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

Потенциальные механизмы лечения депрессии

EMERGING THERAPEUTIC TARGETS


Consider the following novel mechanisms that may become the basis for creating entirely new antidepressants in the foreseeable future, by design, not by serendipity:

• corticotropin-releasing factor (CRF) and glucocorticoids

         – CRF antagonists
           – vasopressin receptor antagonists
           – glucocorticoids as agonists or antagonists

• neurokinin system
• brain derived neurotropic factor (BDNF) and other neurotropins, such as fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF)
• phosphodiesterase inhibitors
• glutamate pathway modulators

        – ketamine (IV infusion with immediate efficacy)
          – α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor modulators
          – glycine

• hypothalamic feeding peptides
• circadian gene products
• other evolving antidepressants

        – K-opioid receptor antagonists
          – CB1 cannabinoid receptor agonists/antagonists
          – cytokines
          – melatonin receptor agonists
          – galanin
          – neuropeptide Y
          – histone deacetylase inhibitors
          – tissue plasminogen activator

 The hazards of serendipity

Бисфенол А, эндокринная дисфункция и патогенез шизофрении

In recent years, numerous substances have been identified as so-called ‘‘endocrine disruptors’’ because exposure to them results in disruption of normal endocrine function with possible adverse health outcomes. The pathologic and behavioral abnormalities attributed to exposure to endocrine disruptors like bisphenol-A (BPA) have been studied in animals. Mental conditions ranging from cognitive impairment to autism have been linked to BPA exposure by more than one investigation. Concurrent with these developments in BPA research, schizophrenia research has continued to find evidence of possible endocrine or neuroendocrine involvement in the disease. Sufficient information now exists for a comparison of the neurotoxicological and behavioral pathology associated with exposure to BPA and other endocrine disruptors to the abnormalities observed in schizophrenia. This review summarizes these findings and proposes a theory of endocrine disruption, like that observed from BPA exposure, as a pathway of schizophrenia pathogenesis

BPA is a common ingredient of many plastic and resin products including food and drink containers, internal linings of food cans, and dental enamels. Also known as 2,2-bis(4-hydroxyphenyl) propane, BPA was invented in the 20th century and is manufactured by combining acetone and phenol. Emerging research indicates BPA is an estrogenic EDC that alters or interferes with normal endocrine development in various vertebrate and invertebrate species.

Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia

Влияние нестероидных противовоспалительных средств на антидепрессивное действие СИОЗС

Cytokines may be important in depression. These immunomodulators are produced by glial cells, regulate brain serotonin and noradrenergic systems, and activate the hypothalamic-pituitary-adrenal axis. Antidepressants increase levels of p11, a specific protein that regulates depression in rodent models and interacts with the serotonin receptor. To learn about possible interactions of antidepressants, cytokines, p11, and anti-inflammatory drugs (NSAIDs), researchers conducted experiments in mice and reanalyzed data from the large STAR*D study.

The selective serotonin reuptake inhibitors citalopram and fluoxetine increased p11 levels in mouse frontal cortex, but coadministered ibuprofen (IBU) or acetylsalicylic acid (ASA) blocked this increase. IBU lowered plasma citalopram levels. The tricyclic desipramine produced a small p11 increase, which was not affected by IBU or ASA. Antidepressant-related p11 increases were dependent on signaling by two cytokines (interferon-gamma and tumor necrosis factor-alpha). In a mouse model of depression, IBU, ASA, and acetaminophen prevented the behavioral response to SSRIs but not to antidepressants of other types.

Of STAR*D patients who took citalopram for 12 weeks, significantly fewer achieved remission if taking NSAIDs than if not taking NSAIDs (45% vs. 55%). Findings were similar in a comparison of other analgesic use with nonuse (37% vs. 54%).

Do Analgesics Interfere with Efficacy of Selective Serotonin Reuptake Inhibitors?

