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

Празозин как препарат выбора при ночных кошмарах в структуре ПТСР

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented. In open-label trials, a chart review, and placebo-controlled trials,prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo. In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.

 PTSD nightmares: Prazosin and atypical antipsychotics

Глюкокортикостероиды и риск суицида

Glucocorticoid medications given in primary care settings are associated with suicidal behaviors and severe neuropsychiatric disorders, new research suggests.

In a large, population-based study of adult patients in the United Kingdom (UK), those receiving glucocorticoids were almost 7 times more likely to commit or attempt suicide, more than 5 times more likely to develop delirium, more than 4 times more likely to develop mania, and almost twice as likely to develop depression than those with the same underlying conditions who did not receive the medications.

In addition, patients younger than 30 years were at particular risk for suicide attempts, women were more at risk for depression, and men were at especially increased risk for mania and delirium/confusion/disorientation. Higher dosages of the medications were also linked to an overall greater risk for adverse outcomes.

 Glucocorticoids Linked to Suicide, Neuropsychiatric Disorders

Запах шизофрении

They collected the sweat from 14 white male patients with schizophrenia and 14 comparable patients with ‘organic brain syndromes’ and found they could train rats to reliably distinguish the odours while a human panel of sweat sniffers seemed to be able to do the same.
Seemingly backed up by the nasal ninja skills of two different species, science attempted to determine the source of the ‘schizophrenic odour’.
Two years later researchers from Washington suggested the smell might be triggered by the bacteria Pseudomonas aeruginosa but an investigation found it was no more common in people with schizophrenia than those without the diagnosis.
But just before the end of the 60s, the original research team dropped a scientific bombshell. They claimed to have identified the schizophrenia specific scent and got their results published in glittery headline journalScience.
Using gas chromotography they identified the ‘odorous substance’ as trans-3-methyl-2-hexenoic acid, now known as TMHA.

Looking back, we now know that TMHA is genuinely an important component in sweat odour. Curiously, it turns out it is largely restricted to Caucasian populations but no link to mental illness or psychiatric disorder has ever been confirmed.
The theory seems like an curious anomaly in the history of psychiatry but it occasionally makes a reappearance. In 2005 study claimed that the odour exists but is “complex and cannot be limited to a single compound, but rather to a global variation of the body odor” but no replications or further investigations followed.

A whiff of madness

Метирапон и психотравмирующие воспоминания

“Metyrapone is a drug that significantly decreases the levels of cortisol, a stress hormone that is involved in memory recall,” explained lead author Marie-France Marin, a doctoral student.

Manipulating cortisol close to the time of forming new memories can decrease the negative emotions that may be associated with them, the researchers said.

“The results show that when we decrease stress hormone levels at the time of recall of a negative event, we can impair the memory for this negative event with a long-lasting effect,” said Sonia Lupien, Ph.D., who directed the research.

The Drug Metyrapone to Erase Bad Memories?

Метаболические расстройства коморбидные с БАР

Chronic stress, which patients experience during both the manic and the depressive phases of bipolar disorder, is associated with increased cortisol levels, lack of cortisol suppression, and changes in hypothalamic-pituitary-adrenal axis responses. This metabolic dysregulation may increase insulin resistance and can lead to hyperglycemia, increased oxidative stress, metabolic syndrome, and atherosclerosis. In addition, patients with bipolar illness have increased activity of the sympathetic nervous system, which may also lead to insulin resistance, metabolic syndrome, and increased risk of sudden cardiac death.2

Depressive syndromes may be neurotoxic. Abnormalities in cellular plasticity, cellular resilience, and intracellular signaling, as well as alterations in the size, shape, and density of neurons and glia, have been found. Studies employing neuroimaging and neuropsychological tests have demonstrated abnormalities in brain morphology and function in patient populations with depressive syndromes and in those with diabetes. Common physiologic mechanisms have been implicated, including insulin-glucose homeostasis, immuno-inflammatory processes, and oxidative stress mechanisms.


Metabolic Comorbidities in Patients With Bipolar Disorder

Волосы как биомаркер стресса и сердечных заболеваний

Cortisol is considered to be a stress hormone. Its secretion is increased during times of stress.

Traditionally it’s been measured in serum, urine and saliva, but that only shows stress at the time of measurement, not over longer periods of time. Cortisol is also captured in the hair shaft.

Koren and Uum believe hair analysis can provide an accurate assessment of stress levels in the months prior to an acute event such as a heart attack.

“We know that on average, hair grows one centimetre (cm) a month, and so if we take a hair sample six cm long, we can determine stress levels for six months by measuring the cortisol level in the hair.”

Hair as Biomarker of Stress and Heart Disease

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

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

Кортизол и память

В Лейденском университете защищена диссертация на тему ''Ускользающее из памяти'' (ориг. на англ. ''Fading memories''). Автор работы - M.Tollenaar (ф-т социальных наук). Исследование посвящено непосредственным и долговременным эффектам гормонов стресса на способность вспомнить что-либо. Исследовательница изучала прежде всего гормоны стресс: кортизол и (нор)адреналин. Диссертация показывает, что стресс или добавление кортизола приводят к ухудшению памяти. Эти эффекты лучше всего просматривались при попытке воспроизведения заученных слов, но практически не затрагивали личные воспоминания. Если под воздействием только стресса люди затруднялись припомнить менее эмоциональные слова, то при добавлении кортизола они уже хуже справлялись с задачей припоминания нейтральных слов. Самым важной новой находкой является то, что острый стресс в сочетании с некоторой дозой кортизола производит также долговременный эффект в части воспоминания нейтральных и эмоциональных слов. Автор не обнаружила воздействия стресса и кортизола на эмоциональные переживания воспоминаний. Исследовательница планирует в будущем исследовать эффекты гормонов стресса на автобиографические воспоминания. Это позволит лучше понять применение кортизола и пропранолола в клинической практике.

МНИИП

эндокринные эффекты нормотимиков

Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was reported to enhance leptin and insulin blood level and increased body weight, whereas topiramate showed an opposite effect. In contrast to thyroid and gonadal hormones, only a few data concern antiepileptic drug action in HPA axis. To this end, no effect of antiepileptic drugs on adrenocorticotropic hormone (ACTH)/cortisol circadian rhytmicity was found. Valproate decreased CRH release in rats, whereas lamotrigine stabilized ACTH/cortisol secretion. Moreover, felbamate was found to inhibit stress-induced corticosterone release in mice. Interestingly, recent data suggest that felbamat and some other new antiepileptic drugs may inhibit transcriptional activity of glucocorticoid receptors. Summing up, the above data suggest that traditional antiepileptic drugs may cause endocrine disturbances, especially in gonadal hormones.
Endocrine effects of antiepileptic drugs

+ Effects of antiepileptic drugs on immune system

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