Pro-inflammatory cytokines in depression

Cytokines are protein molecules. Produced by cells of the thymus gland, immune system, spleen, blood. 90% of cytokines are secreted by B and T lymphocytes. Cytokines perform various functions in the human body, but their main task is to ensure interaction between cells. More than 200 cytokines have been discovered so far. According to the mechanism of action, they are divided into:

  • pro-inflammatory cytokines (interleukin 1,2, 6, 8, interferon);
  • anti-inflammatory cytokines (interleukin 4.10).

Cytokines are essential for the normal development and functioning of the brain. They affect neurotransmitters – serotonin, dopamine, GABA. The introduction of proinflammatory cytokines or the activation of immune cells activate the adaptive capabilities of humans against viruses and bacteria. Promote recovery from traumatic brain injury.

But the constant stimulation of proinflammatory cytokines leads to long-term changes in the level of neurotransmitters , which leads to mental disorders, including depression.

 The effect of cytokines on behavior is associated with the activation of inflammatory processes in the brain, which contributes to the imbalance of monoamines, glutamate, neuropeptides, and a decrease in the production of growth factor – a neurotrophic factor in the brain. In addition, pro-inflammatory cytokines are produced during obesity, childhood mental trauma, stress, poor sleep, which also causes depression.  

Evoked potentials and depression

Evoked potential studies (auditory, cognitive, visual, sympathetic) show changes in the electrical activity of the brain in response to certain stimuli. The amplitude of the evoked potentials is small and ranges from tenths of a microvolt to several microvolts.

When interpreting survey data, methods are used that are independent of the reporting point. Analysis of field strength, dipole signal curves is preferred. Time division into different components is used to isolate a single peak in the signal curve. Evoked potentials from stimulation with simple stimuli are usually investigated.

 In psychiatric practice, stimuli are compared with the cognitive assessment of the signal, the degree of concentration of attention.

By modality, evoked potentials are divided into:

  • auditory;
  • somatosensory;
  • visual;
  • olfactory.

Auditory evoked potentials P50 appear in 50 msec . after clicking. The auditory cortex of the temporal lobe is responsible for the reaction.

Auditory evoked potential N-100 is induced in the superior temporal gyrus and is modulated by attention.

Auditory P300 evoked potentials arise in response to frequent stimuli. The patient must calculate these stimuli at the push of a button. Signals are divided into: P300a and P300b. P300a is a reflection of orientation response, P300b is associated with attention and cognitive ability. The temporal and parietal lobes are responsible for its occurrence. With depression, a change in the shape and amplitude of N100-P200 is observed and reflects serotonergic activity and the intensity of serotonin metabolism.

Withdrawal of SSRI antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression. Withdrawal symptoms may occur after treatment with these drugs. It can start suddenly. It will manifest itself as symptoms of depression, anxiety. At the same time, patients believe that they are depressed again and ask to prescribe medications again.

Withdrawal syndrome depends on the half-life of the drug. The half-life is the time at which the active substance of the drug remains in the blood. Drugs with a short half-life require more frequent administration to maintain adequate drug concentration. If the drug has a long half-life, then it is stable in the blood for a long time and does not undergo changes in concentration. Fluoxetine has a long half-life. Therefore, after stopping its intake, its concentration in the blood decreases slowly. Other antidepressants in the SSRI group have a shortened half-life, so when you stop taking the drug, the patient experiences withdrawal.

In general, long-term use of SSRIs affects the biochemical processes in the brain. The number of serotonin receptors decreases, since the SSRI causes an increased secretion of serotonin – a serotonin burst. At the same time, the number of serotonin receptors in the brain decreases to prevent increased stimulation of brain neurons. After the end of treatment, the receptors become smaller and there is a decrease in serotonin activity.

20% of patients using cipralex , zoloft , paxil experience withdrawal symptoms after depression treatment. Withdrawal symptoms can last from one to seven weeks, and those who have been using SSRIs for many years have long-term withdrawal symptoms. Therefore, in order to avoid withdrawal syndrome, the dose of SSRIs is reduced slowly. If the drug has been used for less than 8 weeks, dose reduction should be carried out within one to two weeks. If the medication was taken for more than 6-8 months, then a dose reduction is required within 6-8 weeks.

