Effects of vortioxetine on functional capacity across different levels of functional impairment in patients with major depressive disorder: a University of California, San Diego Performance-based Skills Assessment (UPSA) analysis.

Objective: To evaluate the consistency of vortioxetine's effects on functional capacity in adults with major depressive disorder (MDD) and self-reported cognitive symptoms at different levels of functional impairment.Methods: An exploratory analysis of data from a randomized, placebo-controlled, duloxetine-referenced study (NCT01564862) involving 529 patients with moderate to severe MDD treated once-daily with vortioxetine 10/20 mg, duloxetine 60 mg, or placebo for 8 weeks. Analysis of the University of California, San Diego Performance-based Skills Assessment (UPSA) composite scores stratified patients into subgroups by baseline functional impairment and assessed clinically important differences using several cutoffs for change from baseline (CFB) (least-square means) in UPSA composite score. A path analysis was also conducted to determine the proportion of direct versus indirect effects of vortioxetine on functional capacity.Results: Vortioxetine significantly separated from placebo across different baseline levels of functional impairment, particularly at the ≤70 cutoff (mean difference = 5.9, 95% confidence interval, 1.5-10.4). A greater proportion of patients treated with vortioxetine than placebo exhibited UPSA composite score response at each threshold analyzed and were classified as responders based on UPSA CFB of ≥7 (p = 0.006) or ≥9 (p = 0.016). No significant effects were observed for duloxetine versus placebo for any baseline levels of functional impairment or response thresholds. Path analysis demonstrated that 96.9% of the effects on functional capacity can be directly attributed to the treatment effect of vortioxetine and are not mediated by improvements in depressive symptoms as measured by MADRS.Conclusion: The effects of vortioxetine on functional capacity is robust across different level of functional impairment in patients with MDD. The effect on functional capacity was largely independent of the effect on depressive symptoms. Trial Registration: ClinicalTrials.gov identifier: NCT01564862: https://clinicaltrials.gov/ct2/show/NCT01564862; European Clinical Trials Database [EudraCT] Number 2011-005298-22: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005298-22/DE.

SAGE-217, A Novel GABAA Receptor Positive Allosteric Modulator: Clinical Pharmacology and Tolerability in Randomized Phase I Dose-Finding Studies.

BACKGROUND: SAGE-217, a novel γ-aminobutyric acid A (GABAA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) studies to assess the safety and pharmacokinetics (PK) of SAGE-217 following administration as an oral solution. METHODS: In the SAD study, subjects were randomized 6:2 to a single dose of SAGE-217 or placebo. Doses ranged from 0.25 to 66 mg across nine cohorts. In the MAD study, subjects were randomized 9:3 and received SAGE-217 (15, 30, or 35 mg) or placebo once daily for 7 days. In both studies, PK, maximum tolerated dose (MTD; against predetermined criteria), safety, and tolerability were assessed. RESULTS: A total of 108 healthy volunteers enrolled in the studies-72 subjects in the SAD study and 36 subjects in the MAD study. SAGE-217 was orally bioavailable, with a terminal-phase half-life of 16-23 h and a tmax of approximately 1 h. The MTDs for the oral solution of SAGE-217 in the SAD and MAD studies were determined to be 55 and 30 mg daily, respectively. In both studies, SAGE-217 was generally well tolerated, and no serious adverse events (SAEs) were reported. Most AEs were mild, dose-dependent, transient, occurred around the tmax, and related to drug pharmacology. CONCLUSIONS: SAGE-217 was generally well tolerated, and its PK profile was well characterized. Based on this profile, SAGE-217 has been advanced into multiple phase II clinical programs and pivotal studies of major depressive disorder and postpartum depression.

Clinical implications of directly switching antidepressants in well-treated depressed patients with treatment-emergent sexual dysfunction: a comparison between vortioxetine and escitalopram.

