Abilify makes me tired

Trending

Filmy, z ktorých mrazí. Top 5 hororov za posledné desaťročia

Označené ako DIY escape room escaperoom lockdown origami rodina Spoločenské hry spoločné aktivity sviatky teória veľkého tresku vianoce

basics and schizophrenia / Habr 9004%

This article is a logical continuation of the post on pathopsychological diagnostics. In it, I will try to tell in an accessible language about the main groups of pharmacological drugs used to treat mental illness, as well as about the mechanisms, structures and components of the human brain that are involved in this process.

Disclaimer : I'm not a psychiatrist, but a psycho. I tested the drugs of all these groups on myself and observed their effects (when I was in a psychiatric hospital). In addition, I have some experience in pharmaceutical selection, but I do not have a formal education in this area. In this regard, as well as the fact that diagnosing oneself according to scientific articles is an extremely wrong thing at its core, I want to warn the reader that, before taking anything described here, it is necessary to consult a specialist. If real welders run into the post and justify the incorrectness of the stated theses, I will only be glad. nine0007

If the above does not scare you, I suggest you plunge into the fascinating world of psychopharmacology. There are a lot of letters and pictures in the post, I warn you right away.

The brain and its structure in the context of psychopharmacology

Before talking about pharmacological treatments for mental illness, it is necessary to consider some aspects of the structure and functioning of the human brain - just to make the following material clear.

Neurons and glia

Most likely, everyone present knows that the brain consists of neurons and neuroglia (special cells that perform a number of functions - trophic, structural, secretory, regulatory and protective [1, 3]) - the former are the main object of our interest, the second is not so important for this article, since most of the modern pharmacology does not have a significant effect on it (more precisely, it has only in the context of side effects).

Neurons look like this:

And glial cells - like this:

Contrary to popular belief, glial cells are quite involved in the transmission of nerve impulses [1], at least indirectly - by influencing the formation of synapses (about them - below), however, all drugs known to us affect not its cells and functions, but neurons and communication between them [4].

Consider an approximate model of the structure of a neuron:

We are interested in dendrites - processes through which the neuron receives messages from its fellows[6] (roughly speaking, the input of the neuron) and axon - the process through which the neuron transmits its message (i.e. its "output")[6 ].

Why is that? Because they are directly related to the signals that neurons transmit to each other, and in these signals the whole “spiritual life” of a person (well, almost all) is encrypted: his thoughts, memories, beliefs, preferences, etc., including, of course, what is considered a manifestation of mental illness - delusional concepts, hallucinations, and so on [4]. nine0007

Thus, the task of treating mental illness is reduced (within the biologization approach , namely, it is the basis of this article, we will talk about others separately) to the task of changing the parameters of the passage of signals between neurons and those events that occur in the neurons themselves in connection with this transfer[4]. Of course, not an arbitrary change, but directed and controlled.

Synapses

Next, we should consider synapse - connection of two neurons. It is important for us because it is in the synapses that the transmission of nerve impulses[6] takes place, which, as mentioned above, determines, among other things, whether a given subject will be mentally ill or not. At the conceptual level, a synapse looks like this:

First of all, it should be said that there are two types of synapses - chemical and electrical (there are also mixed ones, but they are not so interesting for us) [7]. In the first, the signal from one neuron to another is transmitted by release into the interneuronal space (so-called synaptic cleft ) of certain substances ( neurotransmitters or neurotransmitters , depending on which translation you prefer), and secondly - directly, as in the contact of wires - the current flows from one neuron to another.

We are interested in chemical synapses, because all drugs known and used in psychiatry work with them[4]. In fact, they interfere with the signal transmission process in order to change it in such a way as to reduce the manifestations of the disease. Therefore, we will have to first consider how this signal is transmitted naturally, without drugs, then determine what pathological changes in this process take place during the disease, and only then study ways to modify it. nine0007

Signal transmission between neurons

Before proceeding directly to the description of the signal transmission mechanism, we will make two important reservations: firstly, we are only considering chemical synapses here, and secondly, we give a very simplified description of this process, since the volume of the article is limited.

So, it all starts with an impulse that sends the first neuron (it is called presynaptic because it is "in front" of the synaptic cleft). An electrical impulse runs along the axon and transmits a signal that out of vesicles (special containers in which the neurotransmitter is stored) should release a certain number of molecules of the corresponding neurotransmitter into the synaptic cleft. second”, located “behind the synaptic cleft”) neuron. [4,6].

