Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, ketamine can also produce psychotomimetic effects that limit its utility as an antidepressant, raising the question of whether the clinically tolerated NMDAR antagonist memantine possesses antidepressant properties. Despite its similar potency to ketamine as an NMDAR antagonist, clinical data suggest that memantine does not exert rapid antidepressant actions for reasons that are poorly understood. In this study, we recapitulate the ketamine and memantine clinical findings in mice, showing that ketamine, but not memantine, has antidepressant-like effects in behavioral models. Using electrophysiology in cultured hippocampal neurons, we show that ketamine and memantine effectively block NMDAR-mediated miniature excitatory postsynaptic currents in the absence of Mg²⁺. However, in physiological levels of extracellular Mg²⁺, we identified key functional differences between ketamine and memantine in their ability to block NMDAR function at rest. This differential effect of ketamine and memantine extends to intracellular signaling coupled to NMDAR at rest, in that memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2 or augment subsequent expression of BDNF, which are critical determinants of ketamine-mediated antidepressant efficacy. These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDAR-mediated neurotransmission that have impacts on downstream intracellular signaling, which we hypothesize is the trigger for rapid antidepressant responses. These data provide a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission as a critical determinant necessary to elicit rapid antidepressant responses.Ketamine is a noncompetitive glutamate NMDA receptor (NMDAR; also called GluN) antagonist that has been shown to mediate rapid antidepressant efficacy in patients with treatment-resistant major depression (1–3). The antidepressant effects of ketamine are fast-acting, with some patients reporting effects as soon as 30 min to within a few hours following a single i.v. low-dose injection of ketamine. However, ketamine can produce adverse psychotomimetic effects, which may limit its use as an antidepressant. Traditional antidepressant drugs target the monoamine system and typically require several weeks of treatment to mediate a therapeutic effect. There is an urgent need for rapid antidepressant drugs, and the clinical data with ketamine suggest that blocking the NMDAR may be a viable therapeutic target.Memantine is a noncompetitive NMDAR antagonist that has been approved by the US Food and Drug Administration for the treatment of Alzheimer’s disease. Memantine is a generally well-tolerated drug that lacks the aversive effects (4) observed with ketamine at therapeutic doses. However, attempts to test memantine as an antidepressant in individuals with major depression have yielded mixed results following long-term drug treatment, with no evidence of rapid antidepressant effects (5–7). A better understanding of why ketamine, but not memantine, produces a fast-acting antidepressant response has clinical implications and may provide novel information critical for the development of rapid antidepressant therapeutics based on NMDAR antagonism, with fewer side effects.There is much interest in identifying the molecular mechanism that underlies the rapid antidepressant response of ketamine. In recent work, we demonstrated that the fast-acting antidepressant effect of ketamine requires deactivation of eukaryotic elongation factor 2 kinase (eEF2K) and subsequent desuppression of BDNF protein translation in the hippocampus (8, 9). We hypothesize that low-dose ketamine mediates its rapid antidepressant response by blockade of spontaneous glutamate release-mediated NMDAR activity. This blockade, in turn, decreases calcium (Ca²⁺) flow through the receptor, inhibiting eEF2K activity and resulting in decreased levels of phosphorylated eukaryotic elongation factor 2 (eEF2) (10–12) and desuppression of BDNF protein synthesis (8, 9, 13). In this study, we compared ketamine with memantine in their effectiveness to block NMDAR activation during spontaneous neurotransmission, subsequently inhibiting eEF2K and increasing BDNF protein translation. Our results reveal key differences between the effects of ketamine and memantine on resting NMDAR-mediated neurotransmission and subsequent intracellular signaling pathways that may explain the mechanistic differences between these two drugs in eliciting rapid antidepressant effects.     

Culture-negative primary sternal osteomyelitis in a patient with uncontrolled type 2 diabetes mellitus

Primary sternal osteomyelitis (PSO) is a rare condition defined as an infection of the sternal bone marrow with no contiguous source of infection. The overlap in symptoms of PSO with other cutaneous and malignant pathologies often leads to misdiagnosis and delay of appropriate care. In this case report, we outline the presentation of PSO in a 30 year-old male patient who was newly diagnosed with type 2 diabetes mellitus. The patient was successfully treated with antibiotic therapy alone, without need for surgical intervention. Interestingly, the patient''s workup returned with negative microbial cultures. To our knowledge, this patient represents the first reported case of a spontaneously presenting, culture-negative PSO.     

Randomized trial of a web-based tool for prolapse: impact on patient understanding and provider counseling

Introduction and hypothesis

Effective patient/provider communication is important to ensure patient understanding, safety, and satisfaction. Our hypothesis was that interactive patient/provider counseling using a web-based tool (iPad? application) would have a greater impact on patient satisfaction with understanding prolapse symptoms compared with standard counseling (SC).

