These temperature-sensitive liposomes are designed to be stable at the normal physiological temperature of 37°C but become significantly destabilized at slightly higher temperatures (Figure 1). The use of liposomes as the nanocarrier in these formulations is a particularly attractive option with respect to both enhanced tumor site accumulation, as well as facilitated release of the encapsulated drug. This is attributed to the fact that a local increase in temperature has been shown

to enhance extravasation Inhibitors,research,lifescience,medical of liposomes out of circulation resulting in their preferential accumulation to the heated tumor [21], and that liposomes are known to become destabilized at elevated temperatures [1, 2]. For example, we and others have previously shown that liposomes composed of various phospholipids are much Inhibitors,research,lifescience,medical leakier at 37°C than those stored at 4°C [1, 3, 22]. Thus, the use of temperature-sensitive liposomes to deliver encapsulated chemotherapeutics to solid tumors such as breast cancer is an area of promising research, and many Inhibitors,research,lifescience,medical successful constructs have previously been reported. For example, liposomes composed of dipalmitoylphosphatidylcholine (DPPC), monostearoylphosphatidylcholine (MSPC), and distearoylphosphatidylethanolamine (DSPE)-PEG 2000 are currently in Phase II clinical trials for the treatment of recurrent breast cancer (http://www.celsion.com).

These lyso-lipid temperature-sensitive liposomes encapsulate doxorubicin and have previously been shown to exhibit enhanced drug release rates under mild hyperthermic conditions while remaining relatively stable at normal physiological temperature Inhibitors,research,lifescience,medical [23]. More recently, Tagami et al. have reported a similar liposome-based system in which the minor component MSPC is replaced with a nonionic surfactant Brij78 [24]. This new formulation outperformed the lyso-lipid temperature-sensitive liposomes when tested in mice inoculated with a

mammary carcinoma cell line (EMT-6). Chen et al. have also reported promising Inhibitors,research,lifescience,medical results using thermosensitive liposomes prepared with DPPC, 1-myristoyl-2-palmitoyl phosphatidylcholine much (MPPC), and ROCK inhibitor DSPE-PEG 2000 [25]. Figure 1 Temperature-sensitive liposomes designed to remain stable while in circulation at 37°C and become significantly destabilized in the tumor microenvironment at slightly higher temperatures 39–42°C. 2.2. Targeted Liposome-Based Chemotherapeutics Another strategy employed in order to potentially increase the overall therapeutic index of liposome-based drugs involves improving the colocalization between the chemotherapeutic and breast cancer cells. In some cases, this strategy may also involve improvement of cellular internalization of the whole liposome-based drug, particularly when cell-surface receptors known to undergo receptor-mediated endocytosis is concerned.

and Li et al. highlighted problems of missed patients, errors, blanks or illegible items in the Reporting Cards and data entry errors. Similarly, in a pilot study for the NISS designed to examine quality control issues in the ED-based surveillance system, Xie et al [45] reported that 291 out of 1286 registered patients were ‘missed’ (or inadvertently excluded) by the surveillance system, and of 941 Reporting Cards 5.2% were found to contain errors or blanks in the cards and an additional 19% were found to have data entry errors. The studies reported in this Review provide no data to highlight the extent of these concerns. The scale of the research conducted in Inhibitors,research,lifescience,medical these

research studies is indicative of the burden of PS 341 injury facing China’s sizeable population. Despite the limitations in the data reported in these studies, the detail relating to injury mechanism age can provide public health specialists with sufficiently high level information Inhibitors,research,lifescience,medical to develop targeted intervention campaigns. The ability to undertake planning and quality assurance processes would however be significantly enhanced by the adoption of uniform standards in the collection and reporting of clinical

data, such as the Utstein template [13,14] and the ACS Guidelines [9], a need clearly highlighted by this Review. Findings relating to mechanism of injury and patient Inhibitors,research,lifescience,medical characteristics In the setting of provincial, national and global public health priorities, the value of comparable data across jurisdictions cannot be understated. The studies reviewed here highlight the importance of transport, falls, and industrial accidents as the most common causes of injury (Table ​(Table7).7). However, assaults and poisoning

