TYPICAL AND ATYPICAL ANTIPSYCHOTICS: MECHANISM AND EFFECTS - ECONOMÍA - 2024

The antipsychotics or neuroleptics are a group of drugs known for their use in the treatment of psychosis, but can also be applied to other diseases. They are used to reassure patients who are going through an acute phase of a disorder in which they present great agitation and nervousness.

They can be used in patients with brain injury, mania, delirium due to intoxication, depression with agitation or severe anxiety - in the latter case, for a short period of time.

However, the disorder for which antipsychotics have been used the most is schizophrenia - especially to alleviate positive symptoms. It is one of the most devastating diseases that exist, in terms of personal and social cost.

It is estimated that some 20 million people in the world suffer from schizophrenia, with no differences in the incidence rates of the different countries.

Most of these people who have been diagnosed with schizophrenia have to use antipsychotics to make their lives more stable and have fewer periods of hospitalization.

History

Henri Laborit, a military surgeon, was the one who carried out the studies necessary for the discovery of the first drug useful for the pharmacological control of schizophrenia and other forms of psychosis.

Starting in 1949, Laborit carried out pioneering research on the anesthetic use of antihistamine drugs, with the aim of reducing the shock associated with surgery.

In this way, Henri Laborit began to assiduously use the antihistamines Mepyramine and Promethacin in a pre-anesthetic combination.

Subsequently, it was found that antihistamine medication also exerted effects on the central nervous system, thereby helping to limit the signs associated with the shock derived from surgery.

In addition, he noticed certain changes in the mood of the patients who were administered the drug, especially in the case of promethazine, so that people were less anxious and required a lower dose of morphine.

Despite these great discoveries by Laborit, the matter was forgotten for a few years, until this doctor made his research known to Specia Laboratories.

Currently we can find two main types of antipsychotics: classic neuroleptics and atypical neuroleptics.

Typical or classical neuroleptics

They are antagonists of dopamine receptors, and their main pharmacological property is the blockade of D2 receptors, specifically in the mesolimbic pathway.

The most common types of classic neuroleptics that we can find are:

Haloperidol (butiferrons)

Despite the beneficial effects this drug has on the positive symptoms of schizophrenia, its debilitating side effects - such as movement disorders, weight gain, lack of motivation, etc. - must be weighed.

In some cases, it increases the likelihood of physical illnesses such as diabetes or heart disease. For all these reasons, it is recommended to find the appropriate dose to help control the symptoms of schizophrenia with the fewest possible side effects.

Chlorpromazine (phenothiazines)

It is used as a treatment for the manifestations of psychotic disorders, being clearly effective in schizophrenia and in the manic phase of manic-depressive illness.

It also helps to relieve restlessness and apprehension prior to surgery. Chlorpromazine is indicated in the control of severe nausea and vomiting and in the treatment of intractable hiccups.

Levomepromazine (phenothiazines)

It is one of the oldest antipsychotics and has a calming, anxiolytic, sedative and analgesic action. It is also a powerful anesthetic enhancer.

Levomepromazine has a powerful sedative property, enhances ether and hexobarbital anesthesia as well as morphine analgesia. Among its side effects is the drowsiness produced during the first weeks of treatment.

There are also classic neuroleptics with "retard" or depot action, which allow doses more spaced out in time:

• Flufenazide (Modecate).
• Pipothiazide (Lonseren).
• Zuclopentixol (Cisordinol).

In the first two cases, a dose is administered every 3 weeks and, in the last case, every 2 weeks.

These typical or classic neuroleptics are especially indicated for the treatment of:

• Psychosis.
• Agitation and violent behavior.
• Movement disorders –tics- or Gilles de la Tourette syndrome.
• Stimulant poisoning.
• Chronic pain.
• Alcohol deprivation.

Side effects of typical antipsychotics

Among its adverse effects, we can find the following:

• Sedation.
• Drowsiness.
• Incoordination.
• Seizures
• Epileptogenic effect.
• Extrapyramidal effects: dystonias, parkinsonian effects, akathisia, etc.
• Orthostatic hypotension.

Mechanism of action of classical neuroleptics

These drugs are based on the dopaminergic hypothesis, according to which positive psychotic symptoms are related to the overactivity of dopaminergic neurons, especially the mesolimbic pathway.

Therefore, antipsychotic drugs used to treat positive symptoms work by blocking dopamine receptors, particularly dopamine D2 receptors.

The negative symptoms of schizophrenia, described above, may involve other regions of the brain, such as the dorsolateral prefrontal cortex and other neurotransmitters - it may be related to excitatory glutamate hyperactivity.

Atypical neuroleptics

On the other hand, we find the group of atypical neuroleptics, which are those developed more recently.

They constitute a heterogeneous group of substances that act on the positive and negative symptoms of schizophrenia - unlike the classic neuroleptics, which only act on the positive ones.

Some of the best known atypical antipsychotics are the following:

Clozapine (Leponex)

Derivatives of dibenzodiazepines. It is the only drug specifically indicated for the treatment of refractory schizophrenia.

Certain severe clinical conditions in schizophrenia are particularly responsive to clozapine, including persistent auditory hallucinations, violence, aggressiveness, and risk of suicide.

Likewise, the low incidence of tardive dyskinesia should be taken into account as an adverse effect of the drug. Clozapine has also been shown to have a beneficial effect on cognitive function and affective symptoms.

