive disorder (MDD), their associations with suicide are still unclear.
Methods
A total of 811 MDD outpatients of aged between 18 to 64 years were enrolled nationwide in Korea with the suicidality module of the Mini-International Neuropsychiatric Interview (MINI) and the Depression and Somatic Symptom Scale (DSSS).
Results
On stepwise regression analysis, current suicidality scores were most strongly associated with chest pain in men, and neck or shoulder pain in women. Severe chest pain was associated with higher current suicidality scores in men than in women, whereas severe neck or shoulder pain showed no significant differences between the genders. In conclusion, MDD patients of both sexes with suicidal ideation showed significantly more frequent and severe somatic symptoms than those without. Current suicidal risk was associated with chest pain in men, and neck or shoulder pain in women.
Conclusion
We suggest that clinicians pay attention to patients' somatic symptoms in real world practice.
doi:10.4306/pi.2016.13.6.609
PMCID: PMC5128348  PMID: 27909451
Somatic symptom; Suicidality; Gender difference; Chest pain
4.  A COMPREHENSIVE EXAMINATION OF WHITE MATTER TRACTS AND CONNECTOMETRY IN MAJOR DEPRESSIVE DISORDER 
Depression and Anxiety  2015;33(1):56-65.
Background
Major depressive disorder (MDD) is a debilitating disorder characterized by widespread brain abnormalities. The literature is mixed as to whether or not white matter abnormalities are associated with MDD. This study sought to examine fractional anisotropy (FA) in white matter tracts in individuals with MDD using diffusion tensor imaging (DTI).
Methods
139 participants with MDD and 39 healthy controls (HC) in a multisite study were included. DTI scans were acquired in 64 directions and FA was determined in the brain using four methods: region of interest (ROI), tract‐based spatial statistics (TBSS), and diffusion tractography. Diffusion connectometry was used to identify white matter pathways associated with MDD.
Results
There were no significant differences when comparing FA in MDD and HC groups using any method. In the MDD group, there was a significant relationship between depression severity and FA in the right medial orbitofrontal cortex, and between age of onset of MDD and FA in the right caudal anterior cingulate cortex using the ROI method. There was a significant relationship between age of onset and connectivity in the thalamocortical radiation, inferior longitudinal fasciculus, and cerebellar tracts using diffusion connectometry.
Conclusions
The lack of group differences in FA and connectometry analysis may result from the clinically heterogenous nature of MDD. However, the relationship between FA and depression severity may suggest a state biomarker of depression that should be investigated as a potential indicator of response. Age of onset may also be a significant clinical feature to pursue when studying white matter tracts.
doi:10.1002/da.22445
PMCID: PMC4701622  PMID: 26477532
depression; brain imaging/neuroimaging; mood disorders; diffusion tensor imaging; white matter tracts; connectometry, fractional anisotropy; multisite study
5.  A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response 
Neuropsychopharmacology  2015;40(11):2588-2595.
One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the ‘true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of ~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by ~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the ‘true' TE by controlling false negative results associated with excessively high placebo response.
doi:10.1038/npp.2015.105
PMCID: PMC4569948  PMID: 25895454
6.  Anhedonia in melancholic and non-melancholic depressive disorders 
Background
Anhedonia represents a core symptom of major depression and may be a potential marker for melancholia. However, current understanding of this construct in depressive sub-types is limited.
Method
Participants were recruited from the Black Dog Institute (Sydney) and Massachusetts General Hospital (Boston). Diagnostic groups were derived on the basis of agreement between clinician and DSM-IV diagnosis from structured interviews. Currently depressed unipolar melancholic, non-melancholic and healthy control participants were administered a probabilistic reward task (PRT) to assess a behavioural correlate of anhedonia - blunted reward-based learning. Self-reported measures of anhedonia, approach and avoidance motivation were completed by the Sydney sample.
Results
Relative to healthy controls and non-melancholic participants, melancholic depressed participants had reduced response bias, highlighting blunted reward learning. Moreover, although non-melancholic participants were characterized by a delayed response bias, melancholic depressed participants failed to develop a bias throughout blocks. Response bias showed no associations with self-report measures of hedonic tone in depressed participants. Positive associations were observed between response bias, approach and avoidance motivation in non-melancholic participants only.