OBJECTIVE: The objective of this work was to describe treatment-emergent sexual dysfunction (TESD) and tolerability following a switch from selective serotonin reuptake inhibitor (SSRI: citalopram, paroxetine, or sertraline) monotherapy to vortioxetine or escitalopram monotherapy in adults with well-treated major depressive disorder (MDD) and SSRI-induced sexual dysfunction. METHODS: Data were analyzed from the primary study, an 8-week, randomized, double-blind, head-to-head study in which participants with well-treated depressive symptoms but experiencing TESD with SSRIs were directly switched to flexible doses (10/20 mg) of vortioxetine or escitalopram. Sexual functioning was assessed by the Changes in Sexual Functioning Questionnaire-14 (CSFQ-14), efficacy by the Montgomery-Åsberg Depression Rating Scale scores (MADRS) and Clinicians Global Impression of Severity/Improvement (CGI-S/CGI-I), and tolerability by adverse events. Efficacy and tolerability were assessed by pre-switch SSRI therapy where possible, and by participant characteristics. RESULTS: Greater improvements in TESD were seen in the vortioxetine compared with escitalopram groups based on: participant demographics (≤45 years, women; P = 0.045), prior SSRI treatment (P = 0.044), number of prior major depressive episodes (MDEs) (1-3; P = 0.001), and duration of prior SSRI therapy (>1 year; P = 0.001). Prior SSRI treatment did not appear to influence the incidence or severity of TEAEs, except for nausea. Regardless of prior SSRI, both treatments maintained antidepressant efficacy after 8 weeks. CONCLUSION: Results suggest that vortioxetine is a safe and effective switch therapy for treating SSRI-induced sexual dysfunction in adults with well-treated MDD. Also, improvement in sexual dysfunction with vortioxetine or escitalopram may be influenced by prior SSRI usage, sex, age, and history of MDEs.

Effects of Intrinsic Factors on the Clinical Pharmacokinetics of Vortioxetine.

Vortioxetine is an antidepressant agent with multimodal activity that is approved for the treatment of major depressive disorder at doses of 5 to 20 mg once daily. Vortioxetine is a medium-clearance drug that undergoes extensive metabolism via several cytochrome P450 isozymes. A series of single- and multiple-dose pharmacokinetic studies were performed to evaluate the impact of intrinsic (ie, subject-related) factors, such as age, sex, race, and renal and hepatic function, on the pharmacokinetics of vortioxetine. The point estimates on the ratios and their 90% confidence intervals (CIs) for the central values of AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) were obtained by taking the antilog of the differences and 90%CIs in the log-transformed least-squares means. The results demonstrate that there were no clinically meaningful differences (defined as exposure difference between 50% and 2-fold change) in the exposure to vortioxetine (as assessed by AUC and Cmax ) between elderly and younger subjects, men and women, and blacks and whites and among subjects with varying degrees of renal or hepatic impairment. These results suggest that no dosing adjustments of vortioxetine are required for the intrinsic factors investigated in these studies.

Adolescent Female Cannabinoid Exposure Diminishes the Reward-Facilitating Effects of Δ9-Tetrahydrocannabinol and d-Amphetamine in the Adult Male Offspring.

Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to Δ9-tetrahydrocannabinol (Δ9-THC) induces transgenerational effects on the reward-facilitating effects of Δ9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28-50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the Δ9-THC's (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine's (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of Δ9-THC was abolished in the F1 offspring of females that were exposed to Δ9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of Δ9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to Δ9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female Δ9-THC exposure during adolescence can diminish the reward-facilitating effects of Δ9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs.

Determination of a clinically important difference and definition of a responder threshold for the UCSD performance-based skills assessment (UPSA) in patients with major depressive disorder.

