Improving EMS response times for out-of-hospital cardiac arrest in urban areas using drone-like vertical take-off and landing air ambulances: An international, simulation-based cohort study.

BACKGROUND: Advances in vertical take-off and landing (VTOL) technologies may enable drone-like crewed air ambulances to rapidly respond to out-of-hospital cardiac arrest (OHCA) in urban areas. We estimated the impact of incorporating VTOL air ambulances on OHCA response intervals in two large urban centres in France and Canada. METHODS: We included adult OHCAs occurring between Jan. 2017-Dec. 2018 within Greater Paris in France and Metro Vancouver in Canada. Both regions utilize tiered OHCA response with basic (BLS)- and advanced life support (ALS)-capable units. We simulated incorporating 1-2 ALS-capable VTOL air ambulances dedicated to OHCA response in each study region, and computed time intervals from call reception by emergency medical services (EMS) to arrival of the: (1) first ALS unit ("call-to-ALS arrival interval"); and (2) first EMS unit ("call-to-first EMS arrival interval"). RESULTS: There were 6,217 OHCAs included during the study period (3,760 in Greater Paris and 2,457 in Metro Vancouver). Historical median call-to-ALS arrival intervals were 21 min [IQR 16-29] in Greater Paris and 12 min [IQR 9-17] in Metro Vancouver, while median call-to-first EMS arrival intervals were 11 min [IQR 8-14] and 7 min [IQR 5-8] respectively. Incorporating 1-2 VTOL air ambulances improved median call-to-ALS arrival intervals to 7-9 min and call-to-first EMS arrival intervals to 6-8 min in both study regions (all P < 0.001). CONCLUSION: VTOL air ambulances dedicated to OHCA response may improve EMS response intervals, with substantial improvements in ALS response metrics.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation.

Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Association between location of out-of-hospital cardiac arrest, on-scene socioeconomic status, and accessibility to public automated defibrillators in two large metropolitan areas in Canada and France.

AIM: To compare walking access times to automated external defibrillators (AEDs) between area-level quintiles of socioeconomic status (SES) in out-of-hospital cardiac arrest (OHCA) cases occurring in 2 major urban regions of Canada and France. METHODS: This was an international, multicenter, retrospective cohort study of adult, non-traumatic OHCA cases in the metropolitan Vancouver (Canada) and Rhône County (France) regions that occurred between 2014 and 2018. We calculated area-level SES for each case, using quintiles of country-specific scores (Q5 = most deprived). We identified AED locations from local registries. The primary outcome was the simulated walking time from the OHCA location to the closest AED (continuous and dichotomized by a 3-minute 1-way threshold). We fit multivariate models to analyze the association between OHCA-to-AED walking time and outcomes (Q5 vs others). RESULTS: A total of 6,187 and 3,239 cases were included from the Metro Vancouver and Rhône County areas, respectively. In Metro Vancouver Q5 areas (vs Q1-Q4), areas, AEDs were farther from (79 % over 400 m from case vs 67 %, p < 0.001) and required longer walking times to (97 % above 3 min vs 91 %, p < 0.001) cases. In Rhône Q5 areas, AEDs were closer than in other areas (43 % over 400 m from case vs 50 %, p = 0.01), yet similarly poorly accessible (85 % above 3 min vs 86 %, p = 0.79). In multivariate models, AED access time ≥ 3 min was associated with decreased odds of survival at hospital discharge in Metro Vancouver (odds ratio 0.41, 95 % CI [0.23-0.74], p = 0.003). CONCLUSIONS: Accessibility of public AEDs was globally poor in Metro Vancouver and Rhône, and even poorer in Metro Vancouver's socioeconomically deprived areas.

Subgenual activation and the finger of blame: individual differences and depression vulnerability.

