Jayanthi N. Koneru, Department of Internal Medicine, Division of Cardiology and Cardiac Electrophysiology, Virginia Commonwealth University, Richmond, Virginia, USA. Christopher Kogut, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA. Ericka L. Breden Crouse, Department of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, Inhibitors,research,lifescience,medical USA. Jules C. Hancox, School of Physiology

and Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK. Antony Fernandez, Departments of Psychiatry and Virginia Commonwealth University and Mental Health Service Line, Veterans Administration Medical Center, Inhibitors,research,lifescience,medical Richmond, Virginia, USA. Ananda K. Pandurangi, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

It has been over 50 years since Cade first described this simple cation’s therapeutic role in manic illness [Cade, 1949]. Since this discovery, our understanding of its mechanisms of action have developed significantly [Lenox and Hahn, 2000], although the full nature of its effects are yet to be elucidated. Lithium is primarily used in the recovery of bipolar affective disorder, with evidence supporting its role in both Inhibitors,research,lifescience,medical acute mania [Gershon and Soares,

1997; Soares and Gershon, 1998, 2000; Bowden, 2000; Poolsup et al. 2000; Shafti, 2010] and prophylactic treatment [Soares and Gershon, 1998, 2000; Burgess et al. 2001; Geddes et al. 2004, 2010]. It is also efficacious

in the treatment Inhibitors,research,lifescience,medical of unipolar depression [Coppen, 2000], particularly as augmentation therapy in severe refractory depression [Bauer et al. 2003b; Kennedy and Paykel, 2004], and bipolar depression [Lloyd et al. 2011]. In addition, it has been noted to effect aggressiveness [Jones et al. 2011], reduce suicide rates in affective disorders [Tondo and Baldessarini, 2000; Cipriani et al. Inhibitors,research,lifescience,medical 2005] and, more speculatively, has been considered as a possible therapeutic agent for treating chronic neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases [Marmol, 2008; Dudev and Lim, 2011]. Yet, despite nearly lithium’s extensive clinical applications and its ability to provide potentially lifesaving treatment to patients [Nemeroff, 2000; Jope, 2003], the exact mechanisms by which it exerts its therapeutic effects remain incompletely understood [Phiel and Klein, 2001; Gould and Manji, 2005; Haimovich et al. 2012]. Further exploration is required, to determine more fully why lithium provides effective mood stabilisation for patients and allow clearer insight into mood disorder pathophysiology. In addition, lithium’s usage is limited by its narrow therapeutic window and significant range of PI-103 research buy adverse side effects [Livingstone and Rampes, 2006; McKnight et al.

63 The presence of comorbid medical conditions or abnormal laboratory tests has also become an increasing concern given the potentially high rates of metabolic syndrome, smoking, etc. among people with schizophrenia. Randomization strategies Most RCTs use even randomization strategies, which assign equal numbers of patients to each treatment arm. This makes sense since the smallest arm will determine Inhibitors,research,lifescience,medical the statistical power involved in the comparison between treatments. However, there are some situations

where equal randomization might not be appropriate. Equipoise randomization64 has been used in some trials and can provide patient and physician input into the potential options involved in the treatment assignment without doing away with randomization altogether. Adaptive design is another strategy which entails the use of data already collected to influence Inhibitors,research,lifescience,medical subsequent randomization of treatment groups.65 This can be particularly useful in studies involving dose-finding; however, it can also lead to premature closure of a study arm or an entire study based on relatively small amounts of data. Sequential design allows pairing of individuals who are assigned to alternate treatments

with the results of each subsequent pair contributing to an ongoing analysis of the Inhibitors,research,lifescience,medical odds of reaching a significant effect or not.65 This can provide statistical significance with a small number of patients if Inhibitors,research,lifescience,medical the treatment effect is substantial, or it can provide an initial confirmation of the null hypothesis. Such a design has rarely been used in RCTs in schizophrenia,66 but should be considered. Stratified randomization is an WP1130 chemical structure important tool to ensure that the treatment arms are balanced

on a small Inhibitors,research,lifescience,medical number of potentially important mediating or moderating variables. The number of such variables will be determined by the overall sample size. Crossover studies are also conducted in some situations, Carnitine palmitoyltransferase II but given potential medication carryover effects and uncertainty as to how vulnerable patients are to returning to their baseline state make placebo-controlled crossover trials less informative in psychiatry than they might be in some medical conditions. So-called “switch” studies are often done in psychiatry, but unless there is a control group they cannot be considered RCTs. Switch studies are obviously much more informative if patients are randomized to be switched or to stay on the original treatment, in a double-blind fashion. Blinding While blinding/masking is an important feature to minimize expectation biases, blinding patients and providers to the treatment does not match clinical practice.

