Schizophrenia is a complex and chronic psychiatric disorder that significantly impacts patients' quality of life. Ranking 12th among 310 diseases and injuries that result in disability, the number of patients suffering from schizophrenia continues to rise, emphasizing the urgent need for developing effective treatments. Despite the availability of effective antipsychotic drugs, over 80% of patients taking oral antipsychotics experience relapses, primarily caused by non-adherence as the high dosing frequency is required. In this review, we discuss about schizophrenia, its incidence, pathological causes, influencing factors, and the challenges of the current medications. Specifically, we explore nanocrystal technology and its application to paliperidone, making it one of the most successful long-acting antipsychotic drugs introduced to the market. We highlight the clinical advantages of paliperidone nanocrystals, including improved adherence, efficacy, long-term outcomes, patient satisfaction, safety, and cost-effectiveness. Additionally, we address the physicochemical factors influencing the drug's half-life, which crucially contribute to long-acting medications. Further studies on nanocrystal-based long-acting medications are crucial for enhancing their effectiveness and reliability. The successful development of paliperidone nanocrystals holds great promise as a significant approach for drug development, with potential applications for other chronic disease management.

Investigation and analysis of the changes in healthcare resources and burden of schizophrenia in the real world before and after switching from oral antipsychotics (OAPs) to paliperidone palmitate once-monthly (PP1M) could provide evidence to clinicians and patients for choosing treatment modality and data support for health policy optimization.

The first dosage of PP1M was set as mirror point, and patients with mirror point between January 2020 and June 2022 were recruited in the study. The differences in treatment patterns, healthcare resource utilization, and costs within one year before and after the mirror point were compared.

A total of 72 patients transitioning from OAPs to PP1M (mean age, 35.33 years; 43.06% female) were included in the study. Of the 72 patients, the application of PP1M resulted in a significant reduction in the hospitalization times, emergency room visits, and direct medical costs (P < 0.001), while the pharmacy cost and total cost increased by 222.57% (P < 0.001) and 16.35% (P < 0.001), respectively; PP1M accounted for 88.48% of the pharmacy cost. For patients with ≥1 hospitalization during the OAPs phase (n = 25), the number of hospitalizations, hospitalization days and hospitalization expenses decreased by more than 90% (P < 0.001). Total one-year expenses decreased by 37.67% (P < 0.001), and pharmacy expenses increased by 185.21% (P < 0.001). For patients with no hospitalizations during the OAPs phase (n = 47), emergency and outpatient visits decreased by 70% (P < 0.001) and 30.27% (P < 0.05), respectively, while the total cost increased by 117.56% (P < 0.001), and the pharmacy cost increased by 260.15% (P < 0.001) after initiation of PP1M treatment.

After the transition to PP1M, the number of hospitalizations and outpatient and emergency department visits reduced, and healthcare resources were conserved. Switching to PP1M may be more economically beneficial for patients with prior hospitalizations while on OAP regimens. The high price of PP1M might be an obstacle to its widespread use.

The testosterone undecanoate oil solution is the most widely used injection of testosterone for long-acting effects on the market, whereas the formulation carries the potential risk of causing pulmonary vascular embolism, inflammation, and pain at the injection site. Therefore, a sustained-released long-acting injection of testosterone with strong security is urgently exploited. Herein, a poorly water-soluble testosterone-cholesterol prodrug (TST-Chol) was synthesized by esterification. The water solubility of TST-Chol was decreased by 644 folds in comparison to that of testosterone (TST). Moreover, suspensions of TST and TST-Chol were prepared and analyzed in vitro, utilizing three distinct particle sizes: small-sized nanocrystals (SNCs) measuring 300 nm, medium-sized microcrystals (MMCs) measuring 12 μm, and large-sized microcrystals (LMCs) measuring 20 μm. The findings from the in vitro release study indicated that the sustained release of the drug was significantly influenced by the solubility and particle sizes of the suspension. Notably, the suspensions with low water solubility and larger particle sizes exhibited a more desirable sustained-release effect in vitro. Furthermore, the study on pharmacokinetics exhibited that TST-Chol SNCs produced a sustained TST plasma concentration in vivo for up to 40 days and no obvious pathological changes in lung tissue were found. Our study indicated that solubility and particle sizes of suspensions had made a difference in pharmacokinetics and provided a valuable reference for the advancement of long-acting injections.

Lithium is considered to be the first-line treatment for bipolar disorder, and paliperidone was approved for the treatment of schizophrenia and acute bipolar manic/mixed episodes. However, both agents have been associated with thyroid dysfunction and cardiovascular adverse effects like subclinical hypothyroidism, bradycardia, and sinus arrest, even at therapeutic doses.

