Injecting +5 nA for just 100 msec during the chirp interval

caused strictly three additional depolarization–hyperpolarization cycles and the motor pattern of an additional 3-syllable chirp (Fig. 2D). Short current pulses (+5 nA; 10–20 msec), which fell entirely CHIR-258 within a chirp, did not change the singing pattern. When injected during the chirp intervals, however, they reliably triggered a single membrane potential oscillation-cycle with at least two action potentials that strictly elicited the motor pattern of a single syllable. Inhibitors,research,lifescience,medical Each additional chirp evoked by depolarizing current injection to A3-AO reliably reset the chirp rhythm of the singing activity (Fig. 2C and D). After the end of the stimulus, the subsequent chirp started with a delay of 230 ± 34 msec (N = 3, n = 51), which closely matched the duration of the normal chirp intervals (229 ± 20 msec; N = 3, n = 60) before current Inhibitors,research,lifescience,medical injection. Injection of 100 msec and 500 msec current pulses at different moments of the chirp cycle revealed a linear correlation between the stimulation phase Inhibitors,research,lifescience,medical and the resulting phase shift of the chirp rhythm (Fig. 2E). Plotted as a phase–response curve (Pinsker 1977), the data for 100 and 500 msec current pulses were

closely fitted by the linear regression functions y = 1.28 × −0.35 (R2 = 0.95; N = 3, n = 34) and y = 1.37 × +0.75 (R2 = 0.92; N = 3, n = 17), respectively. The trend lines of the two data sets are vertically shifted by 1.1

chirp cycles (mean chirp cycle: 364 ± 43 msec; N = 3, n = 120), which precisely reflect the difference of 400 msec in stimulus duration. As A3-AO activation is sufficient to drive Inhibitors,research,lifescience,medical the syllable motor pattern and also reliably reset the chirp rhythm, this interneuron is clearly a pivotal element of the cricket singing CPG. There was no significant difference between the average opener–closer intervals of fictive singing chirps (21 ± 1 msec; N = 3, n = 90) and chirps induced by current injection in the A3-AO dendrite (20 ± 2 msec; N = 3, n = 90). Just as in the fictive singing pattern, the opener–closer interval of the first syllable in the current-induced Inhibitors,research,lifescience,medical chirps was slightly shorter compared with the following (t-test first vs. second and first vs. third syllable: P < 0.01; second vs. third: P > 0.5; N = 3, n = 21 each). The closer–opener intervals, however, were significantly reduced (t-test: P < 0.0001; N = 3, n = 45) in current-induced 17-DMAG (Alvespimycin) HCl chirps (mean ± SD: 15 ± 2 msec) compared with fictive singing (mean ± SD: 21 ± 2 msec) and did not show the successive increase as in natural chirps (Fig. 2F). Sustained hyperpolarizing current injection was used to test if spike activity in both A3-AO sibling neurons is necessary to maintain fictive singing. Within 15–20 sec of injecting a constant −10 nA current in the dendrite of one A3-AO interneuron, fictive singing stopped and recurred not until 5–10 sec after the current injection.

These encouraging results are currently being Selleck BMS-907351 extended in further studies. The combination of decitabine and pegylated interferon alfa-2b was tested in patients with unresectable or metastatic solid tumours (NCT00701298). In ongoing trials, the combination of azacytidine and entinostat is undergoing testing in resected stage I non-small-cell lung cancer (NCT01207726) and oral Inhibitors,research,lifescience,medical azacytidine in combination with carboplatin or Abraxane (nanoparticle paclitaxel) is being evaluated in patients with refractory solid tumours (NCT01478685). In elderly previously untreated AML patients and high-risk MDS patients the combination of azacytidine and lenalidomide, an immunomodulator drug, is currently

under investigation (NCT01442714). Both

drugs as monotherapies have already shown efficacy in this group of patients so their Inhibitors,research,lifescience,medical combination seems very promising. Sequential treatment of azacytidine and lenalidomide in elderly patients with AML also showed encouraging clinical and biologic activity [83]. In a recent Phase I study decitabine was combined with bortezomib for the treatment of elderly poor risk AML patients and the combination showed good preliminary activity since response rates were very encouraging [84]. 6. Future Promise: Therapeutics The use of epidrugs on the intent to restore sensitivity to cytotoxic Inhibitors,research,lifescience,medical or hormonal drugs is a major goal in the setting of solid tumors [85–87]. Restoring hormonal sensitivity in breast cancer is of uppermost clinical importance and has been intensively studied over the last decades. In total 25% of breast cancers have the estrogen receptor-alpha (ER alpha) repressed mainly due to hypermethylation Inhibitors,research,lifescience,medical of the ER promoter and do not respond to endocrine

