Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility.

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts.

Background: There is evidence for dysregulated cholesterol homeostasis in Huntington's disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD. Objective: To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance. Methods: An in vitro competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053). Results: In vitro, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance. Conclusions: Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD.

Pharmacological characterization of SAGE-718, a novel positive allosteric modulator of N-methyl-d-aspartate receptors.

BACKGROUND AND PURPOSE: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC), which is an N-methyl-d-aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. EXPERIMENTAL APPROACH: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE-718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. KEY RESULTS: SAGE-718 potentiated GluN1/GluN2A-D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE-718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine-evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE-718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)-HC depletion caused by 7-dehydrocholesterol reductase inhibition. Finally, SAGE-718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. CONCLUSIONS AND IMPLICATIONS: These findings provide strong evidence that SAGE-718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.

A fractionation of the physiological burden of the personal protective equipment worn by firefighters.

Load carriage increases physiological strain, reduces work capacity and elevates the risk of work-related injury. In this project, the separate and combined physiological consequences of wearing the personal protective equipment used by firefighters were evaluated. The overall impact upon performance was first measured in 20 subjects during a maximal, job-related obstacle course trial and an incremental treadmill test to exhaustion (with and without protective equipment). The fractional contributions of the thermal protective clothing, helmet, breathing apparatus and boots were then separately determined during steady-state walking (4.8 km h(-1), 0% gradient) and bench stepping (20 cm at 40 steps min(-1)). The protective equipment reduced exercise tolerance by 56% on a treadmill, with the ambulatory oxygen consumption reserve (peak minus steady-state walking) being 31% lower. For the obstacle course, performance declined by 27%. Under steady-state conditions, the footwear exerted the greatest relative metabolic impact during walking and bench stepping, being 8.7 and 6.4 times greater per unit mass than the breathing apparatus. Indeed, the relative influence of the clothing on oxygen cost was at least three times that of the breathing apparatus. Therefore, the most efficient way to reduce the physiological burden of firefighters' protective equipment, and thereby increase safety, would be to reduce the mass of the boots and thermal protective clothing.

Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation.

We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17beta-estradiol (E(2)) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E(2) has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E(2) infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E(2)-induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E(2) infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E(2) infusion in middle-aged, but not aged, females. Intracerebroventricular E(2) infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/Akt and ERK signaling pathways is necessary for E(2) to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E(2)-induced object recognition memory enhancement in young and middle-aged females and that the inability of E(2) to activate these pathways may underlie its failure to enhance object recognition in aged females.

Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features.

Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13 -/- ) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13 -/- neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13 -/- neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13 -/- neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.

Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome.

Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1-/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and ß paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased ß-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3ß, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1-/y mice. Although inhibiting either paralog prevented induction of NMDA receptor-dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis-dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1-/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.

Estradiol-induced enhancement of object memory consolidation involves hippocampal extracellular signal-regulated kinase activation and membrane-bound estrogen receptors.

The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17beta-estradiol (E(2)). Here, we asked whether E(2) modulates memory via ERK activation and putative membrane-bound estrogen receptors (ERs). Using ovariectomized mice, we first demonstrate that intraperitoneal injection of 0.2 mg/kg E(2) significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E(2) administered intraperitoneally (0.2 mg/kg) or via intrahippocampal infusion (5.0 microg/side) immediately after training in an object recognition task significantly enhances memory retention, and that the beneficial effect of intraperitoneal E(2) is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17beta-estradiol (BSA-E(2)), we demonstrate that E(2) binding at membrane-bound ERs can increase dorsal hippocampal ERK activation and enhance object memory consolidation in an ERK-dependent manner. Fourth, we show that this effect is independent of nuclear ERs, but is dependent on the dorsal hippocampus. By demonstrating that E(2) enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E(2) modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E(2)-induced improvements in hippocampal memory consolidation.

The Ethics of Surgery at End of Life.

