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

Антидепрессивный эффект стимуляции NMDA функции схож с эффектом кетамина

Philadelphia, PA, November 18, 2013– Thirteen years ago, an article in this journal first reported that the anesthetic medication, ketamine, showed evidence of producing rapid antidepressant effects in depressed patients who had not responded to prior treatments. Ketamine works by blocking one of the targets for the neurotransmitter glutamate in the brain, the N-methyl-D-aspartate (NMDA) glutamate receptor.

Now, a new study in Biological Psychiatry reports that enhancing, instead of blocking, that same target – the NMDA glutamate receptor – also causes antidepressant-like effects.

Scientists theorize that NMDA receptor activity plays an important role in the pathophysiology of depression, and that normalizing its functioning can, potentially, restore mood to normal levels.

Prior studies have already shown that the underlying biology is quite complex, indicating that both hyperfunction and hypofunction of the NMDA receptor is somehow involved. But, most studies have focused on antagonizing, or blocking, the receptor, and until now, studies investigating NMDA enhancement have been in the early phases.

Sarcosine is one such compound that acts by enhancing NMDA function. Collaborators from China Medical University Hospital in Taiwan and the University of California in Los Angeles studied sarcosine in an animal model of depression and, separately, in a clinical trial of depressed patients.

“We found that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression,” said Dr. Hsien-Yuan Lane, the corresponding author on the article.

In the clinical portion of the study, they conducted a 6-week trial where 40 depressed patients were randomly assigned to receive sarcosine or citalopram (Celexa), an antidepressant already on the market that was used as a comparison drug. Neither the patients nor their doctors knew which one they were receiving.

Compared to citalopram, patients receiving sarcosine reported significantly improved mood scores, were more likely to experience relief of their depression symptoms, and were more likely to continue in the study. There were no major side effects in either group, but patients receiving citalopram reported more relatively minor side effects than the patients being treated with sarcosine.

“It will be important to understand how sarcosine, which enhances NMDA receptor function, produces the interesting effects reported in this study. There are ways that its effects, paradoxically, might converge with those of ketamine, a drug that blocks NMDA receptors,” commented Dr. John Krystal, Editor of Biological Psychiatry. “For example, both compounds may enhance neuroplasticity, the capacity to remodel brain networks through experience. Also, both potentially attenuate signaling through NMDA receptors, ketamine with single doses and sarcosine, with long-term administration, by evoking an adaptive down regulation of NMDA receptors.”

Would an “Anti-Ketamine” Also Treat Depression? 

Мета-анализ: добавление НПВС к терапии антипсихотиками при шизофрении

Objective: To meta-analytically assess the efficacy and tolerability of nonsteroidal anti-inflammatory drugs (NSAIDs) vs placebo in schizophrenia. Method: Searching PubMed, PsycINFO, ISI Web of Science, and the US National Institute of Mental Health clinical trials registry from database inception to December 31, 2012, we conducted a systematic review/meta-analysis of randomized placebo-controlled studies assessing the efficacy of adjunctive NSAIDs. Primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcomes included change in PANSS positive and negative subscores, all-cause discontinuation, and tolerability outcomes. Random effects, pooled, standardized mean changes (Hedges’ g) and risk ratios were calculated. Results: Across 8 studies, including 3 unpublished reports (n = 774), the mean effect size for PANSS total score was −0.236 (95% CI: −0.484 to 0.012, P = .063, I2 = 60.6%), showing only trend-level superiority for NSAIDs over placebo. The mean effect sizes for the PANSS positive and negative scores were −0.189 (95% CI: −0.373 to −0.005, P = .044) and −0.026 (95% CI: −0.169 to 0.117, P = .72), respectively. The relative risk for all-cause discontinuation was 1.13 (95% CI: 0.794 to 1.599, P = .503). Significant superiority of NSAIDs over placebo regarding PANSS total scores was moderated by aspirin treatment (N = 2, P = .017), inpatient status (N = 4, P = .029), first-episode status (N = 2, P = .048), and (in meta-regression analyses) lower PANSS negative subscores (N = 6, P = .026). Interpretation: These results indicate that adjunctive NSAIDs for schizophrenia may not benefit patients treated with first-line antipsychotics judged by PANSS total score change. NSAIDs may have benefits for positive symptoms, but the effect was minimal/small. However, due to a limited database, further controlled studies are needed, especially in first-episode patients.