therapy, and almost all hormone-sensitive tumors turn to be refractory at some point. It appears now that epigenetic therapy seems to offer a promising tool to restore/reverse hormonal sensitivity. Recent studies found that decitabine and histone HDACi such as Inhibitors,research,lifescience,medical trichostatin A, entinostat, and scriptaid can restore expression of ER mRNA and functional protein and aromatase, along with the Dipeptidyl peptidase enzymatic activity of aromatase, indicating a potential to restore long term responsiveness of a subset of ER-negative tumors to endocrine therapy [87–89]. Given the complexity and heterogeneity of the cancer cell epigenome, it is highly likely that some form of epigenomic profiling of individual cancers will be required to inform optimal use of the available agents, which induce modification of the cancer cell epigenome. For example, it would clearly be important to determine the epigenome of chemotherapy resistant cancer cells, to identify potentially deleterious silenced genes, before deploying epigenetic therapeutic strategies in an attempt to pharmacologically reverse resistance. Malignant melanoma is an interesting example of such an approach.

At the time, the authors concluded that trials of antidepressants in medical inpatients did not achieve the pattern of therapeutic responses routinely characterizing comparable interventions

in psychiatric patients with depression.34 However, there are now many studies demonstrating not only good tolerability of the newer antidepressants in the medically ill but also response and remission rates comparable to depressed patients without medical illness. This was confirmed in a Inhibitors,research,lifescience,medical recent, meta-analysis including 18 studies, covering 838 patients with a range of physical diseases (cancer 2, diabetes 1, head injury 1, heart 1, HIV 5, lung 1, multiple sclerosis 1 , renal 1 , stroke 3, mixed 2).35 The results of the meta-analysis

were corroborated by newer randomized controlled trials in patients with coronary heart disease,36-38 diabetes,39 and Inhibitors,research,lifescience,medical stroke.40 The studies above were conducted in patients who all had a medical illness. Clinical trials of antidepressants usually exclude patients with medical comorbidity. However, some studies also addressed the issue of response and remission in depressed patients with and without medical comorbidity. The STAR*D study, which was designed to reflect “real-world” conditions, confirmed that two thirds of depressed patients had at least one concurrent general medical condition.12 Inhibitors,research,lifescience,medical Generally, the remission rates in STAR*D (about 30%) were similar to rates found in uncomplicated, nonchronic symptomatic volunteers enrolled in placebo-controlled, 8-week, randomized controlled trials with selective serotonin reuptake inhibitors.7 Nevertheless, more general medical disorders were associated with lower Inhibitors,research,lifescience,medical remission scores. Furthermore, in a study with 370 depressed Inhibitors,research,lifescience,medical patients, a comorbid medical condition was one of six risk factors for sustainednonremission of depression over 4 years.41 These findings are consistent with another study in 384 depressed outpatients that were enrolled in a 8-week open treatment with fluoxetine. Compared with patients who achieved remission with antidepressant

treatment, those who did not achieve remission had significantly greater medical illness. Importantly, the final Hamilton depression rating Scale score directly correlated and with the total burden of medical illness.42 However, among those patients for whom the first antidepressant treatment with fluoxetine signaling pathway failed to achieve remission and who were randomized cither to increased doses of fluoxetine or to augmentation with lithium or desipramine, medical illness was not associated with likelihood of remission or premature study discontinuation.43 There also exist studies in primary care. Among 601 depressed patients treated in primary care settings with an SSRI and followed over 9 months, physical impairment was one of four independent predictors of nonresponse.

