Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Illness narratives and preferences for treatment among older veterans living with treatment-resistant depression and insomnia.

BACKGROUND: Despite the prevalence of comorbid late-life treatmentresistant depression (LLTRD) and insomnia in older adults, there is a gap in the literature describing patient factors, such as patients' beliefs about their illnesses and preferences for treatment, that can facilitate recovery. Therefore, we explored the perceptions and treatment preferences of older veterans with LLTRD and insomnia. METHODS: Semi-structured interviews were completed with 11 older veterans. A thematic analysis of the interviews was conducted. RESULTS: Four main themes were identified: 1. Insomnia and medical problems were considered to be significant contributors to depression, which was defined by low mood and anhedonia; 2. "Overthinking" was thought to be a cause of insomnia; 3. Participants' preference for psychotherapy was driven by their past experiences with therapy; and 4. Participants viewed patient education as a facilitator for compliance. CONCLUSIONS: Older veterans with LLTRD and insomnia have a preference for behavioral interventions. However, they lack knowledge about available treatment options, such as behavioral interventions for sleep that can improve both their sleep and mood while being a good fit with their illness narratives, such as "overthinking." There is a need for patient education, which should be offered early and often during treatment.

Brief behavioral treatment for insomnia in older adults with late-life treatment-resistant depression and insomnia: a pilot study.

OBJECTIVE: Brief Behavioral Treatment for Insomnia (BBTI) is an efficacious treatment of insomnia in older adults. Behavioral treatments for insomnia can also improve depression. However, it is unknown if BBTI is feasible or has an effect in patients with insomnia and late-life treatment resistant depression (LLTRD). The aims of this study were two-fold, to test: 1) the feasibility (defined by acceptability and retention rates) of BBTI and 2) the therapeutic potency of BBTI on symptoms of insomnia and depression. METHODS: Eleven older Veterans with LLTRD and insomnia were recruited in a randomized control trial to receive immediate (4-weeks of BBTI followed by 3-weeks of phone call check-ins and a final in-person 8-week assessment) or delayed (3-weeks of treatment as usual [wait-list control] followed by 4-weeks of BBTI and a final in-person 8-week assessment) BBTI. The primary outcome measures included the Patient Health Questionnaire (minus the sleep item) and the Insomnia Severity Index. RESULTS: BBTI was found to be feasible in older Veterans with insomnia and LLTRD; all participants recommended BBTI and retention rates were 90.9%. There was no difference in treatment effect between the immediate BBTI and delayed BBTI groups at week 4. After both groups (immediate and delayed) received BBTI, improvements were seen in both insomnia (d = 1.06) and depression (d = 0.54) scores. CONCLUSIONS: BBTI is a feasible treatment for insomnia in older adults with LLTRD. BBTI may be an effective adjunctive treatment for depression. Larger adequately-powered trials are required to confirm these preliminary findings.

Risk Factors for Suicide in Older Inpatient Veterans with Schizophrenia.

Patients with schizophrenia have an elevated risk of suicidal behavior. We explored whether there were age differences in inpatients with schizophrenia admitted for suicidal behavior. We compared demographic/clinical characteristics of 76 inpatients aged > 59 to those < 60. All patients had a score greater > 0 on items 4 (active suicidality) and/or 5 (passive suicidality) on the Beck Scale for Suicidal Ideation for inclusion. There were no significant group differences with respect to race, education, depressive symptoms or negative symptoms. There was evidence suggesting that hallucinations appear to be less prominent in the older group. Future studies will determine whether these age related differences are stable over time and could account for potential age differences in suicidal behavior in individuals with schizophrenia.

Effect of insomnia treatments on depression: A systematic review and meta-analysis.