Data from shotgun-MS, which consists of chromatograms attached to mass spectra, are analyzed by complex computational algorithms to reconstruct the protein sequences based in the masses of all peptides measured and fragmented. This process is known as “bottom-up proteomics.” MS-based proteomics have rapidly developed in the past 10 years. Nowadays, a single LC-MS experiment is able to reveal 3000 to 7000 proteins in an hour, which would only be doable—if at all—by combining 2DE-MS over some

weeks of work. For proteome quantitation, there are Inhibitors,research,lifescience,medical several alternatives that can be taken into consideration13 for a given LC-MS experiment, such as stable AZD6244 nmr isotope labeling in vitro (ie, isotope-coded affinity tags [ICAT]14 and isobaric tags for relative and absolute quantitation [iTRAQ]15) or even in vivo (ie, stable Inhibitors,research,lifescience,medical isotope labeling by/with amino acids in cell culture [SILAC]16 or stable isotope labeling in mammals [SILAM]),

as well as diverse label-free approaches.17 Shotgun-MS still presents difficulty in representing hydrophobic and low abundant proteins depending Inhibitors,research,lifescience,medical on the type of sample preparation and MS acquisition. Moreover, information of intact proteins is lost by conventional bottom-up proteomics, which can be represented by 2DE, as well as the characterization of certain protein post-translational modifications. Proteome findings in patients with depression Brain tissue and cerebrospinal fluid Surprisingly, and unlike other psychiatric disorders such as schizophrenia,18,19 only one research group focused their efforts on the large-scale proteome investigation of postmortem Inhibitors,research,lifescience,medical human brains from depressed patients, through two articles. Samples from the dorsolateral prefrontal cortex (DLPFC) of 24 patients with MDD were compared with 12 controls using a shotgun label-free approach. Some of the protein candidates were further

validated by selected reaction monitoring (SRM). Inhibitors,research,lifescience,medical Several biological functions were associated with MDD, such as energy metabolism, cellular transport, and cell communication and signaling.20 Energy metabolism has already been described for a long time as a pattern for psychiatric disorders in general, via several different Bumetanide techniques.21-23 However, it has been possible to delineate exactly which energy metabolism pathways are more involved in each disorder, by using proteomics. Glycolysis is the main affected pathway in schizophrenia brains,24 whereas in MDD, oxidative phosphorylation is the most affected. Not only have several subunits of oxidative phosphorylation complexes been shown to be expressed differentially, but adenosine triphosphate (ATP) levels were also determined to be lower in MDD.20 Additionally, a proteomic study of a preclinical model for anxiety has shown both pathways to be differentially regulated.

Currently used DAAs include the “ergot-derived” or “ergoline” drugs bromocriptine, cabergoline, lisuride, and pergolide, with chemical structures based on ergot, a plant alkaloid. The newer, “non-ergot” synthetic DAA, piribedil, pramipexole, and ropinirole – chemically unrelated to ergot – are being promoted vigorously. Side effects Inhibitors,research,lifescience,medical typical of all DAAs (as well as levodopa) include nausea, vomiting, dizziness, and orthostatic hypotension.11,15,18-20 At higher doses, DAAs may induce

confusion, hallucinations, and psychosis, although these usually GDC-0973 mw appear in the advanced stages of the disea.se.21 Sedation and insomnia are other reported side effects of some DAAs, as well as of levodopa, and are probably not associated with any specific agonist. Attention has recently been drawn to somnolence as a possible adverse effect of DAAs (including levodopa). Events of a compelling urge to sleep (so-called “sleep attacks”) have been observed in patients treated with DAAs.22-26 Inhibitors,research,lifescience,medical This is a serious side effect, that, may cause driving accidents. This Inhibitors,research,lifescience,medical needs to be considered and explained

