Antipsychotic drugs have been used for decades as a treatment for schizophrenia and psychotic symptoms, and over the years they have evolved.

The first generation of these drugs, the typical neuroleptics, were effective in alleviating the positive symptoms of psychosis (such as delusions and hallucinations), but not so much in terms of the negative symptoms (anhedonia, abulia or emotional numbness). An example of this group of drugs is zuclopenthixol, which we will discuss throughout the article.

Below we explain the characteristics and medical uses of zuclopenthixol , its mechanism of action, the main side effects and contraindications, and its clinical efficacy compared to the group of second generation antipsychotics.

Zuclopenthixol: medical characteristics and uses

Zuclopenthixol is a drug from the group of typical antipsychotics , derived from thioxanthene, which is used in the treatment of schizophrenia and other psychoses. This drug was introduced to the market in 1978 and is currently available in various forms, mainly as intramuscular injections and tablets.

Several generations of neuroleptic drugs have been developed and marketed over the years. The first generation, known as typical antipsychotics, includes zuclopenthixol (from the phenothiazine group) and other classic neuroleptics such as haloperidol and chlorpromazine.

This first generation of drugs for the treatment of psychosis was left behind and replaced by second generation atypical antipsychotics (such as olanzapine or risperidone), with fewer adverse reactions and a more pronounced effect on the negative symptoms of diseases such as schizophrenia (symptoms including anhedonia, abulia or emotional numbness).

Zuclopenthixol is currently marketed in Spain under the name Clopixol , in injectable solutions, ampoules, oral drops and tablets. It is indicated for schizophrenic patients with acute crises, especially with symptoms of agitation and/or depression. Normally, the most commonly used route of administration is injection, since it slowly releases the active ingredient and prevents psychotic symptoms from reappearing in the patient. It is usually administered every 1-4 weeks.

Mechanism of action

The mechanism of action of zuclopenthixol is similar to that of the vast majority of typical antipsychotics. This drug exerts an antagonistic action on the dopamine receptors D1 and D2 , although it acts preferentially on the latter. It also has a high affinity for the adrenergic receptors α1 and for the serotonin 5-HT2 receptors.

In addition, zuclopenthixol has mild histamine H1 receptor blocking activity, and also a poor affinity for cholinergic muscarinic and adrenergic receptors α2. Cytochrome P450 2D6 is known to be responsible for metabolizing this drug, in addition to many other commonly used drugs.

The oral bioavailability of zuclopenthixol is 40%, and it reaches its maximum concentration in blood plasma after 4 hours. It should be noted that food intake does not interfere with its absorption . In the case of intramuscular injection, the maximum plasma concentration occurs after 24-48 hours (in its acetate form), and after 3-7 days (in its decanoate form).

Contraindications

Zuclopenthixol consumption is contraindicated in acute alcohol, barbiturate and opiate intoxication, comatose states, circulatory collapse, hypersensitivity to thioxanthenes, central nervous system depression, blood dyscrasias or spinal cord depression, pheochromocytoma, porphyrias, glaucoma, risk of urinary retention in urethroprostatic persons and liver and/or kidney failure.

Patients with cardiovascular disorders should be especially careful , since the use of zuclopenthixol can cause hypotension and arrhythmias. In people with respiratory problems or asthma, this medicine can produce depressive effects on respiratory function. Epileptic patients should also use caution, because this drug can lower the seizure threshold, especially in high-risk people.

Side effects

The use of zuclopenthixol can lead to a number of side effects and adverse reactions that should be taken into consideration . Among the most worrying are: the neuroleptic malignant syndrome, which is characterized by psychic alterations, muscular rigidity, hyperthermia and symptoms of hyperactivity of the autonomic nervous system; and the extrapyramidal syndrome, which affects the patient’s motor skills and causes several characteristic symptoms.

Let’s see below what are the main organic and psychiatric alterations associated with the consumption of zuclopenthixol.

Neurological disorders

Frequently (more than 10%), there may be tremors, muscle stiffness, parkinsonism, akathisia, dystonia, and dizziness. Occasionally (less than 10%), paresthesia, dyskinesia, tardive dyskinesia, and headache may occur.

Psychological/psychiatric disorders

Frequently, the use of zuclopenthixol can lead to sleep disorders, such as drowsiness problems ; and occasionally, disorders such as asthenia and mental confusion.

Digestive disorders

One of the most common digestive symptoms is dry mouth. In addition, and occasionally, patients using zuclopenthixol may suffer from dyspepsia, nausea and constipation after consumption.

Cardiovascular disorders

The consumption of zuclopenthixol can occasionally generate tachycardia and hypotension .

Ocular disorders

Occasionally, the use of this drug may result in disorders of eye accommodation.

Other alterations

The use of zuclopenthixol occasionally leads to urinary retention , and in some patients there may be excessive sweating.

Clinical efficacy

As we mentioned at the beginning, zuclopenthixol belongs to the group of typical antipsychotics, the first generation of drugs used for the treatment of psychotic symptoms in patients with schizophrenia, mainly. Since the appearance on the market of the second generation antipsychotics, the prescription of typical neuroleptics for schizophrenic patients has been considerably reduced .

In a review of several studies comparing the clinical efficacy of typical (TA) antipsychotics against atypical or second generation (TA) antipsychotics, it was found that TA were not superior to TA in efficacy or tolerability. Another meta-analysis showed that TA used at optimal doses did not have a higher risk of causing extrapyramidal symptoms than AA, although a lower efficacy was observed.

The CATIE study, which evaluated the effectiveness of antipsychotic treatments (using AT and AA) in 1,493 patients with schizophrenia, showed that these drugs were rather moderately effective in treating the disease. In addition, lack of efficacy or occurrence of side effects caused 74% of patients to drop out of the study before it ended.

The authors of the study concluded that olanzapine (AA) was the most effective antipsychotic of those studied and that there was no difference between the others (this includes zuclopenthixol). However, the increased efficacy of olanzapine was offset by an increase in metabolic adverse effects . In any case, such a high withdrawal rate evidences the limitations of antipsychotics (either AT or AA) in terms of efficacy and safety in the treatment of schizophrenia.

Bibliographic references:

  • Arango, C., Bombín, I., González-Salvador, T., García-Cabeza, I., & Bobes, J. (2006). Randomised clinical trial comparing oral versus depot formulations of zuclopenthixol in patients with schizophrenia and previous violence. European psychiatry, 21(1), 34-40.
  • Bermejo, J. C., & Rodicio, S. G. (2007). Typical antipsychotics. Atypical antipsychotics.
  • Jerling, M., Dahl, M. L., Åberg-Wistedt, A., Liljenberg, B., Landell, N. E., Bertilsson, L., & Sjöqvist, F. (1996). The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clinical Pharmacology & Therapeutics, 59(4), 423-428.