Serotonin-norepinephrine reuptake inhibitor antidepressant effects on regional connectivity of the thalamus in persistent depressive disorder: evidence from two randomized, double-blind, placebo-controlled clinical trials.

Previous neuroimaging studies have shown that serotonin-norepinephrine reuptake inhibitor antidepressants alter functional activity in large expanses of brain regions. However, it is not clear how these regions are systemically organized on a connectome level with specific topological properties, which may be crucial to revealing neural mechanisms underlying serotonin-norepinephrine reuptake inhibitor treatment of persistent depressive disorder. To investigate the effect of serotonin-norepinephrine reuptake inhibitor antidepressants on brain functional connectome reconfiguration in persistent depressive disorder and whether this reconfiguration promotes the improvement of clinical symptoms, we combined resting-state functional magnetic resonance imaging (fMRI) scans acquired in two randomized, double-blind, placebo-controlled trial studies of serotonin-norepinephrine reuptake inhibitor antidepressant treatment of patients with persistent depressive disorder. One was a randomized, double-blind, placebo-controlled trial of 10-week duloxetine medication treatment, which included 17 patients in duloxetine group and 17 patients in placebo group (ClinicalTrials.gov Identifier: NCT00360724); the other one was a randomized, double-blind, placebo-controlled trial of 12-week desvenlafaxine medication treatment, which included 16 patients in desvenlafaxine group and 15 patients in placebo group (ClinicalTrials.gov Identifier: NCT01537068). The 24-item Hamilton Depression Rating Scale was used to measure clinical symptoms, and graph theory was employed to examine serotonin-norepinephrine reuptake inhibitor antidepressant treatment effects on the topological properties of whole-brain functional connectome of patients with persistent depressive disorder. We adopted a hierarchical strategy to examine the topological property changes caused by serotonin-norepinephrine reuptake inhibitor antidepressant treatment, calculated their small-worldness, global integration, local segregation and nodal clustering coefficient in turn. Linear regression analysis was used to test associations of treatment, graph properties changes and clinical symptom response. Symptom scores were more significantly reduced after antidepressant than placebo administration (η 2 = 0.18). There was a treatment-by-time effect that optimized the functional connectome in a small-world manner, with increased global integration and increased nodal clustering coefficient in the bilateral thalamus (left thalamus η 2 = 0.21; right thalamus η 2 = 0.23). The nodal clustering coefficient increment of the right thalamus (ratio = 29.86; 95% confidence interval, -4.007 to -0.207) partially mediated the relationship between treatment and symptom improvement, and symptom improvement partially mediated (ratio = 21.21; 95% confidence interval, 0.0243-0.444) the relationship between treatment and nodal clustering coefficient increments of the right thalamus. Our study may indicate a putative mutually reinforcing association between nodal clustering coefficient increment of the right thalamus and symptom improvement from serotonin-norepinephrine reuptake inhibitor antidepressant treatments with duloxetine or desvenlafaxine.

A randomized, controlled trial assessing the acute efficacy of triple chronotherapy in unipolar depression.

BACKGROUND: Triple chronotherapy (wake night [one night without sleep], sleep phase advance, and early morning bright light exposure) demonstrated rapid efficacy primarily in bipolar depression, but has not been as well studied in unipolar depression. Our primary hypothesis is that triple chronotherapy is associated with a significantly greater Week 1 remission rate compared to the alternative protocol. METHODS: Unipolar depressed, nonpsychotic adult outpatients were randomized to triple chronotherapy or an alternative protocol (assigned sleep times without wake night, bright light exposure with blue-green wavelengths filtered out). Symptoms were assessed with Structured Interview Guide for Hamilton Depression Rating Scale with Atypical Supplement (SIGH-ADS) at each visit and a modified form (m-SIGH) daily for the first week. Response was defined as a 50% decrease in m-SIGH score, and remission as m-SIGH≤7, modified Clinical Global Impression-Improvement (m-CGI-I)≤2, and no depressed mood on m-SIGH. RESULTS: 44 patients (84.1% major depressive disorder, 75.0% persistent depressive disorder; 54.5% female; age mean±SD 38.3 ±â€¯15.2 years) were randomized to triple chronotherapy (N = 22) or an alternative protocol (N = 22). Week 1 remission rate was numerically higher but not statistically significant in the triple chronotherapy versus alternative protocol group (25.0% vs. 6.7%, Chi-square=1.76, df=1, p = 0.294). m-SIGH scores and response and remission rates on Days 2-7 were numerically improved without reaching statistical significance in the triple chronotherapy versus alternative protocol group. LIMITATIONS: Predominantly white, educated sample. CONCLUSIONS: This small pilot study demonstrated triple chronotherapy's feasibility and tolerability in unipolar depressed outpatients. Larger randomized trials are warranted to further characterize acute and long-term efficacy.