to the patient, particularly if he or she is involved in activity in which the somnolence, even if not excessive, could endanger them or others. Some of the side effects specifically linked to the ergot derivatives include digital or coronary vasospasm, as well as pleuropulmonary and retroperitoneal fibrosis. These are not associated with the Inhibitors,research,lifescience,medical newer and safer non-ergot DAAs piribedil, ropinirole, and pramipexole.27 A transdermal formulation of the experimental D2 selective agonist rotigotine is currently in development.28 It has been found to reduce daily levodopa doses by 30% in a multicenter phase 2b trial in mild-to-severe PD. Apomorphine is the most, potent DAA, and the only one that stimulates effectively both DA D1 and D2 receptors (as does DA itself). However, its therapeutic effect is

hampered by its complex interindividual pharmaco-kinetics and pharmacodynamic variability and its narrow therapeutic range. Apomorphine cannot Inhibitors,research,lifescience,medical be used as an oral drug, but. subcutaneous injections are very helpful, particularly for patients with prolonged “off” the episodes. Continuous delivery of apomorphine subcutancously through a pump is available, but. is technically complex to use and expensive.29 In order to overcome these difficulties, several attempts to create individualized controlled delivery systems for apomorphine are being explored, eg, transdermal iontophoresis and sublingual delivery of the drug. This will be particularly useful for a rapid effect to control fluctuations.30 In a recent study, a carboxymethyl cellulose powder of apomorphine was tested as intranasal sustained-release formulation. These newer delivery systems will hopefully enhance its use as a rescue medication in severe cases.

They had to have been hospitalized for psychotic symptoms (admission and discharge dates

available) and received at least one dose of quetiapine XR or quetiapine IR at any time during hospitalization (regardless of dose). Patients who were participating in a clinical trial during the study period or who were being treated in forensic care were excluded. Study outcomes The primary outcome was to evaluate the antipsychotic use of quetiapine XR and IR in patients with schizophrenia. Patients who received a total daily dose of at Inhibitors,research,lifescience,medical least 400 mg were regarded as being treated with quetiapine mainly for antipsychotic reasons, whilst those on a total daily dose of less than 400 mg were regarded as having been treated with quetiapine as an add-on to other antipsychotics. The cutoff dose of 400 mg quetiapine was Inhibitors,research,lifescience,medical chosen as quetiapine shows sufficient D2-receptor occupancy and thus antipsychotic properties throughout the dose range of 400–800 mg/day [Kapur et al. 2000]. The following secondary outcomes were also investigated: the use of quetiapine XR/IR treatment in high doses and in lower doses as add-on therapy; simultaneous treatment with quetiapine XR/IR; concomitant medication; patient demographics and comorbidities (ICD10

diagnosis); disease severity at hospital admission and discharge by the Global Assessment of Inhibitors,research,lifescience,medical Functioning (GAF) score; information about previous and current hospitalizations; and electroconvulsive therapy (ECT). Statistical Inhibitors,research,lifescience,medical analyses All analyses were prespecified in a statistical analysis plan and performed using the SAS software, version 9.2. Means were compared by a t test, except for GAF values when an analysis of variance was used with least squared means (LSM) and baseline GAF as covariate. Proportions were compared using a χ2 test. The percentage of patients treated with concomitant drugs was calculated using a Poison regression with length of hospital

Inhibitors,research,lifescience,medical stay as offset variable. The statistical null hypothesis was that the groups had the same average value or proportion and p values for rejecting this hypothesis were calculated. A p value below 0.05 was considered as significant. Results Patient demographics A total of 178 patients were included in the study; 118 (66%) received quetiapine XR and 60 (34%) received quetiapine IR. Demographic data were equal for the two treatment groups (Table 1). Table 1. Patient demographics. Differential dosing in patients on quetiapine XR versus quetiapine IR lifescience Significantly more patients in the quetiapine XR group (64%) compared with the quetiapine Methisazone IR group (40%) were treated with quetiapine in doses of at least 400 mg/day (p = 0.002) (Table 2). Significantly more patients receiving quetiapine XR than IR were also treated with doses of at least 600 mg/day (52% versus 23%, p = 0.0003). Moreover, 27% of the patients in the IR group had a mean quetiapine dose below 200 mg/day during the inpatient stay, while the same was seen in only 13% of the patients in the XR group. Table 2.