Here, we reported a case of a 17-year-old Han Chinese female who developed symptomatic hypothyroidism, sinus bradycardia, and sinus arrest while being treated with lithium and paliperidone for bipolar disorder with psychotic features including auditory hallucinations. Her workup suggested that these adverse effects might be related to the combined lithium and paliperidone treatment, although other causes could not be ruled out. After discontinuing both medications, her thyroid function and heart rhythm normalized over 20 days.

To our knowledge, hypothyroidism, sinus bradycardia, and sinus arrest associated with the combined use of lithium and paliperidone had not been reported previously. Further research is warranted to elucidate the potential risks and benefits of this combination therapy for bipolar disorder with psychotic symptoms.

Paliperidone, an atypical antipsychotic, is widely used to treat schizophrenia. In this study, we explored whether paliperidone inhibited the voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells. Paliperidone reduced Kv channel activity in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50 ) of 16.58 ± 3.03 μM and a Hill coefficient of 0.60 ± 0.04. It did not significantly shift the steady-state activation or inactivation curves, suggesting that the drug did not affect the gating properties of Kv channels. In the presence of paliperidone, the application of 20 repetitive depolarizing pulses at 1 and 2 Hz gradually increased the inhibition of the Kv current. Further, the recovery time constant after Kv channel inactivation was increased by paliperidone, indicating that it inhibited the Kv channel in a use (state)-dependent manner. Its inhibitory effects were reduced by pretreatment with a Kv1.5 subtype inhibitor. However, pretreatment with a Kv2.1 or Kv7 inhibitor did not reduce its inhibitory effect. We conclude that paliperidone inhibits Kv channels (mainly Kv1.5 subtype channels) in a concentration- and use (state)-dependent manner without changing channel gating.

BACKGROUND: Paliperidone is among the most cost-effective antipsychotics in adults with schizophrenia, and it has different formulations, including oral paliperidone extended-release (ER) and long-acting injectable (LAI) paliperidone formulations administered every month (PP1M), 3 months (PP3M), or 6 months (PP6M). However, cost-effectiveness analyses comparing different paliperidone formulations were limited. OBJECTIVE: To compare the cost-effectiveness across different paliperidone formulations. METHODS: A Markov model was developed to simulate 1,000 adults aged 40 years with stable schizophrenia transitioning among stable disease-medication adherent, stable disease-medication nonadherent, relapse with hospitalization, relapse with ambulatory care, and death states every 3 months for 5 years. Drug costs were estimated using the prices listed in the Veterans Affairs Federal Supply Schedule, and costs for treating complications were estimated from published studies. All costs were estimated from the US health care system perspective and standardized to 2022 US dollars using the Consumer Price Index Inflation Calculator. Quality-adjusted life-years (QALYs) were estimated using relapse rates from randomized clinical trials and health-related quality of life scores from observational studies. The estimated future costs and QALYs were discounted at 3%. We reported incremental net monetary benefits between alternative formulations at the $50,000 willingness-to-pay (WTP) threshold with a positive value indicating cost-effectiveness. The impact of parameter uncertainty on study outcomes was assessed using 1-way deterministic and probabilistic sensitivity analyses. RESULTS: In adults with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was associated with increased QALY (PP1M = 0.05, PP3M = 0.14, PP6M = 0.15) and increased cost (PP1M = 49,433, PP3M = 26,698, PP6M = 26,147), leading to a negative incremental net monetary benefit (PP1M = -$46,804, PP3M = -$19,508, PP6M = -$18,886) compared with continuing ER. Among LAI formulations, PP6M was cost-saving with the most QALYs gained (cost = $63,277, QALY = 3.731), followed by PP3M (cost = $63,828, QALY = 3.729) and PP1M (cost = $86,563, QALY = 3.638). At the $50,000 WTP threshold, the probabilities for PP1M, PP3M, and PP6M being cost-effective compared with paliperidone ER were 0.4%, 10.2%, and 9.8%, respectively. The probability of PP6M being cost-effective was 92.6% for the PP6M-PP1M pair and 55.2% for the PP6M-PP3M pair, and 91.1% of PP3M use was cost-effective in the PP3M-PP1M pair. The results were generally robust in the sensitivity analyses, even at the $190,000 WTP threshold. CONCLUSIONS: For patients with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was not cost-effective, suggesting the high drug costs for LAI may not justify the improved quality of life within 5 years. Among LAI formulations, PP6M was cost-effective over PP1M and PP3M.