BACKGROUND: This article reports an evaluation of the psychometric properties and clinically important difference (CID) threshold of the UCSD Performance-Based Skills Assessment (UPSA) in major depressive disorder (MDD), using data from a large-scale study of the effects of vortioxetine on cognitive functioning and functional capacity in MDD patients. METHODS: Adults with moderate-to-severe recurrent MDD and self-reported cognitive dysfunction were randomized to 8 weeks of double-blind treatment with vortioxetine 10/20mg QD (flexible), duloxetine 60mg QD, or placebo. Pearson correlation coefficients were calculated between UPSA composite score and demographic/disease characteristics at baseline to examine construct validity. Two methods (distribution-based and anchor-based) were used to establish a CID threshold. RESULTS: A total of 602 patients were randomized; 528 comprised the full analysis set. For the entire sample mean UPSA composite scores were 77.8 at baseline and 83.9 at week 8 (mean change, +6.1). As hypothesized, at baseline, the UPSA composite score correlated with cognitive functioning (Digit Symbol Substitution Test: r=0.36, P<0.001) and workplace productivity (Work Limitations Questionnaire: r=-0.17, P=0.008), but not depressive symptoms (Montgomery-Åsberg Depression Rating Scale: r=0.02, P=0.707) or subjective cognitive dysfunction (Perceived Deficits Questionnaire: r=-0.02, P=0.698). LIMITATIONS: Two versions of the UPSA were used and no inclusion/exclusion criteria were based on the UPSA. CONCLUSIONS: These results support the construct validity of UPSA for assessing functional capacity independent of mood symptoms. The estimated CID for changes in UPSA scores was quite consistent at +6.4 points and +6.7 based on distribution-based and anchor-based methods, respectively.

Efficacy, safety, and tolerability of vortioxetine for the treatment of major depressive disorder in patients aged 55 years or older.

OBJECTIVE: These post hoc analyses evaluate the efficacy, safety, and tolerability of vortioxetine versus placebo in patients aged ≥55 years with major depressive disorder (MDD). METHODS: Study-level efficacy data from 12 short-term, fixed-dose, randomized, placebo-controlled trials of vortioxetine 5-20 mg/day were assessed using a random-effects meta-analysis. Adverse events (AEs), vital signs, ECG values, liver enzymes, and body weight were pooled from the same studies. Patients had baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores ranging from 22-30. RESULTS: 1508 patients (mean age=62.4 years; range, 55-88 years) were included. Mean differences from placebo in change from baseline to study end (6/8 weeks) in MADRS were -2.56 (5 mg, n=324, P=0.035), -2.87 (10 mg, n=222, P=0.007), -1.32 (15 mg, n=90, P=NS), and -4.65 (20 mg, n=165, P=0.012). Odds ratios for response versus placebo were 1.6 (5 mg, P=NS), 1.8 (10 mg, P=0.002), 1.2 (15 mg, P=NS), and 2.5 (20 mg, P<0.001), and for remission versus placebo were 1.5 (5 mg, P=NS), 1.5 (10 mg, P=NS), 1.4 (15 mg, P=NS), and 2.7 (20 mg, P=0.001). The proportion of patients with AEs for placebo and vortioxetine 5-20 mg was 61.5% and 62.3%, respectively, with no increase at increased doses. Vortioxetine demonstrated a placebo-level incidence of serious AEs (1.2%). AEs occurring in ≥5% of any treatment group were nausea, headache, diarrhea, dizziness, dry mouth, constipation, fatigue, vomiting, and anxiety. No clinically significant mean changes in vital signs, ECG values, liver enzymes, or body weight emerged during treatment. CONCLUSION: Vortioxetine 5-20 mg/day is efficacious and well tolerated in MDD patients aged ≥55 years, a group that is often comorbid with other conditions and treated with other medications.

Attenuation of Cocaine-Induced Conditioned Place Preference and Motor Activity via Cannabinoid CB2 Receptor Agonism and CB1 Receptor Antagonism in Rats.

Background: Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects. Methods: The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats. Results: The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered. Conclusions: Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaine's reinforcing and psychomotor effects.