Gray matter reorganization underpinnings of antidepressant treatment of persistent depressive disorder.

Brain gray matter is organized in a manner with interconnected brain regions, resulting in a notable covariance pattern that recapitulates either the functional coactivation or structural connectivity of brain regions, which is believed to underpin psychiatric disorders such as depression. This study aimed to investigate whether and how antidepressants took effect in treating depression and reducing symptoms by altering the gray matter covariance pattern. We combined structural magnetic resonance imaging (MRI) scans acquired in two randomized, double-blind, placebo-controlled trial (RCT) studies of the treatment using serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant medications in patients with persistent depressive disorder (PDD). One was an RCT of 10-week duloxetine medication that consisted of patients who received duloxetine (N = 21) or placebo (N = 21), and the other was an RCT of 12-week desvenlafaxine medication that consisted of 19 and 17 patients respectively who received desvenlafaxine or placebo. We examined treatment effect on gray matter volume (GMV) and topological organization of GMV covariance pattern (i.e., GMV-based network). We found a treatment-by-time effect on GMV in the angular gyrus and cuneus areas, whereas the GMV change rate of the cuneus was inversely correlated with the response rate. We observed a significant increase in the local efficiency of the GMV-based network following medication treatment compared with placebo. Our findings provide preliminary evidence for a GMV-based network-specific reconfiguration caused by antidepressants compared to placebo and the cuneus may be a possible candidate region to predict antidepressant response.

Deficits of white matter axial diffusivity in bipolar disorder relative to major depressive disorder: No relationship to cerebral perfusion or body mass index.

OBJECTIVE: To compare white matter integrity (WMI) in bipolar disorder (BD) relative to healthy volunteers (HVs) and major depressive disorder (MDD). To determine the relationship of bipolar-specific differences in WMI to cerebral perfusion, body mass index (BMI), and blood pressure as indices of cardiovascular function. METHODS: Thirty-two participants with BD, 44 with MDD, and 41 HV were recruited. All BD and MDD participants were in a major depressive episode, and all but 12 BD participants were medication-free. 64-direction diffusion tensor imaging (DTI) and arterial spin labeling (ASL) sequences were obtained. Tract-based spatial statistics (TBSS) on four DTI indices were employed to distinguish patterns of DTI in BD relative to HV and MDD groups. BMI, blood pressure, and medical histories were also obtained for the BD participants. RESULTS: A cluster of lower axial diffusivity (AD) was found in BD participants in comparison to the HVs in the left posterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and internal capsule. Mean AD in the significant cluster was not associated with cerebral blood flow (CBF) in the region as measured by ASL, and was not associated with BMI or blood pressure. A cluster of lower AD was also found in the BD group when compared to MDD that had spatial overlap with the HV comparison. CONCLUSIONS: The results indicate a deficit of AD in BD when compared to MDD and HV groups. No association between AD values and either cerebral perfusion, BMI, or blood pressure was found in BD.

Desvenlafaxine vs. placebo in the treatment of persistent depressive disorder.

