The Analysis of Antipsychotic Drugs in Human Biosamples by LC-MS - LC-MS in Drug Bioanalysis - page 178

1 Introduction: Treatment of Psychotic Illnesses

1.1 History

Prior to the 1950s, electroconvulsive therapy and psychosurgery were considered
suitable treatments for patients suffering from mental illnesses. Due to a lack of
knowledge surrounding the pathophysiology of psychotic disorders such as schizo-
phrenia, the only pharmacological “treatment” at this time consisted of sedation
with barbiturates and drug-induced epileptic seizures [ 1 ] . The fi rst notable develop-
ment in drug-therapy for people suffering from bipolar disorder—a disorder charac-
terized by alternating manic and depressive episodes, was the discovery of lithium
as a suitable treating agent in the late-1940s [ 2 ]. While the mechanism of action of
lithium still remains unclear, its effectiveness in the treatment of bipolar disorders
has been accepted worldwide and it is still considered the leading prophylactic treat-
ment for this condition, even 60 years after its discovery [ 1 ] .
In the 1950s, a more evidence-based approach to antipsychotic drug (AP) therapy
was undertaken when structural variations of antihistamines were produced by a
French scientist (Paul Charpentier), in order to make use of the “unwanted” sedative
side effect produced by these drugs. Initially used to lower body temperature in
patients undergoing cardiac surgery, chlorpromazine (Fig. 1 I) was the first drug
with antipsychotic properties successfully used in clinical trials [ 3 ] .

1.2 Typical APs

Since its official release in 1952, Chlorpromazine has been considered the prototype
of so-called “typical” APs. Chlorpromazine has a characteristic phenothiazine struc-
ture, which formed the basis of other APs synthesized in subsequent years, such as
fl uphenazine, perphenazine, promazine, promethazine, thioridazine, tri fl uoperazine,
and triflupromazine (Fig. 1 II-VIII). These APs formed the largest subgroup of all
drugs commonly referred to as “Typical APs.” They are also known as “First
Generation APs”. Other subgroups within the typical APs are also characterized by
their chemical structures, such as the butyrophenones (e.g droperidol, haloperidol,
trifluperidol, melperone, and pipamperone (Fig. 1 IX-XIII), the thioxanthenes (e.g.,
flupentixol, zuclopenthixol, chlorprothixene, and thiothixene (Fig. 1 XIV-XVII)),
diphenylbutylpiperidines (e.g., pimozide, fluspirilene, penfluridol (Fig. 1 XVIII-XX)),
indoles (i.e., molindone (Fig. 1 XXI)), and others (e.g., loxapine (Fig. 1 XXII)).
Despite having varying chemical structures, all typical APs have a significant
affinity to dopamine (DA) receptors, mainly the D 2 -type, while also showing
minor antagonism at muscarinic, 5-HT, adrenergic (a), and histaminergic (H1)
receptors. By blocking receptors in the prefrontal cortex and the limbic area of the
brain, both areas which are linked with mood and emotional behavior, an improve-
ment in positive symptoms is achieved. However, the same action of APs in other