However, this issue is still debated and in contrast to the above findings, there are

randomized controlled studies such as the CAPRAF-study that show neutral results.66 Anticoagulation has been proposed as treatment in patients with IAB to prevent embolic stroke. However, prospective controlled trials with a large sample size are needed.67 Conclusion IAB has a largely overlooked pandemic incidence in hospitals, both in- and out-patient settings, with numerous and remarkably significant elements. While identifying IAB is not difficult or complicated Inhibitors,research,lifescience,medical as compared to other ECG abnormalities, it is largely unrecognized, even with reading by ECG computers. As was demonstrated above, the prevalence of IAB is remarkably high in general Inhibitors,research,lifescience,medical hospital populations. Many institutions and investigators, therefore, use P-wave durations ≥120 milliseconds

to identify IAB. Is the standard Protein Tyrosine Kinase inhibitor criterion for ECG diagnosis of IAB (P-wave duration ≥110 milliseconds) inaccurately defined? Since the prevalence of IAB is high, and the standard criterion for ECG diagnosis differs among investigators, it is reasonable for the criterion for IAB to be re-evaluated to set a clinically relevant standard. Inhibitors,research,lifescience,medical However, this has to be established after studies show that a potential increase in the threshold can make a significant difference for further management, with confirmed specificity and sensitivity. Regardless, the standard criterion for ECG diagnosis should be set to a level of relevance where clinicians acknowledge the diagnosis Inhibitors,research,lifescience,medical and follow-up for further investigation. The emphasis on work-up in these patients can potentially prevent future cardiovascular outcomes. Similar to determining other important ECG criteria with modern epidemiologic studies, epidemiologic data for IAB should also be made available and taken into consideration,

evaluating the full 12-lead ECG Inhibitors,research,lifescience,medical to detect the true maximum P-wave duration and P-wave morphology, which increases sensitivity with the number of leads used. Consequently, the importance of multitrials detecting the cut-off values of IAB and risk should be underscored. no Although the clinical consequences of IAB may be grave, absence of sufficient epidermiologic investigations and controlled trials means that no guidelines can be constructed for managing IAB patients. Do these patients need immediate treatment (i.e., ACEI, anticoagulation, and/or antiarrhythmic therapy?) If so, should it be prophylactic, anticipating atrial arrhythmias, i.e., anticoagulation? While such investigations are needed, electrophysiologic studies are inconvenient, costly, and unsuitable as a screening tool among the general population. Clinically, the ECG is an excellent diagnostic tool for demonstrating abnormal interatrial conduction.

Data sources We identified prescriptions for metoprolol and antidepressants from the Ontario Drug Benefit Program, which records prescription medication dispensed to Ontario

residents 65 years of age and older. Admissions for bradycardia were identified from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database, which contains a detailed record of all hospital admissions in Ontario. Inhibitors,research,lifescience,medical Emergency department (ED) visits were obtained from the CIHI National Ambulatory Care Reporting System, which contains detailed information for all ED visits in Ontario. The Ontario Registered Persons Database contains basic demographic information for each Ontario resident. These databases are routinely BMS-345541 order linked to study drug safety, including the clinical consequences Inhibitors,research,lifescience,medical of drug–drug interactions [Fischer et al. 2010; Juurlink et al. 2009; Kelly et al. 2010; Kurdyak et al. 2005]. All analyses were conducted anonymously using an encrypted version of the individual health card number. Observation period We studied older patients whose prescription records allowed us to define a period of continuous metoprolol use. For each patient, observation in the cohort began with the first metoprolol prescription following their 66th birthday. The observation period

Inhibitors,research,lifescience,medical ended with a hospital visit for bradycardia, death, discontinuation of metoprolol, addition of another beta blocker, or the end of the study period, whichever came first. To ensure adherence to metoprolol, we employed an algorithm in which continuous metoprolol use was defined by refills of the drug at intervals not exceeding 1.5 times the days’ supply of the preceding prescription, as done previously [Fischer et al. 2010; Juurlink et al. 2009; Kelly et al. 2010; Kurdyak et al. Inhibitors,research,lifescience,medical 2005]. We did not study patients during their first year of eligibility for prescription drug coverage (age 65 years) to avoid incomplete medication records. Identification Inhibitors,research,lifescience,medical of cases and controls Within the cohort of patients receiving metoprolol, we defined case

patients as those who had undergone a hospital visit for bradycardia. A hospital visit was defined as Adenosine an ED visit with bradycardia as the main diagnosis or hospitalization with bradycardia as a preadmission diagnosis. We used the International Classification of Diseases, 9th revision (ICD-9) codes 426.0, 426.1 and 427.8, and 10th revision (ICD-10) codes R001, I440–I443. The date of hospital admission or ED visit, whichever occurred first, served as the index date for all analyses. Only the first hospital visit was considered for patients with more than one hospitalization or ED visit for bradycardia. We selected up to four controls for each case from the cohort of patients continuously receiving metoprolol, matched for age (within 1 year of birth date) and sex. The selected controls were assigned the same index date as their matched cases.

