Novel treatment options in depression and psychosis

Eva Ceskova, Petr Silhan Department of Psychiatry, University Hospital Ostrava, Ostrava, Czech Republic Abstract: In spite of tremendous development in central nervous system research, current treatment is suboptimal, especially in severe mental disorders. In medicine, there are two main methods of improving the health care provided: seeking new treatment procedures and perfecting (optimizing) the existing ones. Optimization of treatment includes not only practical tools such as therapeutic drug monitoring but also implementation of general trends in the clinical practice. New pharmacological options include new more sophisticated forms of monoaminergic drugs, old drugs rediscovered on the base of a better understanding of pathophysiology of mental illnesses, and drugs aimed at new treatment targets. In depression, treatment resistance to antidepressive pharmacotherapy represents one of the most important clinical challenges. Switching to monotherapy with new multimodal/multifunctional antidepressants and augmentation with new atypical antipsychotics (aripiprazole and brexpiprazole) may be promising options. Further, current evidence supports utility and safety of adjunctive treatment of nutraceuticals. Novel approaches being studied include ketamine and opioids. Recent advances in technology and emerging knowledge about dysfunctional brain circuits and neuroplasticity have led to the development of different new neuromodulation techniques usually used as add-on therapy. Antipsychotics are still the cornerstone of the current treatment of schizophrenia. Two new partial dopamine agonists, brexpiprazole and cariprazine, are now available in addition to aripiprazole. Although the mechanisms of action are similar, the two agents differ in terms of their pharmacodynamic profiles. Further, two new formulations of long-acting injections of second-generation antipsychotics (aripiprazole lauroxil and 3-month paliperidone palmitate) were introduced into clinical practice. New treatment options not yet available include cannabidiol, glutamate modulators, and nicotine receptors agonists. Keywords: optimization of treatment, multimodal/multifunctional antidepressants, partial dopamine agonists, glutamate modulators, nicotine receptors agonist

Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations [Corrigendum]

Mayerova M, Ustohal L, Jarkovsky J, et al. Neuropsychiatr Dis Treat. 2018;14:1535–1543. On page 1539, “Clozapine doses and clozapine PCs” section, second paragraph, line 2, the following sentence was incorrect: “The clozapine PC levels of 67% of patients were outside the proposed reference range (proposed reference range 350–600 ng/mL);28 the levels of 43% were above and 24% of patients had levels below the proposed reference range.” The correct sentence is: “The clozapine PC levels of approximately67% of patients were outside the proposed reference range (proposed reference range 350–600 ng/mL);7 42% of patients had levels below and 25% of patients had levels above the proposed reference range.”On page 1541, “Discussion” section, first paragraph, line 2, the following sentence was incorrect: “In contrast to the study by Couchman, in which more PC levels were below the proposed reference range (42.5% under and 28.4% above), in our study more PC levels were above (43% above and 24% under).”The correct sentence is: “In agreement with the study by Couchman, in which more PC levels were below the proposed reference range (42.5% below and 28.4% above), our study also found more PC levels below (42% below and 25% above).” Read the original articl

Influence of dose, gender, and cigarette smoking on clozapine plasma concentrations

Michaela Mayerova,1–3 Libor Ustohal,1–3 Jiri Jarkovsky,4 Jan Pivnicka,1,5 Tomas Kasparek,1,2 Eva Ceskova1,3 1Faculty of Medicine, Masaryk University, Brno, Czech Republic; 2Department of Psychiatry, University Hospital Brno, Brno, Czech Republic; 3CEITEC – Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 4Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic; 5Institute of Forensic Medicine, St. Anne’s University Hospital, Masaryk University, Brno, Czech Republic Introduction: Therapeutic drug monitoring (TDM) of clozapine is a very useful method for verifying both the correct intake and the interindividual variability of its metabolism, thereby avoiding the risk of toxicity. The purposes of this paper were to discover how many patients using clozapine in common clinical practice have clozapine plasma concentration (PC) levels in the proposed reference range and to identify factors that influence clozapine PC levels. Methods: Our study included 100 inpatients (diagnosed with schizophrenia or schizoaffective disorder) taking standard doses of clozapine (100–700 mg/day). Clozapine concentration was measured by high-performance liquid chromatography. Correlations between doses and PC levels and the influence of smoking and gender on clozapine PC levels were calculated. Results: A large number of the patients (67%) had PC levels outside the proposed reference range. The clozapine PC levels were influenced by dose, gender, and cigarette smoking. Conclusion: The correlations between dose, gender, and cigarette smoking and clozapine PC levels highlighted by our study overlap other research. It was surprising to find such a large number of patients with clozapine PC levels outside the therapeutic range. This result suggests the importance of clozapine TDM due to misunderstood inter- and/or intraindividual variability or misestimated partial therapeutic compliance. Keywords: therapeutic drug monitoring, plasma levels, interindividual variability, schizophrenia, schizoaffective disorde

The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP.

The tumor-suppressor function of p53 relies on its transcriptional activity, which is modulated by post-translational modifications and interactions with regulatory proteins. The prolyl isomerase Pin1 has a central role in transducing phosphorylation of p53 into conformational changes that affect p53 stability and function. We found that Pin1 is required for efficient loading of p53 on target promoters upon stress. In addition, Pin1 is recruited to chromatin by p53 and stimulates binding of the p300 acetyltransferase and consequent p53 acetylation. Accordingly, tumor-associated mutations at Pin1-binding residues within the p53 proline-rich domain hamper acetylation of p53 by p300. After phosphorylation of p53 at Ser46 triggered by cytotoxic stimuli, Pin1 also mediates p53's dissociation from the apoptosis inhibitor iASPP, promoting cell death. In tumors bearing wild-type p53, expression of Pin1 and iASPP are inversely correlated, supporting the clinical relevance of these interactions