Methods

Women with complaints of seeing/sensing a vaginal bulge were enrolled in this randomized controlled trial. Participants completed pre- and postvisit Likert scale questionnaires on satisfaction with prolapse knowledge and related anxiety. After new patient histories and physical examinations, study participants were randomized to SC or SC with iPad?. Ninety participants were required to detect a 30 % difference in satisfaction with prolapse knowledge between the two groups.

Results

Ninety women were randomized to SC (n?=?44) or SC with iPad? (n?=?46). At baseline, 47 % of women were satisfied with their understanding of bulge symptoms (50 % SC vs. 43.5 % SC with iPad?, p?=?0.5). After counseling, 97 % of women reported increased satisfaction with understanding of bulge symptoms (p?<?0.0001), with no difference between groups [42/44 (95.5 %) SC vs. 45/46 (97.8 %) SC with iPad?, p?=?0.5]. Baseline anxiety was high: 70 % (65.9 % SC vs. 73.9 % SC with iPad?, p?=?0.4). After counseling, anxiety decreased to 30 % (p?<?0.0001), with improvement in both groups (31.8 % SC vs. 28.3 % SC with iPad?, p?=?0.7). Counseling times were similar between groups (9.5 min., SC vs. 8.9 min., SC with iPad, p?=?0.4).

Conclusions

Interactive counseling was associated with increased patient satisfaction with understanding bulge symptoms and decreased anxiety whether a web-based tool was used or not.     

Risk factors for lower urinary tract injury at the time of hysterectomy for benign reasons

Objectives

To identify risk factors associated with lower urinary tract injury at the time of performing hysterectomy for benign indications.

Methods

We conducted a multi-center case–control study of women undergoing hysterectomy for benign disease. Cases were identified via ICD-9 codes for lower urinary tract injury at the time of hysterectomy from 2007 to 2011: controls were two subsequent hysterectomies following the index case in the same institution that did not have lower urinary tract injury. Logistic regression was used to perform univariate and multivariate comparisons between groups.

Results

At 7 centers, 135 cases and 270 controls were identified. Cases comprised 118 bladder injuries and 25 ureteral injuries; 8 women had both bladder and ureteral injury. Bladder injury was associated with a history of prior cesarean section OR 2.9 (95 % CI 1.7–5), surgery by a general obstetrician and gynecologist OR 2.4 (95 % CI 1.2–5.2), and total abdominal hysterectomy OR1.9 (95%CI 1.06–3.4). Ureteral injury was more likely among women who underwent laparoscopic-assisted vaginal hysterectomy (LAVH) OR 10.4 (95%CI 2.3–46.6) and total abdominal hysterectomy (TAH) OR 4.7 (95 % CI 1.4–15.6).

Conclusion

Bladder injury at the time of benign hysterectomy is associated with a prior history of Cesarean section and TAH as well as surgery by generalist OB-GYN; ureteral injury is associated with LAVH and TAH.     

Preferences for type 2 diabetes health states among adolescents with or at risk of type 2 diabetes mellitus

Rhodes ET, Prosser LA, Lieu TA, Songer TJ, Ludwig DS, Laffel LM. Preferences for type 2 diabetes health states among adolescents with or at risk of type 2 diabetes mellitus. Objective: We evaluated how adolescents with or at risk of type 2 diabetes (T2DM) and their parent/guardians (parents) value health states associated with T2DM. Methods: We interviewed overweight/obese [Body Mass Index (BMI) ≥ 85th percentile], 12–18‐yr old adolescents with T2DM, prediabetes, or insulin resistance (IR) and a parent. The standard gamble (SG) method elicited preferences (utilities) for seven hypothetical T2DM health states reported on a scale from 0 (dead) to 1 (perfect health). Adolescent's current health was evaluated with the SG and Health Utilities Index (HUI). Results: There were 70 adolescents and 69 parents. Adolescents were 67.1% female and 15.5 ± 2.2 yr old; 30% had T2DM, 30% prediabetes, and 40% IR. Almost half (48.6%) had a BMI > 99th percentile. Parents (83% mothers) were 45.1 ± 7.3 yr old and 75% had at least some college/technical school education. Adolescents and parents rated T2DM with no complications treated with diet as most desirable [median (IQR); adolescent 0.72 (0.54, 0.98); parent 1.0 (0.88, 1.0)] and end‐stage renal disease as least desirable [adolescent 0.51 (0.31, 0.70); parent 0.80 (0.65, 0.94)]. However, adolescents' utilities were significantly lower (p ≤ 0.001) than parents for all health states assessed. Adolescents' assessments of their current health with the SG and HUI were not correlated. Conclusions: Adolescents with or at risk of T2DM rated treatments and sequelae of diabetes as significantly worse than their parents. These adolescent utilities should be considered in the evaluation of treatment strategies for youth with T2DM. Family‐based programs for T2DM must also be prepared to address conflicting preferences in order to promote shared decision‐making.