Neuroleptics: Indications, Mechanism of Action, Administration, Adverse Effects and Contraindications

They are psychiatric medications that are available by prescription.

Health problems in which these drugs are used include:

  • Schizophrenia.
  • Schizoaffective disorder.
  • Some forms of bipolar disorder.
  • Mild depression

Some neuroleptics can also treat anxiety, stress, and psychotic experiences in dementia.

Antipsychotics can be prescribed to be taken in different ways. It is commonly accepted by mouth in tablet or liquid form, but some of these can also be received as depot injections.

Other terms for neuroleptics are antipsychotics and psychotropic drugs.


Neuroleptics, also known as antipsychotic medications, are used to treat and control the symptoms of many psychiatric disorders.

These drugs can be divided into two classes:


  • First-generation or “typical” antipsychotics.
  • Second-generation or “atypical” antipsychotics.

First-generation antipsychotics were initially developed in the 1950s to treat psychosis (e.g., Schizophrenia).

In addition to psychotic illnesses, they have also been approved by the FDA to treat acute mania, agitation, bipolar disorder, Tourette syndrome, and hyperactivity.

Due to the poorly tolerated and often irreversible adverse effects of first-generation antipsychotics, the second class of neuroleptics (second-generation antipsychotics) was established in the 1980s.

These second-generation antipsychotics have been approved by the FDA to treat and manage psychosis and refractory schizophrenia, bipolar disorder, schizoaffective disorder, agitation, and irritability/agitation.

In 2001, 96% of neuroleptics prescribed to new users were the second generation.

Beyond FDA-approved uses, first- and second-generation antipsychotics are also used in several neuropsychiatric conditions currently considered unapproved.

These include:

  • Attention deficit hyperactivity disorder (ADHD).
  • Behavioral disorders in dementia.
  • Old agitation.
  • Depression.
  • Eating disorders.
  • Personality disorders.
  • Insomnia.
  • Generalized anxiety disorder.
  • Obsessive-compulsive disorder.
  • Post-traumatic stress disorder (PTSD).
  • Substance use and dependency disorders.

For many of these conditions, the evidence for its use is inconclusive. With increasing off-label use and high costs, it is essential to assess the evidence for its emerging use in these medical and psychiatric conditions.

Mechanism of action of neuroleptics

First-generation antipsychotics

In first-generation antipsychotic drugs, the postsynaptic blockade of dopamine D2 receptors in the central nervous system is the mechanism of action.

Supporting evidence includes strong antagonism of D2 receptors in cortical and striatal areas, a high association between D2 receptor binding and clinical potency, and a consistent requirement of 65% D2 receptor occupancy for antipsychotic efficacy in functional imaging studies.

This nonspecific location of dopamine binding through the central nervous system (CNS) is consistent with the risk of movement disorders and prolactinoma.

Second-generation antipsychotics

Second-generation antipsychotics differ from first-generation antipsychotics by the transient occupation of D2 receptors and rapidly dissociating to allow normal dopamine neurotransmission.

They also have antagonistic properties at the 5HT2A receptor. These differences explain normal prolactin levels, decreased cognitive deficits, and the preclusion of extrapyramidal symptoms (EPS).


Most first-generation antipsychotic medications are available in oral formulations. Several are also available in injectable intramuscular formulations, which help treat psychotic agitation.

In acute medical settings, intravenous formulations of haloperidol and droperidol are sometimes used to treat psychosis, agitation, or delirium.

The long-acting haloperidol decanoate preparations and fluphenazine can be administered by intramuscular injection once or twice a month, valid for patients who are not adherent to daily oral administration.

Second-generation antipsychotics are available orally. Additionally, aripiprazole is known as an intramuscular injection (immediate release) in acute settings, and olanzapine, risperidone, paliperidone, and aripiprazole are available long-acting injectables for use in non-adherent patients.

Adverse effects

In addition to their everyday activity as D2 antagonists, first-generation antipsychotics have apparent effects on neuronal 5-HT2a, alpha-1, histamine, and muscarinic receptors, corresponding to their side effect profiles.

These pharmacological differences are the basis for the classification of first-generation antipsychotics as high or low potency drugs.

First-generation, high-potency antipsychotics are dosed, such as fluphenazine, trifluoperazine, haloperidol, loxapine, pimozide, perphenazine, and thiothixene in the range of one to tens of milligrams.

They show low activity at histamine and muscarinic receptors. They are associated with weight gain, sedative effects, or anticholinergic activity.

They have a high risk of extrapyramidal side effects:

  • Distonía.
  • Bradykinesia.
  • Rigidity.
  • Temblor.
  • Late dyskinesia due to hypersensitivity to the dopamine receptor and hyperprolactinemia.

