In this discussion, we will talk about the mechanisms of action for different pharmacologic agents used in the treatment of schizophrenia.
The agents discussed are first-generation antipsychotics, second-generation antipsychotics, and third-generation antipsychotics. We will also discuss novel antipsychotics, putative antipsychotics under development, and management for tardive dyskinesia.
First-Generation Antipsychotics (FGAs)
These medications act mainly by blocking dopamine (D2) receptors in the brain. They are not selective, which means that they target the D2 receptors anywhere in the brain (more side effects!)
There are different ways to group these medications:
We can rank them by potency:
High potency:
- Thiothixene
- Fluphenazine
- Haloperidol
Moderate potency:
- Molidone
- Perphenazine
- Trifluoperazine
Low potency:
- Chlorpromazine
- Mesoridazine
We can rank them by their R group:
Aliphatic group:
- Promazine
- Chlorpromazine
- Trifluopromazine
Piperidine group:
- Thioridazine
- Mesoridazine
Piperazine group:
- Trifluoperazine
- Perphenazine
- Fluphenazine
In general, FGAs have the same nucleus, which is a phenothiazine. FGAs are also referred to as typical antipsychotics.
Because they work primarily through D2 receptor blockage, they reduce the excess DA in the mesolimbic pathway. This leads to a reduction in positive symptoms.
FGAs Side Effects
Because they are non-selective. They also block M1 and ACh, leading to anticholinergic side effects, such as dry mouth, blurred vision, constipation, and cognitive blunting.
FGAs also stimulate H1, leading to weight gain. Furthermore, they also stimulate alpha-1, leading to orthostatic hypertension and drowsiness.
Aside from their non-selectivity, their blockage of the D2 receptor can lead to problems when the patient’s on the medication long-term. These side effects are called extra-pyramidal side effects. Think of these as similar to motor effects seen in Parkinson’s.
- Rigidity
- Tremors
- Shuffling gate
Dopamine usually inhibits the cholinergic cells. By blocking dopamine, there is nothing to stop the release of excess ACh, leading to Parkinsonian symptoms.
Quick fact, Parkinson’s is caused by the degeneration of DA cells leading to this same problem and movement disorder.
One of the severe extra-pyramidal side effects is tardive dyskinesia. This is a motor abnormality with long-term DA blocking in the striatal pathway. After a while, the DA receptor is up-regulated, leading to the hyperkinetic motor. The physical symptoms of this are facial and tongue movement, tongue protrusion, chewing abnormality, and jerky movement. This is due to the body trying to overcome the inhibition.
Another side effect of FGAs is a neuroleptic malignant syndrome. This is an impaired thermal regulation in the hypothalamus due to the lack of dopamine. Physical symptoms of this are hyperthermia, altered mental status, muscle rigidity, autonomic dysfunction, labile blood pressure, and dysrhythmias. All of these are due to the modulation of the sympathetic nervous system. It can be lethal, but rapid diagnosis can reduce mortality significantly. This is very rare and is only seen in 1 every 100,00 patients.
The third severe side effect is hyperprolactinemia. This is caused by the blockage of dopamine as well. In this case, the DA in the arcuate nucleus in the hypothalamus works to inhibit prolactin release in the anterior pituitary. Since dopamine is blocked by FGAs, DA is not able to inhibit prolactin secretion, leading to hyper-secretion of prolactin or prolactenemia. Physical symptoms of this are breast secretion and lack of menstruation. It interferes with fertility and leads to a more rapid de-mineralize of bone. Weight gain and sexual dysfunction are also common.
The therapeutic window between the effective dose of FGAs (close to 80% D2 receptor blockage) and the development of extra-pyramidal symptoms (slightly greater than 80% blockage) are very close together, which is why the risk is high for these medications.
Second-Generation Antipsychotics (Atypical)
These medications exhibit a higher ability to block serotonin (5-HT2A) than dopamine (D2) receptors. The mechanism works through the fact that a blockage of SERT leads to an increase in dopamine levels.