feature consistently in these studies. Common to all studies was Inhibitors,research,lifescience,medical the predominance of males Inhibitors,research,lifescience,medical by a ratio of 2:1. Despite little overlap in age groups between the studies, young adults consistently represented a high proportion of presentations. Mortality rates ranged from 0.5% to 8% where reported. Table ​Table77 provides for purposes of comparison the WHO Global Burden of Disease (GBD) 2004 incident estimates for injuries ‘severe enough to require PAK6 medical attention’[46]. The GBD uses ICD-10 to categories external cause of injury and while direct comparison is imperfect, some observations can be made. The rate of poisonings among the ED patients in China appears high, ranging from 4.7% to 8.6% where recorded; in contrast the GBD estimates range from 1.6% to 2.5% in the four regions shown. Within the China series, machine-related injuries, cutting and piercing and ‘blunt’ injuries were prominent among the leading causes of injury. In both the China series and the GBD, transport and falls were leading causes though the order differs. Interestingly, among the 13 Chinese papers reviewed those that included suicide did not code poisons and vice versa, potentially highlighting a significant issue in coding practices.

23 TDR is characterized by a 2-week delay in onset followed by persistent Adriamycin in vitro improvement and PPR is characterized by early, transient, or nonpersistent improvement.23,24 Patients with major depressive disorder who have PPR are more likely to experience relapse compared with those with TDR, and antidepressant continuation appears to be no more effective in preventing depressive relapse than Inhibitors,research,lifescience,medical placebo.23 Biological and cognitive differences in depressed patients with TDR and

PPR We conducted two studies at our center assessing differences in biological and cognitive factors between patients with TDR and PPR. In the first study, we evaluated the relationship between basal ganglia cholinecreatine ratios, as measured by in vivo localized proton magnetic resonance spectroscopy

(MRS), among patients with TDR compared with those without TDR following antidepressant treatment.25 We found a significant difference in the degree of change from baseline to week 8 in choline-creatine ratios between the TDR group (N=8) and the PPR/nonresponse group (N=7); patients with TDR had a 20% increase Inhibitors,research,lifescience,medical in choline-creatine ratios, and those with PPR/nonresponse had a 12% decrease in choline-creatine ratios. Our data suggest that TDR to fluoxetine treatment in depression may be associated with an increase in choline-creatine ratios in the basal ganglia.25 In the second study, we Inhibitors,research,lifescience,medical examined the relationship between cognitive factors and TDR (N=134) and PPR (N=66) to antidepressant treatment.26 We found that after 8 weeks of treatment with an antidepressant, patients with PPR had Inhibitors,research,lifescience,medical significantly lower scores on the Perceived Stress Scale (PSS) and the Beck Hopelessness Scale (BHS) (P<0.001 and P<0.05, respectively) compared with patients with TDR. Our preliminary data suggest that significant

changes in cognitive/psychological factors accompany PPR with antidepressant treatment and differentiate it from the TDR pattern. Predictors of placebo response in depression Illness factors Predictors of placebo response Inhibitors,research,lifescience,medical in depression include a relatively short illness duration, a precipitating event, depression of mild-to-modcratc severity, and a good response to previous antidepressant treatment.27 Bialik and colleagues28 found that the placebo response rate was the highest for women with a single episode of depression (66.7%) and lowest for women with recurrent depressive episodes (13.3%). These authors also found that, among patients second experiencing their first episode, placebo responders had lower Hamilton Rating Scale for Depression (HAMD) total scores at baseline and lower ratings of psychomotor retardation than nonresponders. For patients with a recurrence of an episode, placebo responders had lower baseline ratings of somatic anxiety.28 Stewart and coworkers29 found that the presence of a psychosocial stressor in the context of a depressive episode predicted a higher rate of placebo response.

