Ketamine’s Antidepressant Efficacy is Extended for at Least Four Weeks in Subjects with a Family History of an Alcohol Use Disorder

Background:

A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine’s antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine’s antidepressant efficacy.

Methods:

Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100–200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17).

Results:

FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9).

Conclusions:

Ketamine’s extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.     

Neural Correlates of Suicidal Ideation and Its Reduction in Depression

Background:

The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion.

Methods:

Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5mg/kg for 40 minutes).

Results:

Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=−.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression.

Conclusion:

The infralimbic cortex may be implicated in suicidal ideation.     

Gender differences in clinical features and outcomes of a Portuguese systemic sclerosis cohort

Clinical Rheumatology - Evidence for the role of sex in the clinical manifestations of systemic sclerosis (SSc) patients is emerging. Some multicenter cohorts have shown that male SSc patients have...     

Associations of Left Ventricular Hypertrophy and Geometry with Adverse Outcomes in Patients with CKD and Hypertension

Background and objectives

Left ventricular hypertrophy (LVH) and abnormal left ventricular (LV) geometry predict adverse outcomes in the general and hypertensive populations, but findings in CKD are still inconclusive.

Design, setting, participants, & measurements

We enrolled 445 patients with hypertension and CKD stages 2–5 in two academic nephrology clinics in 1999–2003 who underwent both echocardiography and ambulatory BP monitoring. LVH (LV mass >100 g/m² [women] and >131 g/m² [men]) and relative wall thickness (RWT) were used to define LV geometry: no LVH and RWT≤0.45 (normal), no LVH and RWT>0.45 (remodeling), LVH and RWT≤0.45 (eccentric), and LVH and RWT>0.45 (concentric). We evaluated the prognostic role of LVH and LV geometry on cardiovascular (CV; composite of fatal and nonfatal events) and renal outcomes (composite of ESRD and all-cause death).

Results

Age was 64.1±13.8 years old; 19% had diabetes, and 22% had CV disease. eGFR was 39.9±20.2 ml/min per 1.73 m². LVH was detected in 249 patients (56.0%); of these, 125 had concentric LVH, and 124 had eccentric pattern, whereas 71 patients had concentric remodeling. Age, women, anemia, and nocturnal hypertension were independently associated with both concentric and eccentric LVH, whereas diabetes and history of CV disease associated with eccentric LVH only, and CKD stages 4 and 5 associated with concentric LVH only. During follow-up (median, 5.9 years; range, 0.04–15.3), 188 renal deaths (112 ESRD) and 103 CV events (61 fatal) occurred. Using multivariable Cox analysis, concentric and eccentric LVH was associated with higher risk of CV outcomes (hazard ratio [HR], 2.59; 95% confidence interval [95% CI], 1.39 to 4.84 and HR, 2.79; 95% CI, 1.47 to 5.26, respectively). Similarly, greater risk of renal end point was detected in concentric (HR, 2.33; 95% CI, 1.44 to 3.80) and eccentric (HR, 2.30; 95% CI, 1.42 to 3.74) LVH. Sensitivity analysis using LVH and RWT separately showed that LVH but not RWT was associated with higher cardiorenal risk.

Conclusions

In patients with CKD, LVH is a strong predictor of the risk of poor CV and renal outcomes independent from LV geometry.     

Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.     

Risk of Exclusion From Stroke Rehabilitation in the Oldest Old

Objective

To investigate whether oldest-old age (≥85y) is an independent predictor of exclusion from stroke rehabilitation.

Rectal hyperreactivity to distention in patients with irritable bowel syndrome: role of distention rate.

BACKGROUND AND AIMS: Rectal motor hyperreactivity to distention may be involved in the pathophysiological course of defecatory symptoms in patients with irritable bowel syndrome (IBS), but results of patient studies are conflicting, possibly because of differences in the applied distention rate. Because a fast rate of distention increases the rectal motor response in healthy subjects, it also may show hyperreactivity in patients with IBS. The aim of this study is to compare the effects of 2 distention rates on rectal motor responses and sensations in 16 patients with IBS and 12 healthy subjects. METHODS: Rectal distensibility and the frequency of rectal contractions and sensations were recorded during volume-controlled rectal distentions at 2 distention rates (10 and 100 mL/min). RESULTS: Recta of patients with IBS were significantly less distensible than those of healthy subjects during fast distention (P = 0.0006), but this difference was not statistically significant during slow distention (P = 0.07). The frequency of rectal contractions and sensations, the majority of which were sensations of gas and a desire to defecate, were significantly greater in patients with IBS during both slow and fast distentions (both P < 0.025). CONCLUSIONS: Recta of patients with IBS are hyperreactive to distention, and fast distention magnifies this abnormal motor response. A greater frequency of sensations during a fixed-time distention period may help to characterize the patients.