2. For treatment if the following conditions are the cause •Cardiac arrhythmias, •Cardiac ischemia, •Structural

cardiac or cardiopulmonary disease, •Stroke or focal neurological disorders, or •For pacemaker insertion. The 2009 guidelines added non-sustained ventricular Inhibitors,research,lifescience,medical tachycardia and severe co-morbidities (severe anemia and electrolyte disturbances) to the admission criteria. The American College of Emergency Physicians issued guidelines for management of ED syncope patients in 2001 and 2007[48,53]. The 2001 guidelines recommend admission if any of the following high-risk features is present: 1) History of congestive heart failure or ventricular arrhythmias, 2) Presence of chest pain or acute coronary syndrome, 3) Signs of heart failure or valvular heart disease, or 4) ECG signs of ischemia, Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical arrhythmia, prolonged QT interval, or bundle branch block. The guidelines recommend that GDC 973 hospitalization be considered if any of the following medium-risk features are present:

1) Age >60 years, 2) Abnormal ECG (defined as changes consistent with acute ischemia, dysrhythmias, Inhibitors,research,lifescience,medical or significant conduction abnormalities), 3) Family history of sudden death, or 4) Young patients with unexplained exertional syncope. One study validated the 2001 guidelines retrospectively

but outcomes were limited to cardiac syncope with serious methodological limitations in attributing the cause of syncope as cardiac Inhibitors,research,lifescience,medical [54]. The 2007 guidelines advise hospitalization if any of the following features are present: 1) Older age with associated comorbidities, 2) Abnormal ECG (defined Nature Reviews Genetics as changes consistent with acute ischemia, dysrhythmias, or significant conduction abnormalities), 3) Hematocrit <0.3, or 4) History or presence of congestive heart failure or coronary or structural heart disease. The 2007 guidelines included variables ‘older age with associated comorbidities’ and ‘abnormal ECG’ that were not clearly defined and these guidelines have not been validated. The Canadian Cardiovascular Society published a position paper on the standardized approaches to the management of syncope and identified major and minor risk factors for short-term events [14]. These risk factors have not been validated yet.

30 Decreases in astrocytic immunoreactivity for cellular GFAP and the neuron-specific phosphoprotein B50 (or GAP-45) were detected in CA1 and CA2 in depression.31 The authors suggest that apoptosis may only be a minor contributor to volume changes in the hippocampus in depression, while patterns of reactive astrogliosis and synaptic

reorganization proteins are significantly Inhibitors,research,lifescience,medical altered in only some hippocampal regions in depression. Other reports of hippocampal changes in mood disorders identify a significant decrease in the density of nonpyramidal neurons in the CA2 region and a reduction in reelin-positive cell density in the hilus in subjects with BPD.32,33 Two other studies conducted on the postmortem hippocampal formation in a small sample of subjects with

BPD reveal a decrease in the density and size Inhibitors,research,lifescience,medical of nonpyramidal neurons in the CA2 region and some disorganization in neuronal clusters in layers II and III of the entorhinal cortex.34,35 Neuronal and glial cell packing density and soma size were estimated recently in Nissl-stained sections including the hippocampal subfields in 16 subjects with MDD and 16 age-matched normal control subjects.36 Representative photomicrographs are presented in Figure 2. Prominent abnormalities in the CA regions and dentate gyrus are found in subjects with MDD. There Inhibitors,research,lifescience,medical is a significant increase in the mean density of pyramidal neurons in depressed subjects, as compared with normal control subjects. In the granule cell layer of the dentate gyrus, cell density is significantly increased in MDD. In addition, there is a significant decrease in the mean soma size Inhibitors,research,lifescience,medical of pyramidal neurons in depressed subjects, as compared with normal control subjects. On the basis of covariate analyses, the main findings of increased neuronal density

and decreased neuron Inhibitors,research,lifescience,medical soma size in PH-797804 molecular weight depression are not significantly altered when taking into consideration such factors as gender, age, postmortem interval, tissue pH, brain weight, smoking, antidepressant, drug prescription in the last month of life, or suicide. The substantial increases noted in neuronal packing density and decrease in neuronal (-)-p-Bromotetramisole Oxalate soma size detected in postmortem tissue may be related to the decrease in hippocampal volume noted by some in MDD. Figure 2. Brightfield photomicrographs of coronal sections of the postmortem human hippocampal formation. A. Cresyl violet-stained coronal section from a 54-year-old male (23-h postmortem interval). B. An adjacent coronal section processed byTimm staining. Note … Glial pathology in depression appears to extend beyond the frontal cortex to the hippocampus. A recent study of the hippocampus in a large number of subjects with MDD and aged-matched normal control subjects reports a significant increase in the density of glial cells in all hippocampal CA subfields and the granule cell layer of the dentate gyrus.