A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms.

BACKGROUND: Coexisting anxiety is common in major depressive disorder (MDD) and more difficult to treat than depression without anxiety. This analysis assessed the efficacy, safety, and tolerability of vortioxetine in MDD patients with high levels of anxiety (baseline Hamilton Anxiety Rating Scale [HAM-A] total score ≥20). METHODS: Efficacy was assessed using an aggregated, study-level meta-analysis of 10 randomized, placebo-controlled, 6/8-week trials of vortioxetine 5-20mg/day in adults (18-75 years), with a study in elderly patients (≥65 years) analyzed separately. Outcome measures included mean differences from placebo in change from baseline to endpoint (Δ) in the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A total, and HAM-A subscales. Safety and tolerability were assessed by treatment-emergent adverse events (TEAEs). RESULTS: A total of 1497 (48.6%) vortioxetine-treated and 860 (49.1%) placebo-treated patients had baseline HAM-A≥20. There were significant differences from placebo in MADRS (vortioxetine 5mg/day, n=415, Δ-2.68, P=0.005; 10mg/day, n=373, Δ-3.59, P<0.001; 20mg/day, n=207, Δ-4.30, P=0.005) and HAM-A total (5mg/day, n=419, Δ-1.64, P=0.022; 10mg/day, n=373, Δ-2.04, P=0.003; 20mg/day, n=207, Δ-2.19, P=0.027). There were significantly greater improvements versus placebo on the HAM-A psychic subscale for all doses. The most common TEAEs (≥5.0%) were nausea, headache, dizziness, dry mouth, diarrhea, nasopharyngitis, constipation, and vomiting. Incidence of serious TEAEs was 1.3% (placebo) and ≤1.3% (vortioxetine, across doses). LIMITATIONS: Study heterogeneity limits this analysis. Patients with baseline HAM-A≥20 were not directly compared to baseline HAM-A<20 or total MDD population. CONCLUSIONS: Vortioxetine was efficacious in reducing depressive and anxiety symptoms in patients with MDD and high levels of anxiety.

Lack of Effect of Vortioxetine on the Pharmacokinetics and Pharmacodynamics of Ethanol, Diazepam, and Lithium.

INTRODUCTION: Because the multimodal antidepressant vortioxetine is likely to be coadministered with other central nervous system (CNS)-active drugs, potential drug-drug interactions warrant examination. OBJECTIVE: These studies evaluated whether there are pharmacokinetic and/or pharmacodynamic interactions between vortioxetine and ethanol, diazepam, or lithium. METHODS: This series of phase I studies included healthy men and women (only men in the lithium study) aged 18-45 years. The ethanol study was a randomized, double-blind, two-parallel group, four-period crossover study in which subjects received a single dose of vortioxetine (20 or 40 mg) or placebo with or without ethanol, and the diazepam study was a randomized, double-blind, placebo-controlled, two-sequence, two-period crossover study in which subjects received a single dose of diazepam following multiple doses of vortioxetine 10 mg/day or placebo. These two studies evaluated the effect of coadministration on standardized psychomotor parameters and on selected pharmacokinetic parameters of each drug. The lithium study was a single-blind, single-sequence study evaluating the effect of multiple doses of vortioxetine 10 mg/day on the steady-state pharmacokinetics of lithium. RESULTS: Concomitant administration of vortioxetine and single doses of either ethanol or diazepam had no significant effect on the psychomotor performance of subjects compared with administration of ethanol or diazepam alone. Vortioxetine had no significant effect on the pharmacokinetics of ethanol, diazepam, or lithium, and ethanol had no significant effect on the pharmacokinetics of vortioxetine. CONCLUSIONS: Concomitant administration of these agents with vortioxetine was generally well tolerated, with no clinically relevant drug-drug pharmacokinetic or pharmacodynamic interactions identified.

The safety and tolerability of vortioxetine: Analysis of data from randomized placebo-controlled trials and open-label extension studies.

