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

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

Анти-NMDA-рецепторный энцефалит и шизофрения

CONTEXT Evidence for symptomatic convergence of schizophrenia and N -methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. OBJECTIVES To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis. DESIGN Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined. PARTICIPANTS Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n = 121), MD (n = 70), or BLPD (n = 38). MAIN OUTCOME MEASURES The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. RESULTS Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R. CONCLUSIONS Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.

Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis.

C-реактивный белок как предиктор резистентности к лечению депрессии, инфликсимаб в терапии резистентной депрессии

A new study suggests a drug used to treat autoimmune disorders and rheumatoid arthritis may help individuals with difficult-to-treat depression.

Prior studies have suggested that depressed people with evidence of high inflammation are less likely to respond to traditional treatments for the disorder, including anti-depressant medications and psychotherapy.

The study investigated the use of infliximab, a new biologic drug used to treat autoimmune and inflammatory diseases. Each participant was assigned either to infliximab or to a non-active placebo treatment.

A biologic drug copies the effects of substances naturally made by the body’s immune system. In this case, the drug was an antibody that blocks tumor necrosis factor (TNF), a key molecule in inflammation that has been shown to be elevated in some depressed individuals.

Study participants all had major depression and were moderately resistant to conventional antidepressant treatment.

When investigators looked at the results for the group as a whole, no significant differences were found in the improvement of depression symptoms between the drug and placebo groups.

However, when the subjects with high inflammation were examined separately, they exhibited a much better response to infliximab than to placebo.

Inflammation in this study was measured using a simple blood test that is readily available in most clinics and hospitals and measures C-reactive protein or CRP. The higher the CRP, the higher the inflammation, and the higher the likelihood of responding to the drug.

 Anti-Inflammatory Med May Ease Hard-to-Treat Depression

Маркеры иммунного воспаления в прогнозе обострения при шизофрении

To get a better handle on how IL-6 levels correspond to disease status, they are looking at levels in blood samples taken multiple times over several years in 305 patients enrolled in a study comparing injectable to oral medication. They also are taking one-time measurements in 80 healthy controls and comparing those to levels in 240 patients who are acutely ill, stable outpatients or stable outpatients who smoke marijuana, a drug commonly abused by patients. While many previous studies have excluded drug abusers, marijuana may increase inflammation, so they want to explore the relationship between IL-6 levels and its use, Miller said.

Miller received a five-year, $920,000 National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award to measure IL-6 levels as a potential indicator of how well treatment is working to control disease in these vulnerable patients and whether they are headed to relapse.

Amazingly the contributions of "immune disturbances" to schizophrenia have been debated for about 100 years yet anti-inflammatory drugs aren't routinely given to patients in addition to their antipsychotic medication, Miller said.

Part of the problem is physicians still have no idea what percentage of patients with this very heterogeneous disease have evidence of increased inflammation. In fact, no two patients have the exact constellation of symptoms considered disease hallmarks, such as hallucinations, delusions, disorganized speech and thinking, he said.

But mounting evidence suggests inflammation's impact in schizophrenia. A British study of 50 patients experiencing their first episode of schizophrenic behavior found a handful had indicators of an immune response to their brains, called autoantibodies, and no other conditions, such as a brain infection, to explain them. What amounts to a chronic low-grade flu has been found in some patients and rare immune system disorders such as Sjögren's syndrome, which attacks moisture-producing glands resulting in dry eyes and mouth, also tend to be more common in schizophrenics. Additionally, a handful of clinical trials has shown – not surprisingly – that patients with the highest levels of pro-inflammatory factors had the best response to anti-inflammatory drugs.