INTRODUCTION: Pharmacotherapy of non-major persistent depressive disorder (PDD) is little studied. We report a study of the serotonin-norepinephrine reuptake inhibitor (SNRI) desvenlafaxine (DVLX) for PDD. METHOD: Non-psychotic, non-bipolar outpatients aged 20-65 having PDD without concurrent major depression (MDD) were randomized double-blind to desvenlafaxine or placebo for 12 weeks. All had Hamilton Depression Rating Scale (HDRS-24) score ≥ 12. Open-label DVLX was offered for 12 weeks following the acute trial. RESULTS: Seventy-one subjects having mean baseline HDRS-24 20.27 ±â€¯4.77 were eligible, of whom post-RZ data was available for all 59 randomized. The primary 12 week analysis did not differentiate DVLX-treated subjects' mean HDRS scores from those on placebo (6.53 ±â€¯3.98 vs. 8.24 ±â€¯4.96, F = 3.33, df = 1, p = .07). Several secondary analyses yielded statistically significant results, including Responder, CGI and QIDS. DISCUSSION: As the primary analysis did not reach statistical significance, this is a negative study which does not support the use of DVLX for non-major PDD. Nevertheless, statistically significant secondary analyses suggest the overall negative result could be due to sample size or sampling, suggesting further studies of this medication might be appropriate in this population.

White matter tract integrity is associated with antidepressant response to lurasidone in bipolar depression.

OBJECTIVES: Patients with bipolar disorder spend the most time in the depressed phase, and that phase is associated with the most morbidity and mortality. Treatment of bipolar depression lacks a test to determine who will respond to treatment. White matter disruptions have been found in bipolar disorder. Previous reports suggest that white matter disruptions may be associated with resistance to antidepressant medication, but this has never been investigated in a prospective study using a Food and Drug Administration (FDA)-approved medication. METHODS: Eighteen subjects with bipolar disorder who were in a major depressive episode and off all medications were recruited. Magnetic resonance imaging was acquired using a 64-direction diffusion tensor imaging sequence on a 3T scanner. Subjects were treated with 8 weeks of open-label lurasidone. The Montgomrey-Asberg Depression Rating Scale (MADRS) was completed weekly. Tract-Based Spatial Statistics were utilized to perform a regression analysis of fractional anisotropy (FA) data with treatment outcome as assessed by percent change in MADRS as a regressor while controlling for age and sex, using a threshold of P (threshold-free cluster enhancement-corrected) <.05. RESULTS: FA was positively correlated with antidepressant treatment response in multiple regions of the mean FA skeleton bilaterally, including tracts in the frontal and parietal lobes. CONCLUSIONS: Greater disruptions in the white matter tracts in bipolar disorder were associated with poorer antidepressant response to lurasidone. The disruptions may potentially indicate treatment with a different antidepressant medication class. These results are limited by the open-label study design, sample size and lack of a healthy control group.

Right brain, left brain in depressive disorders: Clinical and theoretical implications of behavioral, electrophysiological and neuroimaging findings.

The right and left side of the brain are asymmetric in anatomy and function. We review electrophysiological (EEG and event-related potential), behavioral (dichotic and visual perceptual asymmetry), and neuroimaging (PET, MRI, NIRS) evidence of right-left asymmetry in depressive disorders. Recent electrophysiological and fMRI studies of emotional processing have provided new evidence of altered laterality in depressive disorders. EEG alpha asymmetry and neuroimaging findings at rest and during cognitive or emotional tasks are consistent with reduced left prefrontal activity in depressed patients, which may impair downregulation of amygdala response to negative emotional information. Dichotic listening and visual hemifield findings for non-verbal or emotional processing have revealed abnormal perceptual asymmetry in depressive disorders, and electrophysiological findings have shown reduced right-lateralized responsivity to emotional stimuli in occipitotemporal or parietotemporal cortex. We discuss models of neural networks underlying these alterations. Of clinical relevance, individual differences among depressed patients on measures of right-left brain function are related to diagnostic subtype of depression, comorbidity with anxiety disorders, and clinical response to antidepressants or cognitive behavioral therapy.

Do social functioning and symptoms improve with continuation antidepressant treatment of persistent depressive disorder? An observational study.

