Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Background Irritable bowel syndrome (IBS) is a common abdominal pain disorder without an organic explanation. Abuse histories (physical, sexual, emotional) are prevalent in IBS. While abuse relates to mood disorders (depression and anxiety) also common in IBS, the influence of abuse on GI symptoms and health-related quality of life (HRQOL) and its independence from psychological symptom comorbidity, has not been studied. Methods Consecutive GI outpatients completed the ROME III Research Diagnostic Questionnaire and questionnaires on trauma (Life-Stress Questionnaire), mood (Beck Depression/Anxiety Inventories), somatic symptoms (PHQ-12) and HRQOL (SF-36). Current GI symptom Severity and Bother were assessed using 10-cm VAS scales. Key Results 272 ROME-defined IBS (47.6±0.9 yrs, 81% female) and 246 non-FGID (51.6±1.0 yrs, 65% female) subjects participated. IBS patients reported greater rates of physical, sexual, and emotional abuse (p < 0.006 each), and higher depression, anxiety, and somatic symptoms (p < 0.001). Greater bowel symptom bother (7.4±0.2 vs 6.7±0.2, p=0.040), severity (7.7±0.2 vs 6.5±0.2, p<0.001), recent symptomatic days (9.8±0.4 vs. 8.5±0.3, p=0.02), and poorer HRQOL (40.9±2.3 vs 55.5±1.7, p<0.001) were noted in IBS with abuse. Abuse effects were additive, with greater IBS symptom severity and poorer HRQOL noted in cases with multiple forms of abuse. Mediation analyses suggested that abuse effects on GI symptoms and HRQOL were partially mediated by mood. Conclusions & Inferences Abuse experiences common among IBS sufferers are associated with reports of greater GI symptoms and poorer HRQOL, particularly in those with multiple forms of abuse; this relationship may be partially mediated by concomitant mood disturbances.

OBJECTIVEInitial treatment with antidepressant medication is insufficiently effective in some patients with type 2 diabetes, and factors predicting treatment outcome are poorly understood.RESEARCH DESIGN AND METHODSAggregate data from two published trials were analyzed to determine the rates and predictors of response to antidepressant pharmacotherapy in adults with type 2 diabetes using conventional markers of initial treatment outcome (improvement, response, partial remission, and remission). Three hundred eighty-seven patients who received up to 16 weeks of open-label, acute-phase treatment using bupropion (n = 93) or sertraline (n = 294) were studied. Logistic regression was used to identify predictors of poor treatment outcome. Candidate predictors included age, race, sex, initial Beck Depression Inventory (iBDI) score, treatment received (sertraline or bupropion), family history of depression, extant diabetes complications (eDC), and A1C level.RESULTSOf 387 patients initiated on treatment, 330 (85.3%) met criteria for improvement, 232 (59.9%) for response, 207 (53.5%) for partial remission, and 179 (46.3%) for full remission. Significant independent predictors of poor outcome included eDC (for no improvement); sertraline treatment, eDC, and younger age (for nonresponse); sertraline treatment, eDC, and higher iBDI (for failure to partially remit); and younger age and higher iBDI (for failure to fully remit). Higher pain scores predicted three of the four markers of poor outcome in the subset with pain data.CONCLUSIONSIn patients with type 2 diabetes, poor initial response to antidepressant medication is predicted by multiple factors. Auxiliary treatment of pain and impairment may be required to achieve better outcomes.

Through unintentional discovery, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were the first antidepressant classes to be used clinically and have been widely available for over half a century. From the 1950s to the 1980s, these two classes of antidepressants were the sole antidepressant tools available to psychiatrists. With the advent of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s and 1990s, the prescribing of the MAOIs and TCAs has fallen significantly worldwide. In this chapter, we take a closer look at the arc of MAOI discovery and clinical use, and how these two classes of drugs compare to each other. This is important because relatively few studies compare these older classes of drugs to the newer classes of antidepressants. Finally, we argue that TCAs, and particularly MAOIs, should continue to play an important role in the modern treatment of depression, especially in the treatment-resistant patient.

SummaryBackgroundWhile opioid prescriptions have increased alarmingly in the United States (US), their use for unexplained chronic gastrointestinal (GI) pain (eg, irritable bowel syndrome) carries an especially high risk for adverse effects and questionable benefit.AimTo compare opioid use among US veterans with structural GI diagnoses (SGID) and those with unexplained GI symptoms or functional GI diagnoses (FGID), a group for whom opioids have no accepted role.MethodsVeterans Health Administration (VHA) administrative data from fiscal year 2012 were used to identify veterans with diagnostic codes recorded for SGID and FGID. This cohort study examined VHA pharmacy data to compare groups receiving ≥ 1 opioid prescription during the year and number of prescriptions filled. Bivariate and multiple logistic regression analyses adjusted for potential confounding factors (demographics, medical diagnoses, social factors) and identified potential mediators (service use, psychiatric comorbidity) of opioid use in these groups.ResultsA greater proportion of veterans with FGID received an opioid prescription during fiscal year 2012 (36.0% of 272 431) compared to only 28.9% of 1 223 744 in the SGID group (Relative Risk [RR] = 1.25). In multivariate logistic regression, personality disorders and drug abuse (OR 1.23 for each group), recent homelessness (OR 1.22), psychotropic medication fills (OR 1.55) and emergency department encounters (OR 1.21) were independently associated with opioid prescription use.ConclusionsDespite the potential for adverse consequences, opioids more often are prescribed for veterans with chronic, unexplained GI symptoms compared to those with structural diagnoses. Psychiatric comorbidities and frequent healthcare encounters mediate some of the opioid use risk.