Researchers pursue red flag for schizophrenia relapse

Потенцирование антидепрессивного действия сертралина целекоксибом

Background
It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD).
Methods
In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale—17 items (Ham-D) score ≥ 18 were randomly assigned to either celecoxib (200 mg twice daily) or placebo in addition to sertraline (200 mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6.
Results
The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI) = 0.42(0.30 to 0.55) pg/ml, t(35) = 6.727, P < 0.001) as well as Ham-D scores (mean difference (95%CI) = 3.35(1.08 to 5.61), t(38) = 2.99, P = 0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P = 0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r = 0.378, P = 0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r = 0.673, P < 0.001).
Limitations
We did not measure other inflammatory biomarkers.
Conclusions
We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant

 Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: Randomized double-blind placebo-controlled study

Аутоиммунные факторы в патогенезе обсессивно-компульсивной симптоматики

Background
Symptoms of obsessive–compulsive disorder (OCD) have been described in neuropsychiatric syndromes associated with streptococcal infections. It is proposed that antibodies raised against streptococcal proteins cross-react with neuronal proteins (antigens) in the brain, particularly in the basal ganglia, which is a brain region implicated in OCD pathogenesis.
Aims
To test the hypothesis that post-streptococcal autoimmunity, directed against neuronal antigens, may contribute to the pathogenesis of OCD in adults.
Method
Ninety-six participants with OCD were tested for the presence of anti-streptolysin-O titres (ASOT) and the presence of anti-basal ganglia antibodies (ABGA) in a cross-sectional study. The ABGA were tested for with western blots using three recombinant antigens; aldolase C, enolase and pyruvate kinase. The findings were compared with those in a control group of individuals with depression (n = 33) and schizophrenia (n = 17).
Results
Positivity for ABGA was observed in 19/96 (19.8%) participants with OCD compared with 2/50 (4%) of controls (Fisher’s exact test P = 0.012). The majority of positive OCD sera (13/19) had antibodies against the enolase antigen. No clinical variables were associated with ABGA positivity. Positivity for ASOT was not associated with ABGA positivity nor found at an increased incidence in participants with OCD compared with controls.
Conclusions
These findings support the hypothesis that central nervous system autoimmunity may have an aetiological role in some adults with OCD. Further study is required to examine whether the antibodies concerned are pathogenic and whether exposure to streptococcal infection in vulnerable individuals is a risk factor for the development of OCD.

Prevalence of anti-basal ganglia antibodies in adult obsessive–compulsive disorder: cross-sectional study

Антитела к глиадину у больных шизофренией

The present work measured circulating antibodies against native gliadins, deamidated gliadin–derived epitopes, and transglutaminase 2 (TGM2) in 473 patients with schizophrenia and 478 control subjects among a Chinese population. The results showed that 27.1% of patients with schizophrenia were positive for the IgA antibody against native gliadins compared with 17.8% of control subjects (χ2 = 11.52, P = .0007, OR = 1.72, 95% CI 1.25–2.35), although this significant difference appeared to be due mainly to low IgA gliadin antibody levels in female controls. A total of 27.6% of female patients were positive for IgA gliadin antibodies compared with 13.9% of female controls (χ2 = 10.46, P = .0012, OR = 2.36, 95% CI 1.39–4.01), and 26.4% of male patients were positive for IgA antibodies compared with 19.8% of male controls (χ2 = 3.26, P = .071, OR = 1.46, 95% CI 0.97–2.19). Of 128 patients who were positive for the IgA antibody against native gliadins, 8 were positive for the IgA antibody against deamidated gliadin epitopes and 1 was positive for IgA anti-TGM2 antibody. However, quantitative analysis demonstrated that the mean levels of IgA antibodies against deamidated gliadin epitopes and TGM2 were significantly lower in patients with schizophrenia than the control subjects (P < .001 and P = .008, respectively). The prevalence of IgG antibodies against native gliadins was not significantly different between the patient group and the control group (χ2 = 2.25, P = .134, OR = 1.32, 95% CI 0.92–1.88). This study suggests that specific gliadin-derived epitopes may be involved in schizophrenia.