The role of the anesthesiologist cannot be understated when it comes to ethical decision making, especially at end of life. To best serve patients within the limits of the law, anesthesiologists must arm themselves with an understanding of how the laws surrounding ethical decision-making impact daily practices. It is also important to know what rights and duties a patient or surrogate has in the decision-making process. With proper understanding of their responsibilities and the available tools, anesthesiologists can fulfill their roles as leaders and advocates for their patients as approaches to ethical decision-making at the end of life evolve.

Neuroactive Steroid N-Methyl-d-aspartate Receptor Positive Allosteric Modulators: Synthesis, SAR, and Pharmacological Activity.

Neuroactive steroids (NASs) play a pivotal role in maintaining homeostasis is the CNS. We have discovered that one NAS in particular, 24(S)-hydroxycholesterol (24(S)-HC), is a positive allosteric modulator (PAM) of NMDA receptors. Using 24(S)-HC as a chemical starting point, we have identified other NASs that have good in vitro potency and efficacy. Herein, we describe the structure activity relationship and pharmacokinetic optimization of this series that ultimately led to SGE-301 (42). We demonstrate that SGE-301 enhances long-term potentiation (LTP) in rat hippocampal slices and, in a dose-dependent manner, improves cognition in a rat social recognition study.

Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice.

This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17 beta-estradiol (E2)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E2, and bilateral dorsal hippocampal infusions of Vehicle, the NMDA receptor antagonist APV (2.5 microg/side), or the cAMP inhibitor Rp-cAMPS (18.0 microg/side). Retention was tested 48 hours later. The enhanced object memory and increased ERK phosphorylation observed with E2 alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus.

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice.

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.

Eccentric cycling emphasising a low cardiopulmonary demand increases leg strength equivalent to workload matched concentric cycling in middle age sedentary males.

OBJECTIVES: This study determined if eccentric endurance cycling, eliciting a low cardiovascular demand, could stimulate muscle strength adaptations in sedentary middle-aged males. DESIGN: Twenty-four middle-aged sedentary males were allocated to concentric (CON) or matched workload eccentric (ECC) cycling (60% peak concentric workload) according to their maximal voluntary isometric quadriceps strength. METHODS: Seventeen participants [42.7±8.3 years, BMI 28.6±5.2, peak oxygen consumption [30.5±5.8mLkg-1min-1] completed 8 weeks (2 sessions per week) of CON (n=8) or ECC (n=9) cycle training. Incline leg press (6RM), maximal voluntary isometric contraction (MVIC) torque of the quadriceps and peak oxygen consumption were measured at baseline and 8 weeks. RESULTS: Eccentric cycle training resulted in low cardiovascular demand (CON 154±2; ECC 95±3bmin-1P<0.05) and ratings of perceived exertion (CON 14.9±0.3; ECC 9.5±0.3/20 P<0.05). Peak oxygen consumption improved within the CON group (Baseline 27.4±2.1; 8 weeks: 30.0±1.7mLkg-1min-1P<0.05) and not within the ECC group (Baseline 33.2±1.5; 8 weeks 33.3±1.6mLkg-1min-1) following training. 6RM (CON 176±20; ECC 192±11kg) and MVIC (CON 199±25; ECC 199±25Nm) strength were equivalent at baseline (P>0.05). Both groups significantly increased 6RM (CON 13.0±3.0; ECC 10.7±3.2%) and MVIC (CON 12.9±4.3; ECC 18.8±3.0%) relative to their own baseline (P<0.05). Therefore, improved leg strength was equivalent between CON and ECC groups despite the varied training (P>0.05). CONCLUSIONS: In sedentary middle age males, eccentric endurance cycling with a low cardiovascular demand, increased both quadriceps isometric and 6RM strength comparable to a matched workload concentric cycling program.

Onset time for sevoflurane/nitrous oxide induction in adults is prolonged with increasing age.

