Suzana Uzun

Theranostic Biomarkers for Schizophrenia

Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.

Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and body mass index change over time in healthy adults.

Obesity is becoming the epidemic health problem worldwide with a very complex etiology. The interaction between diverse genetic and environmental factors contributes to development of obesity. Among myriad of functions in central and peripheral tissues, brain-derived neurotrophic factor (BDNF) also regulates energy homeostasis, food intake and feeding behavior, and has a role in obesity and increased body mass index (BMI). BDNF Val66Met (rs6265) polymorphism is associated with BMI gain, but both positive associations and non-replications are reported. Since BMI changes over time and since genetic influences on BMI vary with age, the aim of the study was to evaluate association between BDNF Val66Met polymorphism and BMI gain in healthy subjects with middle or old age. The study included a cohort of 339 adult healthy Caucasians of Croatian origin, free of eating and metabolic disorders, evaluated in three time periods in the year 1972, 1982 and 2006, when the subjects were around 40, 50 and 70 years old, respectively. The results revealed a significant effect of smoking on BMI, but a lack of significant association between BDNF Val66Met polymorphism and overweight or obesity, and no significant association between BDNF Val66Met and BMI changes over time. These results did not confirm the major role of BDNF Val66Met in the regulation of BMI changes in adult and old healthy subjects.

Monoamine oxidase and agitation in psychiatric patients

Subjects with schizophrenia or conduct disorder display a lifelong pattern of antisocial, aggressive and violent behavior and agitation. Monoamine oxidase (MAO) is an enzyme involved in the degradation of various monoamine neurotransmitters and neuromodulators and therefore has a role in various psychiatric and neurodegenerative disorders and pathological behaviors. Platelet MAO-B activity has been associated with psychopathy- and aggression-related personality traits, while variants of the MAOA and MAOB genes have been associated with diverse clinical phenotypes, including aggressiveness, antisocial problems and violent delinquency. The aim of the study was to evaluate the association of platelet MAO-B activity, MAOB rs1799836 polymorphism and MAOA uVNTR polymorphism with severe agitation in 363 subjects with schizophrenia and conduct disorder. The results demonstrated significant association of severe agitation and smoking, but not diagnosis or age, with platelet MAO-B activity. Higher platelet MAO-B activity was found in subjects with severe agitation compared to non-agitated subjects. Platelet MAO-B activity was not associated with MAOB rs1799836 polymorphism. These results suggested the association between increased platelet MAO-B activity and severe agitation. No significant association was found between severe agitation and MAOA uVNTR or MAOB rs1799836 polymorphism, revealing that these individual polymorphisms in MAO genes are not related to severe agitation in subjects with schizophrenia and conduct disorder. As our study included 363 homogenous Caucasian male subjects, our data showing this negative genetic association will be a useful addition to future meta-analyses.

Cortisol in schizophrenia: No association with tobacco smoking, clinical symptoms or antipsychotic medication

ABSTRACT Cigarette smoking is associated with higher cortisol levels in healthy subjects. In schizophrenia this relationship is not clear. There are divergent results on the association between cortisol with smoking, clinical symptoms and medication in schizophrenia. This study evaluated this association in 196 Caucasian inpatients with schizophrenia (51.30 ± 26.68 years old), subdivided into 123 smokers and 73 non‐smokers. Basal salivary cortisol levels were measured twice, at 08.00 and 09.00 AM, 90–120 min after awakening. The effect of smoking on cortisol was evaluated according to current smoking status, the number of cigarettes/day and the nicotine addiction intensity. The influence of clinical symptoms and/or antipsychotic medication on cortisol was determined using the Positive and Negative Syndrome Scale (PANSS), and chlorpromazine equivalent doses. Non‐smokers were older, received lower doses of antipsychotics, had higher PANSS scores, and had longer duration of illness than smokers. Salivary cortisol was similar in schizophrenic patients subdivided according to the smoking status, the number of cigarettes/day and nicotine addiction intensity. No significant correlation was found between salivary cortisol and PANSS scores, chlorpromazine equivalent doses, age of onset or the duration of illness. The findings revealed no association between salivary cortisol and smoking, nicotine addiction intensity, or clinical symptoms. Our preliminary data showed no correlation between salivary cortisol and chlorpromazine equivalent doses and/or antipsychotic medication. Our findings suggest that smoking does not affect the cortisol response in schizophrenic patients as it has been shown in healthy individuals. Future studies should investigate a possible desensitization of the stress system to smoking. HIGHLIGHTSSaliva cortisol was not associated with smoking in schizophrenia.Saliva cortisol did not differ after the first cigarette smoked that day in smokers.Saliva cortisol was not related to the intensity of nicotine addiction in smokers.Saliva cortisol was not correlated with various clinical symptoms of schizophrenia.Saliva cortisol did not differ in patients treated with different antipsychotics.