Footnotes This work was Selleck CI 1033 supported

with an unrestricted grant from Lundbeck, who had no editorial control over the content of this review. The author has received research grant support, travel support and/or honoraria from each of the companies marketing atypical antipsychotics licensed for the treatment of mania.

In depression a wide range of cognitive deficits is a consistent finding [Ravnkilde et al. 2002]. Cognitive function is a predictor of the functional and psychosocial burden of illness in major depressive disorder (MDD) and consequently a pertinent candidate predictor of treatment response [Austin et al. 2001]. With Inhibitors,research,lifescience,medical recovery from MDD, abnormalities in cognitive function tend to normalize but cognitive Inhibitors,research,lifescience,medical impairment is also seen in recovered patients [Hasselbalch et al. 2010; Kessing, 1998]. Cognitive impairment has been reported in healthy first-degree relatives of patients with MDD, thus in a cross-sectional high-risk case–control study of healthy twins with and without a co-twin history of affective disorder, the healthy twins discordant for unipolar disorder showed lower performance on almost all measures of Inhibitors,research,lifescience,medical cognitive function: selective and sustained attention, executive function, language processing

and working and declarative memory, and also after adjustment for demographic variables, subclinical affective symptoms and other minor psychopathology [Christensen et al. 2006]. Further, decreased immediate recall and recognition memory has been found

in young women with no personal history of depression but with a depressed parent as compared with an age-matched control group with no family history of depression [Mannie et al. 2009]. Previous trials investigating Inhibitors,research,lifescience,medical the effect of selective serotonin receptor inhibitors Inhibitors,research,lifescience,medical (SSRIs) on cognitive function in healthy individuals have given inconsistent findings. In a recent review, concerning the effect of SSRIs in healthy individuals, 18 randomized trials using 39 different neuropsychological tests to investigate cognitive function were identified [Knorr and Kessing, 2010]. Treatment with a SSRI was found to improve [Murphy et al. 2008; Loubinoux (-)-p-Bromotetramisole Oxalate et al. 2005; Harmer et al. 2004; Schmitt et al. 2001; Knutson et al. 1998, 1997], deteriorate [Riedel et al. 2005; Schmitt et al. 2002a, 2001; Fairweather et al. 1997; Ramaekers et al. 1995; Robbe and O'Hanlon, 1995] or have no effect on cognitive function [Peran et al. 2008; Paul et al. 2007, 2002; Wingen et al. 2006, 2005; Loubinoux et al. 2005; Riedel et al. 2005; Siepmann et al. 2003; Schmitt et al. 2002a, 2002b, 2001; Wilson et al. 2002; Allen et al. 1988; Fairweather et al. 1997; Ramaekers et al. 1995; Robbe and O'Hanlon, 1995]. It was concluded that the diverging findings could be a result of a number of methodological drawbacks.

Electrophysiological correlates include loss of gamma-band responses to sensory stimuli and elevated neuronal activity in the default mode.49 Disinhibition of glutamatergic output from the ventral hippocampus would drive the firing of dopaminergic neurons in the ventral tegmental area and enhanced subcortical dopamine release, which in PET studies correlates with psychosis.50 Thus, in this model, Inhibitors,research,lifescience,medical psychosis is a downstream event. Figure 1. Schematic representation

of the synaptic circuitry relevant to the pathophysiology of schizophrenia. NMDA receptor hypofunction can be produced by exogenous antagonists such as ketamine, endogenous antagonists such as N-acetyl aspartyl glutamate (NAAG) … Hypofunction of NMDA receptors could account for other aspects of the disorder. First, given the role of NMDA receptors in neuronal migration,51 it could account for the finding of abnormal distribution of cortical GABAergic interneurons in some cases.52 Inhibitors,research,lifescience,medical Secondly, persistent hypofunction of NMDA receptors is consistent with the reduced pyramidal neuron dendritic complexity, reduced Inhibitors,research,lifescience,medical spine density, and net compaction of the neuropil in schizophrenia.37 Obviously, the pathophysiology of schizophrenia is much more complex and nuanced than selleck chemical suggested by this simplified model. Indeed, a number of putative risk genes encode

