Atypical antipsychotics

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.

Now, antipsychotics are subdivided into two main categories: the first generation or typical antipsychotics, and the second generation or atypical antipsychotics.

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.

Now, in conditions such as schizophrenia, atypical antipsychotics block dopamine D2 receptors in the mesolimbic pathway, thereby alleviating positive symptoms of schizophrenia.

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.

Common atypical antipsychotics include clozapine, olanzapine, quetiapine, paliperidone, risperidone, lurasidone, ziprasidone, and aripiprazole.

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.

Moreover, atypical antipsychotics are typically used as first-line agents for management of acute mania.

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.

Risperidone is the most likely to cause hyperprolactinemia.

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.

The most dangerous side effect is neuroleptic malignant syndrome or NMS, which is characterized by confusion, agitation, muscle rigidity, seizures, and hyperthermia.

If this condition progresses, it will turn into rhabdomyolysis, which is the breakdown of muscles.

Treatment of neuroleptic malignant syndrome includes application of dantrolene, which is a muscle relaxant; and dopamine agonists, such as bromocriptine, which mimics the effect of dopamine.

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.

Atypical antipsychotics can also cause metabolic syndrome, which includes weight gain, diabetes, dyslipidemia, and increased cardiovascular risk.