Olanzapine (Zyprexa)

It is also derived from the dibenzodiazepines, and has structural and pharmacological properties similar to clozapine with mixed activity on multiple receptors.

Although olanzapine has been shown to have antipsychotic activity, its efficacy in resistant schizophrenia and its relative position relative to other atypical antipsychotics, for which there is not too conclusive data, have yet to be demonstrated.

Likewise, the clinical relevance of the effects on negative symptoms that are deduced from the improvement of the negative symptom scales is difficult to interpret and the most rigorous analyzes of the data fail to demonstrate a clear superiority of olanzapine.

Neither can clear recommendations be made for agitation, aggressiveness, and hostility, although it appears less sedating than chlorpromazine and haloperidol. One of the side effects it produces is significant weight gain.

Therefore, more long-term studies are needed to reveal data on tolerance, quality of life, social functioning, suicide, etc.

Risperidone (Risperdal)

Derived from benzoxiooxazoles. It is not yet known whether risperidone is more effective than classical neuroleptics. It appears to have some advantages over haloperidol in terms of limited relief of some symptoms and side effect profile.

It may be more acceptable for patients with schizophrenia, perhaps due to the low sedation it produces, despite its tendency to increase weight.

There are few data on the clinical implications of risperidone use but, surprisingly, there are none in relation to service utilization, hospitalization, or community functioning.

The potential clinical and side effect reduction benefits of risperidone have to be weighed against the higher cost of this drug.

Quetiapine (Seroquel)

It is derived from dibenzothiacipine, and it has been found that the best results that this drug has achieved were achieved in less severe patients and its efficacy on negative symptoms was less consistent and not superior to the classic ones.

The clinical trials that have been carried out are all of short duration - from 3 to 8 weeks - and with a high dropout rate (48-61%).

These data, together with the short clinical experience available to the drug, make it impossible to draw conclusions about its clinical importance.

Ziprasidone

Currently there is also an atypical neuroleptic being introduced, Ziprasidone. The data obtained so far show that it can be as effective as haloperidol for schizophrenia, although it has the disadvantage of causing nausea and vomiting.

The injectable form has the added drawback of causing more pain at the injection site than haloperidol.

More studies are still needed to compare this drug with the other atypical neuroleptics in order to draw conclusions about its true efficacy.

Side effects

Although these neuropsychotics cause fewer extrapyramidal effects than the classic ones, and improve the negative symptoms of schizophrenia, they also have some side effects:

• Tachycardia.
• Dizziness
• Hypotension
• Hyperthermia
• Hypersalivation
• Leukopenia -which sometimes ends in agranulocytosis, mainly due to Clozapine-.

Mechanism of action of atypical neuroleptics

Serotonin-dopaminergic antagonists act as dopamine antagonists -at D2 receptors-, although they also act on serotonin -especially at 5HT2a receptors-.

Typical antipsychotics versus atypical antipsychotics

In schizophrenia, conventional or classic antipsychotics remain the first-line drugs today.

Despite their side effects and limitations, they have been shown to be very effective in acute and maintenance treatment, being well tolerated by many patients.

An additional advantage of these antipsychotics is the availability of some of them in parenteral pharmaceutical forms, of short duration or "depot" preparations.

However, in those cases in which classical antipsychotics are not well tolerated due to their extrapyramidal effects, atypical antipsychotics are a suitable alternative.

The reasons why they are not yet considered first-line drugs in schizophrenia are:

• Little knowledge about its safety and efficacy in maintenance therapy.
• The high cost involved.

Although some authors justify the use of new antipsychotics in the "first" acute episode of schizophrenia and during the illness, based on the hypothesis of a decrease in relapse rates and associated morbidity and an improvement in long-term results, there are no adequate clinical trials assessing these facts.

Possible advantages of outliers

There are also hypotheses about the advantages of atypical antipsychotics in reducing costs (shorter hospital stays, fewer rehospitalizations, etc.).

Although several studies with clozapine and risperidone have shown evidence of the lower cost associated with their use compared to older ones, their results have been criticized for limitations in the experimental design.

Due to the increase in healthcare costs, for the selection of a drug, it is necessary to consider not only its efficacy and safety but also the cost of the different alternatives through drug-economic studies.

This type of study is especially important in the treatment of schizophrenia, since it is a disease with a great cost for health systems due to its early onset and long course.

On the other hand, it is a disease that produces enormous personal and family suffering and great disability in affected individuals. All these facts support the need to carry out adequate pharmacoeconomic studies (evaluating cost-effectiveness, cost-utility), as well as long-term clinical trials to help define the place of new antipsychotics in schizophrenia.

References

1. Elizondo Armendariz, JJ (2008). Clozapine: a historical view and current role in treatment-resistant schizophrenia.
2. Gutiérrez Suela, F. (1998). Current antipsychotic treatment of schizophrenia. Farm Hosp, 22 (4).
3. Lobo, O., & De la Mata Ruiz, I. (2001). New antipsychotics. Inf Ter Sist Nac Salud, 25, 1-8.
4. Peinado-Santiago, A. (2015). Efficacy of second-generation neuroleptic drugs in the treatment of schizophrenia.
5. Tajima, K., Fernández, H., López-Ibor, JJ, Carrasco, JL, & Díaz-Marsá, M. (2009). Treatments for schizophrenia. Critical review on the pharmacology and mechanisms of action of antipsychotics. Actas Esp Psiquiatr, 37 (6), 330-342.