Interestingly, this

age-related difference in connectivity was not noted in the left hemisphere. This may suggest that the disruption in the default network by age might be more of a unilateral process than a bilateral one. Some task-based fMRI Cyclopamine mw studies have already reported hemispheric asymmetry alteration of brain activity by age during the task performance (Cabeza 2002), and resting-state cerebral blood flow (Lu et al. 2011). However, to the best of our knowledge it has not been reported for DMN using resting-state BOLD fMRI data. We also compared our results with those obtained using the prevailing method in Inhibitors,research,lifescience,medical SMP8, which involves the typical spatial normalization by coregistering to MNI152 template and utilizing a set of predefined Inhibitors,research,lifescience,medical regional mask as the ROI across all the subjects in the study. However, utilization of data-driven atlases has gained popularity in recent years. They generate group-specific templates, and then a single standard space is derived from

those templates. Spatial normalization in this case is done in two steps, first Inhibitors,research,lifescience,medical nonlinear registration to group-specific template and then to the standard space template. This can certainly improve the accuracy of the nonlinear registration. However, utilization of highly accurate nonlinear registration for spatial normalization is hampered by overfitting problem. That is why most of the existing software packages (SPM, analysis of functional neuroimages, FSL, etc.) use a mild or moderate level of nonlinear registration in their spatial normalization. In either case, comparing the effectiveness of our approach to normalization with different atlas (data-driven or standard) is beyond the scope of this study, as our native space method totally eliminates the need for spatial Inhibitors,research,lifescience,medical normalization. The standard method produced three significant findings that did not survive Bonferroni correction and did not agree with any of the findings obtained with the new native space method. Only the change Inhibitors,research,lifescience,medical between one region pair (Hi, MOF) was found to be marginally

significant in the same hemisphere (left) in the native space analysis. Figure 6 also shows that spatial smoothing reduces the overall GPX6 mean of the pair-wise correlations between the DMN nodes. The fact that we did not detect any significant changes after Bonferroni correction in elders’ DMN functional connectivity using SPM8 should not be surprising as many existing studies of age-related change in DMN have also failed to detect this difference (Bluhm et al. 2008; Beason-Held et al. 2009; Koch et al. 2010). Erroneous spatial normalization accompanied by strong spatial smoothing can simply cause a blending effect across regions which can deteriorate the contrast of the interregional functional connectivity between two groups. There are growing numbers of studies that consider the decline in functional connectivity in DMN as biomarker/hallmark of age-related cognitive decline.

17 Studies have shown that the majority of physicians in North America and Europe would consider withholding and withdrawing treatment.6,7 There are still great differences between countries. Doctors in Holland and Belgium perform active euthanasia,18,19 whereas in Israel physicians withhold

but do not usually withdraw treatment.20 In fact the withdrawing of ventilators is prohibited by law.21 DIFFERENCES IN GEOGRAPHICAL LOCATION The Ethicus Study7 was a prospective trial performed in European ICUs to determine Inhibitors,research,lifescience,medical the frequency and types of actual end-of-life practices. European countries involved were prospectively divided into three geographical regions: Northern (Denmark, Finland, Ireland, the Netherlands, Sweden, and the United Kingdom), Central (Austria, Belgium, Czechia, Germany, and Switzerland), and Southern (Greece, Inhibitors,research,lifescience,medical Israel, Italy, Portugal, Spain, and Turkey) Europe. The main outcome variable was the end-of-life category (as defined above). In this study, 31,417 patients were admitted to 37 adult ICUs located in 17 countries over a period of 13.5 months. A total of 4,248 patients (13.5%) who died or had life-sustaining treatments limited in some fashion were included in the study. Limitation of life-sustaining Inhibitors,research,lifescience,medical treatment occurred in 3,086

of the 4,248 patients (73%), i.e. in 10% of ICU admissions and 76% of dying patients. Of the 3,086 patients, 2,734 (89%) received mechanical ventilation, and 1,815 (59%) were receiving vasopressors at the first limitation of therapy. There was significant inter-country variability in limitations of care. Twenty percent died with no limitation of therapy and unsuccessful