BACKGROUND: Insomnia is frequently co-morbid with depression, with a bidirectional relationship between these disorders. There is evidence that insomnia-specific interventions, such as cognitive behavioral therapy for insomnia, may lead to improvements in depression. The purpose of this systematic review and meta-analysis is to determine whether treatment of insomnia leads to improved depression outcomes in individuals with both insomnia and depression. METHODS: We conduct a systematic review and meta-analysis to explore the effect of treatment for insomnia disorder on depression in patients with both disorders. RESULTS: Three thousand eight hundred and fifteen studies were reviewed, and 23 studies met inclusion criteria. Although all of the studies suggested a positive clinical effect of insomnia treatment on depression outcomes, most of the results were not statistically significant. Although the interventions and populations were highly variable, the meta-analysis indicates moderate to large effect size (ES) improvement in depression as measured with the Hamilton Depression Rating Scale (ES = -1.29, 95%CI [-2.11, -0.47]) and Beck Depression Inventory (ES = -0.68, 95%CI [-1.29, -0.06]). CONCLUSIONS: These results support that treating insomnia in patients with depression has a positive effect on mood. Future trials are needed to identify the subtypes of patients whose depression improves during treatment with insomnia-specific interventions, and to identify the mechanisms by which treating insomnia improves mood.

The role of late life depressive symptoms on the trajectories of insomnia symptoms during antidepressant treatment.

OBJECTIVE: Sleep disturbances are common in late life depression; however, changes in insomnia symptoms during antidepressant treatment need to be characterized further. The objective of this study was two-fold: 1) to describe longitudinal trajectories of insomnia symptoms in older adults receiving antidepressant treatment and 2) to examine whether baseline depressive symptoms were associated with trajectories of sleep over time. METHODS: Data was obtained from 680 older adults (aged ≥ 60) with major depression who participated in one of two protocolized open-label antidepressant treatment clinical trials (Maintenance Therapies in Late Life Depression [MTLD-3]; Incomplete Response in Late Life Depression: Getting to Remission [IRL-GRey]). Depression (total score minus sleep items) and sleep (sum of sleep items) outcomes were derived from the Hamilton Depression Rating Scale in the MLTD-3 and Montgomery-Asberg Depression Rating Scale in the IRL-GRey. RESULTS: Both datasets identified 5 possible trajectories of insomnia symptoms with about half of the older adults having clinically significant baseline sleep disturbances and minimal improvement following a course of antidepressant treatment (i.e., sub-optimal sleep trajectory). Furthermore, across both datasets, worse baseline depression severity was associated with sub-optimal sleep trajectories. CONCLUSION: In older adults receiving antidepressant treatment, those with clinically significant baseline sleep disturbances and greater depression severity may require adjunctive sleep-focused treatment to ameliorate sleep symptoms.

Specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression.

OBJECTIVE: To identify which specific depressive symptoms predict remission to aripiprazole augmentation in late-life treatment resistant depression. METHODS: This is a secondary analysis of data from a late-life treatment resistant depression trial examining the safety and efficacy of aripiprazole augmentation. Participants aged 60 and above were randomized to aripiprazole augmentation (N = 91) versus placebo (N = 90). The main outcome was depression remission. Clinical predictors included individual Montgomery-Asberg Depression Rating Scale (MADRS) item scores categorized as symptomatic (scores >2) or nonsymptomatic (scores ≤2). RESULTS: Three MADRS items predicted depression remission with aripiprazole augmentation: symptomatic scores on sleep disturbance and nonsymptomatic scores on apparent sadness and inability to feel. The 2-way and 3-way interaction terms of these MADRS items were not significant predictors of remission; therefore, the models' ability to predict remission was not improved by combining the significant MADRS items. CONCLUSIONS: The identification of specific depressive symptoms, which can be clinically assessed, can be used to inform treatment decisions. Older adults with treatment resistant depression that present with sleep disturbances, lack of apparent sadness, or lack of inability to feel should be considered for aripiprazole augmentation.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Reduction of medical hospitalizations in veterans with schizophrenia using home telehealth.

This study tested the hypothesis that addition of telehealth to Intensive Case Monitoring (ICM) would reduce hospital admissions in Veterans with schizophrenia or schizoaffective disorder admitted for psychiatric care in response to suicidal behavior. Participants (n =51) were randomized to ICM or ICM plus telehealth monitoring. Telehealth participants responded to daily electronic queries about depression, suicidality, and medication adherence. Comparisons revealed that participants in the telehealth group had significantly less medical hospitalizations than the control group. This study found that telehealth augmentation is related to decreased number and length of medical hospitalizations in Veterans with schizophrenia and schizoaffective disorder.

Mood Disorders in Middle-Aged and Older Veterans With Multimorbidity.