The safety and tolerability of vortioxetine in adults with major depressive disorder was assessed. Tolerability was based on the nature, incidence and severity of treatment-emergent adverse events (TEAEs) during acute (6/8) week treatment in 11 randomized, double-blind placebo-controlled short-term studies in major depressive disorder: six with an active reference. Symptoms following discontinuation were assessed through the Discontinuation-Emergent Signs and Symptoms checklist in three studies. Long-term (⩽52 weeks) tolerability was evaluated in five open-label extension studies. Patients (n =5701) were acutely treated with either placebo (n=1817), vortioxetine (5-20mg/day; n=3018), venlafaxine XR (225mg/day; n=113) or duloxetine (60mg/day; n=753). The withdrawal rate due to TEAEs during treatment with vortioxetine (5-20mg/day) was 4.5-7.8%, compared with placebo (3.6%), venlafaxine XR (14.2%) or duloxetine (8.8%). Common TEAEs (incidence ⩾5% and >2 × placebo) with vortioxetine (5-20mg/day) were nausea (20.9-31.2%) and vomiting (2.9-6.5%). For vortioxetine (5-20mg/day), the incidence of TEAEs associated with insomnia was 2.0-5.1% versus 4.0% for placebo, and with sexual dysfunction 1.6-1.8% versus 1.0% for placebo. Discontinuation symptoms as assessed by the mean Discontinuation-Emergent Signs and Symptoms total score after abrupt discontinuation were comparable to placebo in the first and second week. Vortioxetine had no effect relative to placebo on clinical laboratory parameters, body weight, heart rate or blood pressure. Vortioxetine showed no clinically relevant effect on ECG parameters, including the QTcF interval. In long-term treatment, no new types of TEAEs were seen; the mean weight gain was 0.7-0.8kg. Thus, vortioxetine (5-20mg/day) appears safe and generally well tolerated in the treatment of major depressive disorder.

Behavioral and neurochemical changes in mesostriatal dopaminergic regions of the rat after chronic administration of the cannabinoid receptor agonist WIN55,212-2.

BACKGROUND: The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat. METHODS: Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments. RESULTS: Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and increased D1 receptor mRNA and binding in nucleus accumbens. Furthermore, both dopamine receptor and transporter binding and mRNA levels were decreased in substantia nigra. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and substantia nigra. CONCLUSIONS: Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region-, dose-, and neurotransmitter-selective manner.

Ropinirole regulates emotionality and neuronal activity markers in the limbic forebrain.

Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D3/D2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D3/D2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety- and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic- and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1-10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D3/D2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions.

Effects of lithium and aripiprazole on brain stimulation reward and neuroplasticity markers in the limbic forebrain.

Bipolar disorder (BD) is a severe pathological condition with impaired reward-related processing. The present study was designed to assess the effects of two commonly used BD medications, the mood stabilizer lithium chloride (LiCl) and the atypical antipsychotic and antimanic agent aripiprazole, in an animal model of reward and motivation and on markers of neuroplasticity in the limbic forebrain in rats. We utilized intracranial self-simulation (ICSS) to assess the effects of acute and chronic administration of LiCl and aripiprazole on brain stimulation reward, and phosphorylation studies to determine their effects on specific cellular neuroplasticity markers, i.e., the phosphorylation of CREB and crucial phosphorylation sites on the GluA1 subunit of AMPA receptors and the NA1 and NA2B subunits of NMDA receptors, in the limbic forebrain. Chronic LiCl induced tolerance to the anhedonic effect of the drug observed after acute administration, while chronic aripiprazole induced a sustained anhedonic effect. These distinct behavioral responses might be related to differences in molecular markers of neuroplasticity. Accordingly, we demonstrated that chronic LiCl, but not aripiprazole, decreased phosphorylation of CREB at the Ser133 site and NA1 at the Ser896 site in the prefrontal cortex and GluA1 at the Ser831 site and NA2B at the Ser1303 site in the ventral striatum. The present study provides evidence for BD medication-evoked changes in reward and motivation processes and in specific markers of neuronal plasticity in the limbic forebrain, promoting the notion that these drugs may blunt dysregulated reward processes in BD by counteracting neuronal plasticity deficits.