Inhibitors,research,lifescience,medical CPR (range 5%–48%), brain death in 8% (range 0%–15%), withholding treatment in 38% (range 16%–70%), withdrawing treatment in 33% (range 5%–69%), and active shortening of the dying process in 2% (range 0%–19%). Of 1,398 patients who underwent withdrawal of treatment, 1,335 (95%) had treatment withheld prior to or together with withdrawing treatment. All patients who underwent shortening Inhibitors,research,lifescience,medical of the dying process already had PR-619 research buy previous treatment withheld or withdrawn. This study highlights several important points. End-of-life decisions and actions are routine in European ICUs. Withholding and withdrawing treatment seem to be accepted by most European intensivists, while active shortening of the dying process was rare. The study provided useful below information for physicians and families regarding approximate times to death after various limitations. For example, death occurred a median of 3.5 (1.5–8.5) hours for shortening of the dying process, 4 (1.0–17.2) hours after withdrawing of therapy, and 14.3 (2.2–67.1) hours after withholding therapy.7 The study showed that respective probabilities of death within 24, 48, and 72 hours were 93%, 97%, and 99% for shortening of the dying process, 80%, 89%, and 93% for withdrawing, and 50%, 61%, and 68% for withholding treatments (Figure 2).7 Figure 2.

However, this drug delivery approach was not exempt of hurdles and technology challenges particularly in the formulation phase as

we will see further. During the development (from nonclinical to clinical), the products had to go back to the formulation stage to optimize their physicochemical properties due to stability, toxicity, or pharmacokinetic issues. Up to three generations of cationic nanoemulsions were then tested and patented over the 10 years of development [23–25]. 3. Formulation Development 3.1. Cationic Agent The surface charge of the nanoemulsion is defined by the zeta potential. It corresponds to the electric potential surrounding the oil nanodroplet at Inhibitors,research,lifescience,medical the plane of hydrodynamic shear. It is measured by electrophoretic mobility. The latter depends on the nature of the cationic Inhibitors,research,lifescience,medical agent, its concentration and the electrolyte environment of the oil nanodroplets. In addition to increasing the residence time on the negatively charged

ocular surface, the positive charge of the cationic agent contributes to the stabilization of the emulsion by creating an electrostatic repulsion between Inhibitors,research,lifescience,medical the oil droplets of the nanoemulsion [26]. Evidence that the specific nature of the cationic molecule may be responsible for improved uptake properties was supplied by Calvo et al. who showed that two different types of cationic indomethacin loaded nanocapsules (coated with poly-L-lysine or chitosan) resulted in completely different drug kinetics Inhibitors,research,lifescience,medical profiles [27]. Therefore, the cationic agent selected needs to be carefully considered prior to starting pharmaceutical development as the success of the formulation is Selleckchem Dapagliflozin highly dependent upon the choice of the cationic agent as will be discussed further. Novagali showed that below a zeta potential of +10mV, nanoemulsions could not Inhibitors,research,lifescience,medical be autoclaved without destabilizing the oil droplets. Therefore, the first challenge

of the Novasorb technology was to make a cationic emulsion with a zeta potential sufficiently high to stabilize the nanoemulsion, yet with a cationic surfactant concentration as low as possible to avoid compromising the safety of the nanoemulsion. The optimal range for the zeta potential was demonstrated second to be between +20mV and +40mV. Review of the literature revealed that of the numerous cationic agents described (Table 2) most of them are surfactants, indeed the positively charged region of the molecule does not enter the oil core of the droplet but instead remains at the surface, rendering them very useful for emulsions. Unfortunately, very few are listed in pharmacopeias or accepted for ophthalmic products due to stability or toxicity issues. Table 2 Chemical structures of common molecules used as cationic agent in drug delivery. Compared to anionic and nonionic surfactants, cationic surfactants are known to be the most toxic surfactants [28].

An association was found without reaching statistical significance (P=0.58) Figure 2. Figure 2 Relation between volume

reduction and pathologic response grade. Correlation between metabolic response by PET/CT scan and pathologic TRG was also studied. A positive but poor correlation was observed (rho =0.32; Spearman test) and without statistical significance (P=0.25). Discussion Currently, one of the most intriguing challenges in the management of patients with LACC is the way to select those who may benefit most from a neoadjuvant strategy. In this sense, the accuracy of imaging seems critical. Reported accuracy rates for CT in the preoperative staging of colon Inhibitors,research,lifescience,medical cancer range between 41% and 82% (11-14). In recent years, the use of oral and rectal contrast agents has improved the determination Inhibitors,research,lifescience,medical of the depth of invasion through the colonic wall, and MDCT has provided the additional capability of using thin collimation that offer an improved quality of MPRs and better spatial resolution. Despite thin sections, however, an intrinsic limitation of CT is the lack of visualization of the individual wall layers. The sensitivity of CT in detection of primary colon cancer is variable and depends on the size of the tumor. In this study we have found an accuracy