Limitations
Possible medication, fatigue and anxiety effects were not controlled; small sample sizes; inclusion criteria may have excluded those with severe melancholia and led to underestimation of group differences.
Conclusions
Melancholia is characterised by a reduced ability to modulate behaviour as a function of reward, and the motivational salience of rewarding stimuli may differ across depressive sub-types. Results support the view that melancholia is a distinct sub-type. Further exploration of reward system functioning in depressive sub-types is warranted.
doi:10.1016/j.jad.2015.05.028
PMCID: PMC4519400  PMID: 26074016
Melancholic; non-melancholic; depression; anhedonia; reward responsiveness; motivation
7.  Test–Retest Reliability of FreeSurfer Measurements Within and Between Sites: Effects of Visual Approval Process 
Human brain mapping  2015;36(9):3472-3485.
In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test–retest reliability of FreeSurfer-derived cortical measures in four groups of subjects—those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test–retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan–Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects’ results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution.
doi:10.1002/hbm.22856
PMCID: PMC4545736  PMID: 26033168
multisite MRI; cerebral cortical thickness; cerebral cortical volume; cerebral cortical surface area; test–retest reliability; FreeSurfer
8.  Telomere Length and Telomerase in a Well-characterized Sample of Individuals with Major Depressive Disorder Compared to Controls 
Psychoneuroendocrinology  2015;58:9-22.
Background
Leukocyte telomere length (LTL) is a marker of cellular turnover and oxidative stress. Studies suggest major depressive disorder (MDD) is associated with oxidative stress, but examinations of MDD and LTL have yielded mixed results, likely because of differences in measurement methods and unmeasured confounding. This study examined LTL and telomerase activity in 166 individuals with MDD compared to 166 age- and gender-matched matched controls free of any psychiatric disorder, using well-validated assays and clinical assessment methods, and controlling for a range of potential confounders.
Methods
Subjects aged 18 to 70 were evaluated by trained raters and provided blood for LTL and telomerase activity measurement. LTL was assayed using Southern blot and replicated with qPCR, and telomerase activity was assayed with a repeat amplification protocol using a commercial kit.
Results
There was no significant difference in telomere length for individuals with MDD [mean (SD)=9.1 (3.0) kbp] compared to controls [mean(SD) =8.9(2.5) kbp] measured by Southern blot (p=0.65) or by confirmatory qPCR (p=0.91) assays. Controlling for potential confounders did not alter the results. Telomerase activity did not differ by MDD diagnosis overall (p=0.40), but the effect of MDD was significantly modified by gender (t(299)= 2.67, p=0.0079) even after controlling for potential confounders, with telomerase activity significantly greater only in males with MDD versus controls.
Conclusion
Our well-characterized, well-powered examination of concurrently assessed telomere length and telomerase activity in individuals with clinically significant, chronic MDD and matched controls failed to provide strong evidence of an association of MDD with shorter LTL, while telomerase activity was lower in men with MDD.
doi:10.1016/j.psyneuen.2015.04.004
PMCID: PMC4461511  PMID: 25932992
Major depressive disorder; telomere length; telomerase
9.  A Computational Analysis of Flanker Interference in Depression 
Psychological medicine  2015;45(11):2333-2344.
Background
Depression is characterized by poor executive function, but—counterintuitively—it is associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study.
Methods
One hundred unmedicated, depressed adults and forty healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials).
Results
Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007).
Conclusions
Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.
doi:10.1017/S0033291715000276
PMCID: PMC4499007  PMID: 25727375
10.  Reward Responsiveness Varies by Smoking Status in Women with a History of Major Depressive Disorder 
Neuropsychopharmacology  2015;40(8):1940-1946.
