18. Antipsychotic drugs

Introduction to psychosis

Psychosis refers to a disordered perception of reality, often characterised by delusions, hallucination and/or disorganized behaviour. It can be a symptom of psychiatric disorders like schizophrenia, bipolar disorder, psychotic depression or drugs like methamphetamine, cannabis or alcohol. In the context of pharmacology “antipsychotic drugs”, also called “neuroleptic drugs” usually refer to those drugs that are used to treat schizophrenia.

Schizophrenia

Schizophrenia (from the Greek words “to split” and “the mind”) is a severe psychiatric disorder characterised by chronic or recurrent psychosis. Most patients experience symptoms for the first time in their 20s.

Etiology:

The exact cause is unknown, but there are strong genetic factors. Frequent use of cannabis increases the risk.

Clinical features:

The clinical features of schizophrenia are usually divided into three groups:

  • Positive symptoms – symptoms that are distortions or exaggerations of normal functions
    • Delusions – where the patient believes something that is true which in reality isn’t
      • For example, the belief that someone is out to get them
    • Hallucinations – where the patient experiences a sensation that is not real
      • For example, hearing voices that aren’t there
    • Disorganized behaviour
    • Catatonia – purposeless motor activity
  • Negative symptoms – symptoms of diminished normal/healthy function
    • Social withdrawal
    • Flattened emotional spectrum
    • Apathy
    • Anhedonia
  • Cognitive symptoms
    • Decreased attention
    • Impaired memory

Pathogenesis:

There is dysregulation of dopaminergic activity, with increased dopaminergic activity in the mesolimbic reward pathway and decreased dopaminergic activity in the prefrontal cortex. The cortex is atrophic, and the ventricles are enlarged.

Treatment:

Two categories of drugs are used to treat schizophrenia:

  • First-generation (typical) antipsychotics
  • Second-generation (atypical) antipsychotics

The second-generation antipsychotics are usually preferred as they cause fewer side-effects.

These drugs block dopamine receptors in the brain, so let’s quickly review some dopaminergic pathways in the CNS.

Dopaminergic pathways of the CNS
Pathway Associated processes Associated disorders
Mesolimbic (reward) pathway Mediates the feeling of reward Schizophrenia
Mesocortical pathway Executive functions Schizophrenia
Nigrostriatal pathway Muscle movement Parkinson’s disease
Tuberoinfundibular pathway Inhibition of prolactin release Hyperprolactinaemia
First-generation antipsychotics

The first-generation antipsychotics (FGAs) were invented in the 1950’s and were used for decades until the second generation was invented in the 1990s. They’re also called the “typical” antipsychotics.

Drugs in this class includes haloperidol, chlorpromazine, trifluoperazine, thioridazine and fluphenazine.

Indications:

  • Schizophrenia
    • FGAs are especially effective at treating the positive symptoms of schizophrenia, but not effective at treating the negative symptoms
  • Acute psychosis
  • To calm down violent or aggressive patients

Dosage:

These drugs are usually given orally, but intramuscular formulations exist for acute cases.

Mechanism of action:

First-generation antipsychotics block postsynaptic dopamine D2 receptors in the CNS.

FGAs are classified as either high-potency or low-potency, according to their affinity to the D2 receptor:

  • High potency first generation antipsychotics – bind strongly to D2 receptors
    • Haloperidol
    • Trifluoperazine
    • Fluphenazine
  • Low potency first generation antipsychotics – binds weakly to D2 receptors
    • Thioridazine
    • Chlorpromazine

These drugs, especially the low potency ones, also block other receptors:

  • Muscarinic receptors
  • α1 adrenergic receptors
  • Histamine H1 receptors

Duration of action:

These drugs are lipophilic and have a large volume of distribution (VD), so they have a long-half life and therefore a long duration of action.

Side effects:

The following side-effects are mostly seen in the low-potency FGAs and are due to the blocking of receptors other than the D2 receptors:

  • Due to blocking of muscarinic receptors
    • Dry mouth
    • Constipation
  • Due to blocking of α1 adrenergic receptors
    • Orthostatic hypotension
  • Due to blocking of histamine H1 receptors
    • Sedation

The following side-effects are mostly seen in the high-potency FGAs and are due to excessive blocking of dopaminergic pathways:

  • Extrapyramidal symptoms
    • Due to blocking of the dopaminergic nigrostriatal pathway, which is involved in muscle movement
    • Acute dystonia
    • Akathisia – restlessness
    • Parkinsonism
      • Bradykinesia
      • Rigidity
      • Tremors
  • Hyperprolactinaemia
    • Due to blocking of the tuberoinfundibular pathway
    • Galactorrhoea
    • Central hypogonadism
  • Neuroleptic malignant syndrome
    • “Lead-pipe” rigidity
    • Fever
    • Altered mental status
    • Rhabdomyolysis

The following symptoms occur with the same frequency in all types of FGAs:

  • Prolonged QT-interval
    • Torsade de pointes
    • Sudden cardiac death

Chlorpromazine can cause corneal deposits, while thioridazine can cause retinal deposits.