In addition, in the postsynaptic neuron, the process of further transmission of the message is triggered by means of a second messenger, a special intracellular signaling molecule released by the postsynaptic neuron in response to the activation of the postsynaptic receptor (more on receptors below). The second messenger instructs the postsynaptic neuron to change its ion currents, propagate or inhibit neuronal electrical impulses, phosphorylate intracellular proteins, and perform many other actions [4]. nine0007

All this ultimately leads to the fact that the expression of certain genes is turned on or off in the nucleus of the postsynaptic neuron [4,8]. After a change in gene expression, a secondary cascade of events is triggered in the postsynaptic neuron. Many of them are not fully understood [4]. But for the purposes of this article, it suffices to say that this leads (or does not lead) to the generation of an impulse in this neuron and further transmission of information.

Receptors

Receptor is a special molecule that is located on the surface of the neuron membrane and reacts by changing the spatial configuration to the addition of a certain substance (neurotransmitter) to it [9]. The substance that activates this receptor is called its ligand .

The feature of receptors is their selectivity. For example, the serotonin receptor does not respond to dopamine and vice versa. This allows you to distinguish between the signals given by different neurons. Especially taking into account the fact that the neurotransmitter can freely “flow” from the synaptic cleft and spread over the adjacent area[4]. nine0007

Receptors are (and this is important for us) not only postsynaptic (i.e. located on the membrane of the "second" neuron), but also presynaptic (i.e. located on the membrane of the first neuron). Why are they there? To organize feedback: the neuron itself reacts to its own neurotransmitter. This is a pretty cool feature, especially considering that the receptors of one ligand can affect the release of another (an example will be below) [4].

Neurotransmitters

Neurotransmitters (or neurotransmitters ) are the very substances by which the signal is transmitted in the chemical synapse. There are quite a few of them, the most famous and interesting to us are serotonin, norepinephrine and dopamine.

An example of an [incomplete] listing of neurotransmitters, divided into groups according to their chemical structure, is presented below [4]: ​​

Psychonauts have a cool saying on this topic: if there is a receptor, there will be a ligand. nine0007

What we need to remember about neurotransmitters is that they are produced by the presynaptic neuron and transmit a message to the postsynaptic neuron by binding to its receptors.

Agonists, antagonists and inverse agonists

According to the principle of action on receptors, substances can be divided into three (well, four, but those that do not affect the receptor are not of interest to us, so three) groups: agonists , antagonists and inverse agonists [4].

Agonists is the easiest thing to understand. They bind to the receptor and cause its response. In the text above, when it was said that the neurotransmitter binds to the postsynaptic receptor, it (the neurotransmitter) acted as an agonist.

The antagonist is a ligand that binds to and "deactivates" the receptor. While the receptor is occupied by the antagonist, the agonist cannot "cling" to it, and, accordingly, the message cannot get through.

An inverse agonist is a substance that, by binding to a receptor, produces physiological effects opposite to those produced by an agonist. Also, it's not hard to understand.

And then there are partial agonists and antagonists - they act in the same way as full ones, but weaker.

An important consequence: if we apply an antagonist of a certain receptor, and then increase the amount of the neurotransmitter, then in some cases the antagonism will be "cancelled". And vice versa, if we simply reduce the amount of the neurotransmitter, the effect will be the same as if we applied the appropriate antagonist. We will need this corollary later in the discussion of atypical antipsychotics. nine0007

Neurotransmitter reuptake

But that is not all. For some neurotransmitters, the mechanism of the so-called. reuptake [10]: once in the synaptic cleft and transmitting a message, the neurotransmitter returns back to the vesicle with the help of a special transporter molecule. This was done to save the neurotransmitter and control its amount in the synaptic cleft.

Each neurotransmitter (to be more precise, each of those subject to reuptake) has its own transporter molecule: SERT for serotonin, DAT for dopamine, etc. nine0007

It should be noted the selectivity of the reuptake mechanism - the transporter cannot capture a “foreign molecule”.

Allosteric modulation

The essence of this phenomenon can be expressed as follows [4]: ​​some receptors are able to interact not only with one ligand, but with two substances. In this case, the first is "basic" and works without the second, and the second affects the receptor only in conjunction with the first, reducing ( allosteric inhibition ) or increasing ( allosteric activation ) the intensity of the response.

- It should be noted that the work of the brain described here is greatly simplified, and in fact everything is much more complicated there.

Mental illnesses and their treatment

How psychopharma works

So, we have considered the main stages of the transmission of a nerve impulse from one neuron to another. Now we can discuss the mechanisms of work of psychopharmacological drugs in a general way [4]. nine0007

What can we do with these drugs? Lots of things, actually. Firstly, the drug can act as a direct agonist (dopaminomimetics) or an antagonist (neuroleptics) of the corresponding receptors.

