The Analysis of Antipsychotic Drugs in Human Biosamples by LC-MS - LC-MS in Drug Bioanalysis - page 182

While typical APs bind with high affinity to the D 2 receptors, these newer
atypical APs possess only moderate affinity to D 2 receptors and high dissociation
constants. They initially occupy D 2 receptors and then rapidly dissociate to allow
normal DA neurotransmission, which ultimately decreases extrapyramidal side
effects [ 15, 16 ] .
Although it was initially thought that atypical APs may be linked with fewer
side effects than their typical counterparts, this is unlikely to be the case; they have
shown to have a similar risk of sudden cardiac death [ 17 ] as the fi rst generation
APs and appear to cause even more problems in regard to metabolic syndrome
(e.g., obesity, type 2 diabetes mellitus) [ 18 ] .
As different APs possess different advantages and disadvantages (not just
depending on the group they belong to but on their individual properties) it is usual
practice to select antipsychotic medication depending on a patient's individual
needs. Therefore, combination therapy is a common occurrence amongst patients
treated with APs [ 19 ] highlighting the need for detection methods that consist of a
large variety of these drugs.

1.4 Off-label Use

The practice of prescribing pharmaceuticals for an unapproved indication is called
“off-label use.” While this article mainly highlights the use of APs for psychotic
disorders such as schizophrenia, it must be noted that there is a significant off-label
use of these drugs worldwide [ 20 ]. This is largely caused by heterogeneous indica-
tions of different APs in different countries. Fleischhacker et al. [ 21 ] present an
overview of the indications of relevant atypical APs and haloperidol in 10 European
countries. Variations in the indication and labeling of APs should be considered in
analytical screening procedures applied in clinical and forensic toxicology.

1.5 Administration of APs

The two main administration routes for APs are peroral (P.O.) and intramuscular
(I.M.). P.O. administration results in a significant first-pass effect; therefore there is
considerable loss of drug after the first liver passage. I.M preparations are usually
synthesized by esterification of the drugs with fatty acids [ 22 ] and can be divided
into short-acting I.M. antipsychotic medications (SAIM) and long acting I.M. antip-
sychotic medications (LAIM). SAIM are used for the treatment of agitation and
aggressive behavior of patients experiencing an acute psychotic phase [ 23, 24 ] .
LAIM are referred to as “depot” injections. I.M. formulations have several advan-
tages such as a higher bioavailability due to the lack of first-pass metabolism and are
preferred in the treatment of patients where compliance issues are likely.