Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active psoriatic arthritis (EQUATOR): results from a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis. METHODS: The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670. FINDINGS: Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p<0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group. INTERPRETATION: Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified. FUNDING: Galapagos and Gilead Sciences.

Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis. METHODS: In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs. Patients were randomly assigned (1:1) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks. Randomisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy. The patients, study team, and study sponsor were masked to treatment assignment. The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12, which was assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug). Safety was assessed according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT03117270. FINDINGS: Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n=58) or placebo (n=58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was -1·47 (SD 1·04) in the filgotinib group and -0·57 (0·82) in the placebo group, with a least squares mean difference between groups of -0·85 (95% CI -1·17 to -0·53; p<0·0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study. INTERPRETATION: Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs. Further investigation of filgotinib for ankylosing spondylitis is warranted. FUNDING: Galapagos and Gilead Sciences.

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

ABT-089, an α4ß2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

R2 and R2* are equally effective in evaluating chronic response to iron chelation.

MRI relaxometry (R2, R2*) has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation, but there have been no longitudinal studies comparing R2 and R2* techniques. We use R2 and R2* liver iron concentration (LIC) estimates, transfusional iron burdens, and drug compliance data to calculate iron chelation efficiency (ICE) in patients undergoing a Phase II trial of SPD602. Fifty-one patients underwent a baseline examination, 39 patients completed 1 year, and 26 patients completed 2 years. Baseline LICR2 and LICR2* estimates were unbiased, but had limits of agreement exceeding 50%, suggesting that these techniques cannot be interchanged with one another in the same patient. However, ICE estimates across the two techniques compared more favorably, with r(2) values reaching 0.89 at 2 years. 95 confidence intervals for efficiency estimates were 0.0 ± 4.1%. These data indicate that clinical trial and clinical effectiveness data calculated using LICR2 and LICR2* estimates can be compared to one another, even though LIC estimates may be disparate on cross-sectional analysis. While the choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, one can have confidence comparing conclusions on clinical effectiveness.

AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials.

Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinson's disease patients with levodopa-induced dyskinesia. Two randomized, double-blind, placebo-controlled, parallel-group, in-patient studies for Parkinson's disease patients with moderate to severe levodopa-induced dyskinesia (study 1) and severe levodopa-induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25-150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4-day down-titration. Primary outcomes were the Lang-Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinson's Disease Rating Scale-part III (both studies). Secondary outcomes included the Unified Parkinson's Disease Rating Scale-part IV items 32-33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056-treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang-Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinson's Disease Rating Scale-part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056-treated patients in study 1, and 3 patients (2 AFQ056-treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy. © 2011 Movement Disorder Society.

A double-blind, randomized, placebo-controlled study of the dopamine D3 receptor antagonist ABT-925 in patients with acute schizophrenia.

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D3 receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D3 receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D3 versus D2 receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D3 receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.

Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925.

Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

Safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches: results of an open-label extension trial in adolescents.

OBJECTIVE: To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents. BACKGROUND: Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data. METHODS: This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries. RESULTS: A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial. CONCLUSIONS: In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.

Divalproex sodium extended-release for the prophylaxis of migraine headache in adolescents: results of a stand-alone, long-term open-label safety study.

OBJECTIVE: The objective of this long-term open-label study in adolescents was to assess the safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches. BACKGROUND: Two formulations of divalproex sodium have demonstrated efficacy in the prevention of migraine headaches in adults. However, no medications are currently approved for this indication in adolescents, and long-term safety data on agents for migraine prevention are lacking for this younger population. Therefore, the current study was conducted to assess the long-term safety and tolerability of divalproex extended-release in adolescents with migraine headaches. METHODS: This was a 12-month, phase 3, open-label, multicenter study of adolescents aged 12 to 17 years with migraine headaches diagnosed by International Headache Society criteria. Divalproex sodium extended-release was initiated at 500 mg/day for 15 days then increased to 1000 mg daily, with subsequent adjustments permitted within a dosing range of 250-1000 mg daily. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety was evaluated by adverse event collection, laboratory assessments, physical and neurological examinations, vital signs, electrocardiograms, the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, the Wechsler Abbreviated Scale of Intelligence, and the Behavioral Assessment Scale for Children. Efficacy was evaluated by following the number of migraine headache days reported in subjects' headache diaries over sequential 4-week intervals for the duration of the trial. RESULTS: A total of 241 subjects were enrolled and treated. The most frequently reported adverse events were nausea (19%), vomiting (18%), weight gain (12%), nasopharyngitis (11%), migraine (10%), and upper respiratory tract infection (10%). Ten (4%) subjects experienced serious adverse events, and 40 (17%) subjects discontinued because of an adverse event. Increases in ammonia levels were observed. No other clinically significant changes were observed in laboratory values, vital signs, rating scales, or electrocardiograms. Median 4-week migraine headache days decreased 75% between the first and the fourth months of the study (from 4.0 to 1.0) and remained at or below this level for the remainder of the study. CONCLUSIONS: In this long-term open-label study of adolescents with migraine, the safety and tolerability profile of divalproex sodium extended-release was consistent with findings from previous trials in adults, as well as 2 studies recently completed in adolescents. In general, divalproex sodium extended-release was well-tolerated in adolescents with migraine.

Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2).

Introduction: While current standard of care (SOC) for idiopathic pulmonary fibrosis (IPF) slows disease progression, prognosis remains poor. Therefore, an unmet need exists for novel, well-tolerated agents that reduce lung function decline and improve quality of life. Here we report the design of two phase III studies of the novel IPF therapy, GLPG1690. Methods and analysis: Two identically designed, phase III, international, randomised, double-blind, placebo-controlled, parallel-group, multicentre studies (ISABELA 1 and 2) were initiated in November 2018. It is planned that, in each study, 750 subjects with IPF will be randomised 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or placebo, once daily, on top of local SOC, for at least 52 weeks. The primary endpoint is rate of decline of forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are week 52 composite endpoint of disease progression or all-cause mortality (defined as composite endpoint of first occurrence of ≥10% absolute decline in per cent predicted FVC or all-cause mortality at week 52); time to first respiratory-related hospitalisation until end of study; and week 52 change from baseline in the St George's Respiratory Questionnaire total score (a quality-of-life measure). Ethics and dissemination: Studies will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. Trial registration numbers: NCT03711162; NCT03733444.

Decreased hippocampal volume on MRI is associated with increased extracellular glutamate in epilepsy patients.

PURPOSE: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients. METHODS: We used quantitative MRI volumetrics to measure the hippocampal volume and zero-flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication-resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined. RESULTS: Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R(2)= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 microM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels. CONCLUSIONS: We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.

Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in adolescents. BACKGROUND: Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability. METHODS: This was a 12-week, phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1:1:1:1 ratio to receive divalproex sodium extended-release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4-week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone-binding globulin levels were collected for postmenarchal females. RESULTS: There was no statistically significant treatment difference between any divalproex sodium extended-release dose group and placebo for the primary efficacy variable, reduction from baseline in 4-week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose-related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose-related increase in sex hormone-binding globulin was observed. CONCLUSIONS: In the current study, divalproex sodium extended-release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well-tolerated in adolescents aged 12 to 17 years.

Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.

BACKGROUND: In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition. OBJECTIVES: To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals. DESIGN: Placebo-controlled, randomized, double-blind psychopharmacologic trial. SETTING AND PARTICIPANTS: Forty-one healthy individuals recruited from the community who completed up to 4 test days. MAIN OUTCOME MEASURES: On each test day, participants received amphetamine (a 1-minute infusion of amphetamine sulfate, 0.25 mg/kg, or saline) and ketamine (a 1-minute intravenous infusion of ketamine, 0.23 mg/kg, followed by a 1-hour infusion of 0.5 mg/kg or an identical saline bolus and infusion). The order of amphetamine and ketamine infusions was randomized. RESULTS: At the doses studied, ketamine and amphetamine produced positive symptoms and euphoria. However, perceptual changes were produced only by ketamine, and hostility, grandiosity, and somatic concern were stimulated only by amphetamine. Amphetamine and ketamine produced conceptual disorganization, but only ketamine produced concrete ideation and unusual mannerisms. Ketamine produced negative symptoms and disrupted delayed recall. Ketamine and amphetamine showed 3 types of interactive effects: (1) amphetamine attenuated the impairment of working memory produced by ketamine; (2) amphetamine and ketamine had additive effects on thought disorder, arousal, and euphoria; and (3) amphetamine and ketamine had less-than-additive effects on psychosis. CONCLUSIONS: These findings implicate N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. However, glutamate and dopamine may differentially contribute to psychosis, thought disorder, and euphoria. Regarding medication development for cognitive dysfunction, the pattern of the interactive effects of ketamine and amphetamine is consistent with the hypothesis that facilitation of prefrontal cortical dopamine levels would attenuate some cognitive impairments associated with deficits in N-methyl-D-aspartate receptor function.

Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.

BACKGROUND: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. METHODS: In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. RESULTS: Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. CONCLUSIONS: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.

RATIONALE: Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. OBJECTIVE: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. METHODS: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. RESULTS: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. CONCLUSIONS: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine.

RATIONALE: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. OBJECTIVES: The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. METHODS: Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. RESULTS: After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. CONCLUSIONS: The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.

Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results.

PURPOSE: Liver biopsy was long considered the reference standard for measuring liver iron concentration. However, its high sampling variability and invasive nature make it poorly suited for serial analyses. To demonstrate the fallibility of liver biopsy, we use serial estimates of iron chelation efficiency (ICE) calculated by R2 and R2* MRI liver iron concentration (LIC) estimates as well as by simulated liver biopsy (over all physically reasonable sampling variability) to compare the robustness of these three techniques. MATERIALS AND METHODS: R2, R2*, transfusional volume, and chelator compliance were obtained from 49 participants in a phase II clinical trial of deferitazole over two years. Liver biopsy LIC results were simulated using sampling errors of 0%, 10%, 20%, 30%, 40% and iron assay variability of 12%. LIC estimates by R2, R2*, and simulated biopsy were used to calculate ICE over time. Bland-Altman limits of agreement were compared across observation intervals of 12, 24, and 48 weeks. RESULTS: At 48 week intervals, LIC estimates by R2, R2* and "perfect" liver biopsy had comparable accuracy in predicting ICE; both MRI methods were superior to any physically realizable liver biopsy (sampling error 10% or higher). LIC by R2* demonstrated the most robust ICE estimates at monitoring intervals of 24 and 12 weeks, but this difference did not remain significant at 48 week intervals. CONCLUSION: MRI relaxometry is superior to liver biopsy for serial LIC observations, such as used in the care of tranfusional siderosis patients, and should also be considered the new standard of LIC determination for regulatory purposes. Among relaxometry techniques, LIC estimates by R2* are more robust for tracking changes in iron balance over intermediate time scales (<=24 weeks).

Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia.

Brain levels of glucose and lactate in the extracellular fluid (ECF), which reflects the environment to which neurons are exposed, have never been studied in humans under conditions of varying glycemia. The authors used intracerebral microdialysis in conscious human subjects undergoing electrophysiologic evaluation for medically intractable epilepsy and measured ECF levels of glucose and lactate under basal conditions and during a hyperglycemia-hypoglycemia clamp study. Only measurements from nonepileptogenic areas were included. Under basal conditions, the authors found the metabolic milieu in the brain to be strikingly different from that in the circulation. In contrast to plasma, lactate levels in brain ECF were threefold higher than glucose. Results from complementary studies in rats were consistent with the human data. During the hyperglycemia-hypoglycemia clamp study the relationship between plasma and brain ECF levels of glucose remained similar, but changes in brain ECF glucose lagged approximately 30 minutes behind changes in plasma. The data demonstrate that the brain is exposed to substantially lower levels of glucose and higher levels of lactate than those in plasma; moreover, the brain appears to be a site of significant anaerobic glycolysis, raising the possibility that glucose-derived lactate is an important fuel for the brain.

Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms.

RATIONALE: Serotonin-2 (5-HT(2)) receptor antagonism has been hypothesized to have antipsychotic activity. However, there has been limited evidence directly linking 5-HT(2) receptor antagonism to symptom control in schizophrenic patients. OBJECTIVES: In order to test this hypothesis this study evaluated the capacity of pretreatment with the 5-HT(2) receptor antagonist ritanserin to attenuate the effects of the 5-HT agonist, m-chlorophenylpiperazine (mCPP). METHODS: Twenty-two male inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder completed 4 test days during which 10 mg ritanserin or matched placebo was administered orally 50 min prior to the intravenous infusion of 0.1 mg/kg mCPP or saline. The test days were conducted in a randomized order under double-blind conditions. RESULTS: mCPP mildly and transiently increased positive symptoms and behavioral activation but not negative symptoms, as assessed by the Brief Psychiatric Rating Scale. mCPP also raised plasma prolactin and cortisol levels. All of these effects were attenuated by ritanserin pretreatment. CONCLUSIONS: These data support a contribution of 5-HT(2) receptor stimulation to symptom exacerbation in schizophrenic patients and a role for 5-HT(2) receptor antagonism in the prevention of this effect.

A randomized, double-blind, placebo-controlled phase 2 study of α4ß2 agonist ABT-894 in adults with ADHD.

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4ß2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4ß2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.