Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS.

Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus-An aripiprazole case study.

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (Cmax) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for Cmax ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data.

Microsampling Techniques Suitable for Therapeutic Drug Monitoring of Antipsychotics.

BACKGROUND: Therapeutic drug monitoring (TDM) of antipsychotics for dose titration or detection of noncompliance is not uncommon in daily practice. Normally, TDM implies measuring a drug concentration in venous blood samples. This technique is invasive and requires trained assistants and patients normally need to go to an outpatient clinic. Over the past decades, sensitivity of analytical equipment has improved leading to a growing interest in microsampling techniques. These techniques are minimally invasive, require a small volume (<100 µL), usually result in stable samples, and can be collected by the patient or a caregiver at home. Before a microsampling technique can be used in daily routine, proper method development and a clinical validation study should be performed. METHOD: For this review, the databases of PubMed and Embase were systematically searched. Currently available microsampling techniques for antipsychotics in blood, serum, or plasma are summarized. Subsequently, it has also been assessed whether these techniques are sufficiently validated for TDM monitoring in daily practice. RESULTS: Several microsampling techniques are available today, for example, dried blood spot sampling, dried plasma extraction cards, and volumetric absorptive microsampling. Eighteen studies were identified in which a microsampling technique for 1 or a few antipsychotics was chemically analytically and clinically validated. However, the majority of these studies have relevant shortcomings that mean its usefulness for different antipsychotics is not yet well established. CONCLUSIONS: Microsampling for TDM can be recommended for patients using clozapine. For TDM of other antipsychotics, it is a very promising development.

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Clozapine and COVID-19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study.

OBJECTIVE: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters. METHODS: We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 µg/L increase compared to baseline) and clozapine alert levels (>1000 µg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine. RESULTS: This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline. CONCLUSION: In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination.

Dose-dependent transcriptional effects of lithium and adverse effect burden in a psychiatric cohort.

Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the "Udvalg for Kliniske Undersøgelser" (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.

The Switch From Paliperidone Long-Acting Injectable 1- to 3-Monthly: Clinical Pharmacokinetic Evaluation in Patients With Schizophrenia (Preliminary Data).

PURPOSE/BACKGROUND: The aim of the study was a preliminary evaluation of the maintenance of clinical efficacy and tolerability of paliperidone palmitate in patients with schizophrenia during the transition phase from 1-monthly paliperidone palmitate formulation (PP1M) to PP3M, with the evaluation of plasma levels of the drug. METHODS/PROCEDURES: A prospective observational study was conducted for 13 months involving 22 outpatients, aged 18 to 66 years and clinically stabilized. Patients were affected by schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria. For each patient, clinical assessment, safety and tolerability, and drug plasma level determination were performed. Clinical efficacy was assessed by Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, and Hamilton Rating Scale for Depression. During the first 4 months of the study, once-monthly paliperidone palmitate was administered, and then during the following 9 months, the 3-monthly formulation was administered. FINDINGS/RESULTS: The time course of the Brief Psychiatric Rating Scale total scores showed a statistically significant (P = 0.006) improvement from T0 to T8; Positive and Negative Symptom Scale scores showed a similar time course, with a statistically significant (P = 0.0016) reduction of the mean total score; Hamilton Rating Scale for Depression mean scores showed a statistically significant (P = 0.003) reduction with substantial maintenance of clinical stabilization of the patients. Only 1 patient dropped out after the first PP3M injection. IMPLICATIONS/CONCLUSIONS: Our preliminary data currently confirm the maintenance of clinical stability shifting from PP1M to PP3M.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

PURPOSE/BACKGROUND: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). METHODS/PROCEDURES: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. FINDINGS/RESULTS: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. IMPLICATIONS/CONCLUSIONS: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

PURPOSE: The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder). METHODS: Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders. RESULTS: A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 µg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 µg/mL. Overall, LAM was well tolerated with no major significant adverse effects. CONCLUSIONS: Most studies showed a minimum LAM threshold level of 3 µg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question.

Absolute and Dose-Adjusted Serum Concentrations of Clozapine in Patients Switching vs. Maintaining Treatment: An Observational Study of 1979 Patients.

