There is a problem with the effectiveness of drug treatment for depression. The mechanism of development of pathological processes in depression is similar to the mechanism of development of pathological processes during prolonged fasting. During fasting, the work of many human organs is disturbed and mental processes are disturbed. Is it possible to cure the symptoms of abnormalities in the work of the organs during fasting, if one tries to restore the mental processes with medicaments? No, medical recovery of mental processes during fasting does not eliminate the symptoms of emerging problems during fasting. Mental processes during fasting will be restored if you restore nutrition. Similarly with depression. The actions on the drug normalization of mental processes do not affect the process initiating depression. In case of fasting, the initiator process is a violation due to lack of food. Depression is part of a much wider problem than the breakdown of mental processes. Depression is not initiated by a disease of the nervous system, but by a disease of the organs by which the nervous system controls. Treatment with antidepressants will not completely eliminate depression. The effect of antidepressants on depression is limited. The goal of research into the influence of drugs on the restoration of mental processes can be considered in the context of a temporary solution to a problem. Drug treatment with antidepressants will not provide a complete solution to major depressive disorder due to the association of depression with other processes that initiate the onset of depression.

Vasil Grigoriev Thank you for your contribution. I partially agree with you, we know that antidepressant drugs do not cure depression but symptoms as their action is limited to correct the biological imbalances of the neurotransmitters involved in the disease but they do not act on all the other etiopathogenic factors that determine it. The turning point to which I refer is related to the speed of action of this new drug that could help to skip the window period necessary to obtain the therapeutic effect of the drugs we have been using so far and therefore dramatically lower the risk of suicide in MDD

Landmark studies lie STAR*D has clearly demonstrated the limitation of our current psychopharmacological armamentarium of MDD with almost 30% of cases left TRD after multiple trials with different augmentative and combination strategies. Moreover, it shows the long upheld monoaminergic hypothesis is really oversimplistic.

This was, and still, the impetus to pursue with newer agents, that can kick-in immediately (cf. 2-week lag of traditional agents), safe, tolerable, effective (esp for the TRD), preferably with anti-suicidal properties (a major threat for untreated depressions)

This, in turn, has ushered a sparkle of what is referred to as RAADs (rapidly acting antidepressants)

Dissecting the complex neurobiology of MDD esp TRD has revealed alternate pathways that can provide a scaffold for novel innovative agents.

These include inflammatory, bioenergetics, HPA, one-carbon cycle, glucose metabolism, opioid, cholinergic, oxidative/nitrosative stress, glutamergic pathways ... just to name a few.

Glutamergic pathway has attracted much attention for circa a decade now and I guess works of Carlos Zarate and his group have contributed at large towards our current understanding.

Ketamine i.v. was the first in order and clinics are rife everywhere. Parenteral route and transient effects albeit very quick remained real impedementa. Esketamine then came as nasal spray, marketed under brand of Spravato. It is really a breakthrough. But .... enrolling REMS, risk of abuse, need to monitor patient 2hs after dosing in a special setting might, in my opinion, water down this 'miraculous' molecule! Besides costs, short-lived effects, and these restrictions on use, time would tell the real position of Spravato in clinical practice.

Mechanistically, NMDA antagonism was felt to be the primary mechanism of action. Now we do believe, AMPA activation, BDNF expression, mTOR pathway activation, opioid system involvement are all pertinent to Esketamine actions.

Of note, I have shortly submitted a new paper on this interesting issue that once published in shaa Allah, gonna share on RG.

Regards

Ahmed Naguy Thanks for your contribution, it was really helpful.

Over 50 percent of people who die by suicide suffer from Depressive Disorder. At the moment the only drugs with scientific evidence of antisuicidal properties are Lithium and Clozapine. Unfortunately, as you correctly mentioned, both have 2-4 week lag. That's why it's really important to have availability of a fast-acting drug.

depression is depend on type the disorder that have can treat ,and this medications and psychological therapy is integrated that creat more effective treatment.however ,every drug is depend on type and degree the disorder or other medical conditions.