Low-potency, first-generation antipsychotics such as chlorpromazine and thioridazine are administered in hundreds of milligrams and have high histamine and muscarinic activity with a corresponding higher prevalence of sedation and anticholinergic effects:

Due to fewer extrapyramidal and anticholinergic effects, second-generation antipsychotics are the first-line treatment for psychotic disorders (e.g., Schizophrenia).

Second-generation antipsychotics are associated with weight gain, type 2 diabetes mellitus, drowsiness, sedation, and QTc prolongation.

Among the second-generation antipsychotics, clozapine is the most effective in reducing psychotic symptoms and suicidality.

However, due to agranulocytosis’s significant adverse side effects, clozapine is reserved for severe psychotic disorders after a patient has had an insufficient response to two fair trials of other antipsychotic medications.

Contraindications of neuroleptics

Due to their wide-ranging adverse effects, neuroleptic medications can cause or aggravate some conditions.

They are contraindicated in patients with:

  • Hepatic injury.
  • Coronary artery disease
  • Cerebrovascular disease
  • Parkinsonism.
  • Bone marrow depression (i.e., clozapine).
  • Hypotension or severe hypertension.
  • Eat or severely depressed states.

They should be used with caution in people with:

  • Seizure disorders
  • Mellitus diabetes.
  • Glaucoma.
  • Prostatic hypertrophy.
  • Peptic ulcer.
  • Chronic respiratory disorders.


First-generation (typical) antipsychotic drugs meet the requirements for therapeutic drug monitoring primarily for compliance control and to avoid extrapyramidal reactions by maintaining chronic exposure to minimum adequate blood levels.

For clozapine, drug safety concerning agranulocytosis is another reason to use therapeutic drug monitoring.

The rationale for monitoring drug levels is debatable with the second-generation antipsychotics, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Positron emission tomography (PET) can measure dopamine D2 receptor occupancy and reveals that receptor occupancy interacts better with plasma concentrations than antipsychotic doses.

There is a constant 65% D2 receptor occupancy requirement for antipsychotic efficacy in functional imaging studies.

About plasma levels related to therapeutic effects, ideal concentrations have been established for clozapine (350 ng / ml to 600 ng / ml), risperidone (20 ng / ml to 60 ng / ml) and olanzapine (20 ng / ml for -80 ng / mL) but not for the other second-generation antipsychotics.


An isolated overdose of neuroleptics is rarely fatal. Toxicity results from blocking some or all of the following receptors:

  • Dopamine: extrapyramidal symptoms.
  • Alpha-1: orthostatic hypotension, reflex tachycardia.
  • Muscarinic: anticholinergic symptoms.
  • Histamine: sedation.

Extrapyramidal symptoms include:

  • Acute dystonia: tongue protrusion, facial grimaces, lockjaw, and oculogyric crisis.
  • Akathisia: the feeling of internal restlessness.

Anticholinergic effects include:

  • Tachycardia.
  • Dry mucous membranes.
  • Dry Skin.
  • Decreased bowel sounds.
  • Delirium.

These symptoms are treated with diphenhydramine 25 mg to 50 mg IV / IM or benztropine 1 mg to 2 mg IV / IM.

ECG changes such as sinus tachycardia and QT interval prolongation may result from neuroleptic toxicity.

With QTc prolongation of more than 500 ms, treatment with magnesium 2 to 4 mg IV for 10 minutes is indicated.

The most life-threatening emergency associated with neuroleptics is neuroleptic malignant syndrome.

This syndrome can occur from a single dose, increased dose, or the same dose.

It is primarily associated with first-generation antipsychotics but can also be seen to a lesser extent with second-generation antipsychotics, antiemetics (metoclopramide, promethazine), and withdrawal of Parkinson’s medication.

Symptoms generally develop within 1 to 3 days, mortality rates are 5% to 20%, and most deaths occur due to complications from muscle stiffness.

The clinical features of the neuroleptic malignant syndrome include:

  • The tetrad of altered mental status.
  • Muscle stiffness
  • Hyperthermia.
  • The autonomic instability.

Administration involves stopping the causative agent.

Warnings on the use of neuroleptics in people with dementia

Neuroleptics worsen health and cognitive function and increase mortality in people with dementia.

These drugs have a narrow therapeutic window, modest efficacy, and numerous and frequent adverse effects. They are considerably more expensive than other psychoactive drugs, which encourages companies to do improper and illegal commercial promotion.

In recent years, their use has increased dramatically, mainly because it has been promoted in clinical situations in which they have not shown efficacy or have an unfavorable benefit-risk ratio (unauthorized indications).

Ineffective and toxic in the elderly with dementia

The technical specifications of the new neuroleptics (marketed since the late 1990s) limit their indications practically to schizophrenia and the manic episodes of bipolar II disorder.

In patients with dementia, the only authorized one is risperidone, but only for the symptomatic and specific treatment (up to 6 weeks) of severe episodes of aggressiveness and severe psychotic symptoms that do not respond to non-pharmacological measures after having ruled out other etiologies.