The effects of ketamine on typical and atypical depressive symptoms.

OBJECTIVE: Ketamine's effects on different dimensions of depressive symptomatology, including typical/melancholic and atypical depression, remain largely unknown. This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). METHODS: Data from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar depression were pooled from three separate, double-blind, placebo-controlled, crossover studies investigating ketamine's efficacy in depression. MDD participants were unmedicated; bipolar participants received therapeutic-dose lithium or valproate. Clinical symptoms were collected preinfusion and up to 14 days postinfusion. Effect sizes were calculated for days 1 and 3 postinfusion. The primary measures of interest for this exploratory analysis were total MADRS, MADRS5, and SAS scores. Individual symptoms were also analyzed in an exploratory manner. RESULTS: Scores improved significantly at Day 1 postinfusion (MADRS: Cohen's d = 0.64; MADRS5: Cohen's d = 0.61; SAS: Cohen's d = 0.41) and continued to be significantly improved over placebo at Day 3 (MADRS: Cohen's d = 0.49; MADRS5: Cohen's d = 0.43; SAS: Cohen's d = 0.39). Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. CONCLUSION: Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former.

Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder.

Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.

The role of adipokines in the rapid antidepressant effects of ketamine.

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines-adiponectin, resistin and leptin-as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg-1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine's antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine's anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

Latent classes of childhood trauma exposure predict the development of behavioral health outcomes in adolescence and young adulthood.

BACKGROUND: To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative behavioral outcomes in adolescence and young adulthood. METHOD: A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences. Latent classes were used to predict psychiatric outcomes at age ⩾13 years, criminal convictions, physical health problems and traumatic experiences reported in young adulthood. RESULTS: Three latent classes of childhood traumatic experiences were supported by the data. One class (8% of sample), primarily female, was characterized by experiences of sexual assault and reported significantly higher rates of a range of psychiatric outcomes by young adulthood. Another class (8%), primarily male, was characterized by experiences of violence exposure and reported higher levels of antisocial personality disorder and post-traumatic stress. The final class (84%) reported low levels of childhood traumatic experiences. Parental psychopathology was related to membership in the sexual assault group. CONCLUSIONS: Classes of childhood traumatic experiences predict specific psychiatric and behavioral outcomes in adolescence and young adulthood. The long-term adverse effects of childhood traumas are primarily concentrated in victims of sexual and non-sexual violence. Gender emerged as a key covariate in the classes of trauma exposure and outcomes.

Ventromedial prefrontal cortex activation and neurofeedback modulation during episodic future thinking for individuals with suicidal thoughts and behaviors.

Individuals experiencing suicidal thoughts and behaviors (STBs) show less specificity and positivity during episodic future thinking (EFT). Here, we present findings from two studies aiming to (1) further our understanding of how STBs may relate to neural responsivity during EFT and (2) examine the feasibility of modulating EFT-related activation using real-time fMRI neurofeedback (rtfMRI-nf). Study 1 involved 30 individuals with major depressive disorder (MDD; half with STBs) who performed an EFT task during fMRI, for which they imagined personally-relevant future positive, negative, or neutral events. Positive EFT elicited greater ventromedial prefrontal cortex (vmPFC) activation compared to negative EFT. Importantly, the MDD + STB group exhibited reduced vmPFC activation across all EFT conditions compared to MDD-STB; although EFT fluency and subjective experience remained consistent across groups. Study 2 included rtfMRI-nf focused on vmPFC modulation during positive EFT for six participants with MDD + STBs. Results support the feasibility and acceptability of the rtfMRI-nf protocol and quantitative and qualitative observations are provided to help inform future, larger studies aiming to examine similar neurofeedback protocols. Results implicate vmPFC blunting as a promising treatment target for MDD + STBs and suggest rtfMRI-nf as one potential technique to explore for enhancing vmPFC engagement.

Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) patients on proton pump inhibitors before breakfast or dinner have acid recovery at night. Bedtime immediate-release omeprazole (IR-OME) demonstrated better control of nocturnal pH than pantoprazole before dinner. AIM: To compare repeated once daily bedtime dosing of IR-OME, lansoprazole and esomeprazole on nocturnal gastric acidity. METHODS: Open-label, randomized, crossover study enrolling 54 patients with nocturnal GERD symptoms comparing IR-OME, lansoprazole and esomeprazole at steady state for nocturnal acid breakthrough (NAB), percentage of time with gastric pH > 4 and median gastric pH. RESULTS: Onset of nocturnal acid control with IR-OME was rapid. During the first half of the night, percentage of time with gastric pH > 4 and median gastric pH were significantly higher after IR-OME compared to esomeprazole or lansoprazole (P < 0.001, both comparisons). Over the 8-h night-time period, acid control with IR-OME was significantly better than lansoprazole (P < 0.001), and comparable to esomeprazole. IR-OME reduced NAB compared with esomeprazole and lansoprazole (61% vs. 92% and 92%; P < 0.001, both comparisons). CONCLUSIONS: Bedtime IR-OME provided more rapid control of night-time gastric pH and decreased NAB compared with esomeprazole and lansoprazole. Nocturnal acid control with IR-OME was superior to lansoprazole and comparable to esomeprazole. Bedtime dosing with IR-OME may be effective for patients with night-time heartburn.

Comparative pharmacokinetics and safety of lansoprazole oral capsules and orally disintegrating tablets in healthy subjects.

BACKGROUND: Many individuals with acid-related gastrointestinal disorders have difficulty in swallowing oral agents. AIM: To compare the bio-availability of a single dose of lansoprazole orally disintegrating tablet with that of an intact capsule. METHODS: One hundred and twenty healthy subjects participated in two prospective, Phase I, open-label, two-period cross-over studies to receive lansoprazole, 15 mg or 30 mg. Within each study, subjects were randomized into two parallel cohorts consisting of 30 subjects per regimen, dispensed in opposing sequence over two periods separated by a 7-day washout period. Blood samples were collected on day 1 of both periods to determine the pharmacokinetic parameters. RESULTS: Tmax occurred at 1.8 and 2.0 h with the 15-mg and 30-mg tablets, respectively. Dose proportional increases in Cmax, AUCt and AUC infinity were observed in the 15-mg and 30-mg groups. The terminal elimination half-lives (t1/2) were identical in both dose groups (1.18 h). Lansoprazole administered as the orally disintegrating tablet was bio-equivalent to the intact capsule formulation with respect to Cmax, AUCt and AUC infinity. CONCLUSIONS: Lansoprazole orally disintegrating tablets, 15 mg and 30 mg, are bio-equivalent to the respective dose administered as the intact capsule. This novel dosage formulation represents an option for patients who have difficulty in swallowing oral agents.

Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia.

BACKGROUND: The relation between Helicobacter pylori infection and nonulcer dyspepsia is uncertain. We tested the hypothesis that curing the infection will relieve symptoms of dyspepsia. METHODS: We randomly assigned 170 H. pylori-infected patients with nonulcer dyspepsia to receive twice-daily treatment with 20 mg of omeprazole, 1000 mg of amoxicillin, and 500 mg of clarithromycin for 14 days and 167 such patients to receive identical-appearing placebos; all patients were then followed through regular visits for 12 months. Symptoms were scored on diary cards for seven days before each visit. A carbon-13 urea breath test was performed at base line and repeated at 1 and 12 months, and endoscopic biopsy was performed at 12 months to determine H. pylori status. Treatment was considered successful if the patient had only mild pain or discomfort or none at all. RESULTS: The rate of eradication of H. pylori infection was 90 percent in the active-treatment group and 2 percent in the placebo group at four to six weeks (P<0.001). At 12 months, there was no significant difference between groups in the rate of successful treatment (46 percent in the active-treatment group and 50 percent in the placebo group; relative likelihood of success with active treatment, 0.93; 95 percent confidence interval, 0.73 to 1.18; P=0.56). There was also no significant difference in the rate of successful treatment at 12 months between patients who were H. pylori-negative and those who were H. pylori-positive (48 percent vs. 49 percent). The rates of successful treatment were also similar when patients were analyzed according to the type of dyspepsia (ulcer-like, reflux-like, or dysmotility-like) and changes in the quality of life. There was no significant association between treatment success and histologic improvement in chronic gastritis at 12 months (P=0.68). CONCLUSIONS: We found no evidence that curing H. pylori infection in patients with nonulcer dyspepsia leads to relief of symptoms.