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Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (1H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.

Background Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. Methods This post hoc analysis used data from the intent-to-treat (ITT) cohort ( N  = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. Results At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p  = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p  = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p  = 0.004) and HAM-D17 (∆ = 6.3%, p  = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p  = 0.031; HAM-D17 ∆ = 5.5%, p  = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p  = 0.004) response (∆ = 10.0%, p  = 0.001) and remission (∆ = 7.9%, p  = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. Conclusions The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. Trial registration Clinicaltrials.gov: NCT02109939 . Registered 10 April 2014.

Patients with major depression were treated with an oral γ-aminobutyric acid type A–receptor modulator for 14 days. At day 15, patients who received the drug had a greater reduction in depressive symptoms than patients who received placebo. Headache was the most common adverse event.

The efficacy and safety of a selective NK 1 antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK 1 ) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18–60, scoring ⩾25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring ⩾4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily ( n =66) or placebo ( n =62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo ( p <0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p <0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial ( p =0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK 1 antagonists (aprepitant and L-759274). NK 1 antagonism is a replicated and generally well-tolerated antidepressant mechanism.

The burden of depression in men is high. Current diagnostic criteria may not fully capture men’s experience with depression. Descriptions of the heterogeneity in depression among men are lacking. The purpose of the study was to characterize latent subtypes of major depression and changes in these subtypes among men receiving citalopram in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Latent transition analysis was applied to data from 387 men who completed baseline and Week 12 study visits in Level 1 of STAR*D. Items from the self-report version of the Quick Inventory of Depressive Symptomatology were used as indicators of latent depression subtypes. Four statuses were identified at baseline and Week 12. Baseline statuses were Mild (10% of men), Moderate (53%), Severe with Psychomotor Slowing (20%), and Severe with Psychomotor Agitation (17%). At Week 12, the statuses were Symptom Resolution (41%), Mild (36%), Moderate (18%), and Severe with Psychomotor Slowing (5%). Men in the Mild status were most likely to transition to Symptom Resolution (probability = 69%). Men in the Severe with Agitation status were least likely to transition to Symptom Resolution (probability = 0%). This work highlights the need to not focus solely on summary rating scores but to also consider patterns of symptoms when treating depression.

Background. Several studies investigated the use of selective serotonin reuptake inhibitors (SSRI) after ischemic stroke to improve motor recovery. However, little is known about the effects of preexisting psychotropic medication use (PPMU), such as antidepressants, on a long-term ischemic stroke functional disability. Objective. We sought to determine the prevalence of PPMU and whether PPMU relates to the long-term clinical outcome in a cohort of patients presenting with acute ischemic strokes. Methods. We retrospectively analyzed 323 consecutive patients who presented with an acute ischemic stroke in a single institution between January 2015 and December 2017. Baseline characteristics, functional disability as measured by the modified Rankin Scale (mRS), and major adverse cardiovascular complications (MACE) within 365 days were recorded. The comparison groups included a control group of ischemic stroke patients who were not on psychotropic medications before and after the index ischemic stroke and a second group of poststroke psychotropic medication use (PoMU), which consisted of patients started on psychotropic medication during the index admission. Results. The prevalence of PPMU in the studied cohort was 21.4% (69/323). There was a greater proportion of females in the PPMU than in the comparison groups (P<0.001), while vascular risk factors were similar in all groups, except for an increased presence of posterior circulation infarcts in the PPMU (37.4% vs. 18.8%, P<0.001). Among the patients with available 1-year follow-up data (n=246), we noted significantly greater improvement in stroke deficits, measured by National Institute of Health Stroke Scale (NIHSS) between PPMU and PoMU vs. control (3 (0-7) versus 1 (0-4), P=0.041). The 1-year mRS was worse in PPMU and PoMU compared to the control group (2 (IQ 1-3) vs. 2 (IQ 0-3) vs. 1 (IQ 0-2), respectively, P=0.013), but delta mRS reflecting the degree of mRS improvement showed no significant difference between any PMU and control patients (P=0.76). There was no statistically significant difference in MACE. Conclusion. PPMU in ischemic stroke is common; it can be beneficial in ischemic stroke in the long-term clinical outcome and is not associated with increased risks of MACE.