OBJECTIVE: To determine efficacy of continued treatment with the serotonin norepinephrine reuptake inhibitor duloxetine on symptom reduction and functional improvement in outpatients with dysthymia. METHOD: Fifty outpatients with DSM-IV-TR diagnosed dysthymia who had participated in a 10 week double-blind, placebo-controlled study of duloxetine received open treatment for three months. Nineteen duloxetine responders continued duloxetine, 24 patients initially treated with placebo started open duloxetine treatment, and 7 duloxetine non-responders were treated with desvenlafaxine or bupropion, selected by clinician choice. RESULTS: Patients continuing duloxetine maintained symptom improvement, 84% meeting response and 63% remission criteria at week 22. Patients initially treated with placebo showed similarly high levels of response (83%) and remission (62%) at week 22, and most duloxetine non-responders subsequently responded to other antidepressants. Duloxetine-continuation patients improved modestly between weeks 10 and 22 on measures of social and cognitive functioning and temperament. Despite this improvement concurrently across several functional domains, 66.7% of patients continuing duloxetine remained in the impaired range of functioning according to the Social Adjustment Scale (SAS). CONCLUSIONS: Continued duloxetine treatment appears to be effective in maintaining symptom response in dysthymic disorder, and has positive effects on social functioning. However, the majority of patients do not show normalization of functioning, even when controlling for remission status. Additional treatments should be considered to target residual impairments in social functioning in mood remitted patients with persistent depressive disorder.

Treatment of Maternal Depression in a Medication Clinical Trial and Its Effect on Children.

(Reprinted from the American Journal of Psychiatry 2015; 172:450-459, with permission from American Psychiatric Association Publishing).

Lateralization for speech predicts therapeutic response to cognitive behavioral therapy for depression.

A prior study (Bruder, G.E., Stewart, J.W., Mercier, M.A., Agosti, V., Leite, P., Donovan, S., Quitkin, F.M., 1997. Outcome of cognitive-behavioral therapy for depression: relation of hemispheric dominance for verbal processing. Journal of Abnormal Psychology 106, 138-144.) found left hemisphere advantage for verbal dichotic listening was predictive of clinical response to cognitive behavioral therapy (CBT) for depression. This study aimed to confirm this finding and to examine the value of neuropsychological tests, which have shown promise for predicting antidepressant response. Twenty depressed patients who subsequently completed 14 weeks of CBT and 74 healthy adults were tested on a Dichotic Fused Words Test (DFWT). Patients were also tested on the National Adult Reading Test to estimate IQ, and word fluency, choice RT, and Stroop neuropsychological tests. Left hemisphere advantage on the DFWT was more than twice as large in CBT responders as in non-responders, and was associated with improvement in depression following treatment. There was no difference between responders and non-responders on neuropsychological tests. The results support the hypothesis that the ability of individuals with strong left hemisphere dominance to recruit frontal and temporal cortical regions involved in verbal dichotic listening predicts CBT response. The large effect size, sensitivity and specificity of DFWT predictions suggest the potential value of this brief and inexpensive test as an indicator of whether a patient will benefit from CBT for depression.

Treatment of maternal depression in a medication clinical trial and its effect on children.

OBJECTIVE: Observational studies show that when a depressed mother's symptoms remit, her children's psychiatric symptoms decrease. Using randomized treatment assignment, the authors sought to determine the differential effects of a depressed mother's treatment on her child. METHOD: The study was a randomized double-blind 12-week trial of escitalopram, bupropion, or the combination of the two in depressed mothers (N=76), with independent assessment of their children (N=135; ages 7-17 years). RESULTS: There were no significant treatment differences in mothers' depressive symptoms or remission. Children's depressive symptoms and functioning improved significantly among those whose mothers were in the escitalopram group (compared with those whose mothers were in the bupropion and combination treatment groups). Only in the escitalopram group was significant improvement of mother's depression associated with improvement in the child's symptoms. Exploratory analyses suggested that this may be due to changes in parental functioning: Mothers in the escitalopram group reported significantly greater improvement, compared with the other groups, in their ability to listen and talk to their children, who as a group reported that their mothers were more caring over the 12 weeks. Maternal baseline negative affectivity appeared to moderate the effect of maternal treatment on children, although the effect was not statistically significant. Children of mothers with low negative affectivity improved in all treatment groups. Children of mothers with high negative affectivity improved significantly only for those whose mothers were in the escitalopram group. CONCLUSIONS: The effects of the depressed mother's improvement on her children may depend on her type of treatment. Depressed mothers with high anxious distress and irritability may require medications that reduce these symptoms in order to show the effect of her remission on her children.