Major depressive disorder (MDD) and nicotine dependence are highly comorbid, with studies showing that ~50% of individuals with MDD smoke. The link between these disorders persists even after the clinical symptoms of depression subside, as indicated by high levels of nicotine dependence among individuals with remitted depression (rMDD). Recent evidence indicates that individuals with rMDD show blunted responses to reward as measured by a probabilistic reward task (PRT), which assesses the ability to modify behavior as a function of reward history. Given nicotine's ability to enhance reward responsiveness, individuals with rMDD might smoke to address this persistent reward deficit. However, it is unclear whether smokers with rMDD show enhanced reward responsiveness relative to rMDD individuals who do not smoke. To test this hypothesis, we evaluated reward responsiveness on the PRT in four groups (N=198): individuals with and without rMDD who were or were not nicotine dependent. As hypothesized, rMDD nonsmokers had lower reward responsiveness relative to both control nonsmokers and rMDD smokers; conversely, smokers with rMDD showed behavioral patterns comparable to those without a history of depression. Given nicotine's ability to enhance reward sensitivity, it is possible that nicotine normalizes the otherwise blunted reward responsiveness in individuals with rMDD. Therapies aimed at enhancing this reward-based deficit may be beneficial in the treatment of both nicotine dependence and MDD.
doi:10.1038/npp.2015.43
PMCID: PMC4839517  PMID: 25662839
11.  Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study 
The American journal of psychiatry  2015;172(9):881-891.
Objective
Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error-(discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures.
Method
A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals.
Results
Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms.
Conclusions
The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures of treatment response.
doi:10.1176/appi.ajp.2015.14050594
PMCID: PMC4858169  PMID: 26183698
12.  Reduced Venous Blood Basophil Count and Anxious Depression in Patients with Major Depressive Disorder 
Psychiatry Investigation  2016;13(3):321-326.
Objective
Anxious depression has a distinct neurobiology, clinical course and treatment response from non-anxious depression. Role of inflammation in anxious depression has not been examined. As an exploratory study to characterize the role of inflammation on a development of anxious depression, we aimed to determine the relationship between white blood cell (WBC) subset counts and anxiety in individuals with major depressive disorder (MDD).
Methods
A total of 709 patients who were newly diagnosed with MDD were recruited. Anxiety levels of participants were evaluated using the Anxiety/ Somatization subitem of the Hamilton Depression Rating Scale. The association between WBC subset fraction and anxiety was evaluated.
Results
Basophil and eosinophil sub-fractions showed significant negative correlations with HAM-D anxiety/somatization factor scores (basophils: r=-0.092, p=0.014 and eosinophils: r=-0.075, p=0.046). When an anxiety score (a sum of somatic and psychic anxiety) was entered as a dependent variable, only basophils showed significant negative association with the anxiety scores after adjusting for all other WBC subset counts and demographic factors (t=-2.57, p=0.010).
Conclusion
This study showed that anxious depression had a decreased basophil subfraction, which might be associated with involvement of inflammation in development of anxious depression.
doi:10.4306/pi.2016.13.3.321
PMCID: PMC4878967  PMID: 27247599
Anxious depression; Basophil; Inflammation
13.  Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Efficacy Results from a Randomized, Double-Blind, Placebo-Controlled Study 
The American journal of psychiatry  2015;172(12):1251-1258.
Objective
To test the efficacy of adjunctive ziprasidone in adults with non-psychotic unipolar major depression experiencing persistent symptoms following 8 weeks of open-label escitalopram.
Method
This was a multi-center, parallel randomized, double-blind, placebo-controlled trial conducted at three academic medical centers in the United States. The participant pool consisted of 139 outpatients with persistent symptoms of major depressive disorder following an 8-week open label trial of escitalopram (phase 1). Subjects were randomized (1:1, n=139) to adjunctive ziprasidone (escitalopram+ziprasidone, n=71) or adjunctive placebo (escitalopram+placebo, n=68), with 8 weekly follow-up assessments. Primary outcome was defined by clinical response according to the 17-item Hamilton Depression Rating Scale (HAMD-17) and determined by a 50% or greater reduction in scale scores. The Hamilton Anxiety Rating scale (HAM-A) and Visual Analogue Scale for Pain were defined a priori as key secondary outcome measures.
Results
Rates of clinical response (35.2% vs. 20.5%, p=0.04) and mean improvement in HAMD-17 total scores (−6.4 ± 6.4 vs. −3.3 ± 6.2, p=0.04) were significantly greater for the escitalopram+ziprasidone group. Several secondary measures of antidepressant efficacy were also in favor of adjunctive ziprasidone. Escitalopram+ziprasidone also resulted in significantly greater improvement in HAM-A, but not Visual Analogue Scale for Pain scores. Ten (14%) patients discontinued escitalopram+ziprasidone due to intolerance versus none for escitalopram+placebo (p<0.01 versus placebo).