Treatment of depression with SSRI drugs should be carried out while monitoring the concentration of the drug in the blood, and when deciding on drug withdrawal, one should also rely on objective criteria.

Optogenetic stimulation and treatment of depression

In recent years, the science of optogenetics , a field of neurobiology , has been developing . Optical and genetic methods are used to study neural connections, neuronal excitation, and the activity of neural networks. A number of microbial opsin proteins are used :

  • ChR2 ( Channelrhodopsins );
  •  VChR1;
  •  galorhodopsin ( Halorhodopsin ); 
  • arherhodopsin ( Archaerhodopsin ) 

Proteins can be injected into neurons and act as ion channels that open or close when exposed to light. When exposed to 470 nm light, Channelrhodopsin-2 transmits Na + into neurons. Using the properties of opsins allows you to improve the method of deep brain stimulation ( Deep Brain Stimulation .   

Selective activation and inactivation of the fibers of the brain substance is a more modern method of treating Parkinson’s disease, cluster headaches. But the technology requires surgical intervention – electrode implantation , but stimulation occurs contactlessly, under the influence of photoactivation . The study of the effects of deep brain stimulation using opsins has just begun. But there is already evidence of the antidepressant effects of optogenetic stimulation of the prefrontal medial cerebral cortex. Devices based on this principle of operation are portable and can be used by the patient at any time of the day. 

Electroconvulsive therapy and treatment of depression

Electroconvulsive therapy has a proven mechanism of action. When using it, the level of norepinephrine and other catecholamines in the hippocampus, frontal cortex, and basal ganglia increases. Dopamine secretion is increased in the striatum.

The indications for the appointment of electroconvulsive therapy (ECT) are:

  • depression in the context of bipolar disorder and paroxysmal schizophrenia; 
  • resistant depressive states.

There are emergency and routine indications for ECT. Emergency indications include:

  • depression with strong motor response and physical exhaustion;
  •  depression with thoughts of sinfulness and suicidal intentions;
  • stuporous depression with longing and refusal to eat;
  • depression with motor retardation, self-blame;
  • depression with Kotard’s delusions (nihilistic statements).

Emergency indications for ECT include:

  • depression with hypochondriacal delirium;
  • depression with paranoid elements.

Before ECT, it is necessary to determine the somatic and neurological status. The patient is examined for a general analysis of blood, urine, EGC, blood biochemical parameters. Consultations are carried out: therapist, ophthalmologist, neuropathologist, gynecologist. X-rays of the spine are taken. 

Contraindications for ECT are: 

  • fevers of an inflammatory nature;
  • heart defects;
  • arrhythmias;
  • aortic aneurysm;
  • tuberculosis;
  • bronchial asthma;
  • osteoporosis;
  • osteomyelitis;
  • ulcerative bleeding;
  • organic lesions of the brain;
  • glaucoma.

Electroconvulsive treatment of depression is carried out using anesthesia, muscle relaxants, atropine, which reduces the risk of complications. And it is a necessary procedure in the treatment of drug-resistant depression. 

Role of neuropeptides in various mental disorders

Neuropeptides are produced in the central nervous system and are implicated in a variety of mental disorders and anxiety conditions. They are involved in the regulation of various processes at the cellular and organ levels. 

At the cell level, a neuropeptide can be involved in the development of mental disorders, since it can interact with a classical neurotransmitter that triggers the disease process. At the organ level, the neuropeptide plays a role in neuronal function.  

Neuropeptides such as substance P, corticotropin- releasing factor, neuropeptide Y, galanin , vasopressin can cause depression and anxiety. The alteration of monoaminergic transmission is the mechanism through which neuropeptides affect mental disorders. Therefore, receptors and neuropeptides are promising targets for drug action in the treatment of depression and anxiety.

 In recent years, agonists and antagonists of neuropeptide receptors, which easily pass through the blood-brain barrier, have been intensively studied . Thus, the action of non-protein antagonists of the CRF receptor subtype as a new drug approach for the treatment of anxiety and depression is of interest . Because clinical studies have shown impaired functions of the hypothalamic-pituitary adrenal axis and increased CRF levels in depression and anxiety.  

Neuropeptides and their effect on them or on their receptors are a new approach to the treatment of depression and anxiety. Advances in science are deepening knowledge of the etiology of depression and anxiety, contributing to a paradigm shift in the diagnosis and treatment of mental illness.