BACKGROUND: Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment. OBJECTIVE: We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service. METHODS: Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005-2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included. RESULTS: In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032). CONCLUSIONS: The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

Multi-analyte LC-MS/MS quantification of 38 antipsychotics and metabolites in plasma: Method validation & application to routine analyses.

The past decades have seen a rise in the prescription of antipsychotic drugs in the European population, despite the risk of extra-pyramidal, metabolic and cardiac side effects. A multi-analyte liquid chromatography - triple quadrupole mass spectrometry method was developed for the quantification of 38 antipsychotic drugs in plasma. Samples were extracted by a straightforward liquid-liquid extraction with methyl-tertiary-butyl-ether and the compounds of interest were chromatographically separated within 6 min. Calibration curves covered the recommended therapeutic range for all compounds, in addition to sub- and supratherapeutic concentrations for most. The method was successfully validated according to the European Medicines Agency guidelines on bioanalytical method validation. Analysis of medico-legal samples confirmed the relatively common use of the second generation antipsychotics quetiapine and olanzapine, as well as the continued presence of the first generation antipsychotic haloperidol.

Serum concentrations of antidepressants, antipsychotics, and antiepileptics over the bariatric surgery procedure.

PURPOSE: As a substantial proportion of bariatric surgery patients use psychotropic/antiepileptic drugs, we investigated the impact of this procedure on serum concentrations. METHODS: In a naturalistic, longitudinal, prospective case series, we compared dose-adjusted trough concentrations of antidepressants, antipsychotics, or antiepileptics in consecutive patients before and after bariatric surgery. Adherence to treatment over 2 weeks preceding each sampling was considered. RESULTS: In all, 85 participants were included (86% female, median age 45 years, median body mass index 42 kg/m2). They were being treated with 18 different psychotropic/antiepileptic drugs (7 substances: 6-17 individuals, 11 substances: 1-4 individuals) and contributed 237 samples over a median of 379 days after surgery. For four out of seven substances with pre-/post-surgery samples available from six or more individuals, the dose-adjusted concentration was reduced (sertraline: 51%, mirtazapine: 41%, duloxetine: 35%, citalopram: 19%). For sertraline and mirtazapine, the low-calorie-diet before surgery entirely explained this reduction. A consistent finding, irrespective of drug, was the association between the mean ratio of the post-/pre-diet dose-adjusted concentration and the lipophilicity of the drug (logD; correlation coefficient: -0.69, P = 0.0005), the low-calorie diet often affecting serum concentration more than the surgery itself. CONCLUSIONS: Serum concentrations of psychotropic/antiepileptic drugs vary after bariatric surgery and can be hard to predict in individual patients, suggesting that therapeutic drug monitoring is of value. Conversely, effects of the pre-surgery, low-calorie diet appear generalizable, with decreased concentrations of highly lipophilic drugs and increased concentrations of highly hydrophilic drugs. Interaction effects (surgery/dose/concentration) were not evident but cannot be excluded.

The role of QT-prolonging medications in a forensic autopsy study from Western Denmark.

Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high.

Therapeutic drug monitoring of olanzapine: Easy and reliable method for clinical correlation.

AIM: The current work establishes an easy, reliable technique for the estimation of serum Olanzapine concentration which correlates it clinically. SUBJECTS AND METHODS: The work was agreed in 61 schizophrenic patients who were on olanzapine. Serum drug amount was estimated by normal-phase high-performance liquid chromatography and brief psychiatry rating scale was used to determine disease progression. RESULTS: Samples provided 61 patients, 40 were under sub-therapeutic range, 18 were under therapeutic range and 3 were above the therapeutic range. CONCLUSION: Therapeutic drug monitoring must be a part of clinical practice in psychiatric hospitals for optimizing the dose of an individual patient along with the correlation of serum concentration with the clinical assessment scales.

Infection is associated with elevated serum concentrations of antipsychotic drugs.