Conclusions
Adjunctive ziprasidone, when added to escitalopram, demonstrated antidepressant efficacy in adult patients with major depressive disorder experiencing persistent symptoms following 8 weeks of open-label escitalopram.
doi:10.1176/appi.ajp.2015.14101251
PMCID: PMC4843798  PMID: 26085041
14.  Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder 
The aim of this study was to evaluate the effects of levomilnacipran extended-release (ER) on depression-related fatigue in adults with major depressive disorder. Post-hoc analyses of five phase III trials were carried out, with evaluation of fatigue symptoms based on score changes in four items: Montgomery–Åsberg Depression Rating Scale (MADRS) item 7 (lassitude), and 17-item Hamilton Depression Rating Scale (HAMD17) items 7 (work/activities), 8 (retardation), and 13 (somatic symptoms). Symptom remission was analyzed on the basis of score shifts from baseline to end of treatment: MADRS item 7 and HAMD17 item 7 (from ≥2 to ≤1); HAMD17 items 8 and 13 (from ≥1 to 0). The mean change in MADRS total score was analyzed in patients with low and high fatigue (MADRS item 7 baseline score <4 and ≥4, respectively). Patients receiving levomilnacipran ER had significantly greater mean improvements and symptom remission (no/minimal residual fatigue) on all fatigue-related items: lassitude (35 vs. 28%), work/activities (43 vs. 35%), retardation (46 vs. 39%), somatic symptoms (26 vs. 18%; all Ps<0.01 versus placebo). The mean change in MADRS total score was significantly greater with levomilnacipran ER versus placebo in both low (least squares mean difference=−2.8, P=0.0018) and high (least squares mean difference=−3.1, P<0.0001) fatigue subgroups. Levomilnacipran ER treatment was effective in reducing depression-related fatigue in adult patients with major depressive disorder and was associated with remission of fatigue symptoms.
doi:10.1097/YIC.0000000000000104
PMCID: PMC4736297  PMID: 26584326
age factors; antidepressant; clinical trial; depression; lassitude; sex factors
15.  Illness Progression, Recent Stress and Morphometry of Hippocampal Subfields and Medial Prefrontal Cortex in Major Depression 
Biological psychiatry  2014;77(3):285-294.
Background
Longitudinal studies of illness progression in Major Depressive Disorder (MDD) indicate that the onset of subsequent depressive episodes becomes increasingly decoupled from external stressors. A possible mechanism underlying this phenomenon is that multiple episodes induce long-lasting neurobiological changes that confer increased risk for recurrence. Prior morphometric studies have frequently reported volumetric reductions in MDD—especially in medial prefrontal cortex (mPFC) and the hippocampus— but few studies have investigated whether these changes are exacerbated by prior episodes.
Methods
We used structural magnetic resonance imaging (sMRI) to examine relationships between number of prior episodes, current stress, and brain volume and cortical thickness in a sample of 103 medication-free depressed patients and never-depressed controls. Volumetric analyses of the hippocampus were performed using a recently-validated subfield segmentation approach, while cortical thickness estimates were obtained using Vertex-Based Cortical Thickness (VBCT). Participants were grouped on the basis of the number of prior depressive episodes as well as current depressive state.
Results
Number of prior episodes was associated with both lower reported stress levels as well as reduced volume in the dentate gyrus. Cortical thinning of the left medial prefrontal cortex (mPFC) was associated with a greater number of prior depressive episodes, but not current depressive state.
Conclusions
Collectively, these findings are consistent with preclinical models suggesting that the dentate gyrus and mPFC are especially vulnerable to stress exposure, and provide evidence for morphometric changes that are consistent with stress-sensitization models of recurrence in MDD.
doi:10.1016/j.biopsych.2014.06.018
PMCID: PMC4277904  PMID: 25109665
MRI; Major Depression; Hippocampus; mPFC; Dentate Gyrus; MAGeT Brain
16.  A placebo-controlled crossover study of iloperidone augmentation for residual anger and irritability in major depressive disorder 
Background:
Even when patients experience remission with antidepressants, many continue to report anger attacks and excessive irritability despite continued treatment. Iloperidone antagonizes 5-HT-2a, D2, and alpha-1 receptors, which can have anti-aggressive effects. We examined iloperidone’s safety and efficacy as an augmentation agent in outpatients with partially remitted major depressive disorder (MDD) with residual symptoms of anger and irritability.