 A Study of Circulating Gliadin Antibodies in Schizophrenia Among a Chinese Population

Исследование влияния диет без глютена или казеина на симптоматику расстройств аутистического спектра

For those children with GI and allergy symptoms, a gluten-free, casein-free diet was more effective in improving ASD behaviors, physiological symptoms and social behaviors compared to children without these symptoms.
Specifically, when a gluten-free, casein-free diet was strictly followed, parents witnessed an improvement in GI symptoms in their children as well as improvements in social behaviors, such as language production, eye contact, engagement, attention span, requesting behavior and social responsiveness.
Autism may be more than a neurological disease, says Laura Cousino Klein, associate professor of bio-behavioral health and human development and family studies—it may involve the GI tract and the immune system.
“There are strong connections between the immune system and the brain, which are mediated through multiple physiological symptoms,” Klein said. “A majority of the pain receptors in the body are located in the gut, so by adhering to a gluten-free, casein-free diet, you’re reducing inflammation and discomfort that may alter brain processing, making the body more receptive to ASD therapies.”
Furthermore, when all gluten and casein was removed from the diet, parents reported that a greater number of ASD behaviors, physiological symptoms and social behaviors improved in their children compared to those whose parents did not eliminate all gluten and casein. Also, parents who implemented the diet for six months or less reported that the diet was less effective in reducing ASD behaviors.
Some of the parents had eliminated only gluten or only casein from the diet, but survey results suggested that parents who completely eliminated both gluten and casein reported the most benefit.

Gluten-Free, Casein-Free Diet Shows Promise for Autism Symptoms

Депрессия, воспаление и сердечно-сосудистые заболевания

Led by Dr. Jesse Stewart, researchers found that depressive symptoms are associated with increases over time in interleukin-6, an inflammatory protein that predicts cardiovascular events.

On the other hand, levels of interleukin-6 were not linked to subsequent increases in depressive symptoms.

Depression leads to increased inflammatory protein linked to heart disease

Психоиммунологические разработки в терапии депрессии

Для повышения эффективности лечения антидепрессантами, в том числе и сертралином, нами предложен комплекс средств патогенетической терапии больных с депрессивными расстройствами, целью применения которого является восстановление иммунного и метаболического гомеостаза.

На первой неделе лечения мы считаем весьма полезным назначение 1,5% соли янтарной кислоты как средства детоксикации и улучшения энергетического метаболизма, который у больных депрессиями существенно снижен. Соль янтарной кислоты обладает выраженным детоксицирующим, антигипоксическим, антиоксидантным, гепато-, нефро- и кардиопротекторным действиями, что обусловлено способностью препарата усиливать аэробный гликолиз, увеличивать внутриклеточный фонд макроэргических соединений — АТФ и креатинфосфата, а также активировать систему АОЗ, снижать выраженность процессов ПОЛ и оказывать мембраностабилизирующий эффект, в том числе в отношении клеток головного мозга. При умеренно выраженных депрессиях мы вводим по 400 мл 1,5% раствора соли янтарной кислоты 2–3 раза с интервалом 1–2 дня между инфузиями. При тяжелых депрессиях реамберин желательно назначать ежедневно по 400 мл на инфузию, а количество инфузий увеличить до 5–6. Клинический опыт показывает, что введение 1,5% раствора соли янтарной кислоты способствует улучшению самочувствия у больных депрессиями, уменьшению астенического компонента и чувства тревоги.

В комплексе лечебных средств у больных депрессиями с целью снижения выраженности СМИ мы широко используем положительно зарекомендовавший себя метод энтеросорбции. Пациенты с первого дня лечения получают современные кремнеземные энтеросорбенты отечественного производства (атоксил, энтеросгель, силлард П и др.) в виде 1–2% водной суспензии 2–3 раза в день в перерывах между приемами пищи и других лекарственных препаратов по 200–250 мл курсами по 10–12 дней с перерывами между ними 7–10 дней. При легкой степени депрессии обычно проводится 2 курса энтеросорбции, при умеренно выраженной — 2–3 курса, у больных с тяжелой депрессией назначают до 5–6 курсов энтеросорбции.

