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.  

Awaken the beast in me: optogenetics turned mice into predators

Scientists have been able to turn on neurons that make mice behave aggressively

Unlike rats, mice appear to us as peaceful creatures that feed on seeds, love cheese and can gnaw on soap in our country house. But what many see as the unshakable foundations of the world order can be changed. “Bearded” joke “Don’t wake the beast in me. – And we are not afraid of hamsters! takes on a new sound. Scientists from Yale University have demonstrated that a rodent, whose jaws are used to eat grains, can be turned into a formidable consumer of the second order, killing prey with one bite, if you turn on his “predatory instinct.” The meaning of the research paper published in the journal Cell  , of course, not in creating an army of bloodthirsty mice or shaking the foundations of the universe by swapping the places of predators and prey. In fact, through this experiment, a network of neurons was identified that is responsible for chasing prey.

Werewolf mice

If you look for videos where a mouse is eating someone, you can probably stumble upon the opposite situation: the mice themselves are eaten by tarantulas, millipedes, and even chickens. Now imagine ordinary mice that walk around the cage and do not give themselves away. But as soon as you turn on the laser, they all turn into “zombies”, which, like in the TV series “The Walking Dead”, begin to chase and bite everything in their path, even sticks and bottle caps.

“We turned on the laser, and they began to jump on objects, grab them with their paws and bite vigorously, as if they were trying to grab and kill prey,” – this is how the head of the research group Ivan de Arujo describes the mouse metamorphoses , an assistant professor of psychiatry at the Yale University School of Medicine from the laboratory named after John Pierce.  

What is the mechanism that made laboratory mice forget about their usual behavioral patterns and start attacking everything? Like werewolves from horror stories under the beam of the full moon, these rodents begin to show predatory habits under the influence of light. But do not rush to break the light bulb in the basement, because ordinary mice will not turn into ferocious and ruthless killers just like that.

The only known exception – the giant descendants of mice, accidentally brought by ships from Gough Island (Tristan da Cunha Archipelago, Atlantic Ocean), which feed on the chicks of the endemic songbird, the Gough Rovettian Bunting , and large sea albatrosses and petrels – only confirms the rule. The rodents that bred in the absence of natural enemies were forced to find a new source of food, and what else can you profit from on the island, where huge numbers of seabirds nest? But even these mice do not kill chicks (whose parents, by the way, can weigh as much as 300 times more predators), but simply bite off pieces of them, eating them alive (although, of course, it sounds and looks no less creepy, and the damage to the population of majestic rodents cause a lot of birds).   

Optogenetics : “bulbs in the head”

Optogenetics , a new method of controlling impulses inside a living organism with the help of light , helped to find brain regions that include the hunting instincts of animals . The possibilities of this approach are impressive: electrochemical impulses are the communication between neurons, so by controlling them, you can interfere with the work of the brain, erasing and changing memories and controlling emotions.

Optogenetics can also set muscles in motion (as it works, for example, in the cyborg stingray, which Indicator.Ru wrote about in his review) and help restore vision, because the proteins on the action of which the method is based are special opsins (in this case, they became kanorhodopsin 2, which in nature helps Reingard’s Chlamydomonas to float into the light ), are related to those that are in our cones and sticks of eyes. The carriers of special opsins (more precisely, the genes encoding them) into the cell are vectors – harmless viruses that embed the desired piece of DNA into the DNA of the cell. Being in the membrane, they change their shape, reacting to light of a certain wavelength, and pass positively charged ions inside the cell, which changes the ratio of charges inside and outside. As a result, a potential difference is formed and an electrochemical signal arises, which activates the chains and networks of nerve cells. 

By selectively manipulating different types of neurons, scientists have found a group that is responsible for stalking prey, and another one responsible for killing victims. The prey was not only non-living objects such as sticks, bottle caps, moving toy beetles, but also living insects (crickets).

Scientists also tried to selectively break the connections between neurons of each type and found that without the work of the ” biting ” mechanism, mice pursue prey, but cannot kill it. The bite force of their jaws in this case is reduced by 50%, and the newly minted would-be hunters are not able to commit the very deadly bite with which real predators kill prey almost instantly.

Where predator instinct dozed

Perhaps, invasive mice on Gough Island cannot overcome the same problem , which is why they practically eat albatross chicks alive. However, the chicks do not run away and cannot offer strong resistance, which, for example, is quite possible to expect from a wildebeest or a deer, whose powerful horns and hooves left no chance for a weak or sluggish predator to eat. Thus, they stimulate natural selection, which spurred wolves, lions and other hunters to learn how to kill quickly, preferably with one bite, because the second attempt may not be presented.

But in mice from the John Pierce Laboratory, if they are shined with a laser, these systems are activated, like in real predators. The systems are located in the amygdala – two groups of nuclei, or clusters of neurons, in the temporal lobes of the brain. These areas are closely related to the formation of emotions, and not only negative ones like fear and aggression, but also pleasure, and are included in the limbic system, which is responsible for the body’s adaptation to environmental conditions. Malfunctioning or damage to the tonsils is a possible cause of increased anxiety, depression, PTSD, and even autism. It is noteworthy that the amygdala is quite different in men and women, and in people of homosexual orientation, the structure of these areas is more similar to that of people of the opposite sex. Men’s amygdala is larger, and under stressful stimuli (including watching horror movies), the left is activated, triggering actions in response to emotions, while in women, the right. It’s funny that the connection of the amygdala with hunting instincts reminds of the old as the world stereotypes about the man-hunter and hunter.