of 62% (27/44) for T stage, within the range of Inhibitors,research,lifescience,medical that reported in the literature (15-17). Another limitation of the CT staging Inhibitors,research,lifescience,medical relies on its inability to definitively distinguish metastatic lymph nodes. Small nodes may harbor tumor, and enlarged nodes may not. As expected, the sensitivity of CT for detection of malignant nodes decreased when applying the 1-cm threshold instead of a 0.8-cm threshold. Accuracy rates for N stage in recent papers range between 22% and 77% (17-19). In the present work, an accuracy of 87% (38/44) was achieved for N stage. 18F-FDG

PET Inhibitors,research,lifescience,medical is a molecular imaging technique that visualizes and quantifies metabolic processes in cancer cells. PET has experienced an explosive growth as a diagnostic modality, Syk inhibitor especially in the realm of oncology for tumor staging, restaging, surveillance of recurrence and monitoring treatment response (20-22). PET/CT scans provide fused functional and morphological imaging, overcoming the isothipendyl lack of anatomical information of FDG-PET. There is an increasing interest in the role of FDG-PET for the prediction of tumor response to therapy, as it has been shown in lymphomas and esophageal cancer (23-26). Predictors of response in LACC are eagerly awaited due to the presumed favorable prognostic value of a complete response to neoadjuvant therapy in terms of improved survival times and the possibility of performing less aggressive surgical approaches (27-29).

The central nucleus of the amygdala has significant projections to several basal forebrain structures, and one

mechanism by which the central nucleus influences cortical processing is by engaging magnocellular basal forebrain neurons (see refs 103,104), whose terminals release acetylcholine onto cortical sensory neurons (GABAergic processes have also been described). Inhibitors,research,lifescience,medical Lesions of the basal forebrain have been shown to impair a host of attentional tasks, and together with physiological studies, reveal the importance of the basal forebrain not only for sustained attention, but also for selective aspects of stimulus processing, including the filtering of irrelevant information.6,7 A final class of modulatory mechanisms click here relies on the frontoparietal attentional network (Figure 3B), including lateral prefrontal

cortex, frontal eye field, and parietal cortex, which modulate visual processing according to an item’s behavioral relevance. These regions are believed to be “control sites” that provide the source of top-down attentional signals.105,106 Importantly, Inhibitors,research,lifescience,medical both frontal eye field and parietal cortex appear to contain a “priority map,” namely a representation of spatial locations containing information that is rich in terms of salience (eg, high-contrast stimuli) and/or relevance (eg, stimuli connected Inhibitors,research,lifescience,medical to current goals).107,108 It is suggested here that the frontoparietal network works closely Inhibitors,research,lifescience,medical with several “evaluative” sites discussed in the first section, such as hypothalamus, amygdala, cingulate cortex, orbitofrontal cortex, and anterior insula, to prioritize processing based on the affective significance of a sensory stimulus (for a related discussion in

the case of motivation, see ref 90). In some of these cases, the direct connections between “evaluative” and “control” regions may be relatively weak, and indirect routes involving one or more intermediate steps Inhibitors,research,lifescience,medical are probably involved. An additional modulatory role is proposed for the pulvinar complex of the thalamus (Figure 3B). Based on anatomical and physiological considerations, it was suggested that the importance of the pulvinar for affective processing is not due to its putative role as part of a subcortical pathway, as often assumed in the literature, but instead because of its Bay 11-7085 connectivity with other cortical regions.19 Briefly, the medial nucleus of the pulvinar, which projects to the amygdala, is part of several thalamocortical loops that include orbitofrontal, cingulate, and insular cortices (in addition to frontal and parietal sites). Given this broad connectivity pattern, the medial nucleus may be involved in two general functions that directly impact emotional processing: determining behavioral relevance and/or value. Therefore, the role of the pulvinar may extend beyond the well-established roles in attention109 and contribute to affective processing.