 Adjunctive Use of Nonsteroidal Anti-inflammatory Drugs for Schizophrenia: A Meta-analytic Investigation of Randomized Controlled Trials

Роль воспалительных процессов в формировании резистентности к лечению депрессии

Inflammation may also be relevant to depression prevention and relapse. There are multiple clinical factors associated with both inflammation and TRD that can be addressed through lifestyle changes. Treating obesity with diet and exercise in patients with increased inflammation is a primary example. In a recent clinical trial of partial treatment responders, depressed patients with increased TNF levels were more likely to respond to an add-on exercise intervention than were patients who were partially responsive to an SSRI. Another consideration is behavioral stress management including compassion meditation training, which has been shown to reduce inflammatory responses to a laboratory psychosocial stressor.

Exercise and meditation have been associated with an increased parasympathetic tone, which, in turn, has been associated with decreased inflammatory tone. These effects are likely related to parasympathetic activation of T cells that produce acetylcholine that binds to the α subunit of the nicotinic acetylcholine receptor, leading to inhibition of NF-κB.41 Finally, optimizing the management of medical illnesses associated with inflammation may also reduce depression symptoms and improve treatment response.

Inflammation and Treatment Resistance in Major Depression: The Perfect Storm

Возможные механизмы антидепрессивного действия антипсихотиков второго поколения

Although the exact mechanism of SGAs for MDD has not yet been clearly elucidated, several plausible underlying mechanisms are listed as follows: modulation of crucial neurotransmitter receptors and transporters such as dopamine, serotonin and noreinephrine resulting in net effect of enhancement of such neurotransmitters' transmission, effects on sleep, alteration of various hormones (ACTH, sex hormones, etc.), modification of immune functions including modulation of inflammation process (cytokines, etc.), antioxidation process and modulation of neurotrophic factors (BDNF, etc).[13]

Specifically, the main pharmacological rationale of SGAs as an antidepressant augmentation would be based on their effects on monoamine transporters or receptors of crucial neurotransmitters such as serotonin, norepinephrine and dopamine, which are also the main target of contemporary antidepressants. The partial agonism at D2 and/or D3 receptors may increase dopamine neurotransmission at the prefrontal cortex. The increase in the dopamine concentration in the prefrontal cortex may be also indirectly related to the antidepressive effect of 5-HT1A receptor agonist.[14,15] The antidepressant effect may also be mediated by 5-HT1A partial agonism and/or antagonism at 5-HT2A receptors.[16–18] Although, still controversial, the antidepressant effect of 5-HT1A receptor agonists may be predominantly mediated by postsynaptic 5-HT1A receptors, while the anxiolytic effect would be mainly associated with presynptic 5-HT1A receptors.[19] The antagonism of the 5-HT2C receptors has been also found to be involved in increased dopamine and norepinephrine transmission.[20] It is also well known that high affinity at the α2-adrenergic receptor may enhance the release of norepinephrine.[21] Unlike any other SGAs, ziprasidone was reported to block synaptic serotonin, norepinephrine and dopamine reuptake in vitro.[22,23] Evidence indicates that both 5-HT6 agonists and antagonists may evoke identical responses in animal models of MDD, although the possible mechanisms of these effects seem to be diverse and are not clearly understood. The augmented effects were notable by combining antidepressants with a selective 5-HT6 receptor antagonist.[24] There is also a considerable amount of evidence supporting a role for the 5-HT7 receptor in MDD. The blockade of the 5-HT7 receptor led to antidepressant-like effects in animal models of MDD. It should be also worthy to mention that augmentation of 5-HT7 receptor antagonists with antidepressants was remarkable in animal models of MDD.[25]

Another mechanism involving in the action of SGAs should be the alteration of the glutamate receptor activity, and thus restoring normal glutamatergic neurotransmission and reducing the chances of excitotoxicity.[26] Some SGA treatment may also cause a decrease in plasma adrenocorticotropic hormone concentration and a normalization of HPA-axis dynamics.[27] An impaired neuroprotection has also been implicated in the pathophysiology of MDD.[28,29] Interestingly, activation of the 5-HT1A receptors was shown to be neuroprotective against various brain insults such as N-methyl-daspartic acid.[30] Some SGAs have also demonstrated such neuroprotective effects indicating a potential role in the protection against excitotoxicity in vivo.[30]