Scientists are now trying to understand what information from the senses enters the amygdala in order to determine what triggers the mechanisms of predator behavior and how two groups of neurons are coordinated, one of which is responsible for the bite, and the other for the pursuit. “We have gained control over their anatomical incarnation, so we hope to be able to control them even more precisely in the future,” says de Arajo .

The Hunger Games

It is interesting that the animals did not bite their relatives, although correlations between the activity of the amygdala and the level of aggressiveness are known. “The system does not just increase aggression,” the authors of the work explain. “It seems to be related to the animal’s interest in getting food.” But hunger turned out to be associated with hunting instincts and forced the mice to actively pursue prey.

In nature, the behavior of predators often takes on complex and complex forms that are characteristic of many jaw- toots ( infratotype Gnathostomata , including the superclasses of fish and tetrapods), including humans. “This is the main evolutionary player in the formation of the brain,” notes de Arajo . “There must be a rudimentary subcortical pathway that connects the signals from the senses with jaw movement and biting .” 

The study grew out of scientists trying to understand which neural mechanisms are responsible for feeding animals. Laboratory staff watched how the mice lived in cages and how they ate. This led them to the idea of ​​studying the areas of the brain associated with hunting and feeding. There are many zones on this list, but one is responsible only for hunting, and not just food in general. This turned out to be the very central nucleus of the amygdala, which can also control the muscles of the jaws and neck involved in hunting. According to the authors of the study, this area is ideal for “switching on” the system of movements characteristic of hunting in maxillary vertebrates.

Russian scientists: depression is rooted in childhood

Scientists from the Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences analyzed the behavior of rat pups and proved that pro-inflammatory stress in childhood leads to the development of anxiety-depressive behavior in adulthood. Research on this phenomenon was supported by a grant from the Russian Science Foundation (RSF); its results were published in the journal Behavioral Brain Research .    

Pro-inflammatory stress is a stressful effect of a different nature, causing inflammation, in particular, in the brain tissue ( neuroinflammation ). At the same time, the cells of brain microglia , which have the properties of macrophages (cells of the immune system that capture and eliminate foreign or toxic particles), and astrocytes , also glial cells, secrete special chemicals, cytokines, which are mediators of inflammation. In the first stage, inflammation is an adaptive and beneficial process, but sometimes it goes too far. In such cases, excessive secretion of cytokines begins and processes develop that contribute to the degeneration and death of cells, in particular neurons.

“The starting point was quite simple: psychiatrists had long noticed that almost the majority of people with depression experienced some kind of serious stress trauma, such as violence, at an early age. In addition, it is known that problems in infancy or even prenatal age – fetal hypoxia or infection – lead to the development of a variety of diseases, including depression, ”said co-author of the article, Doctor of Biological Sciences, Professor Natalia Gulyaeva, head of the Laboratory of Functional Biochemistry of Nervous systems and deputy director of the Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences, head of the grant of the Russian Science Foundation.

The goal of the scientists was to find the mechanisms responsible for the development of the disease, so that, by targeting these mechanisms, subsequently stop the process of the disease or even prevent it.

During the experiment, scientists simulated early pro-inflammatory stress by injecting newborn (3-5 day old) rat pups in a small dose of bacterial lipopolysaccharide – a fragment of the bacterial wall that caused inflammatory processes in the body, in particular neuroinflammation . Then we monitored how the behavior of growing animals changes in comparison with control animals that were not exposed to pro-inflammatory stress in adolescence (for rats – one month) and before reaching puberty – three months. In particular, the scientists watched how the rat pups develop symptoms of depression and anxiety, investigated the synaptic plasticity of the brain, which determines the body’s ability to learn and memory.

As a result, scientists have found that rat pups gradually develop symptoms characteristic of psychoemotional disorders. In adolescence, signs of anxiety appeared and depressive-like behavior began to appear , which was already pronounced in adult animals. The synaptic plasticity of the brains of animals was severely impaired by pro – inflammatory stress already in adolescence. Moreover, the level of corticosterone , the stress hormone, has been increased, which means that these animals have a permanent internal stress factor. In a stressful situation, both in humans and in rats, a large amount of this stress hormone is secreted from the adrenal glands (in humans, the hormone cortisol is the analogue of corticosterone ), and this has an adaptive value, mobilizing metabolic processes to overcome stress. However, if the level of corticosterone (or cortisol in a person) is steadily increased, the additional release of the hormone no longer occurs, and this significantly reduces the body’s resistance to stress. So the excess of corticosterone does a double whammy – depletes metabolic sources and weakens the ability to resist stress.

The researchers hope that the results of their work will be introduced into the clinic both for preventive measures when exposed to extreme factors on the child’s body, and for the development of new approaches to treating depression based on the identified new molecular-cell mechanisms.