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Previously, scientists and doctors believed that neurotransmitters – monoamines, in particular serotonin, dopamine, norepinephrine – play a role in the genesis of depression . This hypothesis arose under the influence of the results of research on antidepressants, but today two more mediators deserve attention – glutamate , which regulates excitation processes, and gamma- aminobutyric acid (GABA), the main mediator of inhibition.

This is supported by evaluations of the effects of ketamine, amantadine , lamotrigine, and anticonvulsants on the severity of depression. These drugs act on the NMDA (N – methyl – D – aspartate ) glutamate receptors. 

The factors that provoke stress play an important role in the development of depression, especially the stress factor is important in the first episode of depression. A person’s predisposition to the effects of stress factors depends on disorders in the regulation of the hypothalamic-pituitary-adrenal system.

Some researchers have found elevated levels of the adrenal hormone cortisol in a large number of depressed patients who have not yet received drug therapy. Moreover, the level of cortisol did not decrease after the administration of dexamethasone. This effect formed the basis for the creation of the dexamethasone test, which was introduced into clinical practice. It detects endogenous depression.

Disturbances in the regulation of the hypothalamic-pituitary-adrenal system occur primarily at the level of secretion of corticotropin- releasing hormone (CRH), which promotes the secretion of adrenocorticotropic hormone (ACTH). A decrease in the level of CRH secretion in patients with high CRH values ​​reduces the production of ACTH by the pituitary gland and subsequently cortisol. A decrease in CRH secretion occurs in response to the introduction of synthetic CRH.

The remissions that occur after episodes of depression can be traced by the dexamethasone test. 

Adults who have suffered severe psychological trauma in childhood are vulnerable to stress, which means to the development of depression, since they have impaired regulation of the hypothalamic-pituitary-adrenal system. Such patients have a tendency to be hyperactive, especially during critical periods of brain development, and a predisposition to depression throughout life, especially in the presence of stress. Numerous changes in the hypothalamic-pituitary-adrenal system, leads to an increase in the secretion of glucorticoids , which leads to structural and functional changes in the limbic system in patients with depression. Antidepressant therapy leads to a decrease in the proliferation of cells in the limbic system of the brain. The modern approach to the genesis of depression does not exclude the role of neuroplasticity in the development of depression. The role of hereditary factors in the development of depression was also noted. 

Drugs that can cause depression include:

• oral contraceptives;
• antimicrobial drugs (ampicillin, evaferents , azithromycin, streptomycin, tetracycline ); 
• anticonvulsants ( leviracetam, vigabatrin, topiramate );
• immunomodulators (alpha interferon, steroids, cyclosporine );
• antihypertensive drugs (beta-blockers, methyldopa , reserpine, flunarizine );
• psychotropic drugs ( levodopa , metaclopramide , amantadine , sedative hypnotics, phenothiazine , disulfiram );
• medicines used in oncology ( vinblastine vincristine );
• barbiturates;
• antihistamines;
• psychoactive substances (amphetamine, cocaine).

Ultrasound examination is not only a diagnostic method for imaging human organs and systems. It can be used as a method of focused treatment of mood disorders. The use of ultrasound as a therapeutic agent depends on the frequency parameters and the type of equipment. In addition, ultrasound facilitates the delivery of a drug across the blood- brain barrier to specific brain structures. 

Thus, ultrasound can be one of the means of neurostimulation .

The use of low-intensity and low-frequency ultrasound as a stimulator of neural networks ultimately leads to the activation of neurons through the influence on the sodium- calcium channels of the cell membrane. ( Tyler with et al , 2008).  

Other possibilities and ways of achieving a similar effect in a non-invasive way remain problematic.

Before the era of pharmacotherapy, mental illness was treated with herbs. Herbal medicine has its own advantages and disadvantages. At this time, there are about thirty drugs, which are based on medicinal herbs. They are used to treat many mental illnesses: obsessive- compulsive syndrome, bipolar, somatoform , psychotic, phobic , seasonal affective disorders, depression, anxiety.

 Medicinal herbs used in psychiatry

Researchers have found that more than twenty phytopreparations have epigenetic, endocrinological, neurochemical effects . 

 There is evidence for the use of St. John’s wort for treating major (major depression) and kava for treating anxiety disorders.

Representative data indicate the effectiveness of St John’s wort and kava in treating depression and anxiety. But there is not enough evidence to support the use of other drugs in treating mental illness.  

The integration of medicinal herbs with synthetic psychotropic drugs is of great interest for practical medicine. But it is also necessary to study the safety issues when using St. John’s wort and kava . 

 Treatment with medicinal herbs for mental illness is a direction that needs to be developed in practical health care.