Effect of Vortioxetine on Cardiac Repolarization in Healthy Adult Male Subjects: Results of a Thorough QT/QTc Study.

This double-blind, randomized, placebo- and positive-controlled, parallel-group study evaluated the effect of vortioxetine (Lu AA21004), an investigational multimodal antidepressant, on QT interval in accordance with current guidelines of the International Conference on Harmonisation (ICH-E14). A total of 340 healthy men were randomized to receive 1 of 4 treatments for 14 days: (1) vortioxetine 10 mg once daily (QD), (2) vortioxetine 40 mg QD, (3) placebo QD, or (4) placebo QD on Days 1 through 13 followed by a single dose of moxifloxacin 400 mg (positive control). The primary endpoint was the largest time-matched, baseline-adjusted least-squares (LS) mean difference for the individual-corrected QT interval (QTcNi [linear]) between vortioxetine and placebo. Alternative QT correction formulas (i.e., Fredericia [QTcF], Bazett [QTcB], Framingham [QTcFm], and QTcNi [nonlinear]) were used as secondary endpoints. The upper bound of the 2-sided 90% confidence interval around the LS mean difference from placebo for baseline-adjusted QTcNi (linear), QTcF, QTcB, QTcFm, and QTcNi (nonlinear) did not exceed 10 ms at any time point after multiple doses of vortioxetine 10 mg (therapeutic) or 40 mg (supratherapeutic). Overall, the study results indicate that vortioxetine is unlikely to affect cardiac repolarization in healthy subjects.

Modulation of neurotransmitter release in orexin/hypocretin-2 receptor knockout mice: a microdialysis study.

Orexinergic neurons are discretely localized within the lateral hypothalamus and have widespread projections to the whole brain. Here, the role of orexin/hypocretin-2 receptors (OX2) in modulating extracellular concentrations of neurotransmitters was evaluated in the hypothalamus and the prefrontal cortex (PFC) of OX2 knockout (KO) mice by using a microdialysis technique. In the hypothalamus, basal concentrations of norephinephrine (NE), acetylcholine (ACh), and histamine (Hist) were significantly higher in KO mice, whereas KCl perfusion (147 mM) resulted in significantly lesser increases in NE, ACh, and Hist release in KO compared with wild-type (WT) mice. No differences in basal concentrations or evoked release of serotonin (5-HT) or dopamine (DA) were found in the hypothalamus between genotypes. In the PFC, no differences in the basal concentrations of the studied neurotransmitters were found between genotypes. After KCl perfusion, significantly higher increases in NE, 5-HT, and DA release were found in KO compared with WT mice. No differences in the evoked release of ACh and Hist in the PFC were found between genotypes. The present results demonstrate that genetic deletion of OX2 receptors differentially modulates extracellular concentrations of distinct neurotransmitters in the somatodendritic region vs. a nerve terminal region of the orexinergic neurons. In the hypothalamus, an inhibitory role of the OX2 receptors in modulating basal concentrations of NE, ACh, and Hist was revealed, which probably accounts for the reduced responsiveness to KCl as well. In the PFC, the evoked release of the monoamines NE, 5-HT, and DA seems to be controlled negatively by OX2 receptors.

Effects of olanzapine on extracellular concentrations and tissue content of neurotensin in rat brain regions.