17 Studies have shown that the majority of physicians in North America and Europe would consider withholding and Venetoclax mouse 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 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 not 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.

Of the 70 patients, 34 underwent transapical TAVI and 36 underwent surgical AVR. The primary endpoint of all-cause mortality, stroke, and renal failure requiring dialysis was elevated in TAVI vs. AVR: 14.7% vs. 2.8%,

P=0.07. Death rate for TAVI was higher (8.8% vs. 0%) as was stroke (5.9% vs. 2.8%). The incidence of moderate/severe aortic insufficiency was 13% vs. 0%. The authors of this small trial concluded that in these lower-risk elderly patients, transapical TAVI may be inferior to surgical AVR. These surgical results resemble those obtained in our own series of elderly (>80 years) surgical AVR patients. Conclusion While Inhibitors,research,lifescience,medical TAVI seems like a low-risk and simple catheter-based therapy compared with surgical AVR, it is still in its Inhibitors,research,lifescience,medical developmental

phase and should be considered a major intervention with the risks of serious early and late complications. It is of proven value in the care of patients considered to be inoperable because of extensive irreversible comorbidities or frailty.16 We feel that in experienced centers, Inhibitors,research,lifescience,medical conventional surgery is feasible in most patients despite advanced age. In our own data, age alone has not been a predictor of mortality, but rather mortality is associated with easily identifiable extensive comorbidities and frailty. It is generally agreed that patients should be seen for a surgical evaluation before a final decision is made to employ TAVI. This recommendation is in agreement with that of the Inhibitors,research,lifescience,medical FDA, which has approved TAVI only for treatment of inoperable patients. Both conventional AVR and TAVI will continue to improve. Results of ongoing and future studies will influence patient selection for each of these valuable therapies. Conflict of Interest Disclosure:

All author has Inhibitors,research,lifescience,medical completed and submitted the Methodist DeBakey Cardiovascular Journal Conflict of Interest Statement and none were reported. Funding/Support: The author has no funding disclosures.
Introduction Degenerative aortic stenosis is the most common acquired valvular heart disease in the developed countries, affecting more than 300,000 people in the United States alone.1 Symptoms of aortic stenosis are latent until there is critical narrowing of the aortic valve that results in left ventricular hypertrophy, increased left ventricular diastolic pressure and left ventricle mass, and increased myocardial oxygen demand causing subendocardial ischemia.2 Once symptoms develop, the prognosis ALOX15 changes dramatically unless the aortic stenosis is corrected.2 Surgical aortic valve replacement (sAVR) is the recommended therapy for patients with symptomatic aortic stenosis. The most recent American College of Cardiology and American Heart Association (ACC/AHA) guidelines for sAVR are found in Table 1.3 It is important to note that none of these Neratinib manufacturer recommendations are based on evidence from large-scale, randomized clinical trials but instead rely on the expert opinion of experienced clinicians.

This represents the first investigation of the direct effects of CES on brain activity using functional neuroimaging simultaneously with cranial stimulation. We hypothesized that CES would result in deactivation in cortical and subcortical (thalamic) regions, in line with evidence that stimulation interferes with oscillatory brain activity and is associated with reduction Inhibitors,research,lifescience,medical of brain wave frequencies (mean alpha power). We also predicted that 0.5- versus 100-Hz stimulation would result in different patterns. In addition, we hypothesized that stimulation would alter intrinsic connectivity networks such as the dorsal fronto-parietal network

