Potential impact on mental health in patients with treatment-resistant schizophrenia - clozapine augmentation with long-acting parenteral antipsychotics: a case series.

INTRODUCTION: The rate of pharmacoresistance among in patients diagnosed with schizophrenia is around 30%. Clozapineis the drug of choice for these patients; however, an adequate response to treatment doesn't always occur. One of the possible augmentation approaches, specifically for non-adherent patients, is the administration of long-acting parenteral antipsychotics. Our goal was to evaluate previous experiences of administering a combination of the atypical antipsychotic clozapine and long-acting injectable antipsychotics to pharmacoresistant patients at the Department of Psychiatry the Czech Republic and to assess the safety and effectiveness of such administration. METHODS: A retrospective evaluation of patient case studies was conducted for those who were hospitalized in the Ward for the therapy of Psychotic disorders between 2016 and 2020 and had a medication history of combining clozapine and depot antipsychotics. RESULTS: Over half of the patients had no illness relapses during the observed period. The clinical manifestation of adverse effects from combination therapy appears low in our patient sample, primarily involving mild and pharmacologically manageable side effects (tachycardia). Only one of the cases recorded neutropenia, which led to discontinuation of clozapine; the patient was maintained on long-acting injectable antipsychotics medication. CONCLUSION: From our findings, it can be inferred that augmenting clozapine with depot antipsychotics is a potential therapeutic intervention that pharmacoresistant patients could benefit from. However, it is essential to emphasize that this therapeutic approach should only be administered after carefully considering the patient's existing treatment. It should be strictly individualized based on the treating physician's or clinical pharmacist's sufficient professional experience.

Validation and verification of predictive salivary biomarkers for oral health.

Oral health is important not only due to the diseases emerging in the oral cavity but also due to the direct relation to systemic health. Thus, early and accurate characterization of the oral health status is of utmost importance. There are several salivary biomarkers as candidates for gingivitis and periodontitis, which are major oral health threats, affecting the gums. These need to be verified and validated for their potential use as differentiators of health, gingivitis and periodontitis status, before they are translated to chair-side for diagnostics and personalized monitoring. We aimed to measure 10 candidates using high sensitivity ELISAs in a well-controlled cohort of 127 individuals from three groups: periodontitis (60), gingivitis (31) and healthy (36). The statistical approaches included univariate statistical tests, receiver operating characteristic curves (ROC) with the corresponding Area Under the Curve (AUC) and Classification and Regression Tree (CART) analysis. The main outcomes were that the combination of multiple biomarker assays, rather than the use of single ones, can offer a predictive accuracy of > 90% for gingivitis versus health groups; and 100% for periodontitis versus health and periodontitis versus gingivitis groups. Furthermore, ratios of biomarkers MMP-8, MMP-9 and TIMP-1 were also proven to be powerful differentiating values compared to the single biomarkers.

Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long-acting formulation.

Mortality in psychiatric patients with severe mental illnesses reaches a 2-3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes. Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.

Olanzapine exposure diminishes perfusion and decreases volume of sensorimotor cortex in rats.

BACKGROUND: Olanzapine is a frequently used atypical antipsychotic drug known to exert structural brain alterations in animals. This study investigated whether chronic olanzapine exposure alters regional blood brain perfusion assessed by Arterial Spin Labelling (ASL) magnetic resonance imaging (MRI) in a validated model of olanzapine-induced metabolic disturbances. An effect of acute olanzapine exposure on brain perfusion was also assessed for comparison. METHODS: Adult Sprague-Dawley female rats were treated by intramuscular depot olanzapine injections (100 mg/kg every 14 days) or vehicle for 8 weeks. ASL scanning was performed on a 9.4 T Bruker BioSpec 94/30USR scanner under isoflurane anesthesia. Serum samples were used to assay leptin and TNF-α level while brains were sliced for histology. Another group received only one non-depot intraperitoneal dose of olanzapine (7 mg/kg) during MRI scanning, thus exposing its acute effect on brain perfusion. RESULTS: Both acute and chronic dosing of olanzapine resulted in decreased perfusion in the sensorimotor cortex, while no effect was observed in the piriform cortex or hippocampus. Furthermore, in the chronically treated group decreased cortex volume was observed. Chronic olanzapine dosing led to increased body weight, adipose tissue mass and leptin level, confirming its expected metabolic effects. CONCLUSION: This study demonstrates region-specific decreases in blood perfusion associated with olanzapine exposure present already after the first dose. These findings extend our understanding of olanzapine-induced functional and structural brain changes.

Aripiprazole-induced adverse metabolic alterations in polyI:C neurodevelopmental model of schizophrenia in rats.

Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY®) was administered once daily via oral gavage for a month. Altered lipid profile in polyI:C model was observed and a trend towards different dynamics of weight gain in polyI:C rats was noted in the absence of significant antipsychotic treatment effect. PolyI:C model was not associated with changes in other parameters i.e. adipokines, gastrointestinal hormones and cytokines levels. Aripiprazole did not influence body weight but it induced alterations in neurohumoral regulations. Leptin and GLP-1 serum levels were significantly reduced, while ghrelin level was elevated. Furthermore aripiprazole decreased serum levels of pro-inflammatory cytokines. Our data indicate dysregulation of adipokines and gastrointestinal hormones present after chronic treatment with aripiprazole which is considered metabolically neutral in the polyI:C model of schizophrenia.

Depot risperidone-induced adverse metabolic alterations in female rats.

Atypical antipsychotics are associated with adverse metabolic effects including weight gain, increased adiposity, dyslipidaemia, alterations in glucose metabolism and insulin resistance. Increasing evidence suggests that metabolic dysregulation precedes weight gain development. The aim of this study was to evaluate alterations in adipokines, hormones and basic serum biochemical parameters induced by chronic treatment with depot risperidone at two doses (20 and 40 mg/kg) in female Sprague-Dawley rats. Dose-dependent metabolic alterations induced by risperidone after 6 weeks of treatment were revealed. Concomitant to weight gain and increased liver weight, an adverse lipid profile with an elevated triglyceride level was observed in the high exposure group, administered a 40 mg/kg dose repeatedly, while the low dose exposure group, administered a 20 mg/kg dose, developed weight gain without alterations in the lipid profile and adipokine levels. An initial peak in leptin serum level after the higher dose was observed in the absence of weight gain. This finding may indicate that the metabolic alterations observed in this study are not consequent to body weight gain. Taken together, these data may support the primary effects of atypical antipsychotics on peripheral tissues.

Olanzapine-depot administration induces time-dependent changes in adipose tissue endocrine function in rats.

OBJECTIVE: Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations. METHODS: The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57. RESULTS: The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study. CONCLUSION: This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics.

[Effectiveness of phytotherapy in supportive treatment of type 2 diabetes mellitus III. Momordica (Momordica charantia)]. / Úcinnost fytoterapie v podpurné lécbe diabetes mellitus typu 2 III. Momordika (Momordica charantia).

Momordica charantia is a thermophilic voluble plant from the tropical and subtropical regions of Asia, Africa and the Caribbean. In central Europe, momordica requires greenhouse plantations. Mature fruits resemble a cucumber or a pumpkin and can be used as other similar vegetables. Crude fruits are very bitter and refreshing. For centuries the plant has been known in Chinese traditional medicine for its antidiabetic effects as well as for the treatment of cancer or infections caused by worms, viruses and malaria. Antidiabetic effects are attributed namely to cucurbitane type triterpenoids, charantin, p-insulin and 9cis-11trans-13trans-conjugated linolenic acid. These substances in momordica preparations show antidiabetic effectiveness in clinical studies by increasing insulin secretion and deceasing insulin resistance or glucose absorption from the gut. Beside this main effect the extract possesses certain neuroprotective and antioxidant effects (especially p9cis-11trans-13trans-conjugated linolenic acid) and contributes to normalize blood lipid and adipokine levels which results in the normalization of metabolic syndrome. Antidiabetic effectiveness of momordica was compared to active treatment with several oral antidiabetic drugs and proved comparable effects. However, the number of studies is limited and their methodological approach variable. Therefore, the evidence is so far inconclusive.

Health safety issues of synthetic food colorants.

Increasing attention has been recently paid to the toxicity of additives used in food. The European Parliament and the Council published the REGULATION (EC) No. 1333/2008 on food additives establishing that the toxicity of food additives evaluated before 20th January 2009 must be re-evaluated by European Food Safety Authority (EFSA). The aim of this review is to survey current knowledge specifically on the toxicity issues of synthetic food colorants using official reports published by the EFSA and other available studies published since the respective report. Synthetic colorants described are Tartrazine, Quinoline Yellow, Sunset Yellow, Azorubine, Ponceau 4R, Erythrosine, Allura Red, Patent Blue, Indigo Carmine, Brilliant Blue FCF, Green S, Brilliant Black and Brown HT. Moreover, a summary of evidence on possible detrimental effects of colorant mixes on children's behaviour is provided and future research directions are outlined.

[Effectiveness of phytotherapy in supportive treatment of type 2 diabetes mellitus II. Fenugreek (Trigonella foenum-graecum)]. / Úcinnost fytoterapie v podpurné lécbe diabetes mellitus typu 2 II. Pískavice recké seno (Trigonella foenum-graecum).