Methods:
A total of 13 outpatients with partially remitted MDD [currently treated with selective serotonin reuptake inhibitors (SSRIs)] received four weeks of iloperidone or placebo, followed by one week of washout. Patients were then crossed over to the other treatment arm for 4 weeks. Treatment arms were randomized and double blind; and two sites were used for the study. Analyses compared treatment response using the Symptom Questionnaire (SQ) Anger/Hostility Subscale as the primary outcome measure.
Results:
There was no significant differential effect of iloperidone × weeks on the SQ Anger/Hostility Subscore over the course of the study, compared with placebo × weeks, regardless of administration order (p = 0.77).
Conclusions:
Iloperidone did not significantly outperform placebo on measures of anger or irritability in patients with partially remitted MDD and residual anger/irritability.
doi:10.1177/2045125315618621
PMCID: PMC4749740  PMID: 26913173
anger; augmentation; iloperidone; irritability; major depressive disorder
17.  Illness Beliefs of Chinese American Immigrants with Major Depressive Disorder in a Primary Care Setting 
Underutilization of mental health services in the U.S. is compounded among racial/ethnic minorities, especially Chinese Americans. Culturally based illness beliefs influence help-seeking behavior and may provide insights into strategies for increasing utilization rates among vulnerable populations. This is the first large descriptive study of depressed Chinese American immigrant patients’ illness beliefs using a standardized instrument. 190 depressed Chinese immigrants seeking primary care at South Cove Community Health Center completed the Explanatory Model Interview Catalogue, which probes different dimensions of illness beliefs: chief complaint, labeling of illness, stigma perception, causal attributions, and help-seeking patterns. Responses were sorted into categories by independent raters and results compared to an earlier study at the same site and using the same instrument. Contrary to prior findings that depressed Chinese individuals tend to present with primarily somatic symptoms, subjects were more likely to report chief complaints and illness labels related to depressed mood than physical symptoms. Nearly half reported they would conceal the name of their problem from others. Mean stigma levels were significantly higher than in the previous study. Most subjects identified psychological stress as the most likely cause of their problem. Chinese immigrants’ illness beliefs were notable for psychological explanations regarding their symptoms, possibly reflecting increased acceptance of Western biomedical frameworks, in accordance with recent research. However, reported stigma regarding these symptoms also increased. As Asian American immigrant populations increasingly accept psychological models of depression, stigma may become an increasingly important target for addressing disparities in mental health service utilization.
doi:10.1016/j.ajp.2014.12.005
PMCID: PMC4390427  PMID: 25563074
Illness beliefs; major depressive disorder; Chinese American; culture; stigma
18.  Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties 
Psychological medicine  2014;45(1):121-131.
Background
Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored.
Methods
In this study 26 unmedicated adults with MDD and 29 matched healthy controls completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psycho-physiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e., monetary gains and penalties).
Results
Relative to controls, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC sub-region in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with more symptoms improvement 12 weeks later.
Conclusions
These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.
doi:10.1017/S0033291714001123
PMCID: PMC4233014  PMID: 25055809
Caudate; Cingulate; Reward; Depression; Treatment Prediction; gPPI
19.  Prenatal antidepressant exposure is associated with risk for attention deficit-hyperactivity disorder but not autism spectrum disorder in a large health system 
Molecular psychiatry  2014;20(6):727-734.
Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease-specificity of this risk has not been addressed and possibility of confounding has not been excluded. Children with ASD or attention deficit-hyperactivity disorder (ADHD) delivered in a large New England health care system were identified from electronic health records, and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and electronic health records to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1,377 children diagnosed with ASD and 2,243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression [OR 1.10 (0.70–1.70)]. Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression [OR 1.81 (1.22–2.70)]. These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.
doi:10.1038/mp.2014.90
PMCID: PMC4427538  PMID: 25155880
20.  Associations among Smoking, Anhedonia, and Reward Learning in Depression 
Behavior therapy  2014;45(5):651-663.