OBJECTIVE: This study identified the prevalence of and relationship between mood disorders and multimorbidity in middle-aged and older veterans. METHOD: Cross-sectional data were obtained from veterans who received primary care services at VA Pittsburgh Healthcare System from January 2007 to December 2011 ( n = 34,786). RESULTS: Most veterans had three or more organ systems with chronic disease (95.3%), of which 4.1% had a depressive disorder, 2.5% had an anxiety disorder, and 0.7% had co-occurring depression and anxiety. The odds of having a mood disorder increased with each additional organ system with chronic disease, with odds being the greatest in those with 10 to 13 organ systems with chronic disease. Younger age, female gender, non-married marital status, and having a service connected disability were also significant predictors of having a mood disorder. DISCUSSION: These findings suggest a need to integrate mental health assessment and treatment in chronic health care management for veterans.

Mental health treatment preferences and challenges of living with multimorbidity from the veteran perspective.

OBJECTIVE: To explore middle-aged and older veterans' current disease-management practices, mental health treatment preferences, and challenges of living with multiple chronic health conditions (i.e., multimorbidity). METHODS: Semi-structured qualitative interviews and self-report measures were collected from 28 middle-aged and older (50 years of age or older) veterans with multimorbidity. RESULTS: Our sample of veterans with multimorbidity was, on average, mildly depressed and anxious with elevated stress and disability. Veterans acknowledged the interaction of physical and emotional symptoms, which caused greater difficulty with health care management and daily functioning. Veterans had many concerns regarding their physical and emotional health conditions, such as continued disease progression and the addition of other emotional and physical health complications. Veterans also identified specific self-care approaches for disease management (e.g., medication, healthy lifestyle practices, and psychological stress management techniques), as well as barriers to engaging in care (e.g., money, transportation, and stigma). Participants preferred a combination of medication, psychotherapy, and healthy lifestyle practices for mental health treatment. The majority of participants (88.5%) agreed that these mental health treatments would be beneficial to integrate into disease management for older veterans with multimorbidity. Lastly, veterans provided an array of recommendations for improving Veteran's Administration services and reducing mental health stigma. CONCLUSIONS: These findings provide support for patient-centered approaches and integrated mental and physical health self-management in the Veteran's Administration for middle-aged and older veterans with multiple chronic conditions. Copyright © 2016 John Wiley & Sons, Ltd.

Using telehealth to augment an intensive case monitoring program in veterans with schizophrenia and suicidal ideation: A pilot trial.

Veterans with schizophrenia admitted for suicidal ideation were recruited into a post-discharge program consisting of Intensive Case Monitoring (ICM) with daily monitoring with the Health Buddy (HB; experimental group) or ICM alone (control group). This study tested the feasibility of the telehealth monitoring intervention in this population. Secondly, we determined whether augmentation of ICM with our intervention for 3 months would result in a reduction in suicidal ideation. Twenty of 25 telehealth participants could set up the device. Monthly adherence for telehealth participants was > 80%. A qualitative analysis of endpoint surveys revealed that the majority of participants had positive responses. In both groups, there were improvements in Beck Scale for Suicidal Ideation (BSS) scores at endpoint relative to baseline. No group differences were present with survival analysis when using remission (i.e., BSS score = 0) as the outcome; however, in a subgroup with a history of suicide attempt, there was a trend (p = .093) for a higher rate of remission for those in the HB condition. In conclusion, telehealth monitoring for this population appears to be feasible for those who are able to start using the system. The pilot data obtained should help investigators design better telehealth interventions for this population.

Sedative hypnotic use among veterans with a newly reported mental health disorder.

BACKGROUND: This study compared sedative hypnotic use by type of mental health diagnosis and determined factors associated with use among older veterans (65+ years) with a newly reported mental health disorder. METHODS: This study used data from veterans who received primary care services at VA Pittsburgh Healthcare System (VAPHS) from January 1, 2007 to December 31, 2011 (n = 879). RESULTS: Sedative hypnotics were commonly used in older veterans within 12-months following a newly reported mental health disorder (19.9%), particularly amongst those with insomnia (41.7%). The number of newly reported mental health disorders was a significant factor associated with sedative hypnotic use, with the odds of use increasing by more than 200% in older adults with two newly reported disorders compared to those with one newly reported mental health disorder. CONCLUSIONS: Continued efforts are needed to improve provider and patient awareness of the risks associated with sedative hypnotic use in older adults, as well as to increase access to and receipt of non-pharmacological mental health treatments for this vulnerable population.