Fenugreek seeds are known for their characteristic smell of soup seasoning and as an ingredient of Indian curry. Traditionally the seeds are used as macerate for the treatment of diabetes, cough, and flatulence, to increase breast milk secretion, and for anti-inflammatory and aphrodisiac effects. The use is limited by its unpleasant smell and bitter taste which can be modified by adding mint leaves to the macerate. Antidiabetic properties are attributed mainly to galactomannan, 4-hydroxyisoleucin (4-OH-Ile), diosgenin and trigonelline. These substances demonstrate direct antidiabetic properties in clinical studies by increasing insulin secretion (4-OH-Ile), decreasing insulin resistance and glucose resorption from the GIT (galactomannan) and improvement in B-cells regeneration (trigonelline). Besides this main effect, the herb improves blood lipid spectre (4-OH-Ile, diosgenin), and has reno-protective (4-OH-Ile, trigonelline), neuroprotective (trigonelline) and antioxidant (diosgenin, trigonelline) effects. Antidiabetic efficacy of trigonelline is comparable to glibenclamide treatment and more effective than sitagliptine therapy. Given the large body of evidence and promising results in comparison with standard pharmacotherapy, fenugreek active substances have a potential to become a source of new antidiabetic medication.Key words: fenugreek Trigonella foenum-graecum diabetes mellitus type 2 biological activity.

[Effectiveness of phytotherapy in supportive treatment of type 2 diabetes mellitus Billberry (Vaccinium myrtillus)]. / Úcinnost fytoterapie v podpurné lécbe diabetes mellitus typu 2 Boruvka cerná (Vaccinium myrtillus).

The billberry is well-known for its tasty blue-dyeing fruits. Historically the leaves and fruits were used to treat diabetes, cardiovascular diseases, dementia and cancer. Antidiabetic properties of the plant are attributed mostly to the content of anthocyanins and polyphenols. These compounds have proven their antidiabetic potential in various studies. Their mechanism of action is an increase in insulin secretion (anthocyanin pelargonidin), reduction of insulin resistance (anthocyanin cyanidin-3-glucoside), glucose resorption from the GIT (polyphenols) and enhancement of beta-cells regeneration. Besides these effects, anthocyanins contribute to the improvement of the lipid spectrum and have antioxidant, anti-inflammatory and cardioprotective activities. Antidiabetic effects of anthocyanin cyanidin-3-galactoside were compared to acarbose (synergistic effect), hypocholesterolemic activity of cyanidin-3-O-glucoside to atorvastatin (synergistic effect) and hypolipidemic properties of blueberry leaf extract to ciprofibrate (extract has a lower effect). However, in many preclinical and clinical studies different species of the Vaccinium genus and other plants with asimilar effect as the billberry were also assessed. Therefore, in order to convincingly assess the efficacy and safety of blueberry herbal medicines more studies are necessary. Such studies should shed light into the variety of anthocyanins, their particular effects and optimal doses and compare their effects with intake of foods generally rich in anthocyanins.Key words: billberry Vaccinium myrtillus diabetes mellitus phytotherapy antocyanines.

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review.

BACKGROUND: There is a growing interest in metabolic alterations in patients with psychiatric disorders due to their increased risk for metabolic syndrome (MetS) development. Inflammation is known to underlie the pathophysiology of schizophrenia and depression as well as MetS. Vulnerability factors for schizophrenia/depression and MetS hence appear to be shared. METHODS AND RESULTS: Based on a Web of Science search, this review examines current evidence for MetS pathophysiology involving dysregulation of adipose tissue signaling - adipokines and pro-inflammatory cytokine, both also known to be aberrant in schizophrenia/depression. Further, gender differences in the incidence and course of schizophrenia/depression were reported. The disturbances linked to the MetS are also described. Therefore, this review further maps the gender differences in the psychiatric-metabolic comorbidities. CONCLUSION: There is evidence supporting a pathological predisposition to MetS in both schizophrenia and depression in both humans and animal models. This predisposition is dramatically enhanced by antipsychotic medication. Further, there are gender differences from clinical findings suggesting women with schizophrenia/depression are more vulnerable to MetS development. This has not yet been assessed in animal studies. We suggest further validation of existing schizophrenia and depression animal models for the assessment of metabolic disturbances to provide tools for developing new antipsychotics and antidepressants with "metabolically inert" profile or improving the metabolic status in schizophrenic/depressed patients.

Metabolic syndrome - dysregulation of adipose tissue endocrine function.