Depression and cigarette smoking co-occur at high rates. However, the etiological mechanisms that contribute to this relationship remain unclear. Anhedonia and associated impairments in reward learning are key features of depression, which also have been linked to the onset and maintenance of cigarette smoking. However, few studies have investigated differences in anhedonia and reward learning among depressed smokers and depressed nonsmokers. The goal of this study was to examine putative differences in anhedonia and reward learning in depressed smokers (n = 36) and depressed nonsmokers (n = 44). To this end, participants completed self-report measures of anhedonia and behavioral activation (BAS reward responsiveness scores) and as well as a probabilistic reward task rooted in signal detection theory, which measures reward learning (Pizzagalli, Jahn, & O’Shea, 2005). When considering self-report measures, depressed smokers reported higher trait anhedonia and reduced BAS reward responsiveness scores compared to depressed nonsmokers. In contrast to self-report measures, nicotine-satiated depressed smokers demonstrated greater acquisition of reward-based learning compared to depressed nonsmokers as indexed by the probabilistic reward task. Findings may point to a potential mechanism underlying the frequent co-occurrence of smoking and depression. These results highlight the importance of continued investigation of the role of anhedonia and reward system functioning in the co-occurrence of depression and nicotine abuse. Results also may support the use of treatments targeting reward learning (e.g., behavioral activation) to enhance smoking cessation among individuals with depression.
doi:10.1016/j.beth.2014.02.004
PMCID: PMC4446716  PMID: 25022776
depression; smoking; anhedonia; reward learning; Veteran
21.  Near-Infrared Transcranial Radiation for Major Depressive Disorder: Proof of Concept Study 
Psychiatry Journal  2015;2015:352979.
Transcranial near-infrared radiation (NIR) is an innovative treatment for major depressive disorder (MDD), but clinical evidence for its efficacy is limited. Our objective was to investigate the tolerability and efficacy of NIR in patients with MDD. We conducted a proof of concept, prospective, double-blind, randomized study of 6 sessions of NIR versus sham treatment for patients with MDD, using a crossover design. Four patients with MDD with mean age 47 ± 14 (SD) years (1 woman and 3 men) were exposed to irradiance of 700 mW/cm2 and a fluence of 84 J/cm2 for a total NIR energy of 2.40 kJ delivered per session for 6 sessions. Baseline mean HAM-D17 scores decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) after treatment (t = 7.905; df = 3; P = 0.004). Patients tolerated the treatment well without any serious adverse events. These findings confirm and extend the preliminary data on NIR as a novel intervention for patients with MDD, but further clinical trials are needed to better understand the efficacy of this new treatment. This trial is registered with ClinicalTrials.gov NCT01538199.
doi:10.1155/2015/352979
PMCID: PMC4556873  PMID: 26356811
22.  College students with depressive symptoms with and without fatigue: Differences in functioning, suicidality, anxiety, and depressive severity 
BACKGROUND
We examined whether fatigue was associated with greater symptomatic burden and functional impairment in college students with depressive symptoms.
METHODS
Using data from the self-report Beck Depression Inventory (BDI), we stratified a group of 287 students endorsing significant symptoms of depression (BDI score ≥13) into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. We then compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.
RESULTS
Approximately 87% of students endorsed at least mild fatigue. Students with moderate/severe fatigue had significantly greater depressive symptom severity compared with those with mild or no fatigue and scored higher on a suicide risk measure than those with mild fatigue. Students with severe fatigue evidenced greater frequency and intensity of anxiety than those with mild or no fatigue. Reported cognitive and functional impairment increased significantly as fatigue worsened.
CONCLUSIONS
Depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. Assessing and treating symptoms of fatigue appears warranted within this population.
PMCID: PMC4539614  PMID: 25954936
23.  Reliability and validity of the Symptoms of Depression Questionnaire (SDQ) 
CNS spectrums  2014;19(6):535-546.