14-16 This amino-acid sequence predicts that the protein DISC1 may act as a scaffolding protein with multiple binding motifs, facilitating formation of protein complexes. The N -terminus (aa 1-347) PF-02341066 supplier contains nuclear

localization signals, whereas the C-terminus (aa 348-854) appears to be important, for microtubule and centrosomal targeting,17-19 although no centrosomal localization has been detected so far for the native protein. Although the precise function of DISC1 in the brain is unknown, a number of DISC1 -interacting partners Inhibitors,research,lifescience,medical have been identified, including fasciculation and elongation protein zeta-1 (FEZ1), nuclear distribution element-like (NUDEL), and lissencephaly 1 (LIS1), which are known to play

a role in neuronal development and functioning. Altered interactions between DISC1 and its binding partners are currently being investigated in order to understand more accurately the biology of DISC1 as a schizophrenia susceptibility gene. DISC1 molecular pathway In an effort Inhibitors,research,lifescience,medical to understand the cellular function of DISC1, yeast-two hybrid studies have been used to identify molecular Inhibitors,research,lifescience,medical interactors of DISC1. It, was found that, DISC1 has numerous binding partners, including NUDEL, FEZ1, activating transcription factor (ATT’) 4/5, and microtubule-associated protein 1 A (MAPI A).15,17,18 NUDEL is a component of a pathway involved in cytoplasmic dynein movement, and is involved in neurofilament assembly, neuronal migration, and development of neurite morphology.20-25 Overexpression of truncated DISC1 protein inhibits neurite outgrowth in PCI 2 cells, suggesting that the DISC1-NUDEL

complex may be involved in neuronal outgrowth.15,25,26 The hypothetical peptide product, resulting from Inhibitors,research,lifescience,medical the Scottish translocation removes the interaction domain for NUDEL. The defective DISC1-NUDEL complex may be a cause of neabnormalities in schizophrenia.19 Recently, it has been shown that NUDEL oligopeptidase activity is under tight, Inhibitors,research,lifescience,medical regulation through binding to DISC1, since a mutation very close to the DISC1-binding site of NUDEL abolishes this activity.27 Interestingly, NUDEL cleaves a number of neuropeptides in vitro, some of which have previously been implicated in the pathophysiology of schizophrenia, including neurotensin (NT).25,29 NT receptor agonists not may be potential antipsychotics; thus, inhibition of NUDEL could lead to increase in local concentration of NT, which may have an antipsychotic effect.27 Altered subcellular distribution of DISC1 has been reported in patients with psychosis and alcohol/substance abuse, with increased ratios of nuclear to cytoplasmic DISC1 protein levels in patients.30 Cell culture studies in cortical neurons have found evidence that DISC1 may colocalize with mitochondrial markers, and that its subcellular targeting is independent of the NUDEL-binding site.

cumulative incidence of 3% of DSM-IV hypomanic

episodes from age 26/27 to 40/41. DSM-IV hypomania was rarely an independent disorder: only 2 of 19 subjects were pure cases; all others suffered also from major (12) or minor depressive disorders (7). Their family history showed an elevated rate of depression and anxiety among firstdegree relatives; in addition there were temperamental Inhibitors,research,lifescience,medical features of both depression and bipolarity (ups and downs of mood and energy, depression, hypomania and bipolarity in the General Behavior Inventory).12 The bind of structured interviews All the most, frequently-used structured interviews: the Structured Clinical Interview for DSM-IV: Inhibitors,research,lifescience,medical Axis I, Disorders-Clinician Version, (SC.I.D-CV),13 Composite International Diagnostic Interview (CIDI),14 and Munich-Composite International Diagnostic Interview (M-CIDI),15 are based on the DSM-IV stem question for mania/hypomania (occurrence of “periods of expansive, elevated or irritable mood”) and restrict, further assessment, of the diagnostic symptoms to subjects who answer “yes” to it. A “no” answer eliminates the subject as bipolar. From a clinical

point of view, there is considerable skepticism about the sensitivity of this stem question, because it. presumes – wrongly – that the subject is always aware of a mood change; there is a serious Inhibitors,research,lifescience,medical problem of false negatives, which cannot, be solved easily. Recent developments beyond the DSM-IV diagnosis of hypomanic episodes To address these recognized difficulties, an international expert committee16 recommended adding the symptom “increased activity” to the stem question

