Связь вариаций CYP2C19 с риском аритмий при приёме циталопрама и эсциталопрама

Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects.

CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation

Тиреоидная функция до и после лечения психотического эпизода

Background
Endocrine function in psychiatric patients may be affected by mental disorder itself as well as by antipsychotic medications.
The aim of this naturalistic observational study was to determine if treatment of acute psychotic episode with antipsychotic medication affects thyroid axis hormone concentrations and if such changes are associated with symptomatic improvement.
Methods
Eighty six adult acute psychotic patients, consecutively admitted to a mental hospital, were recruited for the study. All patients were physically healthy and without thyroid disease. During the hospitalization period all study patients received treatment with antipsychotic medication according to clinical need. Severity of the psychotic episode was evaluated using the Brief Psychiatric Rating Scale (BPRS) and venous blood samples were drawn for analysis of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) concentrations on the day of admission and on the day of discharge from the hospital.
Results
Antipsychotic drug treatment was associated with decrease of mean FT3 (p < 0.001) and FT4 (p = 0.002) concentrations; and with increase of mean TSH (p = 0.016) concentrations. Changes in thyroid hormone concentrations were mostly predicted by baseline hormone concentrations. Individual changes were not limited to decrease in high hormone concentrations; in patients who had low FT3 or FT4 concentrations, treatment resulted in increase in concentrations. Such an increase was established in one-quarter of patients for FT3 concentrations and in one-third of patients for FT4 concentrations. Fall in FT4 concentrations negatively correlated with the improvement in the BPRS score (r = −0.235, p = 0.023).
Conclusions
The study indicates that antipsychotic treatment resulted in a decrease in mean FT3 concentrations and in an increase in mean TSH concentrations after recovery from acute psychosis. Symptomatic improvement was less evident in patients who experienced a decrease in FT4 concentrations.

 Thyroid axis function after in-patient treatment of acute psychosis with antipsychotics: a naturalistic study

Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

В связи с растущей проблемой антибиотикорезистентнтности активно ведутся поиски новых антибактериальных препаратов, действующих как уже на известные «мишени», так на структуры бактериальной клетки, ранее не являвшиеся мишенью действия антибиотиков. Причём если ранее в основном пытались ингибировать важнейшие процессы жизнедеятельности микроорганизмов, то сейчас рассматриваются и варианты воздействия на построение (сборку) отдельных структур микробной клетки.

Исследователями был проведён скрининг большого числа уже применяющихся в клинической практике лекарственных средств на наличие зависимой от температуры способности ингибировать рост Escherichia coli. Одним из препаратов, активность которого наиболее выраженно уменьшалась при снижении температуры, был давно применяющийся противосудорожный препарат ламотригин. В присутствии ламотригина в микробных клетках быстро возрастала концентрация незрелых 30S и 50S субъединиц рибосом. При этом препарат не нарушал процесс трансляции и непосредственно не влиял на синтез белков in vitro и in vivo. Таким образом, ламотригин может стать первым представителем целого нового класса антибактериальных препаратов — ингибиторов сборки бактериальных рибосом.

Однако, несмотря на очевидную перспективность разработки антибиотиков с новыми механизмами действия, вероятность развития к ним устойчивости также возможна. В частности, ряд спонтанных мутаций в домене II фактора инициации трансляции IF2 блокируют присоединение ламотригина к IF2 и, соответственно, нивелируют активность данного препарата в отношении процесса сборки бактериальных рибосом.

 Противосудорожный препарат ламотригин может дать начало новому классу антибиотиков — ингибиторам сборки бактериальных рибосом

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

Антипсихотические свойства варфарина

Warfarin has been linked to a decrease in and even long-term remission of psychotic symptoms in patients with schizophrenia, preliminary research suggests.
A study examining adults at an anticoagulation clinic for deep venous thrombosis (DVT) showed that 5 patients who also had schizophrenia and who received long-term treatment with warfarin for recurrent DVT achieved full psychosis remission. In addition, these patients remained free of any psychotropic medication for 2 to 11 years.
The investigators note that the underlying mechanism could be tissue-plasminogen activator (tPA), a protein that not only promotes the dissolution of blood clots but also plays a role in neurogenesis after severe stress.

Warfarin for Long-term Psychosis Remission?

Эффективность битопертина не подтвердилась

FlashLyte and DayLyte, the first 2 studies discontinued in January 2014, were evaluating bitopertin for negative symptoms, including lack of motivation and social withdrawal. Suboptimally controlled symptoms include hallucinations and delusions.

The primary endpoints were negative symptom factors scores on the Positive and Negative Symptom Scale (PANSS) after 24 weeks of adjunctive treatment with bitopertin vs placebo. Although the active treatment was found to be well tolerated, the PANSS score changes from baseline were not found to be statistically significant.

Bitopertin Disappoints as Schizophrenia Treatment

Оланзапин превзошел ламотриджин в профилактике депрессивной фазы биполярного аффективного расстройства

Background

Bipolar disorder is a highly recurrent disease and has great impact on the function of patients. Depressive symptoms consist of more than 50% of life time during the illness and may lead to self harm or suicidal behaviors. Little is known about the antidepressant effects of olanzapine, an atypical antipsychotic, as monotherapy despite its indication for preventing manic episodes. In contrast, lamotrigine, a mood stabilizer, has been proven to be effective in preventing depression in patients with bipolar disorder. However, no studies have compared the efficacy between lamotrigine and olanzapine in the maintenance treatment of bipolar disorder. This enriched naturalistic study was implemented to assess the effectiveness of olanzapine and lamotrigine as monotherapy in the prevention of recurrence of bipolar disorder.

