## 1 Introduction  
Schizophrenia is a severe and chronic mental disorder characterized by profound disruptions in thinking, which consequently affects language, perception, and the sense of self [1]. This disorder is characterized by positive (psychotic behaviors), negative (disruptions to normal emotions and behaviors), and cognitive symptoms (changes in memory or other aspects of thinking) [1]. Atypical antipsychotics are the mainstay of treatment prescribed to schizophrenic patients. Compared to classic neuroleptics, these drugs induce fewer extrapyramidal syndromes [1, 2].  
Studies have suggested that the pharmacokinetics of atypical antipsychotics involve large inter- and intra-individual differences among patients (age, gender, lifestyle, genetic and metabolic characteristics, and drug interactions). Therefore, therapeutic drug monitoring (TDM) can be extremely useful to establish an effective individual therapeutic dose that maintains plasma drug concentrations within a targeted therapeutic range, thereby avoiding an overdose [3, 4].  
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a highly sensitive and selective technique to analyze drugs in biological fluids quantitatively. Biological fluids are complex matrixes containing endogenous macromolecules that can irreversibly adsorb on the analytical column stationary phase surface, which reduces chromatographic separation efficiency. Moreover, during MS/MS analysis, nonvolatile solutes can suppress ionization (electrospray ionization), which decreases the LC-MS/MS method sensitivity [5]. These difficulties call for sample preparation to diminish the matrix effect. This step increases not only the sensitivity, but also the selectivity of the LC-MS/MS method.  
In-tube solid-phase microextraction (in-tube SPME) is a sample preparation technique that uses a capillary column, as extraction device, directly coupled to a LC system. The in-tube SPME-LC system is fast to operate, easy to automate, and environmentally friendly (organic solvent is only used in the mobile phase). Automated methods always provide better accuracy and precision than manual procedures [5; 6; 7]. Capillary columns with different selective stationary phases (coating), including restricted access media (RAM), molecularly imprinted polymers (MIP), immunosorbents, and monolithic materials, have been used for in-tube SPME systems [8; 9; 10; 11; 12].  
In-tube SPME-LC methods with different organic monolithic capillaries have been applied for analysis of several analytes. For example: poly (methacrylic acid-ethylene glycol dimethacrylate) for basic drugs in human serum [13], and amphetamines in urine [14], NH\({}_{2}\)-MIL-53(Al) incorporated poly(styrene-divinylbenzene-methacrylic acid) (poly(St-DVB-MAA)) for estrogens in human urine [15], and (N-isopropylacrylamide-co-ethylene dimethacrylate) for acid, basic, and neutral compounds [16]. Monolith materials with good control of porosity, diverse surface chemistry, and frit-free are easy to prepare by in situ polymerization [15; 16; 17]. The monolithic porous structure facilitates convective mass transfer (which is preferable during extraction) with reasonably low pressure. Organic-based monoliths are stable within the entire pH range and biocompatible with biological samples [17; 18].  
This manuscript describes an in-tube SPME-UHPLC-MS/MS with an organic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolithic capillary to determine antipsychotics (chloropromazine, clozapine, quetiapine, and olanzapine) and their metabolites (desmethyl chlorpromazine, 7-hydroxy-chlorpromazine, \(N\)-desmethyl clozapine, \(N\)-desmethyl olanzapine, and norquetiapine) in plasma samples from schizophrenic patient. Figure 1 illustrates the metabolic and biotransformation pathways of these antipsychotics.  
Figure 1: Biotransformation pathways of (**a**) Chlorpromazine, (**b**) Clozapine, (**c**) Olanzapine, and (**d**) Quétiapine. CYP = cytochrome P450 complex. CYP1A2, CYP2D6, and CYP3A4 are isoenzymes of cytochrome P450 complex.