Inhaled induction of anesthesia is occasionally used in adults. Using a modified vital capacity sevoflurane/nitrous oxide (N2O) inhaled induction, we evaluated the effect of increasing age on the onset time of anesthesia. Twenty patients, aged 26-65 yr, performed a vital capacity breath followed by regular tidal breathing from an anesthesia circuit primed with sevoflurane 8%/N2O/O2. The following values were recorded: time to loss of eyelash reflex (LOER); time to bispectral index < or =60 (BIS < or =60); expired fraction of sevoflurane at the time of induction, LOER and BIS < or =60. The mean times and 95% confidence intervals to LOER and BIS < or =60 were 54 s (37-70 s) and 175 s (143-207 s), respectively, and were significantly prolonged by aging (r = 0.65; P = 0.002). Times to LOER and BIS < or =60, predicted from the regression line, were 3.9 and 2 times longer in a 60-yr-old than in a 30-yr-old patient. The expired fraction of sevoflurane measured at time to LOER and BIS < or =60 decreases with increase in age. We conclude that inhaled induction with sevoflurane/N2O is dramatically prolonged with increased age.

Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice.

Current medications for depression typically require weeks of treatment before significant clinical improvement is observed, and are only effective in a relatively small subset of patients. Recent human clinical studies have demonstrated that ketamine, an NMDA receptor antagonist, and scopolamine, a muscarinic acetylcholine receptor antagonist, produce rapid antidepressant responses within hours of administration, and are effective in treatment-resistant patients. We hypothesize that efficacy and tolerability may be improved by combining lower doses of both drugs in the treatment of depression. We therefore conducted a preclinical study in mice to assess whether co-treatment of low doses of scopolamine and ketamine that alone are ineffective has antidepressant-like effects in the forced swim test (FST), an assay with predictive validity for antidepressant drugs. Whereas single administration of ketamine (3mg/kg intraperitoneal [i.p.]) or scopolamine (0.1mg/kg i.p.) did not reduce immobility time in the FST, co-administration of both drugs at these doses significantly reduced immobility time by 45% compared to vehicle treated controls. These results suggest that the combination of subeffective doses of ketamine and scopolamine may prove efficacious for the treatment of depression and should be evaluated in human clinical trials.

Atomoxetine and nicotine enhance prepulse inhibition of acoustic startle in C57BL/6 mice.

Deficits in sensory-gating, often measured as deficits in prepulse inhibition of acoustic startle (PPI), are associated multiple with disorders including schizophrenia, attention deficit and hyperactivity disorder (ADHD), and withdrawal from nicotine. Drugs that can reverse deficits in PPI may serve as therapeutic agents for nicotine withdrawal, ADHD, and/or schizophrenia. The present study investigated the effects of acute atomoxetine, a norepinephrine reuptake inhibitor, nicotine, and mecamylamine, a nicotinic acetylcholinergic antagonist, on PPI and acoustic startle in C57BL/6 mice. Three doses of atomoxetine (0.2, 2.0, and 20 mg/kg) were administered prior to testing PPI and startle. The 0.2 and 2.0 mg/kg doses enhanced PPI and the 20 mg/kg dose enhanced startle. A second experiment investigated the effects of 2.0 mg/kg atomoxetine and 1.0mg/kg mecamylamine administered alone or together on PPI and startle. As before, atomoxetine enhanced PPI. Mecamylamine did not alter PPI and did not block the enhancement of PPI by atomoxetine. Neither drug altered startle. A third experiment investigated the effects of 2.0 mg/kg atomoxetine and 0.125 mg/kg nicotine administered alone or together on PPI and startle. Both drugs enhanced PPI when administered alone. However, when co-administered, no enhancement of PPI was seen. Neither nicotine nor atomoxetine altered startle. The present results demonstrate that acute doses of nicotine and atomoxetine enhance PPI independent of effects on startle and that the enhancement of PPI by atomoxetine occurs independent of the nicotinic acetylcholinergic system. Thus, the newly available medication for ADHD, atomoxetine, could be a potential therapeutic agent for disorders associated with disrupted PPI such as withdrawal from nicotine.

An unusual presentation of idiopathic thrombocytopenic purpura in pregnancy.