At the moment about 30 mediators have been found. Dopamine , norepinephrine, and serotonin are involved in the pathogenesis of depression . Norepinephrine is active in the limbic system and hypothalamus. He is responsible for the reaction to stress, memory processes, physiological drives, emotions. Serotonin is responsible for the human emotional sphere. The connections between neurons are plastic and depend on personality traits, stress, hereditary factors, past experience. The transfer of impulses from one neuron to another is carried out using mediators. When transmitting an impulse ,    transition of an electrical impulse into a chemical signal. Mediators accumulating in the axon are released from it and through the synapse are supplied to another neuron. Mediators have a tropism for different types of receptors. After the transfer of information from one neuron to another neurotransmitter is released from the receptor, it is returned into the synapse. There it is incorporated into the transmitting neuron, or is destroyed by monoamine oxidase . The pathogenesis of depression is associated with a decrease in the sensitivity or density of the postsynaptic serotonergic and noradrenergic systems. According to the theory of S.N. Mosolova        the leading theory is the monoamine theory. The theory postulates that depression develops in due to a lack of dopamine, norepinephrine, serotonin.  

 In the late 70s of the twentieth century, the serotonergic theory of the origin of depression was developed . Based on this theory, serotonin has been considered as a neurotransmitter responsible for improving mood. He was also responsible for aggressiveness, sleep-wake cycle, appetite.

 In the 1950s, the catecholamine theory of depression was formulated . The concentration of norepinephrine in the cell is under the control of presynaptic adrenergic receptors . Stimulating these receptors inhibits the release of norepinephrine and decreases neurotransmission .     

The blockade of these receptors by antidepressants leads to an increase in the release of norepinephrine. Studies of the reticular formation of the brain have shown that antidepressants have a psychostimulant effect. Medicines in this group improve wakefulness, enhance perception, memory, thinking, and increase concentration. According to this theory, endogenous depression is caused by a decrease in the concentration of catecholamines, in particular norepinephrine, in different parts of the brain. The activity of the noradrenergic system is assessed by the concentration in the urine of MOFEG (3-methoxy-4-hydroxyphenylethylene glycol).   

 In patients with depression with low MOFEG positive therapeutic effect was observed by desipramine and imipramine .    

Dopamine deficiency may play a role in the development of depression.

Dopamine takes part in the regulation of the motor sphere, is responsible for the formation of certain behavior, and has a psychostimulating effect. This theory is supported by the ability of L-DOPA to promote increased activity. 

Endorphins are to neuropeptides having a dual function -mediatora and hormone. Endorphins are responsible for a person’s sensitivity to pain, which is why their reduced amount in dysthymia leads to pain intolerance in people with depression.  

Various neurochemical processes leading to depression are targeted by drugs. 

Infectious agents such as herpes simplex virus, cytomegalovirus can cause mental manifestations that can be diagnosed as schizophrenia or bipolar disorder. 

In 1907, the American psychiatrist Henry Cotton tried to treat mental illness, fighting various infections in the human body – he removed carious teeth and tonsils. Despite the fact that his views and methods were flawed, already in the 21st century there is a growing body of evidence that viruses and bacteria, and the associated inflammation, are correlated with some mental illness. Some scientists believe that depression is an infectious disease. Even outwardly, patients with depressive disorders look like infectious patients. They look tired, do not want to get out of bed, lose their appetite. In many eastern countries, patients with depression, first of all, complain of physical illness.

Some brain infections, such as Toxoplasma gondii , cause emotional disturbances, mimic mental illness, or cause mental health problems. The same is characteristic of the Epstein- Barr virus , Bourne disease, herpes viruses, herpes zoster, chickenpox.

The experience of the clinic of Doctor of Medical Sciences V.L. Minotko shows that mental illness requires high-quality microbiological and virological laboratory diagnostics. It should include microscopy, RPHA, ELISA, determination of markers of the state of the mucous membrane, cytokine profile and other indicators of inflammation, as well as neuroimaging . Laboratory research should be combined with careful medical history and clinical studies to identify chronic infectious diseases.

Patients taking antidepressants suffer from several side effects. In 63% of cases, there is anxiety, suicidal thoughts, insomnia, weight gain, and sexual disorders. Some patients do not respond to medication at all, and their number is 17%. 

The antidepressant effect of curcumin has been known for a long time. In a study on volunteers, it was found that there was no difference in the effects between curcumin and fluoxetine in the treatment of depression over 6 weeks. Curcumin has been shown to be beneficial in terms of no side effects. It is safe even in large doses – 8 grams per day. The curcumin- based drug is called BCM-95.