Для снижения активности ПОЛ и повышения антиоксидантных потенций крови у больных депрессиями применяют витамины с антиоксидантной активностью — аскорбиновую кислоту до 500 мг в сутки внутрь, а при тяжелых депрессиях также внутривенно в виде 10% раствора по 10 мл 2 раза в день на 40% глюкозе или изотоническом растворе хлорида натрия, токоферола ацетат по 0,2 мл 50% раствора внутрь в капсулах 2–3 раза в день, а при тяжелых депрессиях внутримышечно по 1 мл 10% раствора 1 раз в день в течение 20–40 дней. У больных с фоновой соматической патологией — при хронических гепатитах и начальной фазе цирроза печени — дополнительно назначаем внутрь современные препараты эссенциальных фосфолипидов: ливолин, ливенциале форте или эссенциале Н по 2 капсулы 3 раза в день курсами по 25–30 дней. При необходимости у больных с тяжелыми соматоформными депрессиями этот курс лечения эссенциальными фосфолипидами может быть повторен через 1–1,5 месяца.

Депрессивные расстройства: иммунные и метаболические нарушения и их коррекция

Перспективы лечения БАР

Excitotoxicity
Several lines of evidence suggest that glutamatergic system dysfunction (eg, N-methyl d-aspartate [NMDA] receptor complex) may play a critical role in the pathophysiology of bipolar disorder. In keeping with this view, the use of glutamatergic modulators may be predicted to alleviate symptoms and modify the disease process. Postmortem studies indicate that altered NMDA receptor complexes are observed in the brain tissue of patients with bipolar disorder. Moreover, genetic polymorphisms for genes implicated in the glutamate receptor complex have been associated with this disorder.6
Riluzole, an inhibitor of glutamate release, is approved by the FDA for the treatment of amyotrophic lateral sclerosis. This agent, at a dosage of 50 to 200 mg/d, was evaluated in an 8-week add-on study in combination with lithium in 14 adults with bipolar depression, 6 of whom had bipolar I disorder, and 8 of whom had bipolar II disorder. Eight patients completed the 8-week trial.6 Significant improvement in depressive symptoms was noted in weeks 5 through 8 as measured by the Montgomery Asberg Depression Rating Scale (MADRS).
Ketamine is a noncompetitive NMDA antagonist that has been evaluated in subanesthetic doses in persons with bipolar disorder.7 Results from a double-blind, randomized, placebo-controlled, crossover study indicate that a single intravenous infusion of ketamine(Drug information on ketamine) combined with lithium or valproate(Drug information on valproate) was capable of alleviating depressive symptoms within 40 minutes of administration when compared with placebo.7 The benefit of ketamine was sustained through day 3. Overall, 71% of patients responded to ketamine and 6% responded to placebo at some point during the trial. Ketamine was not associated with significant increases in hypomania or mania but was associated with dissociative symptoms.

Cyclooxygenase-2 (COX-2) inhibitors have been shown to protect against glutamate-induced neurotoxicity; to prevent normal aging-related increases of cytokines, prostaglandins, and TNF in neurons; and to modulate the hypothalamic adrenal axis.10 The COX-2 inhibitor celecoxib(Drug information on celecoxib) was evaluated as a potential antidepressant in adults with bipolar I/II depression (N = 28).10 This drug was administered at a dosage of 400 mg daily in combination with a mood stabilizer or antipsychotic medication as part of a 6-week, randomized, double-blind, placebo-controlled study. Depressive symptoms in both the treatment group and the placebo group improved, with a statistically significant (P = .01) advantage at week 1 in patients treated with celecoxib compared with patients who received placebo. Although there was an advantage in favor of the treatment group at week 1, both the active-treatment and placebo groups had similar reductions for each of the remaining observation points.