Secondly, it can act as an inhibitor (SSRIs - a class of antidepressants) or an inverter (amphetamine) of the neurotransmitter reuptake process. In the first case, the neurotransmitter will not be removed from the synaptic cleft, in the second case, the reuptake system “turns 180 degrees” and, instead of dragging the neurotransmitter into the vesicles, begins to release it from them into the synaptic cleft. nine0007

Thirdly, it is possible to influence the system of secondary messengers (according to some data, some normotimics work in this way) by changing the cascade of events in the receiving (postsynaptic) neuron.

Fourthly, it is possible to act on the presynaptic receptor, block it, thus turning off the negative feedback mechanism and increasing the amount of the neurotransmitter in the synaptic cleft (some antidepressants and atypical antipsychotics).

Fifth, it is possible to activate the mechanism of allosteric modulation and enhance or weaken the action of the corresponding neurotransmitters. nine0007

And, finally, sixthly, it is possible to influence the expression of genes. Drugs in which this mechanism would be the main one are unknown to us, but, for example, valproates have this property [11].

Schizophrenia

The “default mental illness” in our psychiatric hospitals (take this opportunity to say hello to L.S. and other psychiatrists who are used to putting it on everyone without understanding), so famous that it has become a curse word (remember all these “he’s crazy” and “ you're crazy"). nine0007

A small, fairly plausible video that allows you to look inside schizophrenic perception:

In short, it manifests itself in two aspects: in negative and productive symptoms [12]. Productive symptomatology is when the psyche begins to produce what it normally should not produce: hallucinations, ideas of relationships, delusions.

Examples? The author, for example, often sees non-existent cats. One patient I worked with felt like he was being "fucked for his dreams." Another believed that only the intrigues of the FSB prevented him from receiving an award for breaking the RSA algorithm. The third thought that the treacherous Chinese were slipping heroin into his marijuana to make him an addict. There is a popular case in the literature in which the patient believed that the dogs were looking at him and laughing at his frail body [13]. nine0007

Negative symptomatology is the opposite, when the psyche does not produce what it should. These include volitional decline (the patient cannot force himself to bathe or even eat), emotional flattening (the patient is unable to express emotions, seems insensitive) and intellectual decline.

Let's make a reservation that here by schizophrenia we mean not only, in fact, F20, but the whole spectrum of schizophrenia-like disorders F2X, perhaps, with the exception of schizoaffective (F25), which in some cases is closer to affective disorders (more on them later). nine0007

There are quite a few hypotheses regarding the causes of schizophrenia [4,13]: psychoanalysts' "misguided trajectory of life", violations of the rules of abstraction and context (Bateson's theory), the invasion of Grof's transpersonal entities, disruption of dopaminergic transmission, etc.

In the framework of this article, we will consider the latter, since most drugs widely used in psychiatry affect the dopamine system (well, the serotonin system, but these are already subtleties). nine0007

So, in our brain there is such a thing as black body (Substantia nigra) - an accumulation of bodies of dopamine (that is, those that use dopamine as a means of transmitting information) neurons. From there, the axons of these neurons stretch to various areas of the brain, forming the so-called. dopaminergic pathways: mesocortical , mesolimbic , nigrostrial and tuberoinfundibular [4].

Consider their connection with manifestations of schizophrenia. The most interesting for us will be mesolimbic dopamine pathway connecting the tegmental area of ​​the midbrain and the substantia nigra with various structures of the limbic system. Indirectly, it is also projected to the frontal cortex and hypothalamus. Normally, it plays an important role in the process of learning, reward, memory and emotion mechanisms [4].

Drugs that increase dopaminergic transmission in this pathway have been found to lead to psychotic symptoms (delusions, hallucinations - positive symptoms). On the other hand, drugs that lower dopamine levels in these areas have the ability to relieve such symptoms. An interesting fact: psychosis caused by the systematic abuse of stimulants - cocaine, amphetamines, etc., can be practically indistinguishable from schizophrenic psychosis in external manifestations [4]. nine0007

In addition, an association has been established between excessive transmission activity in this pathway and aggression in psychotic patients.

The mesocortical pathway is also very interesting to us, but for a different reason. It connects the ventral tegmentum of the midbrain with the frontal lobe of the cerebral cortex, mainly with the prefrontal cortex, and plays an important role in the processes of motivation, planning, and emotional response.