We have previously shown that both the psychostimulant d-amphetamine and the antipsychotics haloperidol and risperidone affect extracellular concentrations and tissue content of neurotensin (NT) in distinct brain regions. This study investigated the effects of acute olanzapine (1, 5mg/kg, s.c.) on extracellular NT-like immunoreactivity (-LI) concentrations in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC), and the effects of acute d-amphetamine (1.5mg/kg, s.c.) on extracellular NT-LI in these brain regions after a 30-day olanzapine (15mg/kg, p.o.) administration in rats. The effects of a 30-day olanzapine (3, 15mg/kg, p.o.) administration and d-amphetamine (1.5mg/kg, s.c.) coadministration during either the last day (acute) or the last 8days (chronic) on NT-LI tissue content in distinct rat brain regions were also studied. Acute olanzapine increased extracellular NT-LI, in both the vSTR and the mPFC. Chronic olanzapine increased and decreased basal extracellular NT-LI in the vSTR and the mPFC, respectively, and abolished the stimulatory effects of acute d-amphetamine on extracellular NT-LI in these brain regions. Chronic olanzapine as well as acute and chronic d-amphetamine affected NT-LI tissue content in a brain region-dependent manner. Chronic olanzapine prevented the effects of acute and chronic d-amphetamine on NT-LI tissue content in certain brain regions. The fact that olanzapine and d-amphetamine affected extracellular NT-LI in the vSTR and mPFC as well as NT-LI tissue content in distinct brain regions further supports the notion that NT plays a role in the therapeutic actions of antipsychotic drugs and possibly also in the pathophysiology of schizophrenia.

Chronic WIN55,212-2 elicits sustained and conditioned increases in intracranial self-stimulation thresholds in the rat.

The present study sought to examine whether repeated administration of the CB(1) receptor agonist WIN55,212-2 affected intracranial self-stimulation (ICSS) behavior and induced phenomena of tolerance or sensitization, similar to typical addictive drugs. Rats received intraperitoneal injections of vehicle for 5 days, vehicle or WIN55,212-2 (0.1, 0.3 or 1mg/kg) for 20 subsequent days, and vehicle for 5 additional days. Thresholds for ICSS were measured before and after each injection. The initial five injections of vehicle did not affect ICSS thresholds. WIN55,212-2 (1mg/kg) significantly increased ICSS thresholds from the first day of administration, an effect that remained stable across the subsequent days of administration. During the 5 additional days, where WIN55,212-2 was substituted with vehicle, rats demonstrated a conditioned increase in postinjection thresholds that was significant the first 3 days of this period. These findings indicate that repeated WIN55,212-2 administration elicited a sustained increase in ICSS, i.e., phenomena of tolerance or sensitization were not observed. The present data demonstrate cannabinoid-predictive stimuli that may gain affective salience and play an important role in maintaining cannabinoid administration.

Efficacy of the atypical antipsychotic aripiprazole in d-amphetamine-based preclinical models of mania.

The atypical antipsychotic aripiprazole has been demonstrated to reduce symptoms of bipolar mania. To further profile the antimanic-like properties of aripiprazole in relevant preclinical models, we examined its efficacy in d-amphetamine-based behavioural models of acute mania in rats. The effects of acute and repeated administration of aripiprazole were assessed in the facilitation of intracranial self-stimulation (ICSS) and hyperlocomotion after acute d-amphetamine, and in the sensitized facilitation of ICSS function and hyperlocomotion after repeated d-amphetamine. Acutely, aripiprazole (0.75, 1.5 and 2.5 mg/kg i.p.) increased ICSS thresholds, attenuated the reward-facilitating effects of d-amphetamine (0.5 mg/kg i.p.), decreased motor activity and prevented d-amphetamine-induced hyperlocomotion. Co-administration of aripiprazole and d-amphetamine for 7 d resulted in aripiprazole counteracting the d-amphetamine-induced sensitization in facilitation of brain reward function and hyperlocomotion. These results indicate the efficacy of aripiprazole in d-amphetamine-based preclinical models of acute mania that are characterized by increased motivational drive and/or hyperfunction of brain reward.

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain.

This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.