An fMRI study might identify reduced activity in an area. But this need not reflect dysfunction in the integrity of that area. Instead, it may reflect reduced input to this area from another region that is dysfunctional in psychopathy. A different

study, using a task that does not rely on the integrity of the dysfunctional region(s) might show no reduced activity in the area. The IES model follows Patrick’s seminal work stressing the importance of the amygdala.28 The amygdala is critical for stimulus-reinforcement learning; both for aversive and appetitive reinforcements.75,76 Stimulus-reinforcement learning, as indexed by aversive conditioning, is impaired in psychopathy.37 Afatinib in vivo Indeed, Inhibitors,research,lifescience,medical adults with psychopathy show reduced amygdala responses during aversive conditioning (though, it should be noted, it is unclear whether the groups were matched Inhibitors,research,lifescience,medical for IQ in this study).77 The emotional expressions of fear, sadness, and happiness are thought to initiate stimulus-reinforcement learning; they allow the individual to learn the value of the object or action to which they are displayed.51 The amygdala is important for processing these expressions (particularly fear).78 In line with the amygdala dysfunction hypothesis, violent patients with psychopathy show reduced amygdala responses Inhibitors,research,lifescience,medical to fearful expressions.68 According to the IES model,

care-based transgressions come to be regarded as “bad” because of the association of representations of these transgressions with the aversive feedback of the distress of the victims of these transgressions.10 Amygdala dysfunction, and consequent impaired stimulus-reinforcement learning and responsiveness to the distress of others, should result in a deficient response to care-based transgressions. At Inhibitors,research,lifescience,medical the neural Inhibitors,research,lifescience,medical level this should be partly manifested as a reduced

amygdala response to care-based transgressions. The data is consistent with this suggestion.65,66 During instrumental learning tasks, where the individual is attempting to learn an action to gain reward or avoid punishment, the amygdala and/ or striatum feeds reinforcement expectancy information to ventromedial frontal cortex where this information is represented.50 Given the diffusion tensor imaging data showing reduced integrity Suplatast tosilate of the white matter tracts between the amygdala and vmPFC in psychopathy,62-64 it is likely that this feed-forward of reinforcement information occurs less successfully. This suggestion is also consistent with data showing reduced amygdala-vmPFC functional connectivity in adults with psychopathy.64 The representation of expected outcome information (how good or bad the action is) within vmPFC is also thought to be dysfunctional.10 This is consistent with the data from Harenski and colleagues’ moral judgment task.65 However, formal fMRI modeling work that would directly address the issue has only been done in youth with psychopathic traits,53 not adult samples.

11 Thus, CYP genotyping can be recommended as a complement to plasma concentration determination when aberrant metabolic capacity is suspected. Pharmacodynamic drug targets ADs have a wide variety of targets within the neurotransmitter systems, ranging

from neurotransmitter synthesis, degrading enzymes, storage, receptors, and specific transport proteins (Figure 2). Variations in DNA sequences of these genes can alter the function or levels of expression of Inhibitors,research,lifescience,medical neurotransmitters and enzymes and the binding properties of receptors and transport proteins. Newer concepts address signal transduction proteins and other downstream protein polymorphisms. Most notably, the superf amily of G-proteins, which have a key function in signal transduction and are target proteins for more than 50% of available drugs, is becoming a major goal of investigation. Other downstream proteins, such as the kinases or phosphatases, and proteins downstream to transcription

factors, and the expression of proteins are target systems in pharmacogenetics Inhibitors,research,lifescience,medical and pharmacogenomics.12 The proteins, which are related to synaptic and neuronal plasticity have become Inhibitors,research,lifescience,medical special goals of interest in terms of drug response.13 Figure 2. Signal transduction cascade; potential candidate genes for mechanisms of antidepressant action. NE, norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin); R, G-protein-coupled receptor; Gαβγ, G-protein-Gαβγ Inhibitors,research,lifescience,medical … Pharmacogemetic studies of ADs According to the pathophysiological mechanisms of affective disorders, which mainly postulate deficiency in monoaminergic neurotransmission, ADs of various classes affect the serotonin, norepinephrine, and dopamine pathways (Table II). Table II. Pharmacogenetics of antidepressant drugs and candidate genes. SERT, serotonin transporter; 5-HT2a, serotonin receptor 2A; TPH1, tryptophan hydroxylase 1; Inhibitors,research,lifescience,medical Gβ3,