It has been established[4] that a decrease in the level of dopamine in this pathway is associated with the negative symptoms of schizophrenia: flattening of affect, impoverishment of emotional life, speech disorders and, probably, a decrease in intelligence. nine0007

And here's an interesting thing: in schizophrenia, in one pathway (mesolimbic), you need to reduce the level of dopamine, and in the other (mesocortical) - increase [4]. It must be said that modern psychopharmacology has partly solved this problem, then we will explain exactly how, but for now we will briefly consider the remaining two ways in the context of the question of interest to us.

The nigrostriatal pathway , which connects the substantia nigra and ventral tegmentum with the striatum, is involved in the initiation of motor activity, being part of a system called the basal ganglia motor loop. We are interested in the fact that dopamine deficiency in this pathway causes akathisia (restlessness) - a condition in which the patient experiences a compulsive (irresistible) need to move: he is literally unable to sit still[4]. Here is a video of the process:

https://www.youtube.com/watch?v=svoDpICEnsg

By itself, akathisia is not a symptom of schizophrenia, but it is associated with it - this is a fairly common side effect of anti-schizophrenic drugs ( I think the logic is clear: drugs are trying to reduce the level of dopamine in the mesolimbic pathway, but it also decreases in the nigrostriatal one). And there is such a thing as dyskinesia induced by neuroleptics - pathological movements of arbitrary muscle groups ("twisting"). And it is on YouTube:

And, finally, tuberoinfundibular pathway , formed by dopaminergic neurons of the arcuate nucleus of the mediobasal hypothalamus, projecting their axons into the median eminence. The dopamine secreted by them regulates the secretion of prolactin by the anterior pituitary [4]. We are interested in it insofar as many antipsychotic drugs lead to an increase in the level of prolactin, which is especially critical for women: their menstrual cycle goes astray and lactation may begin. nine0007

Antipsychotics (aka antipsychotics)

Generally speaking, this class of drugs is not only used to treat schizophrenia, but is associated with it. Historically, they are divided into two large groups - typical and atypical .

typical antipsychotics include such well-known drugs as haloperidol, chlorpromazine (Aminazine), trifluoperazine (Triftazine). Strictly speaking, neuroleptics, ie. drugs that cause neurolepsy - a state of a significant decrease in motor and mental activity, emotional flatness and indifference to what is happening, are only drugs in this group. The newer, atypical, "neuroleptics" are more properly called antipsychotics, but no one really bothers with this.

The main mechanism of action of these drugs is to block postsynaptic dopamine receptors (mainly D2) [4,14]. From the mechanism of schizophrenia described above, it is clear what the therapeutic effect of these drugs is based on: they block receptors in the mesolimbic pathway (remember that receptor antagonists make these very receptors inactive, as a result of which the signal ceases to be transmitted from one neuron to another). nine0007

The only bad thing is that typical neuroleptics are not limited to mesolimbic pathways, also blocking D2 receptors in the mesocortical pathway, which leads to worsening of negative symptoms (remember that they appear precisely because of insufficient dopaminergic transmission in this pathway) [four]. That is, in fact, they work according to the well-known principle among the people: "we treat one thing, we cripple another. "

And if we take into account that the combination of productive and negative symptoms in schizophrenia is not at all uncommon, then everything becomes quite sad (negative symptoms, other things being equal, mean a less favorable long-term prognosis than productive ones). To reduce the undesirable consequences of taking antipsychotics, special preparations are used - correctors , the most famous of which is trihexyphenidyl ("Cyclodol").

In general, in our experience, it is difficult to distinguish between a person who has severe negative symptoms of schizophrenia and a patient drugged with antipsychotics.

Differences are not visible not only visually or during communication, but also in tests. It often happens that replacing a typical neuroleptic with a more modern drug greatly reduces the severity of intellectual deficit, volitional decline, emotional flattening and other negative symptoms. nine0007

But that's not all bad that can be said about these drugs. Since they block D2 receptors absolutely everywhere, incl. in the nigrostrial pathway, they are the cause of such phenomena as akathisia ("restlessness") and dyskinesia ("twisting") [4].

And almost all drugs in this group lead to an increase in prolactin levels with all the ensuing (gee-gee, Beavis, pun) consequences.

These are the pills. At the same time, they are the most popular drugs of choice in psychiatric hospitals, at least in our region. Why? There are two reasons for this. nine0007

The first is quite rational: they perfectly allow to remove the state of acute psychosis[4]. If the patient is aggressive, in agitation, sees voices and hears aliens, runs after household members with an ax, etc., then an injection of life-giving haloperidol (or another drug of this group) can bring him into a state suitable, if not for conversation, then for transportation to the appropriate institution, much faster than more modern preparations. Not always, but that's the trend.