for hypomanic episodes. Moreover, Inhibitors,research,lifescience,medical two important psychiatric outpatient, studies assessed the criteria! symptoms for hypomania without the stem question, modifying the SCID-CV13 for this purpose.17,18 This resulted in the identification of 66% and 60% of major dépressives as having BP-II. These rates far exceed the ratio of unipolar to Entinostat bipolar disorders reported by the best, epidemiological studies using DSMIV criteria Inhibitors,research,lifescience,medical MYO10 for hypomanic episodes, which consistently found substantially fewer bipolar (10% to 20%) than unipolars (80% to 90%) among those with MDE. Where does the truth lie? Departing from the usual procedure, since 1981 the Zurich Study has applied a more complex stem question, asking interviewees about, “periods of increased enterprise, increased activity, lower fatigability, less need for sleep than usual, talking more, traveling more and doing more other things.” Mood changes were only assessed as symptoms. The stem questions and a list, of 20 hypomanic symptoms, including an open question, were first published in 1991 .19 This procedure allows many more subjects to enter into the interview on hypomanic symptoms, and it. excludes the hierarchical precedence given to euphoria and irritability in the diagnostic manuals.

In the present study, patient condition was classified into seven categories in order to compare the estimated life threat risk to the patients’ state or severity: death confirmed at the

scene (they were not transported to hospital), resulted in death at emergency departments, life-threatening condition with CPA, life-threatening condition without CPA, serious but not life-threatening condition, moderate condition, and mild condition. The data used in this study did not include personal information such as the patients’ names and addresses. Use of data from the city’s computer-based record system was in accordance with two municipal ordinances enacted Inhibitors,research,lifescience,medical by the Yokohama municipal assembly: the Free Access to Information Ordinance (enacted February 25, 2000); and the Protection of Personal Information Inhibitors,research,lifescience,medical Ordinance (enacted February 25, 2000). The study was approved by the ethics committee of the Yokohama City University School of Medicine. Algorithm for estimating a patient’s life threat risk A computer algorithm estimates a patient’s life threat risk. The algorithm was constructed with a logistic model [15]. The probability, P, of the life threat risk as assessed from an emergency

call was expressed as: where β reflects the impact of information x obtained via interview with the caller; ‘x’ consists of information find more regarding the patient’s consciousness level, breathing status, walking ability, position (standing, Inhibitors,research,lifescience,medical sitting, Inhibitors,research,lifescience,medical or lying) and other signs such as cyanosis and sweating. Coefficient β differs by the type of caller: a family member, nursing home staff, or third party (not patients themselves, nor family members, nor nursing home staff). If the value of P was higher than 0.1 (10%), patients were categorized Inhibitors,research,lifescience,medical as A+. The values of the coefficients used in the logistic

models in the computer algorithm are shown in Table ​Table1.1. The coefficients of variables were estimated from a trial (sample size was 4,301) prior to the start of the new system with multivariate logistic analyses, in which the independent variables equals 1 if the patient’s condition resulted in death or was recognized as life-threatening at the ED, and 0 if classified under one of the less serious categories [14]. In the analyses, age strata, consciousness level, breathing status, and walking ability were treated as categorical variables and other variables were treated as dummy variables. Florfenicol No model exists to estimate the life threat risk from calls made by patients themselves. The algorithm had been used under the Yokohama New Emergency System, which started from October 1st, 2008. Table 1 Coefficients of variables in the logistic model applied for estimating the patient’s life threat risk Review of the algorithm for estimating a patient’s life threat risk First, the patient’s estimated life threat risk at the moment of the emergency call was compared with the state or severity of the patient’s condition.

Huge individual variations in the activities of these enzymes have long been demonstrated, much of which have been accounted for with specific allelic variations in the genes encoding these enzymes. For example, CYP2D6 allelic profiles determine whether a particular individual is a poor metabolizer (those with defective genes encoding no enzyme; approximately 2% in Han Chinese and 7% in Caucasians), intermediate metabolizer (those with “less effective” gene; approximately

50% in East Asians), AVL301 extensive metabolizer (those with “wildtype” alleles; approximately 47% in Inhibitors,research,lifescience,medical East Asians) and ultrarapid metabolizer (those with gene duplication or multiplication; about 1% in East Asians and Northern Europeans, but up to 7% in Spaniards and up to 30% in Arabs and Ethiopians).10 Studies involving desipramine and venlafaxine clearly indicate that these CYP2D6 polymorphisms are mainly responsible for the pharmacokinetics, dosing, and side-effect profiles of these CYP2D6 substrates.11,12 Similarly, specific allelic alterations Inhibitors,research,lifescience,medical also have been demonstrated to determine CYP2C19 enzyme activities, and consequently

the dosing and side effect profiles of medications metabolized by this enzyme. In addition, the activity of some of these CYPs also could be significantly altered by exposure to environmental agents, whose mechanisms also have been elucidated. For example, the induction Inhibitors,research,lifescience,medical effect of St John’s wort (and other natural substances) on CYP3A4 is now known to be mediated via the steroid and xenobiotic receptor fSXR], and Inhibitors,research,lifescience,medical the induction of CYP1A2 by constituents of cigarettes is mediated through the activation of the Ah receptor.13