BACKGROUND: Subgenual cingulate cortex (SCC) responses to self-blaming emotion-evoking stimuli were previously found in individuals prone to self-blame with and without a history of major depressive disorder (MDD). This suggested SCC activation reflects self-blaming emotions such as guilt, which are central to models of MDD vulnerability. METHOD: Here, we re-examined these hypotheses in an independent larger sample. A total of 109 medication-free participants (70 with remitted MDD and 39 healthy controls) underwent fMRI whilst judging self- and other-blaming emotion-evoking statements. They also completed validated questionnaires of proneness to self-blaming emotions including those related to internal (autonomy) and external (sociotropy) evaluation, which were subjected to factor analysis. RESULTS: An interaction between group (remitted MDD v. Control) and condition (self- v. other-blame) was observed in the right SCC (BA24). This was due to higher SCC signal for self-blame in remitted MDD and higher other-blame-selective activation in Control participants. Across the whole sample, extracted SCC activation cluster averages for self- v. other-blame were predicted by a regression model which included the reliable components derived from our factor analysis of measures of proneness to self-blaming emotions. Interestingly, this prediction was solely driven by autonomy/self-criticism, and adaptive guilt factors, with no effect of sociotropy/dependency. CONCLUSIONS: Despite confirming the prediction of SCC activation in self-blame-prone individuals and those vulnerable to MDD, our results suggest that SCC activation reflects blame irrespective of where it is directed rather than selective for self. We speculate that self-critical individuals have more extended SCC representations for blame in the context of self-agency.

Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake.

Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the "rumination" and "worry" items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms.

The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

Childhood Adversity Moderates the Effects of HTR2A Epigenetic Regulatory Polymorphisms on Rumination.

The serotonin system has been suggested to moderate the association between childhood maltreatment and rumination, with the latter in its turn reported to be a mediator in the depressogenic effect of childhood maltreatment. Therefore, we investigated whether the associations of two epigenetic regulatory polymorphisms in the HTR2A serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived from the Childhood Trauma Questionnaire) among 1,501 European white adults. We tested post hoc whether the significant associations are due to depression. We also tested the replicability of the significant results within the two subsamples of Budapest and Manchester. We revealed two significant models: both the association of methylation site rs6311 with rumination and that of miRNA binding site rs3125 (supposed to bind miR-1270, miR-1304, miR-202, miR-539 and miR-620) with brooding were a function of childhood adversity, and both interaction findings were significantly present both in the never-depressed and in the ever-depressed group. Moreover, the association of rs3125 with brooding could be replicated across the separate subsamples, and remained significant even when controlling for lifetime depression and the Brief Symptom Inventory depression score. These findings indicate the crucial importance of involving stress factors when considering endophenotypes and suggest that brooding is a more promising endophenotype than a broader measure of rumination. Transdiagnostic relevance of the brooding endophenotype and the potential of targeting epigenetic regulatory polymorphisms of HTR2A in primary and secondary prevention of depression and possibly of other disorders are also discussed.

Genome-wide association analysis reveals KCTD12 and miR-383-binding genes in the background of rumination.

Ruminative response style is a passive and repetitive way of responding to stress, associated with several disorders. Although twin and candidate gene studies have proven the genetic underpinnings of rumination, no genome-wide association study (GWAS) has been conducted yet. We performed a GWAS on ruminative response style and its two subtypes, brooding and reflection, among 1758 European adults recruited in the general population of Budapest, Hungary, and Manchester, United Kingdom. We evaluated single-nucleotide polymorphism (SNP)-based, gene-based and gene set-based tests, together with inferences on genes regulated by our most significant SNPs. While no genome-wide significant hit emerged at the SNP level, the association of rumination survived correction for multiple testing with KCTD12 at the gene level, and with the set of genes binding miR-383 at the gene set level. SNP-level results were concordant between the Budapest and Manchester subsamples for all three rumination phenotypes. SNP-level results and their links to brain expression levels based on external databases supported the role of KCTD12, SRGAP3, and SETD5 in rumination, CDH12 in brooding, and DPYSL5, MAPRE3, KCNK3, ATXN7L3B, and TPH2 in reflection, among others. The relatively low sample size is a limitation of our study. Results of the first GWAS on rumination identified genes previously implicated in psychiatric disorders underscoring the transdiagnostic nature of rumination, and pointed to the possible role of the dorsolateral prefrontal cortex, hippocampus, and cerebellum in this cognitive process.

Significance of risk polymorphisms for depression depends on stress exposure.