The second reason is a banal lack of funding. It often happens that a psychiatrist would be happy to prescribe some kind of aripiprazole, but it simply is not and will never be in the medicine cabinet because it is quite expensive.

Well, and I must say separately: if your psychiatrist has prescribed you a typical antipsychotic, do not rush to quarter it - sometimes they can really be the best choice. But consideration of such subtleties is already beyond the scope of this article.

Now let's talk about atypical antipsychotics (they are simply “ atypicals ”). Typical representatives of the group of atypical antipsychotics are quetiapine, olanzapine, risperidone, etc.

we need to block it only in one, in one - on the contrary, strengthen it, and the other two, if possible, do not touch. nine0007

Atypicals partially solve this problem[4]. From the point of view of pharmacology, they are antagonists of dopamine and serotonin receptors. As you can see, serotonin was added here, which was not in the description of schizophrenia itself (the reader with an asterisk knows about the role of 5-HT-2A receptors, but we decided not to complicate the picture).

The fact is that serotonin inhibits the release of dopamine, and the nature of this inhibition differs in all four dopamine pathways. Thus, by affecting serotonin, we can influence dopamine (indirectly). Let's try to figure it out. nine0007

Dopamine (that is, those that transmit information through dopamine) have a postsynaptic serotonin receptor, by activating which we can reduce the release of dopamine. In fact, it works like a switch: by stimulating the serotonin receptor (5-HT-2A), we inhibit the release of dopamine into the synaptic cleft. The reverse is also true: by blocking the serotonin receptor (5-HT-2A), we increase the release of dopamine. Those. counteract its antagonism.

It is important to understand here: atypicals simultaneously act in opposite directions: they reduce dopaminergic transmission due to antagonism of D2-dopamine receptors and increase it due to blocking of 5-HT-2A-serotonin receptors. Which action "wins" depends on the number of 5-HT-2ª receptors [4]. nine0007

Fortunately, the mesolimbic pathway is the least of them. This means that D2 receptor antagonism “wins” there and dopaminergic transmission is reduced, which is what we want, since this leads to a decrease in productive symptoms.

In the nigrostriatal pathway (which is responsible for dyskinesia and akathisia), additional dopamine release by blocking 5-HT-2A serotonin receptors compensates for the effect of atypicals as D2 receptor agonists.

B mesocortical pathway serotonin receptors are located at a higher density than dopamine receptors, so atypicals here work to increase dopaminergic transmission, which is what we need, since this allows us to deal with negative symptoms. Again, nature itself seems to play along with us.

An interesting fact about atypicals is that in fact the victory of one action over another (increasing dopaminergic transmission over its decrease or vice versa) depends not only on which pathway is in question, but also on the dose of the drug. Therefore, they (atypicals) have a very strong dependence of the clinical effect on the dose of the drug [4]. nine0007

Finally, the third generation of atypicals, aripiprazole and bifenprux, are the most interesting.

They are interesting in that they simultaneously have the properties of partial agonists and antagonists of dopamine (D2) and serotonin (5-HT-1A) receptors [15]. Which properties of the drug will appear depends on the dose and on the presence and amount of the neurotransmitter.

This makes the pharmacological profile of these drugs unique: if dopamine is low, they work as an activator of dopaminergic transmission, and if it is high, then as its inhibitor. nine0007

Personal experience. Instead of a conclusion

A review of antipsychotics would be incomplete without a description of personal experience with this group of drugs. Next, I will briefly describe how it was. Please do not take it as a guide to action, since the selection of psychopharma is an individual process and should be carried out under the guidance of a specialist.

Quetiapine - taken for the relief of manic episodes. He copes with this task perfectly, but he didn’t like it on an ongoing basis: emotional flattening is too pronounced and I really want to sleep. I use it from time to time in order to escape from reality during emotionally significant events that I am unable to endure and as a safety net when taking% ROSCOMNADZOR%. nine0007

Chlorpromazine (Aminazin) - I didn't like it at all. It doesn’t completely eliminate mental disorders, it sedates very strongly, shortens associative chains, and makes it difficult to think. It doesn't help, it only makes it worse.

Amisulpride . The effect is dose dependent. At 400 mg / day. sensations - as if you live in a basin of glycerin: movements are slow, you physically feel air resistance, reality is clouded. It is impossible to think, to express emotions too. At 50 mg - you are activated, it is easy to think, violations of thinking are much less pronounced. nine0007

Aripiprazole . Now I am writing this article on it (in combination with some other drugs), which I could not even dream of before.

- The article turned out to be quite large anyway, so we will talk about the treatment of affective disorders (depression, mania), OCD, GAD and other things in the next article, if this topic is of interest to the community at all.

Literature