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Rationale: Allopregnanolone (ALLO) is an endogenous neuroactive steroid thought to alter the reinforcement value of alcohol (ethanol) due to its actions as a positive modulator of the GABAA receptor (GABAAR). Extrasynaptic GABAARs may be a particularly sensitive target of ethanol and neuroactive steroids. Previous work showed that systemic injections of an ALLO analog, ganaxolone (GAN), or an extrasynaptic GABAAR agonist (gaboxadol; THIP) decreased ethanol intake in male mice with limited access to ethanol., Objectives: The present studies tested whether activation of GABAARs in the nucleus accumbens (NAc) shell by GAN or THIP was sufficient to reduce ethanol intake. C57BL/6J male mice had 2-h access to 10 % ethanol (10E) and water, and 10E intake was measured following site-specific infusions of GAN or THIP., Results: Decreases in limited-access 10E consumption were observed following site-specific bilateral infusions of either drug into the NAc shell. Significant changes in intake were absent when the drugs were infused in a region dorsal to the target site (GAN) or into the lateral ventricle (THIP). Locomotor data confirmed that the decreases in intake were not due to a sedative effect of the drugs., Conclusions: These data demonstrate the sufficiency of GABAAR activation by a positive allosteric modulator or an agonist with selectivity for extrasynaptic GABAARs to decrease ethanol consumption in mice. Importantly, more refined GABAAR-active targets that decrease ethanol intake may enhance our understanding and ability to treat alcohol use disorders.

Objective: To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism., Methods: Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B)., Results: Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR., Conclusion: This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Rationale: Treatment studies for the management of pediatric bipolar disorder are limited., Objectives: This study evaluates the safety and efficacy of paliperidone monotherapy as an acute treatment of mania and related symptoms in youth with bipolar spectrum disorders., Methods: An 8-week, prospective, open-label paliperidone monotherapy trial to assess effectiveness and tolerability in treating pediatric bipolar spectrum and related disorders (depression, psychosis, attention-deficit/hyperactivity disorder [ADHD]). Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impression scale (CGI), Children's Depression Rating Scale-Revised (CDRS-R), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis., Results: Fifteen youth with bipolar spectrum disorders (YMRS at entry: 32.8 ± 6.1) were enrolled in the study and 11 (73 %) completed the 8-week trial. The total daily dose of paliperidone at study endpoint was 3 mg in 12 subjects and 6 mg in three subjects. Treatment with paliperidone was associated with statistically significant levels of improvement in mean YMRS scores (-18.7 ± 13.9, p < 0.001) at endpoint. Paliperidone treatment also resulted in significant improvement in the severity of ADHD and psychotic symptoms. Although treatment with paliperidone was generally well tolerated and was not associated with clinically significant change in cardiovascular or metabolic parameters, increases in body weight (4.1 ± 5.5 lb) were substantial., Conclusions: Open-label paliperidone treatment appears to be beneficial in the treatment of bipolar spectrum disorders and associated conditions in youth. Future placebo-controlled studies are warranted to confirm these findings.

Rationale: Individuals with autistic disorder (autism) frequently exhibit significant irritability marked by severe tantrums, aggression, and self-injury. Despite advances in the treatment of this symptom domain in autism, there remains an ongoing need for more effective and better tolerated pharmacotherapies., Objectives: The aim of this study is to determine the effectiveness and tolerability of paliperidone for irritability in autism., Methods: This is a prospective, 8-week open-label study of paliperidone in 25 adolescents and young adults with autism. Primary outcome measures included the Clinical Global Impressions-Improvement (CGI-I) Scale and the Irritability subscale of the Aberrant Behavior Checklist (ABC-I). Concomitant medications (except antipsychotics) were permitted if dosages were stable for ≥2 months., Results: Twenty-one (84 %) of 25 subjects ages 12-21 years (mean 15.3 years) responded to paliperidone, based on a CGI-I Scale score of 1 or 2 (very much or much improved) and ≥25 % improvement on the ABC-I. The mean final dosage of paliperidone was 7.1 mg/day (range 3-12 mg/day). Two subjects discontinued paliperidone prior to study completion (moderate sedation, n = 1; nonresponse, n = 1). Mild-to-moderate extrapyramidal symptoms were recorded in four subjects. A mean weight gain of 2.2 ± 2.6 kg (range -3.6 to +7.9 kg) was recorded. Mean age- and sex-normed body mass index increased from 23.6 to 24.2 (p ≤ 0.001). Mean serum prolactin increased from 5.3 to 41.4 ng/mL (p ≤ 0.0001)., Conclusions: Paliperidone treatment was associated with significant improvement in irritability and was generally well tolerated. Larger scale, placebo-controlled studies are needed to elucidate the efficacy and tolerability of paliperidone in this population.