transcriptional factors that affect brain development.53 Other risk genes encode products involved in myelination.54 Furthermore, in recognition of the variation in symptoms among patients who satisfy the diagnostic Inhibitors,research,lifescience,medical criteria for schizophrenia and its complex genetics, where literally hundreds of genes of modest effect might be involved, the proposed “pathologic circuit” represents at best a crude first approximation of the pathophysiology of schizophrenia. Inhibitors,research,lifescience,medical Nevertheless,

it does yield a host of potential targets for therapeutic intervention, and many of these are under investigation by the pharmaceutical industry. It is these potential therapeutic targets related to this circuit that are the subject of this review (Figure 2). Of particular interest is the fact that these targets would intervene in the primary cortical pathology of schizophrenia and thus potentially treat the negative symptoms and cognitive deficits. Figure 2. Potential pharmacologic interventions to treat PAK6 schizophrenia: (i) Enhance NMDA receptor function by increasing synaptic glycine concentrations with an inhibitor of GlyT1 , administering exogenous D-serine, inhibiting D-amino acid oxidase or by treating … Targeting the glutamatergic synapse Structure and function of the NMDA receptor The NMDA receptor, with its triple gate for activation, is a critical postsynaptic mediator of activity-dependent synaptic plasticity.

All benzodiazepines interact with the γ-aminobutyric acid receptor (GABAA) and produce similar physiological and clinical effects.43,44 The anxiolytic effect, appears to be mediated by the alpha-2 subunit, of the receptor complex. Preferred terminology refers to these drugs as positive modulators since they do not have any effect in the absence of GABA. With chronic exposure, a number of molecular effects have been reported.43-45 Downregulation of binding sites with a reduction in the number of the GABAA receptors is one molecular phenomenon that has

been proposed as a Inhibitors,research,lifescience,medical mechanism for tolerance. Other changes that have been reported include changes in mRNA, a disturbance in the linking relationship between the benzodiazepine site and GABA, and perturbations in the

rate of turnover Inhibitors,research,lifescience,medical of subunits of the benzodiazepine receptor. Determinations of whether these findings can be OSI-027 manufacturer directly and causally linked to tolerance and discontinuation syndromes have been difficult, because of the differences in timing of the molecular and clinical phenomena.46,47 Molecular changes seem to occur more quickly than the development, of clinical tolerance. Although the benzodiazepines work via a common mechanism of action, there are definite pharmacokinetic and metabolic differences that affect, the presence and concentration of an active entity at the molecular site of action.48 These differences determine the clinical indications Inhibitors,research,lifescience,medical for which a given benzodiazepine Inhibitors,research,lifescience,medical is used, and they also result, in differences in clinical course once an administered medication is discontinued.49-51 The most important factors in this realm arc the speed at which the parent drug is cleared and the presence or absence of pharmacologically active metabolites (Table II). As an example, for a drug such as diazepam, the parent, drug is cleared slowly, and at least, three metabolically Inhibitors,research,lifescience,medical active compounds are generated during the course of its clearance. Some of these compounds are actually separate benzodiazepine entities available for prescription is their own right. After one 10 mg dose of diazepam,

pharmacologically active metabolites are detectable for at least 2 weeks. Hence, even with abrupt, discontinuation of diazepam, an intrinsic tapering process results (Figure 1). The potency of a given benzodiazepine Ketanserin parent drug at the site of activity is not a major determinant of clinical differences, since dosages are adjusted to produce a clinical effect, through the same molecular mechanism. Figure 1 Plasma concentrations of diazepam (blue circles) and its principal pharmacologically active metabolite, desmethyldiazepam (light-blue circles), in a healthy volunteer who took 2.5 mg of diazepam orally twice a day for 15 days. A Plasma levels are shown … Table II. Representative benzodiazepine derivatives in clinical use as antianxiety agents. The usual range of elimination half-life is shown in parentheses. * Prodrug, converted to desmethyldiazepam.