Anxiety and depression

Depression and anxiety are normal human reactions to stress, loss of loved ones, and frustration. They often accompany each other. But in terms of pathogenesis, these are different conditions. Anxiety is the “combat readiness” of the human body for a quick response to stress. And depression is a depressed state with a feeling of hopelessness and loss of the meaning of life. Some depressions develop after anxiety and prolonged stress. These two normal reactions must be distinguished from pathological diseases — anxiety disorders and depression. Diseases are referred to as affective disorders. Depression and anxiety are involved in the development of somatic diseases – bronchial asthma, heart attack, hypertension. Among all mental illnesses, depression and anxiety are the most common. According to statistics, in the United States, major depressive episode occurs in 17.3% of cases, anxiety spectrum disorder – 24.5%, social phobia – 13%, post-traumatic stress disorder – 8%, genetralized anxiety disorder – 5%. The cost of treating a depressive disorder in Europe is one hundred billion euros, and the cost of treating anxiety disorders is forty billion euros.

The characteristics of depression are:

  • weakening of life incentives;
  • dreary, anxious mood;
  • lack of emotional reactions;
  • pessimism in thinking;
  • decrease in cognitive abilities;
  • minimization of physical activity;
  • loss of sexual instinct;
  • suicidal tendencies.

Vegetative and somatic manifestations are often accompanied by headaches, insomnia, loss of appetite, decreased salivation, hypertension, amenorrhea, tachycardia, constipation, mydriasis . Thinking is dominated by: lethargy, ideas of self-destruction, a pessimistic view of the world, lack of planning for the future. It also lacks the ability to predict events and a sense of time.

Anxiety is manifested by anxiety and internal tension, a sense of threat and a pessimistic mood. The main difference between anxiety and fear is objectlessness and orientation to the future. Fear is based on an object, triggers a defense mechanism, and is a reaction to real events.

Depression and anxiety as symptoms accompany many mental illnesses. Therefore, the treatment of these disorders must be carried out according to etiological and pathogenetic criteria.

Antidepressants found to work

Doctors have conducted a new systematic analysis of the effectiveness of antidepressants. According to their findings, such medications do help fight depression, although their effectiveness is not uniform. An article with the results was published in the Lancet .  

Depression is becoming the most common cause of disability in the world, affecting 350 million people, an increase of 20% between 2005 and 2015. At the same time, only every sixth patient in developed countries receives the correct treatment, and in poor countries only one in 27. Scientists conclude that millions of people should be prescribed either medication or some form of psychotherapy.

“Antidepressants are effective at fighting depression,” says first author Andrea Cipriani of the UK’s National Institute for Health Research. “Untreated depression is a huge problem because of the burden on society.” The problem is also compounded by the fact that many patients and doctors are skeptical about antidepressants: in some studies, their effectiveness is not much higher than that of placebo; some believe that pharmaceutical companies are conducting unfair tests; some patients refuse to take mental health pills.

The new work took six years and includes all the available data on studies of the comparative effectiveness of antidepressants in pairs with a placebo or with each other – there were more than 500 such studies. The total number of patients exceeded 116 thousand people. It was possible to obtain data on 21 antidepressants. The most famous drug of this class – Prozac , which after the expiration of the patent is often called fluoxetine – turned out to be one of the least effective. On the other hand, its tolerability was found to be very high: this was measured by the proportion of courses completed and the reported side effects. The most effective was amitriptyline, which became the sixth in the list of tolerances. 

Comparison of the effectiveness of some antidepressants and placebo. One means the same efficiency.

The Lancet / Oxford University

The situation with antidepressants is further complicated by the fact that in many cases the mechanism of their action is not completely clear. Most of them can be classified as selective serotonin reuptake inhibitors. It is believed that they should cause an increase in the amount of the neurotransmitter serotonin in the brain, but there is no absolutely accurate data on this. Scientists attribute the merits of the new work to the fact that it takes into account unpublished data from their own studies of pharmaceutical companies. The analysis showed that sponsorship by drug manufacturers did not affect the conclusions of such studies, which contradicts the view that such results are lobbied .

Scientists urge people to donate their brains to science after death

Scientists around the world are calling on people suffering from mental illnesses such as depression and PTSD to donate their brains to research after death. It is reported by BBC News .  