Metabolic syndrome, acondition increasing cardiovascular morbidity, mortality and risk for diabetes mellitus type 2, is currently worldwide reaching epidemic proportions. This complex disorder represents an urgent challenge for new pharmacotherapeutic strategies formulation. Pathophysiological mechanisms underlying metabolic syndrome are not completely understood, nevertheless growing evidence is supporting the hypothesis that multiple metabolic dysregulations do contribute to its development. Apotential target for pharmacological intervention is considered to be dysregulation of adipose tissue endocrine/paracrine function. Specific adipokines, proteins secreted by the adipose tissue, with some pleiotropic effects, have been identified with strong association to regulation of energy metabolism, appetite, insulin signaling, tissue insulin sensitivity and the proinflammatory state related to metabolic syndrome. The aim of this paper is to provide a brief overview of endocrine/paracrine functions of the adipose tissue with regard to metabolic syndrome development and pathophysiology and particular adipokines as potential targets for innovative pharmacotherapeutic approaches.

A comparison of the impact of amaranth flour and squalene on plasma cholesterol in mice with diet-induced dyslipidemia.

Amaranth was identified as a possible component of an anti-sclerotic diet. To date, particular substances responsible for this effect have not been exactly specified. Squalene, which is contained in amaranth, could be responsible for this effect. However, there are also other potential substances and the hypolipidemic effect of amaranth can be caused by a synergistic effect of several components. This study investigated and compared the impact of amaranth flour and squalene on the total cholesterol (CHOL(TOT)) and LDL cholesterol (CHOL(LDL)) levels in mice with dyslipidemia induced by a cholesterol- and sugar-rich diet. The experiment included 40 inbred mice (C57Bl/6J SPF). After a 7-days acclimatization period, animals were divided into four groups by random. Individual groups were fed different diets for 49 days: control (group C), high energy diet (group HED), high energy diet with amaranth flour (group HED+A) and high energy diet with squalene (group HED+S). The sugar- and cholesterol-rich diet in HED resulted in the significant increase in the levels of CHOL(TOT) by 125% (P < 0.05) and CHOL(LDL) by 304% (P < 0.05), and at the same time in a decrease of HDL cholesterol (CHOL(HDL)) levels by 58% (P < 0.05) compared to group C. To the contrary, amaranth flour enriched diet in group HED+A led to a decrease of CHOL(TOT) levels by 33% (P < 0.05) and CHOL(LDL) by 37% (P < 0.05), compared to HED. Both, amaranth flour and squalene, had a positive impact on CHOL(HDL) levels. Compared to group HED, there was a 47% increase in HED+A and a 60% increase in HED+S. Results proved the favorable impact of amaranth flour on the levels of total cholesterol CHOL(TOT) and also on CHOL(LDL). Furthermore, the results imply that amaranth flour contains besides squalene other substances, which can actively participate in its hypolipidemic effect.

Adiponectin, adipocyte fatty acid binding protein, and epidermal fatty acid binding protein: proteins newly identified in human breast milk.

BACKGROUND: Breastfeeding may protect children from developing metabolic syndrome and other diseases later in life. We investigated novel proteins in human breast milk that might play a role in this process. METHODS: We used ELISA to measure adiponectin, adipocyte and epidermal fatty acid binding proteins (AFABP, EFABP), and leptin concentrations in human breast milk obtained from 59 mothers 48 h after initiation of lactation. Using a questionnaire and medical records, we collected information about the mothers and newborns. RESULTS: Mean (SE) adiponectin concentrations in breast milk were 13.7 (0.8), range 3.9-30.4 microg/L; AFABP concentrations 26.7 (4.4), range 1.2-137.0 microg/L; EFABP concentrations 18.1 (1.4), range 0.8-47.0 microg/L; and leptin concentrations 0.50 (0.05), range 0-1.37 microg/L. We found a significant correlation between AFABP and EFABP concentrations (r = 0.593, P <0.0001). Maternal EFABP concentrations were significantly higher in mothers who delivered boys than in those who delivered girls [21.7 (2.3) vs 15.4 (1.7) microg/L, P = 0.028] and correlated with newborn birth weight (r = 0.266, P = 0.045). Maternal leptin correlated with body weight before pregnancy (r = 0.272, P = 0.043) and at delivery (r = 0.370, P = 0.005), body mass index before pregnancy (r = 0.397, P = 0.003) and at delivery (r = 0.498, P <0.0001), body weight gain during pregnancy (r = 0.267, P = 0.047), and newborn gestational age (r = 0.266, P = 0.048). Leptin was significantly lower in mothers who delivered preterm vs term babies [0.30 (0.09) vs 0.60 (0.05) ug/L, P = 0.026]. CONCLUSIONS: Concentrations of adiponectin, AFABP, and EFABP in human breast milk are related to nutritional variables of mothers and newborns and thus may play a role in the protective effects of breastfeeding.