Влияние энергетической ценности пищи на биодоступность зипрасидона и луразидона

It is interesting to note that ziprasidone and lurasidone are the only psychiatric medications with specific calorie requirements to aid absorption. The precise mechanism is still unknown. The package insert for ziprasidone recommends concomitant intake with food, which provides an up to 2-fold increase in absorption. More specifically, a clinical trial that evaluated the effects of different caloric and fat content on ziprasidone systemic exposure showed that a meal with 500 kcal or more (irrespective of fat content) is required for optimal bioavailability.

The package insert for lurasidone recommends concomitant intake with 350 kcal or more, because lurasidone Cmax and AUC are increased approximately 3- and 2-fold, respectively, compared with fasting condi-tions. (Lurasidone exposure was not affected as calorie content was increased from 350 to 1000 kcal and was independent of meal fat content.)

Food-Drug Interactions in Psychiatry: What Clinicians Need to Know

Не связанные с дофамином механизмы действия антипсихотиков

APs suppress induction of pro-inflammatory cytokines. It is well established that psychotic episodes of schizophrenia are associated with neuroinflammation and elevations of cytokines such as interleukin 1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-γ). These inflammatory biomarkers are released by microglia, which are rapidly activated by psychosis and mediate brain tissue damage during psychosis. APs’ rapid inhibitory action on pro-inflammatory cytokines obviously is neuroprotective.
APs suppress immune-inflammatory pathways. This occurs with atypical agents but not haloperidol and results in decreased IL-1β and IL-6 and transforming growth factor-β.
APs significantly decrease levels of neurotoxic tryptophan catabolites (TRYCATS) such as 3-OHK and QUIN, which mediate the immune-inflammatory effects on neuronal activity. APs also increase levels of neuroprotective TRYCATS such as kynurenic acid.
APs activate cholesterol-transport proteins such as apolipoprotein E (APOE).6 This implies that APs may improve low levels of APOE observed during psychosis and decrease myelination abnormalities and mitigate impairment of synaptic plasticity.
APs increase neurotrophic growth factors that plummet during psychosis, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor. This beneficial effect is seen with SGAs but not first-generation APs (FGAs) and is attributed to strong serotonin 5HT-2A receptor antagonism by SGAs.
SGAs but not FGAs significantly increase the number of newly divided cells in the subventricular zone by 200% to 300%. This enhancement of neurogenesis and increased production of progenitor cells that differentiate into neurons and glia may help regenerate brain tissue lost during psychotic episodes.
Various SGAs have neuroprotective effects:
Clozapine has neuroprotective effects against liposaccharide-induced neurodegeneration and reduces microglial activation by limiting production of reactive oxygen species (free radicals).
Aripiprazole inhibits glutamate-induced neurotoxicity and, in contrast to haloperidol, increases BDNF, glycogen synthase kinase (GSK)-β, and the anti-apoptotic protein Bcl-2.
Olanzapine increases BDNF, GSK-3β, and β-catenin, increases mitosis in neuronal cell culture, and protects against neuronal death in cell cultures that lack nutrients (which fluphenazine or risperidone do not).
Paliperidone demonstrates a higher antioxidant effect than any other SGA and clearly is better than haloperidol, olanzapine, or risperidone in preventing neuronal death when exposed to hydrogen peroxide.
Quetiapine, ziprasidone, and lurasidone have inhibitory effects on nitric oxide release. Quetiapine, but not ziprasidone, inhibits TNF-α.
Ziprasidone inhibits apoptosis and microglial activation and synthesis of nitric oxide and other free radicals.
Lurasidone increases BDNF expression in the prefrontal cortex of rodents.

 Beyond dopamine: The ‘other’ effects of antipsychotics

Lurasidone at 40 mg/day and 80 mg/day did not show a statistically significant improvement over placebo in PANSS total score change at the six-week study endpoint, despite a significant within-group reduction of the total PANSS score after treatment. This clinical trial is viewed as a failed study, as it was unsuccessful in establishing assay sensitivity. Despite the failure, company leaders believe they obtained useful data, which will assist with the design of future studies to support the registration of lurasidone in Japan.

Луразидон

Lurasidone is simply another antipsychotic—no more, no less. The two major clinical trials (Pearl 1 and Pearl 2) have shown inconsistent efficacy results, high rates of side effects such as akathisia (restlessness), parkinsonism (tremor and stiffness), and sedation, and apparent inferiority to Zyprexa. Like several of the newer antipsychotics (such as Ability, Geodon, and Fanapt), Lurasidone causes little weight gain and few metabolic abnormalities. With no clear advantages over its many competitors, Lurasidone will succeed or fail based purely on the strength of its promotional campaign.

