Generality
Antipsychotic drugs - also known as neuroleptics - are drugs used to treat psychosis.
According to the classification of the DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders), psychotic disorders include:
- Schizophrenia;
- Schizophreniform disorder;
- Schizoaffective disorder;
- Delusional disorder;
- Brief psychotic disorder;
- Shared psychotic disorder;
- Substance-induced psychotic disorder (such as, for example, amphetamines, LSD, cocaine, etc.);
- Psychotic disorder due to general medical condition;
- Psychotic disorder not otherwise specified.
Generally, antipsychotics have a calming and anti-hallucinatory effect and stabilize mood in patients with psychosis.
However, due to the side effects - even serious - that antipsychotics can induce, their use should be limited only to the treatment of very serious psychotic disorders, such as - for example - schizophrenia.
Schizophrenia
Schizophrenia is a psychiatric pathology that interferes with the individual's ability to communicate, make judgments, think coherently, manage the emotional sphere and distinguish what is real from what is not.
This pathology is mainly characterized by two types of symptoms:
- Productive symptoms (or positive), these symptoms are associated with the common concept of insanity and are delusions (persecutory, grandeur or mind reading), hallucinations (especially auditory, the so-called "voices"), disorders of thought and behavior bizarre;
- Negative symptomsoften confused with intentional social withdrawal or with a voluntary lack of responsibility towards others. Such symptoms include emotional flattening, loss of vital momentum, and poverty of both qualitative and quantitative thinking.
The causes of schizophrenia are not entirely clear but it seems that both environmental factors and a genetic component are involved.
In an attempt to explain the cause of the onset of this pathology, various neurochemical hypotheses have been formulated. Some of these hypotheses will be briefly illustrated below.
Dopaminergic hypothesis
According to this "hypothesis, schizophrenia is caused by an increase in the dopamine signal or by an" overactivation of D2 type post-synaptic dopamine receptors in the brain.
This hypothesis is supported by the following facts:
- Levodopa (a drug used in the treatment of Parkinson's disease as well as a precursor of dopamine) when administered to schizophrenic patients aggravates their symptoms and - at the same time - can induce hallucinations in parkinsonian patients;
- Drugs inhibiting dopamine synthesis potentiate the action of antipsychotics;
- In schizophrenic patients, elevated dopamine levels have been identified in certain brain areas and an increase in the number of D2 receptors in the limbic and striatum areas of the brain.
Glutamatergic hypothesis
According to this hypothesis, schizophrenia is caused by a deficit of glutamate, an amino acid that plays the role of an excitatory neurotransmitter in the central nervous system.
Serotonergic hypothesis
According to this hypothesis, schizophrenia is caused by a serotonin deficiency. This theory is in agreement with the dopaminergic hypothesis. In fact, serotonin is a negative modulator of the dopaminergic pathways and - a lack of it - can cause an overactivation of the same.
The dopaminergic hypothesis - even if it is not sufficient to explain the causes of schizophrenia - is certainly very accredited, since practically all antipsychotics exert an antagonistic action on dopamine receptors.
However, with the arrival of new antipsychotics (atypical antipsychotics) that also have affinities for other types of receptors - as well as for dopamine receptors - alternative hypotheses on the possible cause of schizophrenia are being developed.
Development of antipsychotics
The first antipsychotic drug - chlorpromazine - was synthesized in 1950 by chemist Paul Charpentier in an attempt to synthesize analogues of promethazine, a phenothiazine with neuroleptic and antihistamine activity.
Later, the French surgeon Laborit and his collaborators discovered the ability of this drug to enhance the effects of anesthesia. They noted that chlorpromazine itself did not produce loss of consciousness, but favored a tendency to sleep and a marked disinterest in the "surrounding environment.
In 1952 the psychiatrists Delay and Deniker hypothesized that chlorpromazine, not only was an agent capable of treating the symptoms of agitation and anxiety, but that it could also have a therapeutic effect in the treatment of psychosis.
From then on, the development of the first class of antipsychotic drugs began, the phenothiazines.
