What generation of antipsychotics are Atypical Antipsychotics?
USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 20-year-old man is brought to the emergency department by his parents because of trying to break into the school’s basketball court. He states that the aliens who are trying to control his mind were hiding in the school and he needs to find them. His parents report that he has been isolating himself recently and avoiding social activities. Mental examination shows a disheveled man who is disorientated to person and time. He is admitted to the psychiatric ward and started on risperidone. Risperidone is an atypical antipsychotic with fewer side effects than the typical antipsychotics. Atypical antipsychotics provide antagonism at which of the following receptors?
Antipsychotics, as their name implies, are mainly used to treat schizophrenia and other psychotic conditions.
Even though the exact cause of schizophrenia is still unknown, there's some evidence that suggests it’s related to altered levels of the neurotransmitter dopamine.
Alright, within the brain, dopamine is found in 4 main dopamine pathways: the mesolimbic pathway, which controls motivation and desire; mesocortical pathway, which helps regulate emotions; nigrostriatal pathway, which contains motor neurons that bypass the medullary pyramids, to control involuntary movements and coordination; and lastly, tuberoinfundibular pathway, which releases dopamine to limit the secretion of prolactin.
Other regions of the central nervous system that are rich in dopamine receptors, include the chemoreceptor trigger zone, which initiates the vomiting reflex; and the medullary periventricular pathway, which regulates eating behavior.
However, in schizophrenia, altered levels of dopamine mainly affect the mesolimbic pathway and mesocortical pathway.
There’s usually high levels of dopamine in the mesolimbic pathway, which cause positive symptoms of schizophrenia, such as delusions, hallucinations, and disorganized thought.
On the other hand, low levels of dopamine in the mesocortical pathway cause negative symptoms of schizophrenia, such as lack of motivation, social withdrawal and “flat affect”, which basically means lack of emotions.
But, they also block serotonin 5-HT2A receptors in the mesocortical pathway.
These receptors are found on inhibitory neurons that regulate dopaminergic neurons and decrease dopamine release.
When atypical antipsychotics block them, dopaminergic neurons have no inhibitory signals, so dopamine release actually increases in the mesocortical pathway. This will help alleviate the negative symptoms of schizophrenia which makes atypical antipsychotics the preferred medication over the older, typical antipsychotics, which only treat positive symptoms.
Besides its effect on D2 and 5-HT2A receptors, aripiprazole partially stimulates D2 and 5-HT1 receptors.
Other common indications for atypical antipsychotics include bipolar disorder, obsessive-compulsive disorder or OCD, anxiety, depression, and Tourette syndrome, which is a neurological disorder characterized by repetitive, involuntary movements and vocalizations called tics.
Alright, moving on to side effects. Besides D2 receptors in the mesolimbic pathway, atypical antipsychotics also block dopamine receptors in the tuberoinfundibular pathway, causing hyperprolactinemia.
Furthermore, high levels of prolactin indirectly decrease levels of GnRH, LH, and FSH, causing oligomenorrhea, galactorrhea, and gynecomastia, which is an enlargement of the male breasts.
Furthermore, atypical antipsychotics block dopamine receptors in the nigrostriatal pathway causing extrapyramidal symptoms.
These symptoms can be subdivided into 2 main groups: acute extrapyramidal symptoms, which include dystonia, akathisia, and pseudoparkinsonism, also known as drug-induced Parkinsonism; and tardive, or delayed extrapyramidal symptoms, which include tardive dyskinesia.
If this condition progresses, it will turn into rhabdomyolysis, which is the breakdown of muscles.
Now, in contrast to typical antipsychotics, which bind very tightly to D2 receptors, atypical antipsychotics bind to D2 receptors more loosely, so they can be kicked off if there’s lots of dopamine around.
This is why they cause fewer extrapyramidal symptoms than typical antipsychotics.
Besides dopamine D2 receptors and serotonin 5-HT2A receptors, atypical antipsychotics also block: histamine H1 receptors causing sedation; alpha-1 receptors, causing orthostatic hypotension; and muscarinic receptors, causing atropine-like (anticholinergic) side effects, such as dry mouth, blurred vision, urinary retention, and constipation.
- "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
- "Rang and Dale's Pharmacology" Elsevier (2019)
- "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
- "Atypical antipsychotics: mechanism of action" Can J Psychiatry (2002)
- "Neuroleptic Malignant Syndrome" Annals of Pharmacotherapy (2016)
- "Second-Generation Antipsychotics and Extrapyramidal Adverse Effects" BioMed Research International (2014)
- "Lack of extrapyramidal side effects predicts quality of life in outpatients treated with clozapine or with typical antipsychotics" Psychiatry Research (2005)