Following

A sign of depression is called anhedonia. I define depression as an artificial deficiency of neurotransmitters and in particular dopamine. I managed to start the process that is causing the deficit and the balance of neurotransmitters is instantly restored. You can start the process of restoring balance even after many years of deficiency of neurotransmitters. For example, it could be 10 years of neurotransmitter deficiency, which says that the neurotransmitter processing functionality is not damaged, but there is a shortage of neurotransmitters. It is as if a dam is installed on a river and the river becomes shallow, but if the dam is removed, the river will immediately recover. A lack of neurotransmitters leads to the destruction of the reward system and to the occurrence of depression. I have found that some elements of the reward system practically do not work. The normal balance of neurotransmitters is ensured by the normal functioning of some vital processes that are supported by the reward system. These processes are associated with many other important processes and are the basis for the functioning of a person, but they may not be involved in the work, as the body has ways to satisfy some vital needs without the participation of these processes. There is a situation that there is a vital part of the nervous system, which is unused. The person has satisfied his needs, but there is no signal of successful satisfaction. A person systematically satisfies his vital needs without the participation of the apparatus of the system, which is built into the chain of meeting these needs. The chain of management of these needs is broken. The part of the human nervous system that provides some vital needs is working, this part of the person is not turned off, but is not involved in the process of meeting these vital needs and as a result, degrades and depression occurs.

Good article in Psychiatry Times covering Ketamine for Depression and Stress-related psychopathology. Good overview. See Attached article.

Bryan Hopping thank you, it was really helpful

Vasil Grigoriev Your theory is really very interesting, but I would like to better deepen some points. I understand that you believe that serotonergic drugs cure depression, but depression is nothing but the consequence of the breakdown of the reward system. So we are treating the symptom and not the cause? And if dopamine lack is the key point of the reward system failure, are we able to restore this deficiency and in which pathway?

Francesco Lusciano Drugs that artificially change the concentration of neurotransmitters may enable the brain to adapt to the adverse situation that has arisen. But then the primary cause of the depression must be eliminated. If the primary cause is not eliminated, a multistep process of adaptation to the gradual deterioration of the balance of neurotransmitters occurs in parallel with the intake of drugs. Artificially changing the concentration of neurotransmitters does not eliminate the primary cause of the lack of neurotransmitters and does not ensure the complete elimination of depression. I discovered a powerful source of dopamine and other neurotransmitters. This is a natural balanced source of neurotransmitters. It is powerful because it is built into the process of providing some basic human needs, the correct functioning of which the brain generously rewards. In spite of the fact that the brain generously rewards the functioning of these basic processes, now the situation has developed that in 99% of the population the functionality of individual elements of these basic processes is impaired. This is a paradoxical situation where, on the one hand, the brain provides the most powerful support and reward for the proper functioning of some basic processes, and on the other hand, a person almost completely ignores this support of the brain. There is a shortage of neurotransmitters. Violated the correct course of some system processes. There is a dualism of negative and positive. The imbalance of neurotransmitters is a consequence of the disruption of the functioning of basic elementary processes, and the solution is to normalize the functioning of these processes. I observe how actively the brain can support some basic processes. Being under pressure from the deficiency of neurotransmitters, the brain can nevertheless adapt to such difficult conditions, which demonstrates the great adaptive capacity of the brain.

Vasil Grigoriev Thank you, it was really helpful

There are many theories as to how and why ketamine works the way it does in treating depression. I'll offer a short summary of my thoughts, which are based on a recent ENCORE-D model, seeArticle Encoding, Consolidation, and Renormalization in Depression: ...

Ketamine's antidepressant effects become evident within hours from the infusion, reach their peak around 24 hours and are sustained for up to a week or two.

To me the rapid-action indicates that immediate changes in the function of neural networks take place, and that these changes are enough to ameliorate depressive mood. Indeed, various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. A recent study in rodents demonstrated that acute changes in cortical ensembles were required for antidepressant-like behavioral changes, while synaptogenesis was associated with more sustained responses, see

Article Sustained rescue of prefrontal circuit dysfunction by antide...

The initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. We have shown in rodents that the emegence of slow EEG activity coincides with the activation of several molecular cascades implicated in ketamine's antidepressant effects, including TrkB, GSK3B and mTOR signaling, see Article Cortical Excitability and Activation of TrkB Signaling Durin...

With recent studies showing a connection of increased sleep EEG slow-wave activity and the antidepressant effects of ketamine,

seeArticle Concomitant BDNF and sleep slow wave changes indicate ketami...

it remains plausible that processes during sleep contribute to the formation of neural changes that mediate sustained responses, and the peaking of the antidepressant effects 24h after treatment - i.e. after a night of sleep. Indeed, there are studies demonstrating altered global functional connectivity the day following ketamine treatment. Some studies have also shown that these changes in connectivity are lost in a week or so, which corresponds to the re-emergence of depressive symptoms after ketamine.

I feel that understanding the interaction of rapid-acting antidepressants with the neurobiology of sleep will provide important advances towards uncovering the mechanisms underlying ketamine's effects.

Depression is a lack of knowledge and coping abilities