We aimed to investigate the effects of infection on serum concentrations of different antipsychotics in inpatients with respiratory tract infections treated with psychiatric drugs, including risperidone, clozapine, quetiapine, and aripiprazole. All patients underwent therapeutic drug monitoring (TDM) and routine blood tests during infection and noninfection periods. The Wilcoxon signed-rank test was used to analyze intra-individual differences in dose-corrected serum concentrations (C/D) levels in infection and noninfection periods. To study the effects of infection intensity on drug concentrations, white blood cells (WBCs) parameters and C/D levels were analyzed by Spearman's correlation analysis using all samples. The median C/D levels of risperidone (risperidone + 9-OH, n = 36) and clozapine (n = 42) were significantly higher (P < 0.001), whereas the median C/D levels of quetiapine (n = 21) and aripiprazole (n = 13) were slightly significantly higher (P < 0.01) in infection than in noninfection period. A significant positive association between C/D levels and WBC parameters was observed for risperidone, clozapine, and quetiapine. These results indicated reduced clearance of all drugs evaluated, especially clozapine and risperidone, due to infection. Therefore, during infection in patients receiving risperidone, clozapine, quetiapine, or aripiprazole, TDM should be performed to minimize the possible adverse effects associated with elevated drug concentrations.

Development, validation, and application of a simple UPLC-MS/MS method for simultaneous quantification of five traditional antipsychotics in human plasma.

A UPLC-MS/MS method was developed to determine the levels of five traditional antipsychotics (APs) (chlorprothixene, perphenazine, fluphenazine, thioridazine, and promethazine) in human plasma with carbamazepine as the internal standard. Samples were extracted using simple liquid-liquid extraction (ethyl acetate/methyl tert-butyl ether, 2:3 v/v); then the analytes were subjected to gradient elution chromatography with a mobile phase composed of 0.1% formic acid in water and acetonitrile. The analytes were separated using a Waters XBridge BEH C18 column (100 × 2.1 mm, 2.5 µm). The linear ranges of chlorprothixene, perphenazine, fluphenazine, thioridazine, and promethazine are 2-250 ng/mL, r > 0.995. The limit of quantitation is 2 ng/mL, and the limit of detection is in the range of 0.1-0.5 ng/mL. The inter-day and intra-day relative standard deviations are less than 10%, and the relative errors are in the range of -5.70 to 7.20%. The recoveries of the five drugs are in the range of 70-109%. The results of methodology verification indicate that this method is simple, economical, sensitive, and suitable for the simultaneous quantification of five traditional APs in human plasma.

Clinical response in patients treated with once-monthly paliperidone palmitate: analysis of a therapeutic drug monitoring (TDM) database.

To investigate pharmacokinetic correlates of clinical response in patients treated with once-monthly paliperidone palmitate (PP1M) injections at steady state. Plasma concentrations and dose-adjusted-plasma concentrations (C/D) of paliperidone from a naturalistic therapeutic drug monitoring (TDM) database were compared between responders and non-responders using the Clinical Global Impressions-Improvement scale (CGI-I) ratings. Analyses were based on the non-parametric Mann-Whitney U test and the Pearson Chi-squared test (χ2) with a significance level of 0.05. Subgroup analyses were performed separately in patients with schizophrenia spectrum, schizoaffective disorders and bipolar disorders. Comparing 93 responders with 80 non-responders, we detected no significant differences in the proportion of females, age, and body mass index (p's ranging 0.18-0.83); there were more smokers in the group of non-responders (p = 0.04), which also included more patients with bipolar disorders (p = 0.014). Despite the lack of differences for prescribed PP1M doses and dose intervals (p = 0.42 and p = 0.11, respectively), non-responders had higher paliperidone plasma concentrations and C/D levels (p = 0.033 and p = 0.021, respectively). Subgroup analyses did not yield differences for paliperidone plasma and C/D levels between non-responders and responders with schizophrenia spectrum (p = 0.099 and p = 0.14, respectively) and bipolar disorders (p = 0.95 and p = 0.75, respectively); dose-adjusted plasma concentrations were higher in non-responders compared to responders with schizoaffective disorders (p = 0.039), while no differences were reported for plasma levels (p = 0. 15). Our results show that paliperidone plasma concentrations over injection doses may be associated with patterns of clinical response suggesting potential utility of TDM as part of PP1M-based maintenance treatment.