Behavioral activation therapy for return to work in medication-responsive chronic depression with persistent psychosocial dysfunction.

OBJECTIVE: Chronic depression is associated with significant impairment in work functioning, relationships, and health. Such impairment often persists following medication-induced remission of depressive symptoms. We adapted and tested Behavioral Activation therapy with a goal of return to work (BA-W) in subjects with chronic depression who had responded to medication treatment but remained unemployed. METHOD: Sixteen adults aged 18-65 with DSM-IV diagnosed Dysthymic Disorder or chronic Major Depression were recruited from clinical trials taking place at the New York State Psychiatric Institute between 4/2009 and 12/2012 and enrolled in 12 weeks of individual manual-driven BA-W. Functioning was measured at intake, post-treatment and at 24 week follow-up. RESULTS: Eighty-seven percent (n=14) of subjects completed the full 12 weeks of BA-W. Hours of work related activity (p<.005, d=0.83), hours of paid work (p<.0003, d=0.54), and work productivity (p<.0004, d=-0.48) increased significantly over the study period. Earned income increased post-treatment (p=.068) with significant changes by 24 week follow-up (p=.011). Secondary outcomes including behavioral avoidance (p<.004, d=-0.56), and global functioning (p<.0003, d=1.42) were also significantly improved post-treatment. Effect sizes, including for outcomes with non-significant changes, were generally in the range of 0.5-0.8. CONCLUSIONS: This pilot study provides preliminary evidence of the efficacy of a work-targeted psychotherapy to remediate vocational impairment in subjects with chronic depression. Data suggests that further testing of BA-W using a randomized controlled trial is warranted and may represent a significant advance in treatment for the residual disability present after successful pharmacotherapy.

Does negative affectivity predict differential response to an SSRI versus a non-SSRI antidepressant?

OBJECTIVE: This work tested the hypothesis that patients with high negative affectivity (NA) would have a better response to a serotonergic agent (escitalopram) than to one not thought to act directly on serotonin (bupropion). METHOD: Data from a study conducted between August 2007 and July 2011 were reanalyzed retrospectively. Patients (N = 245) meeting criteria for major depressive disorder (MDD), diagnosed with DSM-IV-TR, were randomly assigned to double-blind treatment with bupropion extended-release, escitalopram, or the combination. Negative affectivity score was estimated using the guilt, hostility/irritability, and fear/anxiety items of the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, the Quick Inventory of Depressive Symptoms, and the Social Adjustment Scale. We felt that these items captured published descriptions of the NA construct. A Clinical Global Impressions-Severity of Illness (CGI-S) score ≤ 2 defined response. Because combined treatment addressed both serotonin and non-serotonin systems, patients treated with both medications did not test the hypothesis and so were excluded from the analyses. RESULTS: Analysis of covariance with treatment as a grouping variable, NA as covariate, and CGI-S as dependent variable showed a significant 2-way interaction between treatment and NA (F1,156 = 4.82, P < .03). In the low-NA group, response rates were similar between treatments (escitalopram: 28/42 [67%]; bupropion: 23/40 [58%]; NS), while there was a significant advantage for escitalopram in patients with high NA (escitalopram: 24/40 [60%]; bupropion = 14/41 [34%]; P = .017). CONCLUSIONS: These data suggest that patients with high negative affectivity respond preferentially to antidepressants that selectively enhance serotonin neurotransmission. Although patients with low NA appear to benefit from serotonin enhancement as well, they also improved with bupropion, an antidepressant not thought to directly affect serotonin neurotransmission. These findings come from retrospective analyses using unproven approximation of NA, so no clinical inferences should be made before independent replication utilizing accepted NA measurement. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00519428.

Neurocognitive predictors of antidepressant clinical response.