Although less well documented, a number of genes other than the CYPs also influence the process of pharmacokinetics, and thus are likely to also affect the dosing and side-effect profiles of ADs. These include genes encoding transferases, such as glutathione-S-transf erase (GST) and UDP-glucurunosyltransferases (UGTs), which are responsible for drug conjugation; multldrug-resistance Inhibitors,research,lifescience,medical gene (MDR1) encoding the P-glycoprotein responsible for exporting lipophilic compounds to the extracellular space (and thus reducing drug absorption in the gut as well as inhibiting their crossing the blood-brain barrier)14,15; and, enough orosomucoid 1 and 2 (ORM1 and ORM2) encoding the alpha-1-acid glycoproteins responsible for most of the often extensive binding of psychotropics to plasma proteins.16,17 (Table I) Table I. Candidate genes and corresponding single nucleotide polymorphism (SNP) densities (pharmacokinetics). Genes encoding therapeutic targets of ADs (pharmacodynamics) A number of monoamine neurotransmitter systems, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA), may all play crucial roles in mediating vulnerability to depressive disorders.

This work did not detect any changes in mTOR regulation, although analysis of the brain fractionates occurred earlier (30 minutes) than in the studies that showed changes in mTOR. This study also showed that drug effects were due to enhanced plasticity occurring in tonic resting glutamatergic neurons’ spontaneous neurotransmission and could not be elicited by evoked neurotransmission. The authors posited that this supports the hypothesis that spontaneous and evoked forms of glutamatergic

signalling are segregated. The ubiquitous Inhibitors,research,lifescience,medical protein kinase glycogen synthase kinase 3 (GSK-3) has been identified as a regulator of a diverse range of signalling pathways and has a key role in a number of cellular functions including Inhibitors,research,lifescience,medical inflammatory CYT387 chemical structure responses. Modulation of GSK-3 is held as one of the mechanisms by which lithium exerts its effects [Brown and Tracy, 2013]. Beurel and colleagues

demonstrated that ketamine administration to mice rapidly inhibited GSK-3, and in this study such action was necessary for its rapid antidepressant effects [Beurel et al. 2011]. Effects on circadian patterns Many depressive disorders have established diurnal patterns of mood change and dysregulated sleep. The therapeutic role of ameliorating pathological sleep and circadian patterns has received renewed interest in recent times through evaluation of the novel antidepressant agomelatine. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical This melatonergic analogue acts as a melatonin MT1 and MT2 agonist, as well as a 5-HT2C antagonist and has been shown to be efficacious as an antidepressant [Pompili et al. 2013]. The melatonergic system has been implicated in depressive disorders [De Berardis et al. 2013] and some of the effects of agomelatine appear to be through the resynchronization of circadian rhythms [Grassi-Zucconi et al. 1996]. Ketamine has Inhibitors,research,lifescience,medical been shown in animal studies to change NMDA and AMPA circadian rhythmicity [Colwell and Menaker, 1992], and inhibit light induction in the suprachiasmatic nucleus [Abe et al. 1992], a centre for temporal patterns of gene transcription

and neuroendocrine function. Work by Bellet and colleagues showed that ketamine induced a dose-dependent reduction in the circadian transcription Electron transport chain of genes driven by the key CLOCK:BMAL-1 heterodimeric complex, and that such action was attenuated by administration of the GSK-3B antagonist SB21673 [Bellet et al. 2011]. The authors argue that the rapid effects of ketamine might at least in part be accounted for by changes to clock gene expression. However, a study by Ma and colleagues found that whilst single-dose ketamine produced antidepressant effects in mice, sustained up to the 8-day study cut-off, the GSK-3 inhibitor SB216763 did not, challenging the role of GSK-3 as part of the effect of ketamine, and thus the therapeutic role if any for modulation of this pathway by ketamine remains uncertain [Ma et al. 2013].