 The use of curcumin itself is limited by poor absorption in the gastrointestinal tract, rapid destruction in the intestines, and slow absorption into the bloodstream. But the restored mixture of curcumin – the BCM-95 preparation does not have such disadvantages.

Clinical trials on volunteers have established that the bioavailability of BCM-95 is 7 times higher than that of curcumin . The active ingredient curcumin increases neurogenesis in the hippocampus , stimulates the synthesis of neurotrophic factor, and promotes the growth of new neurons. In addition, curcumin inhibits MAO-A and MAO-B monoamine oxidase isoenzymes , and affects the concentration of serotonin and dopamine in the brain.  

It also has anti-inflammatory effects, reduces the secretion of inflammatory markers of astrocytes , inhibits cyclooxygenase-2, nuclear factor-kappa B (NF-kappa B), nitric oxide synthetase ( iNOS ), interleukin-1.  

Curcumin- based drugs may become the mainstay in the treatment of depressive disorders.

Atypical antipsychotics are used in the treatment of the depressive phase of bipolar disorder. The use of classical antipsychotics is limited to a number of points. Patients with bipolar disorder after treatment with classical antipsychotics are at risk of developing extrapyramidal disorders and dyskinesia. Classical antipsychotics also cause depression, so atypical antipsychotics should be preferred. 

When studying the effect of olanzapine and quetiapine , a decrease in psychotic symptoms, good tolerance, and antidepressant effect were found. Monotherapy with olanzapine and its combination with fluoxetine are also effective . Moreover, the combined use of drugs was more effective than monotherapy . The time to depression for olanzapine was 57 days, and 32 days for combined therapy.  

Side effects when using drugs: drowsiness, weight gain, increased appetite, dry mouth.

Quentiapine monotherapy was well tolerated in the treatment of depression in patients with bipolar disorder . But the following side effects were observed: sedation , dry mouth, dizziness. Quentiapine also reduced anxiety.

A study by Doree JP et al. In patients with resistant depression showed that supplementation with quentiapine and lithium improved the condition of patients. Moreover, the antidepressant / quetiapine combination was found to be more effective than the antidepressant / lithium combination.

The antidepressant effect of risperidone has not received evidence, but it potentiated the effect of citalopram in resistant depression ( Rapaport MN et al ., 2004). Small doses of amisulpride also had antidepressant effects

Atypical antipsychotics affect not only the main symptoms of depressive disorders, but are effective against psychotic symptoms.

Neuroplasticity and Depressive Disorder

Depressive disorder is associated with decreased neuroplasticity and decreased concentration of glutamate , which is a neurotransmitter of arousal.

Some monoamines act on secondary messengers – mitogen- activated protein kinase , contribute to the normalization of neuroplasticity and glutamate content . Some drugs cause an increase in glutamate secretion, act on synapsogenesis, and improve mood (eg ketamine). But the effect is short-lived. 

Electroconvulsive therapy and antidepressants at the cellular level cause an increase in the expression of neuroprotective proteins – the neurotrophic factor BDNF, which promotes neuronal life and regulates synaptic connections.

In experiments on rats, electroconvulsive therapy and antidepressants increase the secretion of neurons in the dentate gyrus of the hippocampus and reduce the effects of the action of the hypothalamic-pituitary-adrenal axis in depression.

In post-traumatic stress disorder, antidepressants restore the limbic system and the hippocampus . 

But in Russian medicine, these changes are not taken into account by clinicians, like the content of glutamate and the processes of neuroplasticity in depression.

Prolonged stress reduces the volume of the hippocampus, the number of neurons, and leads to neuronal atrophy.

Depression is one of the not fully understood diseases. Its symptoms are:

• weight loss;
• weight gain;
• insomnia;
• psychomotor agitation;
• feeling of worthlessness, guilt.

The main symptom of depression is anhedonia – a loss of interest in pleasure, reward, cognitive impairment, a deficit in social cognition, and a slowdown in information processing.

Cognitive impairment cannot always be cured with pharmacological drugs. But, for example, fluoxetine enhances cognitive function to a greater extent than desipramine and amitriptyline. And SSRIs enhance memory, indirectly, by improving mood.  

Cognitive drugs may be new treatments for depression. Thus, donesepil helps to reduce the signs of depression, which has been proven by positive ratings of the depression scale. Experiments have shown that the enhancement of cholinergic and serotonergic transmission with drugs leads to a change in neuroplasticity , network synchrony between the amygdala and hippocampus.  

Depression is associated with chronic social damage and is reflected at the proteome level. This is confirmed by the action of fluoxetine, which affects the expression of many proteins.

Thus, the search for mediator, molecular markers of depression will reveal the pathogenesis of the disease and prescribe drugs not by trial and error, but based on objective criteria .