At the end of the 1950s another antipsychotic was synthesized which is still widely used today and belongs to the class of butyrophenones, haloperidol.
Haloperidol was discovered by chance by researcher Paul Janssen and his collaborators in an attempt to obtain drugs analogues of meperidine (an opioid analgesic) with increased analgesic activity. The modifications made to the meperidine molecule led to the development of an analog that possessed so increased analgesic activity, but which - at the same time - had antipsychotic effects similar to those of chlorpromazine.
Janssen and his collaborators understood that with appropriate structural modifications in the molecule of the analogue obtained they could eliminate the analgesic action in favor of neuroleptic activity. Following these modifications, haloperidol was finally obtained. This drug was marketed in Europe starting in 1958 and in the United States starting in 1967.
Classes of antipsychotic drugs
As stated above, the first class of antipsychotic drugs to be developed was that of phenothiazines, followed by the class of butyrophenones.
Subsequently, research in this field continued and allowed the synthesis of new classes of drugs, up to the discovery of the most recent atypical antipsychotics.
Phenothiazines
In reality, the term phenothiazines indicates a group of molecules that possess both antipsychotic and antihistamine activity. In this case, only phenothiazines with antipsychotic properties will be considered.
Neuroleptic phenothiazines are typical antipsychotic drugs that work by antagonizing dopamine D2 receptors. The chlorpromazine, the perphenazine, the thioridazine, the fluphenazine, the prochlorperazine, the perphenazine and the "acetofenzain.
In addition to their neuroleptic properties, phenothiazines also boast antiemetic (i.e. antivomiting) properties.
Butyrophenones
Butyrophenones act by antagonizing dopamine D2 receptors and also have a certain affinity towards serotonin 5-HT2 receptors. Butyrophenones also boast antiemetic properties in addition to antipsychotic ones.
They belong to this class l "haloperidol, the droperidol, the trifluperidol and it spiperone.
Benzamide derivatives
To this category belongs the sulpiride, an atypical antipsychotic drug. It works by antagonizing dopamine D2 receptors. Sulpiride - like all atypical antipsychotics - produces minor extrapyramidal side effects.
Benzazepine derivatives
The drugs belonging to this category are all atypical antipsychotics and therefore have a lower "incidence of extrapyramidal side effects than typical antipsychotics.
They work by antagonizing dopamine D2 and serotonin 5-HT2 receptors.
They belong to this category of drugs clozapine, L"olanzapine, the quetiapine and the loxapine.
Other atypical antipsychotics
Other atypical antipsychotics still used in therapy are risperidone and the "aripiprazole.
Side effects
The side effects induced by antipsychotics are attributable to the fact that these drugs - in addition to antagonizing the dopamine and serotonin receptors - also exert an antagonistic effect on other receptor systems of the central nervous system, such as the adrenergic, histaminergic or cholinergic system.
Some of the side effects that antipsychotics can cause are:
- Sedation;
- Hypotension;
- Gastrointestinal disorders;
- Eye and vision problems;
- Bladder Disorders;
- Sexual dysfunctions.
The extrapyramidal effects are mainly caused by typical antipsychotics, while atypical antipsychotics have a "lower incidence of these effects (but are not entirely devoid of them).
Extrapyramidal effects are also referred to as "Parkinson-like effects" because they resemble the symptoms that occur in individuals with Parkinson's disease.
These effects are caused by the antagonism of antipsychotics against dopamine D2 receptors found in the nigrostriatal areas of the brain.
Extrapyramidal symptoms include:
- Dystonia;
- Akathisia (inability to sit still);
- Involuntary movements;
- Bradykinesia;
- Muscle stiffness;
- Tremors
- Shuffling gait.
Finally, antipsychotics can cause the onset of a particular disorder known as neuroleptic malignant syndrome. This syndrome is a neurological disorder characterized by:
- Fever;
- Dehydration;
- Muscle stiffness;
- Akinesia;
- Sweating;
- Tachycardia;
- Arrhythmia;
- Changes in the state of consciousness that can progress to stupor and coma.
If these symptoms appear, you should immediately stop taking the drug and contact a doctor right away.