Several case reports and case series suggest that insulin sensitizers (eg, rosiglitazone(Drug information on rosiglitazone)) may offer an antidepressant effect in persons with major depressive disorder. Studies are currently under way in bipolar disorder. For example, several studies are evaluating the antidepressant effects of intranasal insulin and insulin secretagogues (eg, incretins) in bipolar disorder. Moreover, there is ongoing research to determine whether weight loss, bariatric surgery, and dietary modification (eg, ketogenic diet) improve depressive symptoms in persons with bipolar disorder.

Results from a randomized, double-blind, multicenter, placebo-controlled study of adults with bipolar disorder (N = 75) indicate that N-acetylcysteine (1 g bid) adjunctive to usual medications was capable of alleviating depressive symptoms as measured by the MADRS.14 The benefit on depressive symptoms was noted at week 20 as part of this 24-week study. Benefits were noted by week 8 on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale. N-acetylcysteine did not induce hypomania or mania and was well tolerated. Adverse events reported in more than 15% of the N-acetylcysteine group included change in energy, headaches, heartburn, and increased joint pain.

Armodafinil is the longer-lasting isomer of modafinil, and its therapeutic indications are similar to those of the racemic agent modafinil. Armodafinil at a dosage of 150 mg/d was evaluated as an antidepressant in adults with bipolar disorder who received either olanzapine, lithium, or valproic acid as part of an 8-week double-blind placebo-controlled study.

Novel Treatment Avenues for Bipolar Depression

Перинатальные инфекции и риск шизофрении

These studies have yielded a series of intriguing associations (reviewed in Brown and Derkits)[2] and are briefly summarized here. Our group demonstrated that prenatal exposure to rubella was related to a greater than 5-fold increased risk of nonaffective psychosis during young adulthood[12] and in midadulthood over 20% of subjects who were exposed in utero to rubella were diagnosed with schizophrenia or a schizophrenia spectrum disorder.[13] Influenza exposure documented by quantification of maternal antibody titers during pregnancy was associated with a 3-fold increased risk of schizophrenia for exposure in mid to late gestation and a 7-fold elevation in risk of the disorder following first trimester exposure.[14] Elevated maternal IgG antibodies to Toxoplasma gondii, an intracellular parasite and a well-known infectious cause of central nervous system (CNS) congenital anomalies,[1,15] was related to greater than 2-fold increased risk of schizophrenia,[16] a finding which was essentially replicated in a Danish sample that capitalized on filter paper blood spots taken from the infant within the first week of birth.[17] In 3 studies, elevated maternal IgG antibody to (HSV-2) was related to an increased risk of psychotic disorders, including schizophrenia,[18,19,20] while the finding was not replicated in a different birth cohort.[21] Maternal genital/reproductive infections, broadly defined, were, however, associated with a 5-fold increased risk of schizophrenia when the exposure occurred during the periconceptional period.[22] Exposure to maternal respiratory infection was related to a 2-fold elevated schizophrenia risk,[23] as well as bacterial infections broadly defined.[24]

In summary, birth cohort studies have provided several key methodological advantages that have allowed for more rigorous testing of relationships between maternal infection and schizophrenia. Birth cohort studies conducted to date have provided further support for the hypothesis that maternal viral, protozoal, and bacterial infections increase the risk for schizophrenia in adult offspring.

Although cytokines represent a leading candidate agent for the effect of infection on schizophrenia risk, other possible mediators include hyperthermia, which is teratogenic to animals;[32] fetal hypoxia, which has been associated with schizophrenia;[33,34] and over the counter remedies taken for influenza such as aspirin, which has been associated with anomalies of the CNS.

Maternal Infection and Schizophrenia

Восприимчивость к глютену в норме, при шизофрении и при целиакии

Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia.

In contrast to previous reports, we found no evidence for celiac disease in patients with chronic schizophrenia as manifested by the presence of serum IgA anti-endomysial antibodies. It is unlikely that there is an association between gluten sensitivity and schizophrenia.

"Bread madness" revisited: screening for specific celiac antibodies among schizophrenia patients.