(FPN) (Corbetta and Shulman 2002) (due to evidence of improvements in attention with CES [Southworth 1999]), and the sensorimotor network (SMN) (Mantini et al. 2007; Schopf et al. 2010) (due to evidence of clinical efficacy for pain [Tan et al. 2011]). We also predicted it would alter connectivity within the default mode network (DMN), as the EEG beta band (which CES 100 Hz may affect [Schroeder and Barr 2001]) has been found to correlate Inhibitors,research,lifescience,medical with this network (Mantini et al. 2007; Laufs 2008). Material and Methods Participants The UCLA Institutional Review Inhibitors,research,lifescience,medical Board approved the study protocol. Informed consent was obtained

after the nature and possible consequences of the studies were explained. Eleven healthy right-handed male and female participants aged 18–65 were recruited from the community. We administered the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al. 1998) and excluded participants if they met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for any Axis I psychiatric disorder including Inhibitors,research,lifescience,medical active substance abuse, and any participants whom the investigator judged were suicidal. Other exclusion criteria included any neurological disorders or any medical disorders that could affect cerebral metabolism. Participants were excluded Inhibitors,research,lifescience,medical if they were taking any psychotropic medications or any other medications with psychoactive properties. Pregnant or breastfeeding women and those of childbearing potential who were not practicing

a reliable form of contraception were also excluded from the study. Due to constraints of magnetic resonance imaging (MRI) scanning, we excluded individuals who weighed greater than 280 lbs and Phosphatidylinositol diacylglycerol-lyase those with implanted electronic devices or ferromagnetic materials. CES device We used the Alpha-Stim® 100 microcurrent and cranial electrotherapy stimulator for the experiment, provided by the manufacturer Electromedical Products, International (Mineral Wells, TX). The AlphaStim® 100 provides cranial electrical stimulation by generating bipolar asymmetric learn more rectangular waves with a frequency of 0.5, 1.5, or 100 Hz, and a current intensity that can be adjusted continuously to provide between 10 and 600 μA (http://www.alpha-stim.com). We tested 0.

Buyse and colleagues demonstrated that DEO concentrations

after intravesical instillation were similar to oxybutynin, whereas oral therapy produced metabolite concentrations that were, on average, 7 times higher than those of oxybutynin.28 Although very effective in treating neurogenic OAB with minimal adverse effects, the inconvenience of the instillation procedure is often the reason for discontinuation of intravesical therapy. Rectal suppositories may represent an interesting option for OAB treatment, especially in patients who have an aversion to oral medication or Inhibitors,research,lifescience,medical develop allergic contact LY2835219 price sensitivity to transdermal oxybutynin. Rectal oxybutynin suppositories minimize presystemic metabolism by avoiding the hepatic first-pass effect. Despite the lower DEO levels, Winkler and Sand reported the anticholinergic adverse events of dry

mouth (48%) and constipation (14.3%), which were comparable to OXY-IR.27 Although not commercially manufactured, oxybutynin suppositories are often obtained from compounding Inhibitors,research,lifescience,medical pharmacies that specialize in customizing medications to meet Inhibitors,research,lifescience,medical the needs and preferences of each individual client. Conclusions Oxybutynin has been the most prescribed agent for the treatment of OAB. Initially limited by its tolerability and poor patient compliance, oxybutynin’s transformation into alternative delivery systems has improved its tolerability while maintaining its effectiveness. The newer delivery systems maintain steady-state characteristics and, most importantly, avoid the presystemic metabolism of oxybutynin. This reduction in DEO levels appears to improve the therapeutic tolerability of oxybutynin. Although no head-to-head trials have been performed Inhibitors,research,lifescience,medical comparing extended-release and transdermal preparations, the various oxybutynin formulations (OXY-IR, 10 mg, OXY-ER, 10 mg, OXY-TDS, and OXY-OTG) appear to have similar efficacy based on available clinical information. OXY-IR and OXY-ER have the distinct advantage of being FDA Inhibitors,research,lifescience,medical approved for use in the pediatric population. The use

of oxybutynin in the elderly remains a concern. OXY-IR was not studied in geriatric patients and has had the most reported problems with CNS, memory, and cognition side effects. Early data on transdermal formulations appear to demonstrate improved cognitive tolerability in the elderly, possibly related to the DEO concentration. Generally, transdermal delivery of oxybutynin provides significant Dipeptidyl peptidase anticholinergic tolerability advantages over the oral preparations. Of the 2 transdermal preparations, OXY-OTG has fewer dermatitis reactions and may be the optimal route of administration for this safe and effective drug in properly selected patients. Knowledge of the unique attributes of the various oxybutynin delivery systems can enhance a provider’s skill set in selecting the most appropriate oxybutynin formulation for patients.