Дексаметазоновый тест и критерии DSM

Starting from discoveries in the early 19th century about the basics of the endocrine system, it traces the identification of adrenal steroids in the early 20th century and finally the landmark clinical studies of the 1970s and 1980s that almost resulted in the DST becoming a standard of psychiatric diagnosis. Unfortunately, DSM-III diagnostic criteria did not reliably identify patients with positive DST results. Instead of questioning the DSM criteria, the DST was discarded as faulty.

Endocrine Psychiatry: The Dexamethasone Suppression Test and Electroconvulsive Therapy

Семейная история тревожных и депрессивных расстройств и утренний уровень кортизола

Background

It is unclear whether altered hypothalamic–pituitary–adrenal (HPA) axis regulation, which frequently accompanies depression and anxiety disorders, represents a trait rather than a state factor.

Aims

To examine whether HPA axis dysregulation represents a biological vulnerability for these disorders, we compared cortisol levels in unaffected people with and without a parental history of depressive or anxiety disorders. We additionally examined whether possible HPA axis dysregulations resemble those observed in participants with depression or anxiety disorders.

Method

Data were from the Netherlands Study of Depression and Anxiety. Within the participants without a lifetime diagnoses of depression or anxiety disorders, three groups were distinguished: 180 people without parental history, 114 with self-reported parental history and 74 with CIDI-diagnosed parental history. These groups were additionally compared with people with major depressive disorder or panic disorder with agoraphobia (n = 1262). Salivary cortisol samples were obtained upon awakening, and 30, 45 and 60 min later.

Results

As compared with unaffected participants without parental history, unaffected individuals with diagnosed parental history of depression or anxiety showed a significantly higher cortisol awakening curve (effect size (d) = 0.50), which was similar to that observed in the participants with depression or anxiety disorders. Unaffected people with self-reported parental history did not differ in awakening cortisol levels from unaffected people without parental history.

Conclusions

Unaffected individuals with parental history of depression or anxiety showed a higher cortisol awakening curve, similar to that of the participants with depression or anxiety disorders. This suggests that a higher cortisol awakening curve reflects a trait marker, indicating an underlying biological vulnerability for the development of depressive and anxiety disorders.
Parental history of depression or anxiety and the cortisol awakening response

Длительность нелеченного психоза и длительность нелеченного заболевания

An 8 year prospective study conducted in first episode patients found that DUP was an independent predictor of prognosis in the medium to long term and that outcomes for psychopathological domains were significantly worse when DUP exceeded 3 months.23 Subsequent studies confirmed the association between a longer DUP and a worse outcome of negative symptoms3 as well as a poor influence on cognitive symptoms.24 In addition, other studies with large samples indicating a worse outcome in schizophrenics with longer DUP in terms of more severe positive, negative, and cognitive symptoms have been recently reported.9,10,25-27 In two previous studies by our group, an association between a longer DUP and a greater number of suicide attempters and a higher number of recurrences were found.28,29

In relation to neurobiological mechanisms, it has been hypothesized that the adverse effects on outcome associated with untreated psychosis may be biologically mediated. One toxicity model suggests that N-methyl-d-aspartic (NMDA) acid receptor hypofunctioning may induce psychosis and produce glutamatergically-medicated excitotoxic damage in neurons at the same time.30,31 For the latter, NMDA receptor hypofunction would result in reduced activation of GABAergic inhibitory neurons, leading to an excitotoxic state.31 Alternatively, prolonged stress, including stress resulting from untreated psychosis, may activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to greater glucocorticoid secretion which may contribute to neuronal damage.32 However, the evidence for neurotoxicity stemming from untreated psychosis is still an object of debate and there is as yet little evidence of an effect of long DUP on brain morphology. Furthermore, the possibility of cognitive dysfunction being a neurotoxic consequence of delayed treatment with antipsychotic drugs has been advanced, but this is only a hypothesis given that cognitive impairment may begin prior to the onset of psychosis and is poorly affected by available antipsychotics.

