Determinants of cognitive function in individuals with type 2 diabetes mellitus: A meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with deficits across multiple cognitive domains; however, the determinants of cognitive impairment in T2DM are not well characterized. We aimed to evaluate body mass index (BMI), glycemic control, and T2DM duration as moderators of cognitive dysfunction in T2DM. METHODS: We conducted a meta-analytic review of the literature reporting data on BMI, hemoglobin A1c (HbA1c), T2DM duration, and validated measures of processing speed (ie, Digit Symbol Substitution Test, Trail Making Test [TMT]-A), verbal learning and memory (ie, Rey Auditory Verbal Learning Test), and working memory/executive function (ie, TMT-B) among individuals with vs without T2DM. RESULTS: Individuals with T2DM demonstrated deficits across multiple cognitive domains (k = 40; n = 4,252 T2DM; n = 22,322 non-T2DM; effect sizes 0.21 to 0.35). Illness duration and BMI did not significantly moderate measures of cognition; however, higher HbA1c levels were significantly associated with deficits in measures of processing speed (R2 values 0.41 to 0.73, P < .01) and working memory/executive function (R2 = 0.62, P < .001). CONCLUSIONS: Adults with T2DM exhibited significant deficits across multiple domains of cognitive function. Additionally, we identified an association between poorer glycemic control and cognitive dysfunction. A clinical translation of our findings relates to the reduction in morbidity by improving glycemic control.

Antidepressants in the treatment for chronic low back pain: questioning the validity of meta-analyses.

OBJECTIVES: To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). METHODS: In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. RESULTS: Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was - 0.7 (0.15) (P < 0.0001). Overall response rates were significantly larger with duloxetine than with placebo. CONCLUSIONS: Due to the diversity of previous studies and the pooling methods used, the conclusions regarding the analgesic effect of antidepressants in CLBP drawn from systematic reviews must be interpreted with caution. Appropriately designed and powered studies similar to recently published duloxetine studies are recommended to demonstrate the analgesic effect of antidepressants.

The noradrenergic paradox: implications in the management of depression and anxiety.

Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these studies was anxiety a treatment-emergent adverse effect. This review argues against the impression that enhanced generalized noradrenergic activity promotes the emergence of anxiety.