BACKGROUND: Executive dysfunction and psychomotor slowing in depressed patients have been associated with poor antidepressant clinical response, but little is known about the value of neurocognitive tests for differential prediction of response. METHODS: This report presents new findings for 70 depressed patients tested on neurocogntive tests before receiving treatment with a SSRI (escitalopram or citalopram), NDRI (bupropion) or dual mechanism therapy including a serotonergic agent, and for 57 healthy controls. RESULTS: As predicted from previous research, patients who did not respond to a SSRI or dual therapy showed poorer word fluency than responders, whereas this was not seen for patients treated with bupropion alone. Longer choice reaction time (RT) was also found in nonresponders to a SSRI or dual therapy, but the opposite trend was seen for bupropion. Using a combined index of word fluency and RT (with normative performance as a cutoff) yielded differential predictions of response. Equal to or above normal performance predicted good response to a SSRI or dual therapy, with high positive predictive value (90%) and specificity (78%) but lower sensitivity (53%). In contrast, less than normal performance predicted good response to bupropion alone (positive predictive value=82%; specificity=67%; sensitivity=90%). LIMITATIONS: Relatively small sample size, no placebo control, and combining across SSRI alone and dual treatments. CONCLUSIONS: Although findings are preliminary due to small sample size, brief tests of word fluency and psychomotor speed may help identify depressed patients who are unresponsive to a serotonergic agent, but who may respond to bupropion alone.

The role of patient expectancy in placebo and nocebo effects in antidepressant trials.

OBJECTIVE: To determine whether patient expectancy plays a role in observed placebo and nocebo effects in 2 clinical trials. METHOD: Data were reanalyzed from 2 fluoxetine-discontinuation studies conducted from March 1990 to September 1992 and from May 1997 to December 2002. The 673 outpatients included were aged 18-65 years with DSM-III-R major depressive disorder (MDD), responded to 12-week duration open treatment, and were randomized to continued fluoxetine or placebo for an additional year. Participants in 1 of the included studies received a fixed dose of fluoxetine 20 mg daily, while the second study utilized flexible fluoxetine doses up to 60 mg daily. Mixed effects longitudinal models determined whether the possible randomization to placebo at 12 weeks resulted in significant depressive symptom worsening across treatments. Correlations were computed between early symptom change (weeks 1-3 of open treatment) and postrandomization symptom change (weeks 13-16 following randomization). RESULTS: Participants continuing to receive fluoxetine and those switched to placebo had significantly higher mean Hamilton Depression Rating Scale (HDRS) scores immediately postrandomization compared to the final weeks of open treatment (P < .001 for both fluoxetine- and placebo-treated patients). In both studies, early HDRS change was significantly correlated with postrandomization HDRS change for patients receiving fluoxetine (r = -0.46, P < .001) as well as placebo (r = -0.48, P < .001). CONCLUSIONS: The possibility of receiving placebo following 12 weeks of open fluoxetine was associated with significant symptom worsening in 2 large fluoxetine discontinuation studies. Worsening depression scores following randomization were significantly associated with the degree of improvement participants experienced during weeks 1-3 of open treatment. These results suggest that treatment changes influence patients' expectations of improvement, which, in turn, affect their depressive symptoms.

How treatable is refractory depression?

INTRODUCTION: Patients who do not remit following one or more attempts at treatment present a clinical challenge, as well as prolonged suffering and disability. Discouragement is common, so knowledge of likelihood of eventual remission as well as which treatments might ultimately be effective would help patient and clinician alike. METHOD: Thirty-one patients with major depression were recruited, 28 beginning study treatment. All had remained significantly depressed following adequate (4 weeks taking ≥ PDR maximum dose) trials on ≥ two antidepressants having different presumed mechanisms. Patients were begun on tranylcypromine to 60 mg/d, were then treated with up to 120 mg/d and then had dextroamphetamine added. Following two week wash-out, patients were then treated with nortriptyline+lithium, and then phenelzine was added. Each successive phase was entered only if remission had not been achieved, and phases could be skipped. RESULTS: Eighteen of the 28 patients (65%) remitted in one of the five phases of the study, plus 5 additional patients with open post-study treatment (total remitting, 82%). By study phase, Eight of 27 (30%) patients remitted with initial dosing of tranylcypromine up to 60 mg/d, 6/18 (33%) remitted with above PDR dosing of tranylcypromine up to 120 mg/d, and 1/6 (17%) to adding dextroamphetamine. With nortriptyline, 1/10 (10%) remitted with nortriptyline+lithium, and 1/5 (20%) when phenelzine was added. Eighteen of the 28 patients (64%), or 78% of those who remitted, maintained their good benefit for at least six months. DISCUSSION: The majority of depressed patients refractory to two or more adequately utilized differently acting antidepressant medications can still remit and about half may maintain remission for extended periods. "Refractory depression" appears to be a relative description for many unresponsive depressed patients.

