Pharmacotherapy for neuropsychiatric disorders, such as anxiety and depression, has been characterized by significant inter-individual variability in drug response and the development of side effects. Pharmacogenetics, as a key part of personalized medicine, aims to optimize therapy according to a patient’s individual genetic signature by targeting genetic variations involved in pharmacokinetic or pharmacodynamic processes. Pharmacokinetic variability refers to variations in a drug’s absorption, distribution, metabolism, and elimination, whereas pharmacodynamic variability results from variable interactions of an active drug with its target molecules. Pharmacogenetic research on depression and anxiety has focused on genetic polymorphisms affecting metabolizing cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, P-glycoprotein ATP-binding cassette (ABC) transporters, and monoamine and γ-aminobutyric acid (GABA) metabolic enzymes, transporters, and receptors. Recent pharmacogenetic studies have revealed that more efficient and safer treatments with antidepressants and anxiolytics could be achieved through genotype-guided decisions. However, because pharmacogenetics cannot explain all observed heritable variations in drug response, an emerging field of pharmacoepigenetics investigates how epigenetic mechanisms, which modify gene expression without altering the genetic code, might influence individual responses to drugs. By understanding the epi(genetic) variability of a patient’s response to pharmacotherapy, clinicians could select more effective drugs while minimizing the likelihood of adverse reactions and therefore improve the quality of treatment.

Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF−/− C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF−/−; MIF−/−+Bet; TAA group, which received TAA; TAA+Bet; MIF−/−+TAA; and MIF−/−+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.

Background/Objectives: Mental diseases are one of the leading groups of health disorders worldwide, with depressive and anxiety disorders being the most prevalent. Depressive disorders can be treated with pharmacotherapy, psychotherapy, or a combination of both. In cases where these approaches prove ineffective, electroconvulsive therapy may be considered as an alternative. The drugs of choice for treating depressive disorders are selective serotonin reuptake inhibitors (SSRIs). In the Republic of Serbia, commonly prescribed SSRIs include fluoxetine, citalopram, paroxetine, sertraline, and escitalopram. Methods: Data on drug sales for human medicine from the Agency for Medicines and Medical Devices of Serbia (ALIMS) were used for the analysis of consumption in the period 2018–2022. Data on drug consumption in other European countries were obtained from the respective national registers. Results: From 2018 to 2021, sertraline was the best-selling drug in this group, but with a statistically significant decrease (R² = 0.7948, p = 0.042), while escitalopram showed a statistically significant increase (p = 0.006) and became the best-selling drug in the SSRI group in 2022. Overall, SSRI group consumption fluctuated from 2018 to 2022, with the highest values in 2020. However, these variations were not statistically significant (p = 0.6223). Compared to Serbia, out of 12 European countries, 8 had higher and 4 had lower consumption in 2019 and 2020. A positive correlation was found between antidepressant consumption and GDP per capita. Conclusions: Sertraline was the most commonly prescribed SSRI drug in Serbia from 2018 to 2021. However, in 2022, escitalopram became the most commonly used drug in this group both in Serbia and worldwide, with a consistent increase in consumption.

Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4⁺ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes’ mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

Zaleplon is a positive allosteric modulator of the γ-aminobutyric acid (GABA)_A receptor approved for the short-term treatment of insomnia. Previous publications on zaleplon have not addressed the proteins involved in its mechanism of action but have mostly referred to behavioral or pharmacological studies. Since both GABAergic and glutamatergic signaling have been shown to regulate wakefulness and sleep, we examined the effects of prolonged zaleplon treatment (0.625 mg/kg for 5 days) on these systems in the hippocampus of male Wistar rats. Western blot and immunohistochemical analyses showed that the upregulated components of GABAergic signaling (glutamate decarboxylase, vesicular GABA transporter, GABA, and α1 subunit of the GABA_A receptor) were accompanied by increased protein levels in the glutamatergic system (vesicular glutamate transporter 1 and NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptor). Our results, showing that zaleplon enhances GABA neurotransmission in the hippocampus, were not surprising. However, we found that treatment also increased glutamatergic signaling. This could be the result of the downregulation of adenosine A1 receptors, important modulators of the glutamatergic system. Further studies are needed to investigate the effects of the zaleplon-induced increase in hippocampal glutamatergic neurotransmission and the possible involvement of the adenosine system in zaleplon’s mechanism of action.

Benzodiazepines (BZDs) are among the most widely prescribed psychotropic drugs in modern healthcare, primarily used as anxiolytics, hypnotics, anticonvulsants, and muscle relaxants. However, rising global consumption and prolonged use raise significant concerns about safety and dependence. Recent studies report that up to 35.8% of patients continue BZD therapy beyond three months, with long-term use observed in over 5% of the general population. These patterns highlight the need for evidence-based strategies to improve prescribing practices. BZDs are recommended primarily for short-term management of severe anxiety or transient insomnia, typically limited to 2–4 weeks. In anxiety disorders, SSRIs and SNRIs are first-line treatments. BZD use is particularly discouraged in older adults due to increased risks of cognitive impairment, falls, and dependence. Rational prescribing requires individualized assessment, minimal effective dosing, gradual withdrawal protocols, and patient education. Enhanced regulatory oversight and improved access to psychotherapy are essential for safer benzodiazepine use.