These medications also have higher dissociation rates and are more likely to block dopamine in cortical and limbic regions than nigrostriatal. This means fewer extrapyramidal effects!
Some of the agents are risperidone (high SERT, moderate D2), ziprasidone (high SERT, moderate D2), olanzapine (moderate SERT, low D2), clozapine (low SERT, very low D2), and quetiapine (low SERT, very low D2.)
Clozapine is discussed later in this article. Asenapine is one of the newer atypical antipsychotics. It shares similarities in structure with mirtazapine. Because of this, asenapine shares many mirtazapine binding properties, such as 5HT2A, 5HT2C, H1, alpha-2, and D2 antagonisms.
SGAs in a Nutshell
In the prefrontal cortex pyramidal neuron, there is a glutamate pyramidal neuron. On this neuron, there are 5-HT2A receptors. When serotonin is released from other axons, they bind to these receptors and increase glutamate. Since this is where atypical SGAs function, they ultimately block the release of glutamate in substantial nigra. How does this lead to an increase in dopamine?
Remember that in patients with schizophrenia, the meso-corticol pathway is not producing enough dopamine, so we want to increase this. By decreasing the glutamate in the substantia nigra, there is no glutamate to stimulate GABA neurons, which usually inhibit the DA release. So without GABA, the DA release is increased in the motor striatum and cortex.
Treatment of Resistant Schizophrenia
About 30% of patients with schizophrenia do not respond to two consecutive antipsychotics in a certain timeframe. This is referred to as treatment-resistant.
In these patients, clozapine, an SGA, is the most effective option. There are rare side effects associated with clozapine, which are agranulocytosis, myocarditis, and convulsions.
Third-Generation Antipsychotics
These are aripiprazole, brexpiprazole, and cariprazine. Sometimes these are bunched together into SGAs. These agents are partial agonists of dopamine receptors. They work through the inhibition of cAMP accumulation through the dopamine D2 receptor.
Aripiprazole is also a dopamine stabilizer because it also binds to additional receptors.
Atypical antipsychotics have a much lower threshold for effectiveness. This means there are larger windows between the therapeutic level and the EPS and hyperprolactinemia threshold.
Novel Antipsychotic – Lumateperone
Brand name Caplyta, lumateperone is a first in class to act synergistically through multiple systems (serotonergic, dopaminergic, and glutamatergic.) It’s approved for schizophrenia, and being used off-label for dementia and BD.
This medication is a potent antagonist at 5HT2A, D1, and D2. It acts as an indirect modulator of glutamate with D1-dependent augmentation of both NMDA and AMPA activity.
This leads to a potent and rapid antidepressant effect. It provides a robust improvement in depressive and psychotic symptoms.
This pathway is the same believed to be used by ketamine for its antidepressant effect.
Other Antipsychotics Under Development
- Olanzapine/Samidorphan – samidorphan is a mu receptor antagonist, which reduces olanzapine weight gain and reduces the metabolic effect.
- Roluperidone – a cyclic amide derivative that reduces negative symptoms of schizophrenia
- TAAR-1 Agonist – a G-protein receptor that helps regulate the synthesis and release of dopamine. MoA is unclear.
- D2 and D3 dimerization – novel mechanism?
Parkinson’s Disease Psychosis:
Pimavanserin (Nuplazid) was approved in 2016 to treat patients with Parkinson’s. It has selective inverse agonism at 5-HT2A in the mesolimbic DA pathway. It also has a very long half-life of nearly 200 hours.
Treatment of Tardive Dyskinesia
If a patient experiences tardive dyskinesia, it is recommended that the agent is switched to a lesser risk agent. If the symptoms persist, then a VMAT2 inhibition, such as valbenazine and deutetrabenazine, should be used. These are DA transporter, and if DA is not transported, it is degraded. This leads to a depletion of presynaptic DA level, which reduces the release of DA, and thus, reduces post-synaptic DA stimulations.
It has also been used in Huntington’s disease.