Psychopathology and functioning among children of treated depressed fathers and mothers.

OBJECTIVE: Recent findings suggest that remissions of maternal depression are associated with decrease in offspring psychopathology. Little is known about the offspring effects of decrease in paternal depression. METHOD: The offspring of married fathers and married mothers were compared. The analysis was restricted to married parents to control for the confounding effect of single parenthood which was more prevalent among depressed mothers. At baseline all parents met criteria for major depressive disorder (MDD), and participated in a 3 month randomized controlled trial to treat depression with a 6 month follow-up. Married parents (N=43) and their children aged 7-17 years (N=78) were assessed independently through direct interviews of children and parents at baseline and followed for 9 months. Child assessors were blind to the clinical status of parents and uninvolved in their treatment. RESULTS: At baseline, children of depressed fathers, compared to children of depressed mothers, had significantly fewer psychiatric disorders (11% vs. 37%; p=0.012) and less impairment as measured by the Columbia Impairment Scale (6.5 vs. 11.6; p=0.009). Over time, with treatment of parental depression, the prevalence of most child symptoms decreased among children of depressed mothers, but changed little among children of depressed fathers. LIMITATIONS: The main limitation of the study is the small number of fathers and their offspring included in the study. CONCLUSION: Maternal as compared to paternal depression had a greater impact on children. With treatment of parental depression the differential prevalence of child symptoms by parental gender narrowed over time. The clinical implication is that children may benefit from treatment of their depressed parents.

Combination antidepressant therapy for major depressive disorder: speed and probability of remission.

INTRODUCTION: Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment. This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug. METHOD: Two hundred forty-five outpatients aged 18-65 having non-psychotic, non-bipolar major depression were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and/or escitalopram 40 mg/d for 12 weeks. A Montgomery-Asberg Depression Rating Scale score of 22 was required for randomization, while a Hamilton Rating Scale for Depression score ≤ 7 defined remission. We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission. RESULTS: Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate. All three treatments were well tolerated. DISCUSSION: These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response. CLINICAL TRIALS REGISTRATION: NCT00519428.

Is depression with atypical features associated with trauma history?

OBJECTIVE: Although studies have linked childhood trauma to depression resembling the atypical subtype, a majority of these studies did not use DSM-IV criteria for atypical features nor assess trauma both before and after depression onset. This study examined the relationship between atypical depression and lifetime trauma with the hypothesis that atypically depressed patients would report a higher number of trauma exposures than nonatypically depressed patients. METHOD: Raters blind to depressive subtype investigated trauma history by reviewing the Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P) posttraumatic stress disorder modules and social history sections in charts of depressed outpatients who had participated in treatment studies between 1985 and 2010. Rates of trauma both before and after depression onset were compared for 292 depressed patients with and without DSM-IV-defined atypical features using χ2 tests and binary logistic regressions. This chart review was conducted from 2009 to 2011. RESULTS: Lifetime trauma was reported significantly more often by depressed patients with atypical features than by those without (P < .001). Patients with atypical features reported significantly more traumatic experiences both prior to (P = .012) and following (P = .015) depression onset. When sex and age at onset or duration of depression were used as covariates, depressive subtype was a significant predictor of reported trauma both prior to (P = .028) and following (P = .011) depression onset. CONCLUSIONS: These results suggest that a relationship exists between atypical depression and lifetime trauma that may be more complex than the etiologic pathways outlined in prior research. Rather, trauma and atypical depression may be interrelated throughout life.