Recently, researchers have found a link between the shape of the human brain and mental or neurological disorders. Now experts want to develop new treatments for these disorders.

One of the largest brain banks, the Harvard Brain Tissue Resource Center at McLean Psychiatric Hospital near Boston houses more than 3,000 brains. Most of the samples were obtained from people with mental or neurological disorders. Researchers are requesting samples to find new treatments for Parkinson’s, Alzheimer’s, and other mental disorders. However, there are still not enough samples to carry out comprehensive studies.

New treatments for many mental and neurological diseases are within reach of the scientific community, according to McLean Kerry Ressler , Chief Research Fellow at McLean Hospital . However, a lack of brain tissue samples is holding back the development of these methods.

“If people think that there are no changes in the brains of those who suffer from depression or PTSD, then there is no point in donating their brains for research, because they think that nothing can be found there. But this concept is fundamentally wrong from a biological point of view, ”said Sabina Beretta , Scientific Director of the Harvard Brain Tissue Resource Center.  

In Russia, they learned how to diagnose depressive disorders by hair

Neurobiologists from the Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences have developed a non-invasive method for analyzing the level of cortisol in the body. A new method for determining the stress hormone in hair will help in the treatment and prevention of depression. Scientists have submitted their work in the journal Metabolic Brain Disease . The research was supported by a grant from the Russian Science Foundation.     

Chronic stress is responsible for a variety of mental disorders, including depressive disorders. The pace of modern life creates additional stress factors that accompany urbanization, the continuous increase in the volume of current information, and the complication of social and personal life. The accumulation of negative emotions leads to the fact that the prevalence of depression is steadily increasing, and, according to the forecast of the World Health Organization, by 2030 depression will move to the first place among diseases.

The body’s stress reactivity, that is, its response to stressful stimuli, largely determines the likelihood of developing depression. Therefore, the assessment of stress reactivity allows us to assess the propensity of a person to develop post-stress depression.

“In accordance with our working hypothesis, the pathogenesis of depressive disorders is closely related to the patient’s inability to adequately respond to stress. In other words, impaired stress reactivity is a central biological component of this group of diseases, and its study allows not only understanding the patterns of depression development, but also assessing the patient’s condition and the effectiveness of his treatment, ”says Natalia Gulyaeva, head of the RSF grant.

The stress response is formed by the so-called hypothalamus-pituitary-adrenal axis. The hypothalamus produces a neurohormone , corticotropin- releasing factor (CRF), which stimulates the formation of the hormone adrenocorticotropin (ACTH) in the pituitary gland . This hormone enters the bloodstream and causes the adrenal cortex to secrete stress hormones corticosteroids, mainly cortisol. Cortisol, which travels through the blood to all cells in the body, alters its metabolism, providing the substances that are necessary to adequately respond to stress.

Correction of impaired stress reactivity is a promising approach for effective treatment and prevention of depression. The main molecular and cellular mechanisms underlying stress reactivity and its disturbances are the functioning of the hypothalamic-pituitary-adrenal neuroendocrine axis, and in the brain – the balance of neurotransmitters and neurotrophic factors, as well as the cytokine system. Disruption of these interconnected systems, leading to numerous structural and functional changes in the brain, underlies the pathogenesis of depression. It is these systems and processes that are potential targets for the prevention and treatment of depressive disorders.

However, the validity of a single determination of cortisol in human biological fluids, primarily in blood, is not high due to significant fluctuations in the level of this hormone during the day. Now biologists have developed and tested in practice a new method of non-invasive (without penetration into the body) assessment of the level of cortisol in the human body.

“Determination of cortisol in the hair of depressed patients and healthy people allowed us to compare the functioning of their main stress-implementing link during the month before the examination. Hair cortisol levels were significantly lower in women with depressive disorder than in healthy women of the corresponding age, with hair cortisol levels being lower as the severity of depression increased. This indicates suppression of the hypothalamic-pituitary-adrenal axis in female patients with depression, which is the basis of their impaired stress reactivity, ”Gulyaeva said.

Currently, on the basis of the SPC of Psychoneurology named after Z.P. Soloviev of the Moscow Healthcare Department, which took an active part in the project, clinical trials are continuing using the developed method. This approach provides scientists and clinicians with an effective, non-invasive means of assessing disease progression and the effectiveness of treatment for depression.