Depression is a polygenic and multifactorial disorder where environmental effects exert a significant impact, yet most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS and between human studies and animal models. Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects. This Bayesian analysis indicated a gene-environment interaction whose significance was also tested with a traditional multivariate analysis using general linear models. The investigated genetic factors were only relevant in the moderate and/or high stress exposure groups. Rank order of genes was GALR2 > BDNF > P2RX7 > HTR1A > SLC6A4 > CB1 > HTR2A, with strong relevance for the first four. Robust gene-gene-environment interaction was found between BDNF and HTR1A. Gene-environment interaction effect was confirmed, namely no main effect of genes, but a significant modulatory effect on environment-induced development of depression were found. Our data support the strong causative role of the environment modified by genetic factors, similar to animal models. Gene-environment interactions point to epigenetic factors associated with risk SNPs. Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants.

Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.

BACKGROUND: Evidence suggests that anti-inflammatory medication may be effective in the treatment of depressive symptoms. In this study, we aimed to investigate whether minocycline added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression will lead to an improvement in depressive symptoms. METHODS: Multi-site, 12-week, double-blind, placebo-controlled, pilot trial of minocycline added to TAU for patients suffering from DSM-5 major depressive disorder, whose current episode has failed to respond to at least two antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D) quality-of-life questionnaire. Side-effect checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg after 2 weeks. RESULTS: A total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (standardised effect size (ES) -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (odds ratio (OR): 17.6, p < 0.001). PHQ-9, GAD-7 and EQ-5D total showed more moderate improvements (ES ~ 0.4-0.5). CONCLUSION: The findings indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, our findings require replication in a larger sample. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02263872, registered October 2014.

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.

This corrects the article DOI: 10.1038/npp.2016.289.

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence.

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.

Effects of Acute Ketamine Infusion on Visual Working Memory: Event-Related Potentials.

BACKGROUND: Working memory (WM) deficits are a core feature of schizophrenia. Electrophysiological studies suggest that impaired early visual processing may contribute to impaired WM in the visual domain. Abnormal N-methyl-D-aspartate (NMDA) receptor function has been implicated both in WM and in early visual processing deficits in schizophrenia. We investigated whether ketamine, a noncompetitive NMDA antagonist, would replicate in healthy volunteers the WM performance and early visual processing abnormalities we and others have reported in patients with schizophrenia. METHODS: Forty-four healthy volunteers were randomly assigned to receive intravenous ketamine or placebo. During infusion, the effects of ketamine were recorded using standardized psychiatric scales. Visual evoked potentials (P100 and P300 components) were recorded during performance of a delayed matching to sample task. RESULTS: Ketamine induced mild psychosis-like symptoms and impaired WM performance. It also significantly increased the P100 amplitude, while P300 amplitude decreased in a load-dependent manner. Amplitudes of P100 during retrieval correlated with cognitive performance only in the placebo group. CONCLUSIONS: We confirmed previous studies showing that ketamine reproduces the impairment of WM performance and smaller P300 amplitudes observed in schizophrenia. However, ketamine increased visual P100 amplitude in contrast to our observation of reduced P100 amplitudes in established schizophrenia. The effects of ketamine on WM and P300 are likely to involve impaired NMDA function, as these receptors are implicated in changes of synaptic strength underlying associative learning and memory. Increased P100 amplitude may reflect the secondary disinhibition of cortical glutamate release that occurs after NMDA blockade.

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a study protocol for a multicenter factorial design randomized controlled trial.

BACKGROUND: Evidence suggests that the use of anti-inflammatory agents may improve depressive symptoms in patients with bipolar affective disorder. However, there are few well-designed clinical trials demonstrating the efficacy of these newer treatment strategies. PATIENTS AND METHODS: This is a multicenter, 3-month, randomized, placebo-controlled, double-blind, factorial design trial of minocycline and/or celecoxib added to TAU for the treatment of depressive symptoms in patients experiencing a DSM-5 bipolar I or II disorder and a current major depressive episode. A total of 240 participants will undergo screening and randomization followed by four assessment visits. The primary outcome measure will be mean change from baseline to week 12 on the Hamilton Depression Scale scores. Clinical assessments using the Clinical Global Impression scale, Patient Health Questionnaire-9, and the Generalized Anxiety Disorder 7-item scale will be carried out at every visit as secondary outcomes. Side-effect checklists will be used to monitor the adverse events at each visit. Complete blood count and plasma C-reactive protein will be measured at baseline and at the end of the treatment. Minocycline will be started at 100 mg once daily and increased to 200 mg at 2 weeks. Celecoxib will be started at 200 mg once daily and increased to 400 mg at 2 weeks. DISCUSSION: Anti-inflammatory agents have been shown to be potentially efficacious in the treatment of depressive symptoms. The aim of this study is to determine whether the addition of minocycline and/or celecoxib to TAU improves depressive symptoms in patients with bipolar affective disorder.