Stephen Stahl + Lurasidone: The Hired Guns Come to Town

LURASIDONE DEMONSTRATED EFFICACY IN TREATING PATIENTS WITH SCHIZOPHRENIA IN PIVOTAL PHASE 3 STUDY

Dainippon Sumitomo Pharma Announces Lurasidone Phase III Data In Patients With Schizophrenia

Ларазидон: сравнение эффективности доз

Table 1. Comparison of Symptom Reduction

Intervention	PANSS Positive Score Change	PANSS Negative Score Change
Placebo	-5.4	-3.6
Lurasidone 40 mg	-7.7	-6.0
Lurasidone 120 mg	-7.7	-5.2
Olanzapine	-9.3	-6.2

Lurasidone, a novel antipsychotic agent submitted for review to the Food and Drug Administration, with high binding affinities for D2, 5-HT-7, 5-HT-2A, and 5-HT-1A receptors, and is being studied as an antipsychotic with reduced likelihood of causing weight gain, central nervous system depression, and orthostatic hypotension. The multi-center, phase 3 Program to Evaluate Antipsychotic Response to Lurasidone (PEARL 2) trial was conducted to evaluate the efficacy of 2 doses of lurasidone in the treatment of individuals experiencing an acute exacerbation of schizophrenia.

Lurasidone: A Novel, Weight-Neutral Antipsychotic Agent

Lurasidone Demonstrated Efficacy In Treating Patients - phase 3 study

Lurasidone 40 and 120 mg, taken once-daily, demonstrated significantly greater improvement versus placebo on the primary efficacy measure, the Positive and Negative Syndrome Scale (PANSS) total score, at study endpoint. PANSS score changes from baseline for lurasidone 40 and 120 mg/day versus placebo were -25.7 and -23.6 vs. -16.0, respectively, at study endpoint. A total of 53% of patients on lurasidone 40 mg/day and 47% of patients on lurasidone 120 mg/day demonstrated a 30% or more improvement on the PANSS total score from baseline versus 38% on placebo.

The effect of lurasidone on weight was similar to placebo, median weight change: 0.9 kg (2 lbs) for 40 mg/day, 0.5 kg (1.1lbs) for 120 mg/day vs. 0 kg for placebo at study endpoint. The incidence of clinically significant weight gain (greater than or equal to 7% increase from baseline to study endpoint) was 7.6% for lurasidone 40 mg/day, 4.2% for lurasidone 120 mg/day and 7.0% for placebo.

Lurasidone was also well-tolerated with an overall discontinuation rate similar to placebo (40% vs. 39% placebo) and few adverse event-related discontinuations (9% for both the overall lurasidone group and placebo). Adverse events seen in the trial were generally mild. The most commonly reported adverse events for lurasidone 40 and 120 mg/day combined (greater than 5% and at least twice the rate of placebo) were akathisia (17.3% vs. 0.9% placebo), somnolence (12.2% vs. 4.3% placebo), sedation (11.4% vs. 3.4% placebo), parkinsonism (10.1% vs. 1.7% placebo), nausea (9.3% vs. 4.3% placebo), and dystonia (5.5% vs. 0.9% placebo).

Lurasidone is an atypical antipsychotic discovered and developed by DSP with a unique chemical structure. Lurasidone has high affinities for dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A, and noradrenalin alpha2C receptors and minimal-to-no affinity for histamine H1 or cholinergic M1 receptors.

Thread: Lurasidone Demonstrated Efficacy In Treating Patients - phase 3 study

Newer Treatments for Schizophrenia May Offer New Benefits and Drawbacks

The benefit of this therapy is that physicians can determine who may best respond. Studies have identified 6 genetic markers that are associated with iloperidone effectiveness and safety. Patients with 0 to 2 markers have approximately a 15% clinical response to iloperidone treatment. Those with 3 markers have approximately a 40% likelihood of improvement, and those with 4 markersare approximately 60% likely to improve. Almost all patients with 5 or 6 markers were shown to respond to treatment. “Even if you don’t know anything about a patient, there is still about a 48% chance of a clinical response to treatment, according to Potkin.
Newer Treatments for Schizophrenia May Offer New Benefits and Drawbacks