Prevalence and Specificity of the Abnormal Niacin Response: A Potential Endophenotype Marker in Schizophrenia.

The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families, appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may prove to be a useful SZ endophenotype. Using a laser Doppler flowmeter, we undertook this study to estimate the prevalence of NRA in SZ (n = 70), bipolar disorder (BP, n = 59), and healthy control (HC, n = 87) groups, and to estimate its specificity for the illness. From the dose-response curves, we calculated the concentration of methylnicotinate required to elicit a half-maximal blood flow (MBF) response (EC50 value) and MBF value for each subject. The median log10EC50 of the SZ was above the third quartile of log10EC50 of either the HC or BP groups, whereas the MBF was significantly lower in the SZ than in the HC or BP groups. With a definition of NRA of having both EC50 above the ninetieth percentile of the control samples and MBF response below the sixtieth percentile for the control range, the NRA predicted SZ with 31% sensitivity and 97% specificity. Moreover, the NRA was not influenced by age, gender, race, and cigarette smoking. In summary, the NRA may define a SZ subtype with a clinically significant phospholipid signaling defect. Understanding its molecular origins may shed light on the pathophysiology of SZ and suggest new tools for its early diagnosis and treatment.

Trajectories of suicidal ideation in depressed older adults undergoing antidepressant treatment.

Suicide is a public health concern in older adults. Recent cross sectional studies suggest that impairments in executive functioning, memory and attention are associated with suicidal ideation in older adults. It is unknown whether these neuropsychological features predict persistent suicidal ideation. We analyzed data from 468 individuals ≥ age 60 with major depression who received venlafaxine XR monotherapy for up to 16 weeks. We used latent class growth modeling to classify groups of individuals based on trajectories of suicidal ideation. We also examined whether cognitive dysfunction predicted suicidal ideation while controlling for time-dependent variables including depression severity, and age and education. The optimal model using a zero inflated Poisson link classified individuals into four groups, each with a distinct temporal trajectory of suicidal ideation: those with 'minimal suicidal ideation' across time points; those with 'low suicidal ideation'; those with 'rapidly decreasing suicidal ideation'; and those with 'high and persistent suicidal ideation'. Participants in the 'high and persistent suicidal ideation' group had worse scores relative to those in the "rapidly decreasing suicidal ideation" group on the Color-Word 'inhibition/switching' subtest from the Delis-Kaplan Executive Function Scale, worse attention index scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and worse total RBANS index scores. These findings suggest that individuals with poorer ability to switch between inhibitory and non-inhibitory responses as well as worse attention and worse overall cognitive status are more likely to have persistently higher levels of suicidal ideation. CLINICALTRIAL. GOV NUMBER: NCT00892047.

Telehealth Monitoring of Patients with Schizophrenia and Suicidal Ideation.

A telehealth system was developed to monitor risk following hospitalization for suicidal ideation. We hypothesized that 3 months of telehealth monitoring will result in a greater reduction in suicidal ideation. Veterans with schizophrenia admitted with recent suicidal ideation and/or a suicidal attempt were recruited into a discharge program of VA Usual Care with daily Health Buddy© monitoring (HB) or Usual Care (UC) alone. Fifteen of 25 were randomized to HB and 10 received UC. Daily adherence in the use of the HB system during months 1-3 was, respectively, 86.9%, 86.3%, and 84.1%. There were significant improvements in Beck Scale for Suicide Ideation scores in HB participants. There were no changes in depressive symptoms. Telehealth monitoring for this population of patients appears to be feasible.

Levels of symptom severity and functioning in four different definitions of subthreshold posttraumatic stress disorder in primary care veterans.

Four definitions of subthreshold posttraumatic stress disorder (PTSD) were compared in 815 veterans seen in Veterans Affairs Medical Center primary care clinics. We compared PTSD Checklist (PCL) scores and Short Form 36 (SF-36) scores between participants meeting criteria for one of the subthreshold PTSD definitions (based on Schnurr, Marshall, Blanchard, or Stein) to those with and without PTSD. Using regression, those meeting subthreshold criteria by any of the four definitions had lower mental and physical health functioning and higher PCL scores relative to those without PTSD; they also had higher mental health functioning and lower PCL scores relative to those with PTSD. With SF-36 physical functioning scores, only those meeting the Stein definition differed from the group with PTSD. Thus, these definitions appear to distinguish individuals who are qualitatively different from individuals with no PTSD or with PTSD and are nearly equivalent in their ability to discriminate individuals.