Long-acting injectable antipsychotics (LAIs) have proven to be effective in the maintenance treatment of patients suffering from schizophrenia, and their safety and tolerability profiles represent a key factor in their long-term use and choice in clinical practice. Paliperidone palmitate (PP) is the only second-generation LAI (SGA-LAI), available in both one- (PP1M) and 3-month (PP3M) formulations. However, real-world prospective studies on PP1M and PP3M are still few and mostly conducted on small samples. In this context, we aimed to better define the safety and tolerability profile of PP using real world pharmacovigilance data.

We retrospectively analyzed the publicly available data regarding Individual Case Safety Reports (ICSRs), presenting PP1M and/or PP3M as suspected drugs, reported on EUDRAVigilance between 2011 and June 30th, 2022. ICSRs relative to at least one SGA-LAI other than PP, reported between 2003 and June 30th, 2022, were also examined as reference group. Data were evaluated with a descriptive analysis, and then, as disproportionality measures, crude reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated.

A total of 8,152 ICSRs met the inclusion criteria, of those 77.7% (n = 6,332) presented as suspected drug PP1M, 21.2% (n = 1,731) PP3M, while 89 cases indicated both PP1M and PP3M. Significantly higher probabilities of reporting in PP-related reports were observed for the primary Standardized MedDRA Queries "Sexual Dysfunctions" (ROR = 1.45; 95% CI 1.23-1.70), "Haemodynamic oedema, effusions and fluid overload" (ROR = 1.42; 1.18-1.70), as well as "Fertility disorders" (ROR = 2.69; 1.51-4.80).

Our analysis indicates that the tolerability and safety profiles of PP are in line with what is known for the other SGA-LAIs. However, differences regarding endocrine system ADRs have been noticed. The results presented in this work do not discourage the prescription of SGA-LAI formulations but aim to enhance their safety.

Schizophrenia is a severe mental disorder and antipsychotics are drugs usually used to treat this condition. Chronic hepatitis is a condition that can significantly impair hepatic functions. Most antipsychotics are metabolized by the liver, except for paliperidone, which undergoes the least amount of hepatic metabolism. This systematic review was conducted to investigate paliperidone's effectiveness and safety in patients with schizophrenia and concurrent chronic hepatitis. A detailed search using two databases, PubMed and Google Scholar, was done from June 2022 to July 2022. The PubMed search yielded 443 results and three more results were identified from Google Scholar. After a thorough screening, seven results pertinent to our study were taken into consideration for this review. All of the studies suggested that paliperidone is a safe and effective drug for the treatment of schizophrenia and since it does not undergo major hepatic metabolism and has no drug-drug interactions with antiviral drugs given in the treatment of chronic hepatitis, It can be safely used to treat schizophrenia with chronic hepatitis as a comorbid condition.

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D 2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.

Whether long-acting injectable antipsychotics (LAI) are superior to oral antipsychotics remains a controversial question, and results vary depending on the study design. Our study was performed to compare outcomes of oral antipsychotics and paliperidone palmitate (PP) in clinical practice by investigating the numbers of admissions and bed days.

We performed a retrospective observational mirror-image study at a single medical center, reviewing medical charts to obtain the clinical data. Forty-six patients with a diagnosis of schizophrenia or schizoaffective disorder who had received at least two doses of PP were included in the analysis. The Wilcoxon signed-rank test was used to compare the numbers of bed days and admissions 1 year before starting PP with those numbers at 1 year after.

The mean number of admissions fell from 0.83 to 0.17 per patient (p < 0.0002), and the median fell from 1 to 0. The mean number of bed days decreased significantly, from 24.85 to 8.74 days (p < 0.006). The outcomes remained similar in sensitivity analyses set up with different mirror points.

Our results indicate that initiating PP reduced the mean numbers of hospital admissions and bed days compared with prior oral medication. LAIs may thus be cost effective in practice; its use bringing about cost reductions greater than its purchase cost.

More than 40 years of research and clinical practice have proven the effectiveness of dopamine receptor antagonists in the pharmacological treatment of tics. A blockade of the striatal dopamine-D2 receptors is mainly responsible for their tic-reducing effect. A broad spectrum of dopamine-modulating agents, such as typical and atypical antipsychotics, but also dopamine receptor agonists are used with an immanent discord between experts about which of them should be considered as first choice. The present Review outlines the state of the art on pharmacological treatment of tics with dopamine-modulating agents by giving an systematic overview of studies on their effectiveness and a critical discussion of their specific adverse effects. It is considered as an update of a previous review of our research group published in 2013. The Review closes with a description of the current resulting treatment recommendations including the results of a first published revised survey on European expert's prescription preferences. Based on the enormously growing evidence on its effectiveness and safety, aripiprazole currently seems to be the most promising agent in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride), which are commonly used in Europe, have proven their excellent effectiveness-tolerability profile over decades in clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, pharmacological treatment of tics remains an indiviual choice depending on each patient's own specific needs.