White Matter Deficits Assessed by Diffusion Tensor Imaging and Cognitive Dysfunction in Psychostimulant Users With Comorbid Human Immunodeficiency Virus Infection

Background Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function. Methods Twenty-one subjects (mean age 37.5 ± 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 ± 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health. Results The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests. Conclusions White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required

A comparison of the metabolic side-effects of the second-generation antipsychotic drugs risperidone and paliperidone in animal models.

BackgroundThe second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals.MethodsAdult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp.ResultsFasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance.ConclusionsIn preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose

Metabolic side-effects of the novel second-generation antipsychotic drugs asenapine and iloperidone: a comparison with olanzapine.

The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist

An evaluation of the effects of the novel antipsychotic drug lurasidone on glucose tolerance and insulin resistance: a comparison with olanzapine.

Over the past two decades, there has been a notable rise in the use of antipsychotic drugs, as they are used to treat an increasing number of neuropsychiatric disorders. This rise has been led predominantly by greater use of the second generation antipsychotic (SGA) drugs, which have a low incidence of neurological side-effects. However, many SGAs cause metabolic dysregulation, including glucose intolerance and insulin resistance, thus increasing the risk of cardiometabolic disorders. The metabolic effects of the novel SGA lurasidone, which was approved by the Food and Drug Administration in 2010, remain largely unknown. As rodent models accurately predict the metabolic effects of SGAs in humans, the aim of the present study was to use sophisticated animal models of glucose tolerance and insulin resistance to measure the metabolic effects of lurasidone. In parallel, we compared the SGA olanzapine, which has established metabolic effects. Adult female rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (10.0 mg/kg, s.c.) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (1.5 and 15 mg/kg, s.c.) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC). Compared to vehicle treated animals, lurasidone caused mild glucose intolerance in the GTT with a single dose, but there was no effect on insulin resistance in the GTT, measured by HOMA-IR. The HIEC also confirmed no effect of lurasidone on insulin resistance. In contrast, olanzapine demonstrated dose-dependent and potent glucose intolerance, and insulin resistance in both tests. Thus, in preclinical models, lurasidone demonstrates mild metabolic liability compared to existing SGAs such as olanzapine. However, confirmation of these effects in humans with equivalent tests should be confirmed

Acute effects of the antipsychotic drug asenapine on glucose levels in adult female rats.

<p>(<b>A</b>) Animals (n = 8–10 per group) received a single injection of vehicle or asenapine (0.01, 0.05, 0.1, 0.5, 1 mg/kg, s.c). Glucose levels were recorded prior to drug treatment in overnight-fasted rats at Time 0, and then 30 minutes following drug administration (<i>x-axis</i>). Immediately following this glucose measurement, all rats were subjected to a glucose tolerance test by receiving an intraperitoneal challenge injection of 1 mg/ml/kg of glucose, and blood glucose levels were measured every 15 minutes for the next two hours. Total cumulative glucose levels for each treatment group are summed as the “area under the curve” during the glucose tolerance test by graph inset (<i>top right</i>). Values represent group means ± SEM. (<b>B</b>) A separate cohort of animals (n = 6–8 per group) were fasted overnight and subjected to the hyperinsulinemic-euglycemic clamp. After animals reached euglycemia (three consecutive blood glucose readings of 6.0±0.4 mmol/L), rats were treated with vehicle, low (0.1 mg/kg) or high dose (1.0 mg/kg) asenapine (arrow at t = 0 min). Glucose levels were recorded every 10 minutes and the glucose infusion rate was adjusted as needed. Glucose infusion rates for each treatment group are presented as change in glucose infusion rate from euglycemia. Values represent group means ± SEM.</p

Mean concentration of fasting glucose, insulin and HOMA-IR scores in antipsychotic drug treated rats.

<p>I₀ = fasting insulin levels (µU/ml); G₀ =  fasting glucose levels (mmol/L); HOMA-IR = homeostasis model assessment of insulin resistance (µU⋅mmol)/(ml⋅L).</p><p>Rats were treated with five separate doses of asenapine, iloperidone, olanzapine or vehicle. Values represented as means ± SEM at t = 30 min during the IGTT.</p>*<p>indicates different from vehicle-treated animals, p<0.05.</p

Acute effects of the SGA drugs lurasidone and olanzapine on glucose levels in adult female rats in the glucose tolerance test.

<p>Animals (n = 8 per group) received a single injection of vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c) or olanzapine (10 mg/kg, s.c.) in a volume 1 ml/kg. Glucose levels were recorded prior to drug treatment in overnight-fasted rats at Time 0, and then 30 minutes following drug administration (<i>x-axis</i>). Immediately following this glucose measurement, all rats were subjected to a glucose tolerance test by receiving an intraperitoneal challenge injection of 1 g/ml/kg of glucose, and blood glucose levels were measured every 15 minutes for the next two hours. Total cumulative glucose levels for each treatment group are summed as the “area under the curve” during the glucose tolerance test by graph inset (<i>top right</i>). Values represent group means ± SEM; *indicates different from vehicle-treated animals, p<0.01; **indicates different from vehicle-treated animals, p<0.001.</p

Acute effects of the SGA drugs lurasidone and olanzapine in adult female rats in the hyperinsulinemic-euglycemic clamp.

<p>Animals (n = 6–10 per group) were fasted overnight and subjected to the hyperinsulinemic-euglycemic clamp. After animals reached euglycemia (three consecutive blood glucose readings of 6.0±0.4 mmol/L), rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c) or olanzapine (1.5 or 15 mg/kg, s.c.) in a volume 1 ml/kg. Glucose levels were recorded every 10 minutes and the glucose infusion rate was adjusted as needed. Glucose infusion rates for each treatment group are presented as change in glucose infusion rate from euglycemia. Values represent group means ± SEM. *indicates different from vehicle-treated animals, p<0.05; **indicates different from vehicle-treated animals, p<0.01.</p

Experimental protocol.

<p>Describing (<b>A</b>) the intraperitoneal glucose tolerance test and (<b>B</b>) the hyperinsulinemic-euglycemic clamp with acute antipsychotic drug treatment.</p