Treatment of post traumatic stress disorder symptoms in emotionally distressed individuals.

Older individuals with emotional distress and a history of psychologic trauma are at risk for post traumatic stress disorder (PTSD) and major depression. This study was an exploratory, secondary analysis of data from the study "Prevention of Depression in Older African Americans". It examined whether Problem Solving Therapy-Primary Care (PST-PC) would lead to improvement in PTSD symptoms in patients with subsyndromal depression and a history of psychologic trauma. The control condition was dietary education (DIET). Participants (n=60) were age 50 or older with scores on the Center for Epidemiologic Studies-Depression scale of 11 or greater and history of psychologic trauma. Exclusions stipulated no major depression and substance dependence within a year. Participants were randomized to 6-8 sessions of either PST-PC or DIET and followed 2 years with booster sessions every 6 months; 29 participants were in the PST-PC group and 31 were in the DIET group. Mixed effects models showed that improvement of PTSD Check List scores was significantly greater in the DIET group over two years than in the PST-PC group (based on a group time interaction). We observed no intervention⁎time interactions in Beck Depression Inventory or Brief Symptom Inventory-Anxiety subscale scores.

Early intervention to preempt major depression among older black and white adults.

OBJECTIVE: The study objective was to assess the efficacy of problem-solving therapy for primary care (PST-PC) for preventing episodes of major depression and mitigating depressive symptoms of older black and white adults. The comparison group received dietary coaching. METHODS: A total of 247 participants (90 blacks, 154 whites, and three Asians) with subsyndromal depressive symptoms were recruited into a randomized depression prevention trial that compared effects of individually delivered PST-PC and dietary coaching on time to major depressive episode and level of depressive symptoms (Beck Depression Inventory) over two years. Cumulative intervention time averaged 5.5-6.0 hours in each study arm. RESULTS: The two groups did not differ significantly in time to major depressive episodes, and incidence of such episodes was low (blacks, N=8, 9%; whites, N=13, 8%), compared with published rates of 20%-25% over one year among persons with subsyndromal symptoms and receiving care as usual. Participants also showed a mean decrease of 4 points in depressive symptoms, sustained over two years. Despite greater burden of depression risk factors among blacks, no significant differences from whites were found in the primary outcome. CONCLUSIONS: Both PST-PC and dietary coaching are potentially effective in protecting older black and white adults with subsyndromal depressive symptoms from developing episodes of major depression over two years. Absent a control for concurrent usual care, this conclusion is preliminary. If confirmed, both interventions hold promise as scalable, safe, nonstigmatizing interventions for delaying or preventing episodes of major depression in the nation's increasingly diverse older population.

Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis.

Central regulation of hypothalamo-pituitary-adrenocortical (HPA) axis stress responses is mediated by a relatively circumscribed group of projections to the paraventricular hypothalamus (PVN). The dorsomedial hypothalamus (DMH), medial preoptic area (mPOA), and bed nucleus of the stria terminalis (BST) provide direct, predominantly inhibitory, innervation of the PVN. These PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including the prefrontal cortex, amygdala, hippocampus, and septum. The neurochemical phenotype of limbic circuits targeting PVN relays has not been systematically analyzed. The current study combined retrograde tracing and immunohistochemistry/in situ hybridization to identify the specific sites of glutamatergic and GABAergic inputs to the DMH, mPOA, and BST. Following Fluoro-gold (FG) injections in the DMH, retrogradely labeled cells co-localized with vesicular glutamate transporter mRNA in the prefrontal cortex, ventral hippocampus, and paraventricular thalamus. Co-localization of FG and glutamic acid decarboxylase mRNA was present throughout the central and medial amygdaloid nuclei and septal area. In addition, the mPOA received predominantly GABAergic input from the septum, amygdala, and BST. The BST received glutamatergic projections from the hippocampus and basomedial amygdala, whereas, GABAergic inputs arose from central and medial amygdaloid nuclei. Thus, discrete sets of neurons in the hypothalamus and BST are positioned to summate limbic inputs into PVN regulation and may play a role in HPA dysfunction and stress-related illness.