Rationale: Atypical antipsychotics are commonly prescribed to clinically referred youngsters for treatment of heightened aggressive behavior associated with various psychiatric disorders. Previously, we demonstrated risperidone's anti-aggressive effects using a well-validated animal model of offensive aggression. Paliperidone, the main active metabolite of risperidone, is a potent serotonin-2A and dopamine-2 receptor antagonist with slightly different pharmacodynamic properties compared to risperidone. Given that much of risperidone's therapeutic efficacy is due to its active metabolite, paliperidone may effectively suppress aggression with fewer adverse side effects., Objectives: Investigate whether paliperidone administration would reduce heightened aggressive behavior induced by low-dose cocaine exposure in a developmentally sensitive model of offensive aggression., Materials and Methods: Male Syrian hamsters (n = 12/group) were administered an acute dose of paliperidone (0.05, 0.1, 0.2, and 0.3 mg/kg) and then tested for aggressive behavior using the resident-intruder paradigm. To investigate the effects of chronic paliperidone administration, a separate set of animals (n = 12/group) was exposed to repeated paliperidone administration (0.1 mg kg(-1) day(-1)) during different developmental periods and varying lengths of time (1-4 weeks)., Results: Experiment 1 results revealed a dose-dependent decrease in bite and attack behaviors with an effective dose observed at 0.1 mg/kg. In Experiment 2, the maximal reduction in aggressive behavior in response to chronic paliperidone treatment was observed in animals treated during the third week of adolescence, and this reduction occurred without concomitant alterations in non-aggressive behaviors., Conclusions: These results support the specific aggression-suppressing properties of paliperidone and the potential use of this compound in the treatment of maladaptive aggression in clinical settings.

Rationale: Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects., Objectives: In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose., Materials and Methods: Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated., Results: The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex., Conclusions: The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.

Rationale: Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)2 antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites., Objectives: The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone., Materials and Methods: Risperidone and paliperidone were administered to Sprague-Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology., Results: Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT(1A) receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone., Conclusion: These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.

Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific distribution of RSP and 9-OH-RSP in various brain regions was also studied after administration of 6 mg/kg per day oral dose for 15 days. After RSP treatment, concentrations of 9-OH-RSP were higher than those of RSP in plasma and tissues except in brain, where both compounds were present in nearly equal concentrations. Similarly, after 9-OH-RSP treatment, levels of 9-OH-RSP were higher than levels of either RSP or 9-OH-RSP or the sum of RSP and 9-OH-RSP levels measured after treatment with RSP. There was a moderate relationship between RSP dose and tissue levels of RSP and 9-OH-RSP (all rs > or = 0.62, P < 0.01), except in fat. There was also a strong relationship between the dose and tissue levels of 9-OH-RSP (all rs > or = 0.68, P < 0.005). A significant relationship was found between plasma levels of RSP and brain levels of RSP and 9-OH-RSP (all rs > or = 0.57, P < 0.03) after treatment with RSP. After 9-OH-RSP treatment, a much stronger relationship was observed between plasma and brain 9-OH-RSP levels (rs > or = 0.90, P < 0.005). The plasma concentrations of RSP and 9-OH-RSP appear to reflect their concentrations in brain. The tissue-to-plasma ratios of RSP and 9-OH-RSP were relatively low compared to other antipsychotics. In liver, kidney and lung the tissue to plasma ratio for RSP and 9-OH-RSP after treating with RSP ranged from 0.85 to 3.4. The brain to plasma ratio for RSP and 9-OH-RSP was several-fold lower than that in peripheral tissues. After RSP administration, the mean brain to plasma level ratio for RSP was 0.22, and for 9-OH-RSP to it was 0.04. The brain to plasma ratio of 9-OH-RSP after giving 9-OH-RSP was similarly low (0.04). The low brain/plasma ratio of high potency RSP and 9-OH-RSP may in part be due to their low lipophilicity, log P = 3.04 and 2.32, respectively, resulting in limited non-specific accumulation in brain tissue.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action. The absorption, plasma levels and regional brain distribution of risperidone, metabolically formed 9-hydroxy-risperidone and total radioactivity were studied in the male Wistar rat after single subcutaneous administration of radiolabelled risperidone at 0.02 mg/kg. Concentrations were determined by HPLC separation, and off-line determination of the radioactivity with liquid scintillation counting. Risperidone was well absorbed. Maximum plasma concentrations were reached at 0.5-1 h after subcutaneous administration. Plasma concentrations of 9-hydroxy-risperidone were higher than those of risperidone from 2h after dosing. In plasma, the apparent elimination half-life of risperidone was 1.0 h, and mean residence times were 1.5 h for risperidone and 2.5 h for its 9-hydroxy metabolite. Plasma levels of the radioactivity increased dose proportionally between 0.02 and 1.3 mg/kg. Risperidone was rapidly distributed to brain tissues. The elimination of the radioactivity from the frontal cortex and striatum--brain regions with high concentrations of 5-HT2 or dopamine-D2 receptors--became more gradual with decreasing dose levels. After a subcutaneous dose of 0.02 mg/kg, the ED50 for central 5-HT2 antagonism in male rats, half-lives in frontal cortex and striatum were 3-4 h for risperidone, whereas mean residence times were 4-6 h for risperidone and about 12 h for 9-hydroxy-risperidone. These half-lives and mean residence times were 3-5 times longer than in plasma and in cerebellum, a region with very low concentrations of 5-HT2 and D2 receptors. Frontal cortex and striatum to plasma concentration ratios increased during the experiment. The distribution of 9-hydroxy-risperidone to the different brain regions, including frontal cortex and striatum, was more limited than that of risperidone itself. This indicated that 9-hydroxy-risperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted from plasma levels. AUCs of both active compounds in frontal cortex and striatum were 10-18 times higher than those in cerebellum. No retention of metabolites other than 9-hydroxy-risperidone was observed in any of the brain regions investigated.

The behavioral effects of the GABA-related drugs SL 75102 (4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino]butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the fixed-interval schedule. Neither SL 75102 (1.0-30.0 mg/kg) nor THIP (0.1-3.0 mg/kg) significantly altered rates of either suppressed or nonsuppressed responding, whereas lorazepam (0.01-0.3 mg/kg) produced dose-related increases in response rate under both schedules. Pretreatment with 1.0 mg/kg SL 75102 significantly enhanced the rate-increasing effects of lorazepam on suppressed responding. Pretreatment with 10.0 mg/kg SL 75102 also enhanced the rate-increasing effects of lorazepam on nonsuppressed responding. In contrast, the rate-increasing effects of lorazepam were not enhanced by pretreatment with 0.3 or 1.0 mg/kg THIP under either schedule. Moreover, pretreatment with 1.0 mg/kg THIP attenuated the rate-increasing effects of lorazepam on nonsuppressed responding. Enhancement of the behavioral effects of lorazepam by SL 75102 may reflect positive allosteric interactions between the two drugs at the benzodiazepine-GABA receptor complex.