G-protein β3 subunit; NET, norepinephrine transporter; MAO-A, monoamine oxidase … The serotonin transporter (5-HTT) is the initial target of most ADs, especially the widely used selective serotonin reuptake inhibitors (SSRIs). A functional variant was identified in the promoter region of the 5-HTT gene with an insertion/deletion of 44 bp, resulting in short (S) from and long (L) alleles. The S allele reduces the transcriptional activity of the 5-HTT gene promoter, leading to reduced 5-HTT expression and 5-HT uptake.14 A number of casecontrol association studies have outlined that individuals carrying at least one L allele, respond more favorably and rapidly to SSRIs, such as fluvoxamine and paroxetine,15 and the S/S genotype had been associated with Pomalidomide molecular weight nonremission in citalopram and fluvoxamine treatment.15 Taking all the findings together, the emerging picture suggests a marked influence of the 5-HTT promoter polymorphism on response to SSRIs in Caucasian population.

24,29,36 The FFM and personality disorders One of the strengths of

the FFM is its robustness, which follows naturally from its coverage of essentially all of the trait terms within a variety of languages. The FFM has been used effectively as a basis for comparing, contrasting, and integrating broad sets of personality scales and traits considered within diverse areas of research.37 Widiger and Costa38 similarly proposed that Inhibitors,research,lifescience,medical the personality disorders included within DSM-IV-TR2 could be understood as maladaptive and/or extreme variants of the domains and facets of the FFM. The FFM accommodates the diagnostic features of each DSM-IV-TR personality disorder and goes beyond the criterion sets to provide fuller, more comprehensive descriptions.20 For example,

the FFM includes the traits of DSM-IV-TR antisocial Inhibitors,research,lifescience,medical personality disorder, such as deception, exploitation, manipulation, and aggression (facets of antagonism), irresponsibility, negligence, and rashness (facets of low conscientiousness), and excitement-seeking and assertiveness (facets of extraversion). However, it also goes beyond DSM-IV-TR to include traits that are unique to the widely popular Psychopathy Checklist-Revised (PCL-R39), such as glib charm (low self-consciousness), arrogance (low modesty), Inhibitors,research,lifescience,medical and lack of empathy (tough-minded callousness) and goes even further to include traits of psychopathy Inhibitors,research,lifescience,medical emphasized originally by Cleckley40 but not included in either the DSM-IV-TR or the PCL-R, such as low anxiousness and low vulnerability or fearlessness.39,41 The FFM has the withdrawal evident in both the avoidant and schizoid personality disorders (facets of introversion), but also the anxiousness and self-consciousness that distinguishes the avoidant from the schizoid (facets of neuroticism), as well as the anhedonia (low positive emotions) that distinguishes the schizoid from the avoidant.42

The FFM includes the intense attachment needs (high warmth of extraversion), the deference Inhibitors,research,lifescience,medical (high compliance of agreeableness), and the self-conscious anxiousness of the dependent personality disorder,43,44 the perfectionism and workaholism of the selleck kinase inhibitor obsessive-compulsive (high Cytidine deaminase conscientiousness45,46), and the fragile vulnerability and emotional dysregulation of the borderline patient.47 A compelling body of empirical research has now accumulated in support of this understanding.9,48 O’Connor49 conducted inter-battery factor analyses with previously published correlations involving FFM variables and the scales of 28 other normal and abnormal personality inventories published in approximately 75 studies. He concluded that “the basic dimensions that exist in other personality inventories can thus be considered’ well captured’ by the FFM” (p 198).