These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8.

Novel immune response to gluten in individuals with schizophrenia

We report the unexpected resolution of longstanding schizophrenic symptoms after starting a low-carbohydrate ketogenic diet. After a review of the literature, possible reasons for this include the metabolic consequences from the elimination of gluten from the diet, and the modulation of the disease of schizophrenia at the cellular level.

Schizophrenia, gluten, and low-carbohydrate, ketogenic diets: a case report and
review of the literature

There are several case reports of coexistence of coeliac sprue and depression, schizophrenia and anxiety. Coeliac disease should be taken into consideration in patients with psychiatric disorders, particularly if they are not responsive to psychopharmacological therapy, because withdrawal of gluten from the diet usually results in disappearance of symptoms.

Psychiatric symptoms and coeliac disease.

A double-blind control trial of gluten-free versus a gluten-containing diet was carried out in a ward of maximum security hospital: 24 patients were studied for 14 weeks. Most suffered from psychotic disorders, particularly schizophrenia. Various dimensions of behaviour were rated on the Psychotic In-Patient profile (PIP) at different stages. There were beneficial changes in the whole group of patients between pre-trial and gluten-free period in five dimensions of the PIP, maintained during the gluten challenge period; these changes could be attributed to the attention the patients received. Two patients improved during the gluten-free period and relapsed when the gluten diet was reintroduced.

A double-blind gluten-free/gluten-load controlled trial in a secure ward population.

Непереносимость глютена и шизофрения

Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race. Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (chi(2) = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (chi(2) = 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity.

Prevalence of Celiac Disease and Gluten Sensitivity in the United States Clinical Antipsychotic Trials of Intervention Effectiveness Study Population.

Инфекционная теория шизофрении: вирус HERV-W

By the 1980s he began working with Robert Yolken, an infectious-diseases specialist at Johns Hopkins University in Baltimore, to search for a pathogen that could account for these symptoms. The two researchers found that schizophrenics often carried antibodies for toxoplasma, a parasite spread by house cats; Epstein-Barr virus, which causes mononucleosis; and cytomegalovirus. These people had clearly been exposed to those infectious agents at some point, but Torrey and Yolken never found the pathogens themselves in the patients’ bodies. The infection always seemed to have happened years before.

Torrey wondered if the moment of infection might in fact have occurred during early childhood. If schizophrenia was sparked by a disease that was more common during winter and early spring, that could explain the birth-month effect. “The psychiatrists thought I was psychotic myself,” Torrey says. “Some of them still do.”

While Torrey and Yolken were chasing their theory, another scientist unwittingly entered the fray. Hervé Perron, then a graduate student at Grenoble University in France, dropped his Ph.D. project in 1987 to pursue something more challenging and controversial: He wanted to learn if new ideas about retroviruses—a type of virus that converts RNA into DNA—could be relevant to multiple sclerosis.

Robert Gallo, the director of the Institute of Human Virology at the University of Maryland School of Medicine and co­discoverer of HIV, had speculated that a virus might trigger the paralytic brain lesions in MS. People had already looked at the herpes virus (HHV-6), cytomegalovirus, Epstein-Barr virus, and the retroviruses HTLV-1 and HTLV-2 as possible causes of the disease. But they always came up empty-handed.

Perron learned from their failures. “I decided that I should not have an a priori idea of what I would find,” he says. Rather than looking for one virus, as others had done, he tried to detect any retrovirus, whether or not it was known to science. He extracted fluids from the spinal columns of MS patients and tested for an enzyme, called reverse transcriptase, that is carried by all retroviruses. Sure enough, Perron saw faint traces of retroviral activity. Soon he obtained fuzzy electron microscope images of the retrovirus itself.