The hypothesis that not only schizophrenia and psychotic spectrum disorders but also depressive disorders tend to show anatomical deficits with the progression of the illness has been recently supported by a large meta-analysis conducted on 64 studies which reported that compared to healthy controls, depressed patients showed large volume reductions in frontal regions, particularly in the anterior cingulate and orbitofrontal cortex with smaller reductions in the prefrontal cortex. In addition, the hippocampus, putamen, and caudate nucleus showed moderate volume reductions.35 As a consequence, the hypothesis that early effective antidepressant treatments may block and partially reverse the neurobiological modifications occurring with the progression of the untreated depressive episode may be advanced.

To date, studies specifically investigating the role of the DUI in anxiety disorders have been conducted in panic disorder, generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD). Indeed, a study examining the cause and length of delays in reaching primary care and specialist services amongst patients with anxiety disorders indicated that patients with social phobia reported longer delays in reaching specialist care (>9 years) compared with patients with GAD or panic disorder.70

Duration of Untreated Psychosis and Duration of Untreated Illness: New Vistas

SeCA-депрессия

Тревога, сниженный фон настроения, (ауто)агрессивность часто взаимосвязаны, так же как и нозологические категории расстройств настроения и тревожных расстройств. Вследствие этого возникают сложности и в клинической практике, и в исследовательской работе. В клинике перед врачом встают вопросы: какие симптомы или расстройства надо лечить? Надо ли лечить все? В исследовательской работе - какие симптомы или расстройства коррелирует с полученными данными? Для решения этих проблем предложено два подхода: правила иерархического исключения и комбинированные диагнозы. Применение первого подхода является не вполне адекватным, так как ни одна проблема не может быть решена путем ее исключения. Второй подход, связанным с применением комбинированного диагноза, к примеру, атипичная депрессия, или смешанные тревожно-депрессивные расстройства, также не вполне правомочен. Предложенная нами недавно концепция “тревожно-агрессивной депрессии, провоцируемой стрессом, индуцируемой кортизолом и связанной с серотонином” (СеТА депрессии) определяет (пока гипотетически) подтип депрессии, при которой неконтролируемую чувства тревоги и агрессивность предшествуют и задают ритм снижению настроения. Повышенная ранимость, обусловленная невротическими особенностями личности, предрасполагает к возникновению СеТАдепрессии. В основе ее развития от психотравмирующих переживаний к психопатологии - сначала тревоги и агрессивности, а затем депрессии — лежит нарушение функции опальной связи между серотонинергической и гипоталамо-гипофизарно-адренокортикальной системами.

Депрессия, тревожные расстройства, агрессия: попытки распутать гордиев узел

Антидепрессанты и нейрогенез

Antidepressants and Neurogenesis in Humans

Кортиколиберин-дексаметазоновый тест

Кортиколиберин-дексаметазоновый тест имеет большую специфичность в отношении депрессивных больных по сравнению с дексаметазоновым тестом. Если специфичность дексаметазонового теста не превышала 50%, то, по данным зарубежных авторов, специфичность кортиколиберин-дексаметазонового теста составляет 80-90% (11).

Тест состоит в том, что вечером больной получает дексаметазон - синтетический глюкокортикоид, по принципу обратной связи тормозящий активность гипоталамо-гипофизарно-надпочечниковой оси. На следующий день в 15.00 больному внутривенно вводят кортиколиберин, стимулирующий выброс АКТГ. В норме уровень кортизола и АКТГ остаётся очень низким, т.к. после подавления дексаметазоном ГГН-ось какое-то время не реагирует на стимуляцию. У пациентов с депрессией уровень кортизола и АКТГ резко возрастает через час после введения кортиколиберина, то есть подавление дексаметазоном оказывается недостаточным. Это отмечается в 90% случаев, что делает этот тест достаточно убедительным.
Я.А.Кочетков. - Депрессия и гипоталамо-гипофизарно-надпочечниковая система: новые стратегии изучения