A 35-year-old, 39-week pregnant woman underwent an uneventful emergent cesarean delivery for suspected placental abruption or uterine dehiscence. Given the urgency of the situation and the unremarkable airway anatomy, general anesthesia was the chosen technique. Four hours after her surgery, she returned to the operating room for persistent vaginal bleeding. Hematology tests performed before the cesarean delivery revealed severe thrombocytopenia. This was later diagnosed as idiopathic thrombocytopenia, which was treated successfully with steroid therapy.

Marketing or strategy? Defining the best approach to expand the anesthesiology workforce in Israel.

There is a chronic shortage of anesthesiologists in Israel. The study by Cohen et al. suggests that a marketing campaign may be one method of addressing this shortage. This commentary argues for a more comprehensive strategy based on the US experience. This would not only involve marketing as suggested by Cohen et al. but would also involve a fundamental change in the Israel anesthesia care model, as well as providing substantial financial incentives to young physicians. We believe that a combination of these approaches will help to alleviate the shortage of anesthesia providers in Israel. Creating a new class of physician extenders, namely, anesthesiologist assistants, would also provide an employment pathway for the skilled medical technicians trained by the Israel Defense Forces, and other non-physicians with an interest in anesthesiology.

Geriatrics and the Perioperative Surgical Home.

An ever-changing health care system with a constantly increasing aging surgical population creates both opportunities for providing improved health care as well as significant challenges. Coordinated health care initiatives are needed if one is to adequately balance the need for evidence-based improved patient outcomes and the often-associated increased costs. In this article the authors postulate that a protocol-driven, multidisciplinary approach may be a pathway for implementing an effective triple aim to health care, especially in a frail geriatric population.

Costs, resource utilization, and treatment patterns for patients with metastatic melanoma in a commercially insured setting.

OBJECTIVE: To estimate real-world healthcare costs, resource utilization, and treatment patterns among metastatic melanoma (MM) patients who received a therapy recommended in current treatment guidelines during 2011 and 2012, following approval in the US of novel therapies (ipilimumab and vemurafenib). RESEARCH DESIGN AND METHODS: Administrative claims data were used in a retrospective, longitudinal, open cohort study. Adult MM patients were identified using ICD-9 codes. Therapy-based patient cohorts and index dates were defined by the first receipt of a therapy of interest: ipilimumab, vemurafenib, paclitaxel (alone and in combination), interleukin-2, dacarbazine (alone and in combination), or temozolomide. The follow-up period extended until the end of eligibility or data availability. A multivariate regression model was used to compare outcomes of the ipilimumab and vemurafenib cohorts, controlling for baseline and demographic characteristics. MAIN OUTCOME MEASURES: Direct healthcare costs (2013 US dollars) and utilization (incidence rates) were measured on a per-patient-per-month (PPPM) basis for each treatment cohort. Treatment patterns were assessed, including the frequency of patients receiving a second therapy of interest. RESULTS: The study population included 834 patients (265 ipilimumab, 234 vemurafenib, 174 paclitaxel, 104 interleukin-2, 46 dacarbazine, and 11 temozolomide). Costs ranged from $10,879 PPPM (temozolomide) to $35,472 PPPM (ipilimumab). Adjusted total costs were $18,337 PPPM higher for the ipilimumab vs. the vemurafenib cohort (p < 0.001), primarily due to higher outpatient costs. Multivariate analysis did not find significant differences in resource utilization between ipilimumab and vemurafenib, except that ipilimumab patients had fewer outpatient visits (excluding treatment visits). Ipilimumab and vemurafenib patients received a second therapy of interest (12% and 11%, respectively) less frequently than interleukin-2 and dacarbazine patients. CONCLUSIONS: The cost and resource utilization burden of MM is high and varies substantially across treatment cohorts. The two novel therapies, ipilimumab and vemurafenib, have quickly been adopted and are the most frequently used therapies. The results observed during the approximately 6 month follow-up period may not be representative of the full clinical experience of patients with MM.