The lack of association between catechol-O-methyl-transferase Val108/158Met polymorphism and smoking in schizophrenia and alcohol dependence

Nikolac M., Šagud M., Nedić G., Nenadić Šviglin K., Mihaljević Peleš A., Uzun S., Vuksan Ćusa B., Kozumplik O., Živković M., Mustapić M., Jakovljević M., Pavlović M., Muck-Šeler D., Borovečki F., Pivac N. (2013) The lack of association between catechol-O-methyl-transferase Val108/158Met polymorphism and smoking in schizophrenia and alcohol dependence. Psychiatry Research, 205 (1-2). pp. 179-80. ISSN 0165-1781

Sex-specific characteristics of involuntary hospitalization in Croatia

The aim of this study was to investigate sex-specific characteristics related to involuntary hospitalization. Medical records from two psychiatric hospitals in Croatia in a 6-month period were surveyed. The sample comprised 380 men and 335 women hospitalized voluntary and 48 men and 125 women hospitalized involuntary. Results showed that both male and female patients were most often admitted because of psychosis, but the second diagnosis related to involuntary hospitalization in female patients was mood disorders, whereas in male patients it was alcoholism. There was no difference in the length of hospitalization between voluntarily and involuntarily hospitalized male patients, whereas in the female sample involuntary hospitalization lasted longer than voluntary. Involuntary hospitalization in the male sample was related to younger age but was not related to marital status. In contrast, in the female sample involuntary hospitalization was related to older age and to ?having no spouse?. In conclusion, there are some sex-specific factors related to involuntary hospitalization in Croatia.The aim of this study was to investigate sex-specific characteristics related to involuntary hospitalization. Medical records from two psychiatric hospitals in Croatia in a 6-month period were surveyed. The sample comprised 380 men and 335 women hospitalized voluntary and 48 men and 125 women hospitalized involuntary. Results showed that both male and female patients were most often admitted because of psychosis, but the second diagnosis related to involuntary hospitalization in female patients was mood disorders, whereas in male patients it was alcoholism. There was no difference in the length of hospitalization between voluntarily and involuntarily hospitalized male patients, whereas in the female sample involuntary hospitalization lasted longer than voluntary. Involuntary hospitalization in the male sample was related to younger age but was not related to marital status. In contrast, in the female sample involuntary hospitalization was related to older age and to ?having no spouse?. In conclusion, ther...

Metabolomic and glycomic findings in posttraumatic stress disorder

Abstract Posttraumatic stress disorder (PTSD) is a stressor‐related disorder that develops in a subset of individuals exposed to a traumatic experience. Factors associated with vulnerability to PTSD are still not fully understood. PTSD is frequently comorbid with various psychiatric and somatic disorders, moderate response to treatment and remission rates. The term “theranostics” combines diagnosis, prognosis, and therapy and offers targeted therapy based on specific analyses. Theranostics, combined with novel techniques and approaches called “omics”, which integrate genomics, transcriptomic, proteomics and metabolomics, might improve knowledge about biological underpinning of PTSD, and offer novel therapeutic strategies. The focus of this review is on metabolomic and glycomic data in PTSD. Metabolomics evaluates changes in the metabolome of an organism by exploring the set of small molecules (metabolites), while glycomics studies the glycome, a complete repertoire of glycan structures with their functional roles in biological systems. Both metabolome and glycome reflect the physiological and pathological conditions in individuals. Only a few studies evaluated metabolic and glycomic changes in patients with PTSD. The metabolomics studies in PTSD patients uncovered different metabolites that might be associated with psychopathological alterations in PTSD. The glycomics study in PTSD patients determined nine N‐glycan structures and found accelerated and premature aging in traumatized subjects and subjects with PTSD based on a GlycoAge index. Therefore, further larger studies and replications are needed. Better understanding of the biological basis of PTSD, including metabolomic and glycomic data, and their integration with other “omics” approaches, might identify new molecular targets and might provide improved therapeutic approaches. HighlightsFactors associated with vulnerability to develop PTSD are still not fully understood.Combination of “omics” approaches might improve knowledge about PTSD.Metabolomics and glycomics data in patients with PTSD are scarce.Metabolomics and glycomics might identify novel diagnostics, prognostics, and possibly theranostics biomarkers in PTSD.

Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia

Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.

The problem of informed consent of persons with neurocognitive disorders in clinical investigations

Podatci s pocetka milenija ukazivali su na prevalenciju Alzheimerove bolesti od 24, 3 milijuna oboljelih u svijetu, ali i na ocekivani znacajni godisnji porast broja novih slucajeva demencije, koji sada iznosi vec 4, 6 milijuna. Sto se tice najnovijih globalnih procjena možemo se osloniti na procjenu ADI-a (Alzheimer Disease International), krovne udruge koja okuplja 80 nacionalnih Alzheimer organizacija, iz koje je razvidno da danas u svijetu ima vise od 47 milijuna osoba s demencijom. No, zabrinjava tvrdnja da ce broj oboljelih i nadalje progresivno rasti. Biomedicinska istraživanja su neprocjenjiv (i jedini) izvor novih spoznaja i znanja zahvaljujuci kojima je postignut znacajan napredak u podrucju medicine u proslom stoljecu (a sto traje i danas). U podrucju klinickih istraživanja osobe s demencijom su vulnerabilna skupina. Zakonska odredba prema kojoj se onemogucava davanje pristanka za sudjelovanje u istraživanjima od strane zakonskog zastupnika je potencijalno ogranicavajuci faktor u kontekstu istraživanja koja ukljucuju osobe s demencijom. U podrucju psihijatrije nužna je procjena pacijentove sposobnosti za davanje informiranog pristanka. S obzirom na specificnosti mentalnih poremecaja ova procjena je nužna u cilju zastite bolesnika i njegova prava na izbor medicinskog postupka kao i u cilju izbjegavanja zloporaba u svakodnevnoj klinickoj praksi. / From the beginning of the millennium showed that the prevalence of Alzheimers disease was at 24.3 million of patients globally, but also anticipated a significant increase of the number of new cases of dementia, which are currently at 4.6 million. Currently, based on estimates from the ADI (Alzheimer Disease International), a head association that aggregates data 80 national Alzheimer organizations, it is apparent that there are more than 47 million persons with dementia in the world today. However, what is concerning is the statement that this number will continue to grow progressively. Biomedical investigations are an invaluable (and the only) source of new knowledge, thanks to which significant progress has been achieved in medicine during previous century and continues to be achieved today. ln the field of clinical investigations, persons with dementia represent a vulnerable group. The legal representative of the person with dementia cannot give consent for participation in clinical investigation, which represents a potentially limiting factor for clinical investigations that include persons with dementia. In psychiatry, the evaluation of patient competence for giving informed consent is necessary. Given the specificity of mental disorders, this evaluation is necessary in order to protect the patient and their choice of medical procedure as well as to avoid misuse in everyday clinical practice.

OCCURRENCE OF POST-INJECTION DELIRIUM/SEDATION SYNDROME AFTER APPLICATION OF OLANZAPINE LONG-ACTING INJECTION DURING ONE YEAR PERIOD

INTRODUCTION The aim was to report the occurrence of after application of olanzapine long-acting injection (OLAI) in patients with schizophrenia during one year period. SUBJECTS AND METHODS During one year period, OLAI was applied to 30 patients with schizophrenia (18 men, 12 women) who were non-adherent to previous treatment with oral olanzapine. Patients were 20-58 years of age (39 years old on average), diagnosed with SCID based on DSM-IV-TR criteria. Patients received OLAI in dosage between 210-405 mg (287±62 (mean ± SD)) every 2-4 weeks. RESULTS Out of 30 patients that received OLAI, 29 patients improved significantly without side-effects, and one patient developed post-injection delirium/sedation syndrome (PDSS). The patients somatic condition stabilized and treatment with OLAI was discontinued due to the PDSS. CONCLUSION The occurrence of PDSS is not common and when it occurs, in our experience, it was reversible.