To compare the frequency of anxiety disorders in older and younger persons with major depressive disorder with psychotic features. Cross-sectional. University medical centers. Two hundred fifty-nine persons (N = 117 aged 18–59 years and N = 142 aged ≥60 years) with major depressive disorder with psychotic features who were enrolled in the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) defined anxiety disorders were determined by Structured Clinical Interview for DSM-IV interview at baseline assessment. Younger and older participants were compared on the frequencies of any current anxiety disorder and any lifetime anxiety disorder, as well as the frequencies of individual anxiety disorders. Older persons had significantly lower frequencies of any current anxiety disorder and any lifetime anxiety disorder, even after controlling for relevant demographic and clinical variables. With respect to specific anxiety disorders, older persons had significantly lower frequencies of current and lifetime panic disorder, current and lifetime social anxiety disorder, and current and lifetime posttraumatic stress disorder. The findings of this study are consistent with those of community-based epidemiologic surveys that anxiety disorders are less prevalent in older than younger adults. Because of the rigorous assessment used in STOP-PD, our findings suggest that the age-related decline in the prevalence of anxiety disorders is not simply due to a failure to detect cases in older people, as has been previously suggested.

AbstractDiffusion tensor imaging (DTI) studies in depression show decreased structural connectivity in the left anterior limb of the internal capsule and the genu of the corpus callosum but no such studies exist in peripartum depression (PPD), which affects 1 in 8 women. We analyzed fractional anisotropy (FA) as a measure of white matter integrity of these two tracts using tract-based spatial statistics (TBSS). We then conducted an exploratory whole-brain analysis to identify additional regions implicated in PPD. Seventy-five pregnant, medication-free women were evaluated with the Edinburgh Postnatal Depression Scale (EPDS) and Structured Clinical Interview (SCID) for DSM-IV-TR in pregnancy and in the postpartum. Structural MRI and DTI sequences were acquired in forty-four women within 2–8 weeks postpartum. TBSS data were analyzed between healthy comparison postpartum women (HCW) and women who developed PPD to determine differences in white matter integrity within the left anterior limb of the internal capsule and the genu of the corpus callosum, then analyzed across participants to explore correlation between FA and the EPDS score. An exploratory whole-brain analysis was also conducted to identify other potential regions showing differences in white matter integrity between groups, as well as correlation between EPDS and FA across groups. All results were corrected for multiple comparisons and analyses conducted using FSL, p < 0.05, K > 10. In comparison to HCW, women with PPD had significantly lower FA in left anterior limb of the internal capsule (p = 0.010). FA was negatively correlated with EPDS scores in the left anterior limb of the internal capsule (p = 0.019). In the whole-brain analysis, FA in the right retrolenticular internal capsule (p = 0.03) and two clusters within the body of the corpus callosum (p = 0.044, p = 0.050) were negatively correlated with EPDS; there were no between-group differences in FA. Reduced FA in the left anterior limb of the internal capsule suggests disruption of fronto-subcortical circuits in PPD. A negative correlation between FA within the body of the corpus callosum and EPDS total score could additionally reflect disrupted interhemispheric structural connectivity in women with depressive symptoms.

Some data suggest that antipsychotics may adversely affect brain structure. We examined the relationship among olanzapine exposure, relapse, and changes in brain structure in patients with major depressive disorder with psychotic features. We analyzed data from the Study of the Pharmacotherapy of Psychotic Depression II trial (STOP-PD II), a randomized, placebo-controlled trial in patients with psychotic depression who attained remission on sertraline and olanzapine and were randomized to continue sertraline plus olanzapine or placebo for 36 weeks. Olanzapine steady state concentration (SSC) were calculated based on sparsely-sampled levels. Rates of relapse and changes in brain structure were assessed as outcomes. There were significant associations between dosage and relapse rates ( N  = 118; HR = 0.94, 95% CI [0.897, 0.977], p  = 0.002) or changes in left cortical thickness ( N  = 44; B = −2.0 × 10 −3 , 95% CI [−3.1 × 10 −3 , −9.6 × 10 −4 ], p  < 0.001) and between SSC and changes in left cortical thickness ( N  = 44; B = −8.7 × 10 −4 , 95% CI [−1.4 × 10 −3 , −3.6 × 10 −4 ], p  = 0.001). Similar results were found for the right cortex. These associations were no longer significant when the analysis was restricted to participants treated with olanzapine. Our findings suggest that, within its therapeutic range, the effect of olanzapine on relapse or cortical thickness does not depend on its dosage or SSC. Further research is needed on the effect of olanzapine and other antipsychotics on mood symptoms and brain structure.

Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory. One hundred and twenty-six persons aged 18-85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics. Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model. Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.