These drugs reduced the IFN-γ production significantly, while sertraline and clomipramine additionally raised the IL-10 production.61 Regarding other in-vitro studies, a significantly reduced production of IFN-γ, IL-2, and sIL-2R was found after antidepressant treatment compared with pretreatment values.63 A I-BET151 purchase downregulation of the IL-6 production was observed during amitriptyline treatment; in treatment responders, the TNF-α production decreased

to normal.66 There are also studies, however, showing no effect of antidepressants to the in-vitro stimulation of cytokines (overview, ref 67) but methodological issues have to be taken into Inhibitors,research,lifescience,medical account. There is significant evidence suggesting that antidepressants of different classes induce downregulation of the type 1 cytokine production in vitro,67 including noradrenaline reuptake inhibitors68 Inhibitors,research,lifescience,medical and the ”dual“ serotonin and noradrenalin reuptake inhibitors.69 Several researchers have observed a reduction of IL-6 during treatment with the serotonin reuptake inhibitor fluoxetine.70 A decrease of IL-6 serum levels during therapy with different antidepressants has been observed by other researchers.71 The shift of imbalanced IFNγ/IL-4 towards normal after 6 weeks’ antidepressant

treatment has also Inhibitors,research,lifescience,medical been reported.41 On the other hand, other groups did not find any effect of Inhibitors,research,lifescience,medical some antidepressants on serum levels of different cytokines.61,72 Since IL-6

stimulates PGE2 and antidepressants inhibit IL-6 production, an inhibiting action of antidepressants on PGE2 would be expected, too.73 Over 30 years ago it was suggested that antidepressants inhibit PGE2.74 A recent invitro study showed that both tricyclic antidepressants and selective serotonin inhibitors attenuated cytokine-induced PGE2 and nitric oxide production by inflammatory cells.75 Nonpharmacological therapies: electroconvulsive Inhibitors,research,lifescience,medical therapy and sleep deprivation Electroconvulsive therapy (ECT) was found to downregulate Olopatadine increased levels of the proinflammatorycytokine TNF-α in patients with MD.76 An immune analysis during sleep showed an increase in the type-1 monocyte derived cytokines TNF-α and IL-12 and a decrease of the type-2 IL-10 producing monocytes.77 In contrary, continuous wakefulness blocked the increase of type-1 and decrease of type-2 cytokines (T. Lange and S. Dimitrov, personal communication). Thus, sleep deprivation may exert therapeutic effects through a low suppression of type-1 cytokines. Antidepressant pharmacotherapy, but also other antidepressant therapeutic agents or techniques, have a downregulating effect on proinflammatory cytokines.

This is not to say that these two types of KRX-0401 research buy explanation are always mutually exclusive, because both types of explanation can lead to therapeutic approaches that can be applied concurrently and be of help to the patient from the point of view of a practical clinician. For example, if a patient develops depression after a stroke to the frontal lobes Inhibitors,research,lifescience,medical and the primary explanation

is that the brain damage caused the depression, there is no doubt that the patient as a person is greatly helped by developing, through psychotherapy, a narrative that helps him or her tie together the adjustment to both the stroke and the depression, while he or she moves forward with his or her life. Specific neurologic diseases Attention now shifts to discussion of psychopathology in the context of specific diseases. The diseases discussed here are chosen both because they are the most common, and for paradigmatic purposes, Inhibitors,research,lifescience,medical because they demonstrate

