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49. Antipsychotic drugs

Psychosis refers to a disordered perception of reality, characterised by delusions, hallucinations 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, but these drugs are used for other indications as well. Many have a sedative effect and are used for this effect.

These drugs don’t have any addictive potential, but they have a significant side effect profile.

Schizophrenia

Schizophrenia (from the Greek words “to split” and “the mind”) is a severe psychiatric disorder characterised by chronic or recurrent psychosis, as well as other psychiatric symptoms.

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

Antipsychotics are important in the treatment of schizophrenia as they reduce the symptoms. The second-generation antipsychotics are usually preferred as they cause fewer side-effects.

Dopaminergic pathways of the CNS

These drugs block dopamine receptors in the brain, so let’s quickly review some dopaminergic pathways in 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 the main treatment for schizophrenia for decades until the second generation was invented in the 1990s. They’re also called the “typical” antipsychotics. They’re classified according to their potency.

Compounds

High-potency antipsychotics:

  • Haloperidol (Haldol®)
  • Fluphenazine
  • Droperidol
  • Flupentixol
  • Zuclopenthixol
  • Chlorprothixene

Low-potency antipsychotics:

  • Chlorpromazine
  • Levomepromazine
  • Thioridazine

.. and many more, however these should be the most important.

Indications

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

Dosage

These drugs are usually given orally, but intramuscular formulations exist as well. These may be used for acute cases, or for chronic cases when given as a slow-release (depot injection). Depot injections are useful for certain cases as they only need to be administered every 2 – 4 weeks.

The high-potency FGAs are usually dosed in the range of 1 – 10 mg, while the low-potency ones are dosed in hundreds of miligrams. Low-potency drugs may be used in lower doses for their sedative properties.

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
  • Low potency first generation antipsychotics – binds weakly to D2 receptors

The high dose of the low potency antipsychotics causes them to also block other receptors, like:

  • 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 seen more in the low-potency FGAs compared to the high-potency ones and are due to the blocking of receptors other than the D2 receptors:

  • Due to blocking of histamine H1 receptors
    • Sedation
  • Due to blocking of muscarinic receptors (anticholinergic side effects)
    • Dry mouth
    • Constipation
  • Due to blocking of α1 adrenergic receptors
    • Orthostatic hypotension

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

  • Extrapyramidal symptoms
    • Acute dystonia
    • Akathisia (restlessness)
    • Parkinsonism
      • Bradykinesia
      • Rigidity
      • Tremors
    • Tardive dyskinesia (after long-term treatment)
  • Hyperprolactinaemia
    • Due to blocking of the tuberoinfundibular pathway
    • Galactorrhoea
    • Central hypogonadism
  • Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is an acute life-threatening complication of antipsychotic drugs. It’s characterised by muscle rigidity, fever, and altered mental status. The syndrome may cause rhabdomyolysis, acute renal failure, arrhythmias, and death.

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

  • Intellectual and emotional flattening
  • 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.

SGAs range from high potency to low potency as well, but these drugs are not usually classified according to potency like the FGAs are.

Compounds

  • Clozapine (Leponex®)
  • Olanzapine (Zyprexa®)
  • Risperidone
  • Quetiapine (Seroquel®)
  • Paliperidone
  • Aripiprazole (Abilify®)
  • Brexpiprazole
  • Cariprazine

Aripiprazole, brexpiprazole, and cariprazine are newer antipsychotics, sometimes called “third generation” (or ABC drugs) but technically belonging to the second generation.

Indications

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

Clozapine is highly effective for schizophrenia but not a first-line drug due to high risk of severe side effects. It may be used in treatment-resistant schizophrenia.

Dosage

These drugs are usually given orally, but intramuscular formulations exist as well. These may be used for acute cases, or for chronic cases when given as a slow-release (depot injection). Depot injections are useful for certain cases as they only need to be administered every 2 – 4 weeks.

Mechanism of action

Like the first-generation antipsychotics, these drugs also block postsynaptic dopamine D2 receptors in the CNS, but less strongly 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

Second generation antipsychotics cause more metabolic than neurological side effects, as well as more sedation.

  • 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
  • Metabolic symptoms
    • Weight gain
    • Dyslipidaemia
    • Diabetes
  • Decrease the threshold for seizures
  • Prolonged QT interval
    • Torsade de pointes
    • Sudden cardiac death

Side effects specific for clozapine:

  • Agranulocytosis and other blood dyscrasias
  • Cardiomyopathy
  • Myocarditis

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

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