By the time Perron made his discovery, Torrey and Yolken had spent about 15 years looking for a pathogen that causes schizophrenia. They found lots of antibodies but never the bug itself. Then Håkan Karlsson, who was a postdoctoral fellow in Yolken’s lab, became interested in studies showing that retroviruses sometimes triggered psychosis in AIDS patients. The team wondered if other retroviruses might cause these symptoms in separate diseases such as schizophrenia. So they used an experiment, similar to Perron’s, that would detect any retrovirus (by finding sequences encoding reverse transcriptase enzyme)—even if it was one that had never been catalogued before. In 2001 they nabbed a possible culprit. It turned out to be HERV-W.

Several other studies have since found similar active elements of HERV-W in the blood or brain fluids of people with schizophrenia. One, published by Perron in 2008, found HERV-W in the blood of 49 percent of people with schizophrenia, compared with just 4 percent of healthy people. “The more HERV-W they had,” Perron says, “the more inflammation they had.” He now sees HERV-W as key to understanding many cases of both MS and schizophrenia. “I’ve been doubting for so many years,” he says. “I’m convinced now.”

Through this research, a rough account is emerging of how HERV-W could trigger diseases like schizophrenia, bipolar disorder, and MS. Although the body works hard to keep its ERVs under tight control, infections around the time of birth destabilize this tense standoff. Scribbled onto the marker board in Yolken’s office is a list of infections that are now known to awaken HERV-W—including herpes, toxoplasma, cytomegalovirus, and a dozen others. The HERV-W viruses that pour into the newborn’s blood and brain fluid during these infections contain proteins that may enrage the infant immune system. White blood cells vomit forth inflammatory molecules called cytokines, attracting more immune cells like riot police to a prison break.

In one experiment, Perron isolated HERV-W virus from people with MS and injected it into mice. The mice became clumsy, then paralyzed, then died of brain hemorrhages. But if Perron depleted the mice of immune cells known as T cells, the animals survived their encounter with HERV-W. It was an extreme experiment, but to Perron it made an important point. Whether people develop MS or schizophrenia may depend on how their immune system responds to HERV-W, he says. In MS the immune system directly attacks and kills brain cells, causing paralysis. In schizophrenia it may be that inflammation damages neurons indirectly by overstimulating them. “The neuron is discharging neurotransmitters, being excited by these inflammatory signals,” Perron says. “This is when you develop hallucinations, delusions, paranoia, and hyper-suicidal tendencies.”

Gene studies have failed to provide simple explanations for ailments like schizophrenia and MS. Torrey’s theory may explain why. Genes may come into play only in conjunction with certain environmental kicks. Our genome’s thousands of parasites might provide part of that kick.

“The ‘genes’ that can respond to environmental triggers or toxic pathogens are the dark side of the genome,” Perron says. Retroviruses, including HIV, are known to be awakened by inflammation—possibly the result of infection, cigarette smoke, or pollutants in drinking water. (This stress response may be written into these parasites’ basic evolutionary strategy, since stressed hosts may be more likely to spread or contract infections.) The era of writing off endogenous retroviruses and other seemingly inert parts of the genome as genetic fossils is drawing to an end, Perron says. “It’s not completely junk DNA, it’s not dead DNA,” he asserts. “It’s an incredible source of interaction with the environment.” Those interactions may trigger disease in ways that we are only just beginning to imagine.

Torrey and Yolken hope to add a new, more hopeful chapter to this story. Yolken’s wife, Faith Dickerson, is a clinical psychologist at Sheppard Pratt Health System in Baltimore. She is running a clinical trial to examine whether adding an anti-infective agent called artemisinin to the drugs that patients are already taking can lessen the symptoms of schizophrenia. The drug would hit HERV-W indirectly by tamping down the infections that awaken it. “If we can treat the toxoplasmosis,” Torrey says, “presumably we can get a better outcome than by treating [neurotransmitter] abnormalities that have occurred 14 steps down the line, which is what we’re doing now.”