Pharmacokinetics:

There is significant individual variation in the absorption, oral bioavailability and therapeutic window. Some people have clinical response at very low plasma concentration while some have no clinical response even at very high plasma concentration. For these reasons the correct dosage must be found by trial and error.

Fortunately, there are no severe symptoms associated with overdose of antipsychotics.

Second-generation antipsychotics

The second-generation antipsychotics (SGAs, also called “atypical” antipsychotics) have similar mechanism of action as the first generation, but cause fewer neurologic side effects but more metabolic side effects. Their pharmacokinetics are similar.

The drugs belonging to this class are clozapine, quetiapine, olanzapine, risperidone, ziprasidone and aripiprazole.

Indications:

  • Schizophrenia
    • Unlike FGAs the SGAs are effective at treating the negative symptoms as well as the positive symptoms
  • Bipolar disorder
  • Treatment-resistant depression
  • Obsessive-compulsive disorder (OCD)
    • In addition to SSRIs

Risperidone can treat also Tourette syndrome.

Dosage:

These drugs are usually given orally, but intramuscular formulations exist for acute cases.

Mechanism of action:

Like the first-generation antipsychotics these drugs also block postsynaptic dopamine D2 receptors in the CNS, but more weakly than the first-generation ones. They also block numerous other receptors, like:

  • 5-HT2A serotonin receptors
  • Histamine H1 receptors
  • α1 adrenergic receptors
  • Muscarinic receptors

Side effects:

  • Due to blocking of muscarinic receptors
    • Especially with clozapine
    • Dry mouth
    • Constipation
  • Due to blocking of α1 adrenergic receptors
    • Orthostatic hypotension
  • Due to blocking of histamine H1 receptors
    • Sedation
  • Metabolic symptoms
    • Especially with clozapine and olanzapine
    • Weight gain
    • Dyslipidaemia
    • Diabetes
  • Decrease the threshold for seizures
    • Especially with clozapine
  • Prolonged QT interval
    • Torsade de pointes
    • Sudden cardiac death

Side effects specific for clozapine:

  • Neutropaenia or agranulocytosis
  • Cardiomyopathy
  • Myocarditis

While neurologic symptoms are less common with second-generation antipsychotics than with first-generations, they can still occur:

  • Extrapyramidal symptoms
    • Due to blocking of the dopaminergic nigrostriatal pathway, which is involved in muscle movement
    • Acute dystonia
    • Akathisia – restlessness
    • Parkinsonism
      • Bradykinesia
      • Rigidity
      • Tremors
  • Hyperprolactinaemia
    • Due to blocking of the tuberoinfundibular pathway
    • Galactorrhoea
    • Central hypogonadism
  • Neuroleptic malignant syndrome
    • “Lead-pipe” rigidity
    • Fever
    • Altered mental status
    • Rhabdomyolysis

Differences between first and second generation antipsychotics:

Property First generation Second generation
Treats positive symptoms of schizophrenia Yes Yes
Treats negative symptoms of schizophrenia No Yes
Metabolic symptoms Absent Present
Neurological symptoms More frequent Less frequent
Main blocked receptors Mainly D2 dopamine D2 dopamine and 5-HT2A serotonin

Previous page:
17. Alcohols. Pharmacology, toxicology

Next page:
19. Antidepressants

3 thoughts on “18. Antipsychotic drugs”

  1. Hi ☺️
    Why dont you divide the first generation into phenothiazines, thioxanthenes and butyrophenons like the lecture? Thanks in advance

    1. Rang & Dale’s, Amboss and the Norwegian drug manual don’t bother with those classifications, so I didn’t either.

Leave a Reply

Only the "Comment" field must be filled in. It is not compulsory to fill out your name; you can remain anonymous. Do not fill out e-mail or website; if you do, your comment will not be published.