Reduced ability on cognitive tasks sensitive to frontal lobe damage seems to be associated with a higher risk of psychotic symptoms in AD,43,48 supporting the hypothesis that symptoms such as hallucinations and delusions could be produced by pathological frontal circuitry. Correlation between “frontal” tasks and psychotic symptoms has also been demonstrated in patients with FTD,93 confirming that, independently of the type of dementia, frontal lobe involvement is the main requisite Inhibitors,research,lifescience,medical for the appearance of behavioral manifestations. Generally, however, studies do not explicitly take into account the potential cause-effect relationship between the two types of

manifestations. Namely, although hypothesized, it has never been specifically explored Inhibitors,research,lifescience,medical whether cognitive and noncognitive disorders can both be traced back to the same check details neural damage, or whether behavioral disorders might to some extent represent

a “reaction” to the cognitive deficit. Indeed, it is likely that any limitation of cognitive resources could reduce a patient’s ability to efficiently react to environmental stimulation in order to generate adequate behavioral responses. The memory disorder, to mention the most common example, Inhibitors,research,lifescience,medical typical of AD but also frequent in other types of dementia, might produce such severe functional limitation as to generate reactive depression in amnesic subjects with good insight. Theory of mind and Inhibitors,research,lifescience,medical behavior in

FTD The hypothesis of a direct relationship between cognition and behavior in FTD is now currently proposed in the neuropsychological literature. In particular, it has been proposed that the impairment of “high-level” competences of the frontal lobe might generate behavioral changes, mostly in personality and social conduct. Particular attention has been devoted to the theory of mind (TofM). TofM is the ability to make inferences about others5 mental states, thoughts, and feelings in order to predict and understand their behavior. Inhibitors,research,lifescience,medical TofM is strictly related to the concept of “empathy,” that is, the ability to spread emotions to other people and to understand other people’s emotions. A deficit in TofM, originally proposed to account for developmental disorders in social cognition of subjects affected by pathologies such as autism or Asperger’s syndrome,94,95 could also explain some aspects of the pathological behavior typical of patients Dichloromethane dehalogenase with FTD. The effects of frontal lobe damage on behavior, and in particular of damage in the orbital and ventral regions, have long been known.96 The neurocircuitry of TofM has been delineated by both lesional and functional studies. There is basic agreement in considering the amygdala97 and the orbitofrontal cortex,95 and also the medial prefrontal cortex98 as the anatomical base for TofM (see also ref 99).

117 Oxidative stress markers are also correlated with decreased telomerase activity.118 Further, diminished levels of antioxidants reportedly lower BDNF activity.119 Interestingly, antidepressants decrease oxidative stress.120 Since cellular oxidative damage may be an important component of the aging process, prolonged or repeated Inhibitors,research,lifescience,medical exposure to oxidative stress might accelerate aspects of biological aging and promote the development of aging-related diseases in depressed individuals.114 It is unknown whether antioxidant treatment would retard stress- or depressionrelated aging; this is discussed below under “novel treatment implications.” Brain-derived

neurotrophic factor The “neurotrophic model” of depression74 emphasizes the centrality of neurogenesis

and neuronal plasticity in the pathophysiology of depression. It posits that diminished hippocampal Inhibitors,research,lifescience,medical BDNF Galunisertib solubility dmso activity, caused by stress or excessive GCs, impairs the ability of stem cells in the subgranular zone of the dentate gyrus (as well Inhibitors,research,lifescience,medical as cells in the subventricular zone, projecting to the prefrontal cortex) to remain viable and to proliferate into mature cells. It is not known whether such effects can cause depression, but they may be relevant to the mechanism of action of antidepressant treatments.121 Unmedicated patients with depression have decreased hippocampal (at autopsy) and serum concentrations of BDNF121,122 Over 20 studies have documented decreased serum concentrations of BDNF in unmedicated depressed individuals; this is now one of the most consistently replicated biochemical Inhibitors,research,lifescience,medical findings in major depression.121,123 Further, serum BDNF concentrations increase with antidepressant treatment.121,123 The relationship

of peripheral BDNF concentrations to central ones is Inhibitors,research,lifescience,medical not known, but even peripherally administered BDNF abrogates depressive and anxiety-like behaviors and increases hippocampal neurogenesis in mice, suggesting that serum BDNF concentrations are functionally significant for brain function and are more than merely a biomarker.124 A role of BDNF in antidepressant mechanisms of action is supported by findings that hippocampal others neurogenesis (in animals) and serum BDNF concentrations (in depressed humans) increase with antidepressant treatment,121,123 and that hippocampal neurogenesis and intact BDNF expression are required for behavioral effects of antidepressants in animals.125,126 Apart from its direct neurotrophic actions, BDNF also has anti-inflammatory and antioxidant effects that may contribute to its neuroprotective efficacy,127 and BDNF, in concert with telomerase (discussed below) promotes the growth of developing neurons.