Overall 5-HT2A antagonism should be a commonly shared biological relevance for most of the SGAs as a potential mechanism of their antidepressant effect. Interactive effects with the dopaminergic system may be more distinct with the action mechanism of amisulpride and aripiprazole, while norepinephrine- and/or serotonin-reuptake inhibition should be the unique case with quetiapine or ziprasidone.[31] Each antipsychotic has a distinct profile of affinities towards different neurotransmitter receptors, which should be associated mainly with mediation of antidepressant-like effects.

Second-generation Antipsychotics in the Treatment of Major Depressive Disorder

Упражнения, депрессии, цитокины

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P < 0.0001). In addition, a significant positive correlation between change in IL-1β and change in depression symptom scores was observed (P = 0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes.

 Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder

Schizophrenia, “Just the Facts” 5. Treatment and prevention Past, present, and future

ЭСТ в сравнении с антидепрессивным эффектом анестезии изофлюраном

Deep-inhalation isoflurane anesthesia has an antidepressant effect that approaches the effect of electroconvulsive therapy (ECT), with fewer cognitive side effects, preliminary results indicate.

Anesthetic a Better Alternative to ECT in Resistant Depression?

N-ацетилцистеин как корректор раздражительности при детском аутизме

Background

This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD).

Method

Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked.

Results

The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect.

Conclusions

Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well.

A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders

Влияние высоких доз фамотидина на симптомы шизофрении

Famotidine has been used for the treatment of heartburn since the 1980s, but at regular dosing, famotidine almost does not enter the brain at all, since the brain is protected by the blood-brain barrier. By increasing the dosage five-fold the drug is able to enter the brain and affect the histamine system.

"Already after one week the symptoms of persons suffering from schizophrenia started to decrease and after four weeks of treatment the symptoms had decreased statistically significantly. The patients that participated in the study were also positively disposed towards the treatment," says Ekelund.

Thirty persons suffering from schizophrenia participated in the study. The patients had been on sickness pension for at least five years and were randomly divided into two groups, one which received famotidine and one which received placebo. All of the patients who took famotidine responded positively to the treatment while the symptoms of those who were on a placebo did not change.

Schizophrenia is the most common and severe psychotic disorder, and is the cause of at least half of all psychiatric hospital treatment days. No randomized, controlled trials in humans that test the effect of H2 blockade in schizophrenia have been published so far.

 New Treatment for Schizophrenia?

РКИ: Влияние противовирусной терапии на когнитивную симптоматику шизофрении у больных с HSV-1

Abstract

Objective To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).

Methods Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.

Results Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.

Conclusions Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.

Antiherpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Метаболизм сфинголипидов и шизофрения

There is considerable evidence for specific pathology of lipid metabolism in schizophrenia, affecting polyunsaturated fatty acids and in particular sphingolipids. These deficits are assumed to interfere with neuronal membrane functioning and the development and maintenance of myelin sheaths. Recent studies suggest that some of these lipid pathologies might also be detected in peripheral skin tests. In this study, we examined different skin lipids and their relation to schizophrenia. We assessed epidermal lipid profiles in 22 first-episode antipsychotic-naïve schizophrenia patients and 22 healthy controls matched for age and gender using a hexan/ethanol extraction technique and combined high-performance thin-layer chromatography/gas-chromatography. We found highly significant increase of ceramide AH and NH/AS classes in patients and decrease of EOS and NP ceramide classes. This is the first demonstration of specific peripheral sphingolipid alterations in schizophrenia. The results support recent models of systemic lipid pathology and in particular of specific sphingolipids, which are crucial in neuronal membrane integrity. Given recent findings showing amelioration of psychopathology using fatty acid supplementation, our findings also bear relevance for sphingolipids as potential biomarkers of the disease.

 Skin Ceramide Alterations in First-Episode Schizophrenia Indicate Abnormal Sphingolipid Metabolism

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