Rumination in migraine: Mediating effects of brooding and reflection between migraine and psychological distress.

OBJECTIVE: The relationship between migraine and psychological distress has been consistently reported in cross-sectional and longitudinal studies. We hypothesised that a stable tendency to perseverative thoughts such as rumination would mediate the relationship between migraine and psychological distress. Design and Main Outcomes Measures: Self-report questionnaires measuring depressive rumination, current psychological distress and migraine symptoms in two independent European population cohorts, recruited from Budapest (N = 1139) and Manchester (N = 2004), were used. Structural regression analysis within structural equation modelling was applied to test the mediational role of brooding and reflection, the components of rumination, between migraine and psychological distress. Sex, age and lifetime depression were controlled for in the analysis. RESULTS: Migraine predicted higher brooding and reflection scores, and brooding proved to be a mediator between migraine and psychological distress in both samples, while reflection mediated the relationship significantly only in the Budapest sample. CONCLUSIONS: Elevated psychological distress in migraine is partially attributed to ruminative response style. Further studies are needed to expand our findings to clinical samples and to examine how rumination links to the adjustment to migraine.

Effects of acute tryptophan depletion on central processing of CT-targeted and discriminatory touch in humans.

C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4 h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. In addition, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were similar across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function.

An investigation into aripiprazole's partial D2 agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers.

RATIONALE: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. OBJECTIVES: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole's prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole's unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. METHOD: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. RESULTS: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d') and speeded reaction times. In contrast to aripiprazole's neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d' and additionally had reduced errors of commission compared with placebo. CONCLUSION: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone's serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade.

Subgenual Cingulate-Amygdala Functional Disconnection and Vulnerability to Melancholic Depression.

The syndromic heterogeneity of major depressive disorder (MDD) hinders understanding of the etiology of predisposing vulnerability traits and underscores the importance of identifying neurobiologically valid phenotypes. Distinctive fMRI biomarkers of vulnerability to MDD subtypes are currently lacking. This study investigated whether remitted melancholic MDD patients, who are at an elevated lifetime risk for depressive episodes, demonstrate distinctive patterns of resting-state connectivity with the subgenual cingulate cortex (SCC), known to be of core pathophysiological importance for severe and familial forms of MDD. We hypothesized that patterns of disrupted SCC connectivity would be a distinguishing feature of melancholia. A total of 63 medication-free remitted MDD (rMDD) patients (33 melancholic and 30 nonmelancholic) and 39 never-depressed healthy controls (HC) underwent resting-state fMRI scanning. SCC connectivity was investigated with closely connected bilateral a priori regions of interest (ROIs) relevant to MDD (anterior temporal, ventromedial prefrontal, dorsomedial prefrontal cortices, amygdala, hippocampus, septal region, and hypothalamus). Decreased (less positive) SCC connectivity with the right parahippocampal gyrus and left amygdala distinguished melancholic rMDD patients from the nonmelancholic rMDD and HC groups (cluster-based familywise error-corrected p⩽0.007 over individual a priori ROIs corresponding to approximate Bonferroni-corrected p⩽0.05 across all seven a priori ROIs). No areas demonstrating increased (more positive) connectivity were observed. Abnormally decreased connectivity of the SCC with the amygdala and parahippocampal gyrus distinguished melancholic from nonmelancholic rMDD. These results provide the first resting-state neural signature distinctive of melancholic rMDD and may reflect a subtype-specific primary vulnerability factor given a lack of association with the number of previous episodes.