the emergence of psychopathology in diseases of different pathogenetic origins. Thus, the discussion focuses on the following conditions: TBI, an example of acute trauma to the brain with both focal and diffuse effects. Stroke, typically unexpected, occurring in someone Inhibitors,research,lifescience,medical with significant risk factors such as hypertension, diabetes, and heart disease, causing primarily focal damage, although often against the backdrop of chronic vascular insufficiency. PD, an example of a neurodegenerative Inhibitors,research,lifescience,medical disease with origins in the subcortex. AD, an example of a neurodegenerative disease with origins in the cortex. MS, a demylenating condition, usually episodic,

affecting the white matter diffusely in the brain and spinal cord. Epilepsy, in which repetitive abnormal electrical discharges Inhibitors,research,lifescience,medical occur, but in which there is likely additional brain pathology, typically unknown, so that psychiatric disturbance might arise both in relationship to the seizures, or in relationship to underlying brain damage. While an overview is provided here in the context of the current synthetic discussion, the reader (-)-p-Bromotetramisole Oxalate is referred to a recent textbook for a more comprehensive discussion3 or to a practical clinical volume4 that provides guidance for the clinical care of the psychiatric conditions seen in patients with these neurologic diseases. Traumatic brain injury TBI5 has an annual incidence of about f .5 million cases in the United States, and is associated with both neurological and psychiatric consequences. Typically, the neurologic consequences stabilize with time but the psychiatric disturbances tend to remit and relapse for many years after the injury. Patients who suffer TBI frequently have premorbid histories of alcohol use, impulsive behavior, lack of social support, drug use, and other psychiatric disturbances.

15 In this trial, patients with BP-I or II were randomly assigned to treatment with bupropion, paroxetine, or placebo added to an FDAapproved antimanic agent. The trial employed an equipoise-stratified randomization design; thus, psychiatrists could choose from three strata, (placebo vs bupropion, placebo vs paroxetine, or placebo vs either antidepressant) to allow research participation, even if the patient held a clear preference for one antidepressant versus another. A total of 366 patients enrolled in the study and were randomized to receive either a mood stabilizer plus

placebo (N=187) or a mood stabilizer plus an antidepressant. (N=179). As opposed to Inhibitors,research,lifescience,medical simple measurements of response, durable recovery was uniquely chosen as the primary outcome measure, defined as a state of euthymia for 8 consecutive weeks. Secondary outcomes included traditional rates of response based on a ≥ 50% improvement

on the Structured Clinical Interview for DSM-IV continuous symptom subscale for depression. In the end, rates of durable Inhibitors,research,lifescience,medical recovery were similar between the antidepressant (23.5%) and placebo (27.3%) groups (P=0.4). Response rates also did not differ between groups, and BP-I subjects Inhibitors,research,lifescience,medical were as likely to respond (25.4%) as were BP-II subjects (20.4%). Adjunctive antidepressant administration was not found to confer a greater benefit than mood-stabilizer monotherapy in the treatment, of bipolar depression. Additionally, antidepressants were not associated with an increase in cycling between the depressive and manic poles. In summary, the study found neither an advantage nor disadvantage associated with use of the antidepressants bupropion or paroxetine. Conventional mood stabilizers

Inhibitors,research,lifescience,medical and atypical antipsychotics lithium Although lithium is the oldest, agent Inhibitors,research,lifescience,medical studied for the acute treatment of bipolar depression, it remains a viable and underutilized option with established efficacy in various trial selleck inhibitor designs and clinical experience. Zornberg and Pope,16 in a comprehensive review of controlled investigations of lithium, identified eight, studies that demonstrated lithium to be more effective than placebo in the treatment of acute bipolar depression. Nevertheless, most of the constituent studies in their analysis were older investigations (ie, published ADP ribosylation factor prior to 1978), or limited by several methodological shortcomings. For instance, our search strategy was unable to identify any moderately sized studies of lithium for the acute treatment of bipolar depression. Furthermore, early trials employed crossover as opposed to parallel designs introducing the possibility for carryover effects. The abrupt, discontinuation of lithium may also have biased efficacy assessments, as acute withdrawal of lithium leads to, and hastens, a high probability of relapse.