The Insanity Virus

шизовирус

TO THE EDITOR: The review article by Alan S. Brown, M.D., M.P.H., and Elena J. Derkits, B.A. (1), published in the March 2010 issue of the Journal, provided further evidence of a possible role of prenatal infection and maternal immune response in the etiology of schizophrenia. The authors also emphasized the importance of gene-environment interplay in neurodevelopmental disturbance leading to schizophrenia. However, the hypothesis of the single prenatal viral or immunological effect on the developing brain as a predisposing factor to schizophrenia cannot explain the variable long-term course of the illness.

A recent discovery of intracellular RNA-based gene inactivation machinery (short interfering RNA-induced silen cing complex) (2) suggested a mechanism of the natural defense against neurotropic viruses. RNA-induced silencing complex is the natural mechanism that prevents viruses from producing functional proteins. Such cellular defense can inhibit production of HIV and poliovirus (2–3). In some cases, the viral infection can be cleared; in other cases a virus can escape (4).

A hypothetical genetic variation in RNA-induced silencing complex may explain a variability of illness progression in schizophrenia: in some affected individuals, RNA-induced silencing complex controls an expression of schizovirus, while in others genetic polymorphism in RNA-induced silencing complex may lead to overstimulation of the cellular defense with temporary silencing of both schizoviral RNA and some host cell RNAs. Such dysregulation in the RNA-induced silencing complex response may increase dopamine production in affected neurons and lead to transient positive symptoms of schizophrenia, a clinical presentation consistent with "cycloid psychosis"(5). In some other patients, the underresponsive defense leads to a fast progression of neuronal damage and early development of deficit schizophrenia (6). In a majority of cases, overstimulation of RNA-induced silencing complex and eventual viral escape from the short interfering RNA inhibition is represented by often intermittent positive psychotic symptoms and progression of negative symptoms. Thus, suggested polymorphisms in the RNA-induced silencing complex genes may be related to genetic vulnerability to schizophrenia and a progression of the disease.

There is a lack of studies of RNA-induced silencing complex activity in humans. It is tempting, however, to suggest that a study of intracellular RNA defense may help to identify infectious agents, predisposing to schizophrenia, and that a development of short interfering RNA therapy may potentially cure some schizophrenia spectrum disorders.

Natural Antiviral Cellular Defense in Relation to Positive and Negative Symptoms of Schizophrenia?

Вакцина от кокаиновой зависимости

Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier.

Pharmacotherapy for cocaine dependence: Most evidence is weak

Study	Design	Results
Disulfiram
Pani et al, 20108	Meta-analysis of 7 studies with 492 cocaine-dependent patients	Researchers found ‘low evidence’ supporting disulfiram for treating cocaine dependence
Modafinil
Dackis et al, 20059	62 cocaine-dependent patients randomized to modafinil, 400 mg/d, or placebo for 8 weeks	Patients receiving modafinil provided significantly more BE-negative urine samples and were significantly more likely to achieve ≥3 weeks of cocaine abstinence
Anderson et al, 200910	210 cocaine-dependent patients randomized to modafinil, 200 mg/d or 400 mg/d, or placebo for 12 weeks	Modafinil significantly reduced cocaine craving but did not significantly improve the average weekly percentage of cocaine non-use days
Tiagabine
Winhusen et al, 200711	141 cocaine-dependent patients randomized to tiagabine, 20 mg/d, or placebo for 12 weeks	No significant changes in cocaine use vs placebo as measured by self-report and urine BE
Baclofen
Kahn et al, 200912	Cocaine-dependent patients randomized to baclofen, 60 mg/d, or placebo for 8 weeks	No significant difference between groups in cocaine use as measured by urine BE
Ondansetron
Johnson et al, 200613	63 cocaine-dependent patients randomized to ondansetron, 0.25 mg, 1 mg, or 4 mg twice daily, or placebo for 10 weeks	The odansetron 4 mg group had a significantly greater rate of improvement in percentage of patients with a cocaine-free week compared with the placebo group
BE: benzoylecgonine

Vaccine for cocaine addiction: A promising new immunotherapy