Atypical Antipsychotic - Pharmacology

Pharmacology

The mechanism of action of these agents is unknown, and differs greatly from drug to drug. The variation in the receptor binding profile is such that the only effect all have in common is an anti-psychotic effect; the side effect profiles vary tremendously. The mechanisms behind atypical antipsychotic action are not clear. All antipsychotics work on the dopamine system but all vary in regards to the affinity to the dopamine receptors. There are 5 types of dopamine receptors in humans. There are the “D1-like” group which are types 1 and 5 which are similar in structure and drug sensitivity. The “D2-like” group includes dopamine receptors 2, 3 and 4 and have a very similar structure but very different sensitivities to antipsychotic drugs.

The “D1-like” receptors have been found to not be clinically relevant in therapeutic action. If D1 receptors were a critical component of the mechanism of AAP blocking just the D1 receptor would improve the psychiatric symptoms that are exhibited. If D1 receptor binding was a critical component of the action of antipsychotics they would need to be present in maintenance dosages. This is not seen. They are not present or present in low or negligible levels which would not even maintain the elimination of the symptoms that are seen.

The “D2-like” group of dopamine receptors are classified together based on structure but not drug sensitivity. It has been shown that D2 receptor blockade is necessary for action. All antipsychotics block D2 receptors to some degree, but the affinity of the antipsychotics vary from drug to drug and it has been hypothesized that it is the varying in affinities that causes a change in effectiveness (Horacek et al., 2002).

One theory for how atypicals work is the “fast-off” theory. This theory of antipsychotic action is that AAP have low affinities for the D2 receptor and only bind loosely to the receptor and are rapidly released. In fact, the AAP bind more loosely to the D2 receptor than dopamine itself. The AAP effectively interfere with the phasic release of endogenous dopamine. The AAP transiently bind and rapidly dissociate from the D2 receptor to allow normal dopamine transmission. It is this transient binding that that keeps prolactin levels normal, spares cognition and obviates EPS.

From a historical point of view there has been interest in the role of serotonin and treatment with the use antipsychotics. Experience with LSD suggests that 5-HT2A receptor blockade may be a promising method of treating schizophrenia; see also LSD and schizophrenia. One problem with this is the fact that psychotic symptoms caused by 5-HT2 receptor agonists differs substantially from the symptoms of schizophrenic psychoses. One promising factor of this is where the 5-HT2A receptors are located in the brain. They are localized on hippocampal and cortical pyramidal cells and have a high density in the fifth neocortex layer where the inputs of various cortical and subcortical brain areas are integrated. This makes the blocking of this receptor an interesting area considering these areas in the brain are of interest in the development of schizophrenia. This is an area of research that could prove convincing but has not yielded any convincing results. Evidence points to the fact that serotonin is not sufficient to produce an antipsychotic effect but serotonergic activity in combination with D2 receptor blockade may be responsible. Regardless of the neurotransmitters these AAP have an effect on antipsychotic drugs appear to work by inducing restructuring of neuronal networks. They are able to induce these structural changes.