Methods

Patients with bipolar disorder in a euthymic state (Young's Mania Rating Scale (YMRS) score < 12, and 21-item Hamilton Depression Rating Scale (HAM-D) score < 7) for at least two months, having already received either olanzapine or lamotrigine as the maintenance treatment were recruited. The patients maintained with olanzapine (n = 22) were applied to olanzapine group whereas those maintained with lamotrigine (n = 29) were applied to lamotrigine group. They were followed up for 12 months. Differences in the efficacy between olanzapine and lamotrigine in recurrence prevention were analyzed. The Kaplan-Meier method was used to generate time-to-recurrence curves, and differences between the two groups were compared using the log-rank test.

Results

Olanzapine had a significantly lower recurrence rate of depressive episodes than lamotrigine (20.0% vs. 57.7%, chi2 = 6.62, p = .010). However, olanzapine and lamotrigine had similar mania (15.0% vs. 0%, chi2 = 4.17, p = .075, Fisher's exact test) and any mood episode (35.0% vs. 57.7%, chi2 = 2.33, p = .127) recurrence rates. Olanzapine was significantly superior to lamotrigine in the time to recurrence of depressive episodes (chi2 = 4.55, df = 1, p = .033), but there was no difference in the time to recurrence of any mood episode (chi2 = 1.68, df = 1, p = .195).

Conclusions

This prospective naturalistic study suggests that olanzapine is more effective than lamotrigine in the prevention of depressive episodes in patients with bipolar disorder. Future large-scale randomized studies are warranted to validate our results.

 Olanzapine is superior to lamotrigine in the prevention of bipolar depression: a naturalistic observational study

Эйкозапентаеновая кислота как корректор интерферон-индуцированной депрессии

Background

Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression.

Methods

We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis.

Results

Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.

Conclusions

EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.

Omega-3 Fatty Acids in the Prevention of Interferon-Alpha-Induced Depression: Results from a Randomized, Controlled Trial 

Акампросат, механизм действия

Throughout the years, however, the molecular target of acamprosate has remained elusive. Because of structural similarities, initial hypotheses centered on the possibility that acamprosate may act as a GABA-mimic or otherwise modulate GABA-ergic transmission. There is, however, little in the in vivo profile of acamprosate to suggest similarities with drugs known to enhance GABA-ergic transmission. In fact, a lack of sedative–ataxic or addictive properties is among the clinical advantages of acamprosate. Once it became clear that acamprosate’s mechanism of action is likely to involve modulation of glutamatergic function, several potential mechanisms were explored. For instance, acamprosate was shown to possess some partial agonist activity on the NMDA receptor complex via actions at its polyamine site. This would potentially allow it to act as a functional antagonist during hyperglutamatergic states. However, experiments failed to demonstrate this kind of functional activity. More recently, focus shifted to potential activity of acamprosate at metabotropic glutamate receptors (mGluRs). This was prompted, for example, by observations that acamprosate blocked neurotoxicity induced by trans-ACPD, an mGluR agonist with affinity for mGluR1 and mGluR5 receptors (Kiefer and Mann, 2010).

Over the years, the notion has become widely accepted that, although we may not know its exact mechanism of action, acamprosate is ‘a functional glutamate antagonist’. The paper by Spanagel et al (2005) in this issue fundamentally challenges this notion. The paper presents multiple lines of evidence that the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries. The authors first thoroughly excluded agonist as well as antagonist activity of acamprosate at the glycine or glutamate sites of the NMDA receptor, respectively, as well as at the mGluR5 receptor. They then went on to demonstrate in vivo that, in contrast to the Ca++ salt, the sodium salt of acamprosate did not suppress relapse-like drinking. Conversely, the delivery of comparable amounts of Ca++ using a different carrier, gluconate, replicated suppression of relapse-like drinking. These animal findings are supported by secondary analyses of clinical trial data, which indicate that in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.

Acamprosate: An Alcoholism Treatment That May Not Be What We Thought

Перспективные методы лечения депрессий

Long-term stress harms cells in the brain and body. Stressful experiences are believed to be closely associated with the development of psychological alterations and, thus, neuropsychiatric disorders.
In conditions of chronic stress exposure, nerve cells in the hippocampus begin to atrophy. (The hippocampus is a part of the brain involved with emotions, learning, and memory formation.)
The new depression theories “should not be viewed as separate entities because they are highly interconnected,” researchers write.
“Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved.”
Such biomarkers are molecules in the body that can be indicators of depression. The authors identify more than a dozen potential biomarkers depression, including monoamine regulators; proinflammatory cytokines and other inflammatory mediators; mediators of glutaminergic activity and GABAergic activity; and regulators of neurogenesis.
A bevy of new depression treatments are currently offered or on the horizon include corticotropin-releasing hormone antagonists; dexamethasone; partial adrenalectomy; long-term cognitive behavioral therapy; ketamine and other NMDA antagonists. Other treatments include benzodiazepines; anesthetics; deep brain stimulation; transcranial magnetic stimulation; exogenous brain-derived neurotrophic factor; selective serotonin reuptake inhibitors; tricyclic antidepressants; atypical antidepressants; reduction in inflammation; and anti-inflammatory drugs.

 Beyond Antidepressants: Taking Stock of New Treatments