Etoperidone is an atypical antidepressant , or second generation tricyclic, used to treat depressive disorders and was developed decades ago, although it is currently discontinued. Other new generation antidepressants are now being used that have fewer side effects than drugs in the tixag family.

In this article we explain what etoperidone is and what effects it produces, what is its mechanism of action and that of tricyclic antidepressants, what side effects it causes and what are the main contraindications if this drug is to be used.

What is etoperidone and what effects does it have?

Etoperidone is a drug from the atypical antidepressant group (second generation tricyclic) that was developed in the 1970s by the Italian pharmaceutical company Angelini and is no longer marketed.

It belongs to the group of phenylpiperazine , and has a chemical structure similar to other drugs such as trazodone and nefazodone, both also second-generation antidepressants that act as antagonists and inhibitors of serotonin reuptake, with anxiolytic and hypnotic effects.

Although etoperidone has certain sedative effects, it differs from other minor tranquilizers in some fundamental aspects: in its interaction with the main brain amines; by the absence of anticonvulsant effects; and in its different spectrum of effects at the behavioral level when consumed in high doses.

Etoperidone, however, is similar in some respects to neuroleptic drugs (drugs used to treat psychosis and states of extreme agitation), such as chlorpromazine, as it produces analgesic and sedative effects at low doses; although unlike these, it does not block dopamine receptors at the central level.

How does this drug work?

Etoperidone acts as a multi-receptor antagonist drug, including those for serotonin and adrenergics . It also appears to have a mild affinity for blocking dopamine, histamine, and acetylcholine (muscarinic type) receptors.

In addition to blocking these receptors, this drug also has a weak affinity for the monoamine transporters: serotonin, noradrenaline, and dopamine. The administration of this type of antidepressant in the acute phase mainly increases the availability of noradrenaline and, to a certain extent, 5-HT, by blocking its reuptake in the synaptic cleft.

Prolonged use negatively regulates post-synaptic membrane alpha-adrenergic receptors , a possible common endpoint of the antidepressant activity of these drugs.

On the other hand, etoperidone, in its metabolization, produces a substance or active metabolite called mCPP, probably the one responsible for the serotonergic effects; a substance that can cause undesirable and unpleasant effects in the subjects who consume or used this antidepressant.

Second generation atypical or tricyclic antidepressants

Etoperidone belongs to the group of atypical or tricyclic antidepressants, often used in patients suffering from major depression and who respond inadequately or endure intolerable side effects during first-line treatment with serotonin reuptake inhibitor antidepressants.

Tricyclic antidepressants have been used for decades and have some chemical and, to a lesser extent, pharmacological similarity to phenothiazines , used to treat severe mental and emotional disorders. Although this type of antidepressant was initially thought to be useful as an antihistamine, over time its use was limited to the treatment of depression and other similar conditions.

This type of antidepressant is highly effective , although due to the number of side effects it produces, it is usually recommended to start treatment with a low dose and increase it according to the tolerance each patient has and the antidepressant effect achieved, until a balance is found between the greatest possible effectiveness and the least amount of side effects.

Given its sedative profile, this type of drug can also be used to treat patients with depressions that concur with a high level of anxiety , helping them to calm the nervousness and agitation that they usually present in certain circumstances.

At present, this type of antidepressant has been gradually replaced by other new generation ones, with fewer side effects and a more specific and selective mechanism of action, such as venlafaxine or mirtazapine, two inhibitors of the reuptake of serotonin and noradrenaline.

Side effects

The most common side effects when taking drugs from the atypical or heterocyclic antidepressant group, such as etoperidone, include a range of effects at the somatic level, such as the following:

  • Nausea
  • Fatigue
  • Nervousness
  • Dry mouth
  • Dizziness
  • Diarrhea
  • Headaches
  • Insomnia

Contraindications

Although at the time and when they were developed these types of antidepressant drugs were effective, they are now used less and less, as their overdose is toxic and they have more adverse effects than the more modern antidepressants . These side effects are mainly due to muscarinic and histamine blocks and alpha-adrenergic actions.

Many of the atypical antidepressants have potent anticholinergic properties and are therefore not suitable for the elderly or for patients suffering from benign prostatic hypertrophy, glaucoma or chronic constipation. Furthermore, the vast majority of drugs of this type lower the seizure threshold, with the consequent danger for people who are prone to seizures.

Specific contraindications for the use of etoperidone include the following:

  • Allergy to etoperidone, trazodone or other phenylpiperazine.
  • Bipolar disorders and manic states: this drug can accelerate the transition to the hypomanic or manic phase and induce a rapid and reversible cycle between mania and depression.
  • Cardiovascular alterations: increases the risk of arrhythmias, congestive heart failure, myocardial infarction or cardiovascular accident.
  • Schizophrenia and psychosis: may increase the risk of psychotic disorders.
  • Hyperthyroidism: due to the risk of cardiovascular toxicity
  • Liver failure: since it is mainly metabolized in the liver, the dosage must be adjusted to the functional degree of the liver in each patient.
  • Kidney failure: since the drug is mostly eliminated through the kidney, the dosage must be adjusted according to the level of kidney function.

Bibliographic references:

  • Heerlein A. Antidepressants. In: Heerlein A (ed): Clinical Psychiatry. Santiago de Chile, Ediciones de la Sociedad de Neurología, Psiquiatría y Neurocirugía, 2000
  • Raffa, RB; Shank, RP; Vaught, JL (1992). “Etoperidone, trazodone and MCPP: in vitro and in vivo identification of serotonin 5-HT1A (antagonistic) activity. Psychopharmacology. 108(3): 320-6
  • Rodríguez, N. H. (2015). Effectiveness of atypical antidepressants and serotonin and noradrenaline reuptake inhibitors versus classical serotonin reuptake inhibitors. PHARMACIENCE, 3(1), 39-42.
  • Tordera RM, Monge A, Del Rio J, Lasheras B. Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT(1A) receptors. Eur J Pharmacol 2002; 442(1-2):63-71