Current measures for major depressive disorder focus primarily on the assessment of depressive symptoms, while often omitting other common features. However, the presence of comorbid features in the anxiety spectrum influences outcome and may effect treatment. More comprehensive measures of depression are needed that include the assessment of symptoms in the anxiety–depression spectrum. This study examines the reliability and validity of the Symptoms of Depression Questionnaire (SDQ), which assesses irritability, anger attacks, and anxiety symptoms together with the commonly considered symptoms of depression. Analysis of the factor structure of the SDQ identified 5 subscales, including one in the anxiety–depression spectrum, with adequate internal consistency and concurrent validity. The SDQ may be a valuable new tool to better characterize depression and identify and administer more targeted interventions.
doi:10.1017/S1092852914000406
PMCID: PMC4524555  PMID: 25275853
anxious depression; assessment; depression
24.  Correlates of Irritability in College Students With Depressive Symptoms 
Depression is a prevalent psychiatric disorder associated with significant personal and societal burden. There is accumulating evidence for the presence of a subtype of depression characterized by the presence of irritability that is associated with increased morbidity, risk for suicidal ideation, and functional impairments in adults. Little is known about the features of depressive symptoms with and without irritability among young adults in college. The primary aim of this study was to characterize the presentation of college students with depressive symptoms and irritability. Two-hundred eighty-seven undergraduate college students with depressive symptoms with and without irritability were compared across several psychiatric and functional outcome variables. Independent samples t-tests or logistic regressions were conducted for each outcome variable using the irritability item of the Beck Depression Inventory as a dichotomous grouping variable. Analyses were conducted separately for the men and the women. Both male and female students with depressive symptoms and severe irritability reported a greater severity of depressive symptoms compared with their peers with no or mild irritability. In the women, the presence of irritability was associated with greater symptoms of anxiety, whereas in the men, it was associated with increased likelihood of engaging in risky behaviors, including compulsive use of alcohol, illicit drugs, and prescription drugs. The male and female college students with depressive symptoms with and without irritability did not differ on severity of suicidal ideation, hopelessness, or cognitive functioning. The findings from this study suggest that depressive symptoms and irritability may characterize a subtype of college students who have a greater symptom burden and with the potential need for more aggressive and prompt treatment.
doi:10.1097/NMD.0000000000000038
PMCID: PMC4524561  PMID: 24177482
Depression; irritability; young adults; risky behavior
25.  Association between physician beliefs regarding assigned treatment and clinical response: Re-analysis of data from the Hypericum Depression Trial Study Group 
Background
We have previously shown an association between patient belief and treatment response in the Hypericum Depression Trial Study Group's 2002 study. We re-examined these data to determine whether clinical improvement was associated with physician belief about assigned therapy.
Methods
340 adults with major depression and baseline scores ≥20 on the 17-item Hamilton Depression Scale (HDRS-17) were randomized to Hypericum 900-1500 mg/d, sertraline 50-100 mg/d, or placebo for 8 weeks. At week 8, physicians guessed their patients' treatment. We analyzed 277 subjects with at least one post-baseline visit and physician guess data. We examined association between guess and improvement in HDRS-17 and whether treatment assignment moderated the effect of belief on remission (final HDRS-17 score <8).
Results
Patient and doctor guesses agreed at 53% for sertraline, 68% for Hypericum, and 52% for placebo (kappa = 0.37). Doctors guessed placebo correctly (38%) more than sertraline (18%) or Hypericum (19%) (p = 0.001). Adverse event scores were significantly greater among subjects for which the clinicians guessed Hypericum (p < 0.001) or sertraline (p = 0.005) compared to placebo. Significant improvements in HDRS-17 score were found when comparing the Hypericum-guess (p < 0.001) or the sertraline-guess group (p < 0.001) against the placebo-guess group. Remission rates were significantly greater for subjects whose clinicians guessed sertraline (p < 0.001) or Hypericum (p < 0.001) versus placebo.
Conclusion
Doctors tended to guess placebo more easily than Hypericum or sertraline, and their guesses tended to favor active therapies when improvement was more robust. Results show association but not causation, and merit more careful investigation.
doi:10.1016/j.ajp.2014.12.002
PMCID: PMC4518843  PMID: 25544195
Major Depressive Disorder; Hypericum; St. John's Wort; sertraline; placebo; physician; treatment guess

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