Ärevushäirete psühhofarmakoloogia Schmiedebergist homseni

Keemilisi ühendeid on inimesed ärevuse leevendamiseks tarvitanud juba eelajaloolistel aegadel. XIX sajandil hakati vaigistava toimega farmakone laialdaselt kasutama psühhiaatrilises praktikas. Sada aastat tagasi loodud barbituraadid tõid sellesse uue kvaliteedi ning järgmise põhimõttelise sammu võimaldas teha 1,4-bensodiasepiinide juhuslik avastamine 1950. aastatel. Bensodiasepiiniretseptorite kaudu toimivad rahustid mitte ainult ei leevenda kiiresti ärevust, vaid avaldavad ka krambivastast, lihaseid lõõgastavat ja uinutavat toimet. Kuigi bensodiasepiinid on ravimina suhteliselt ohutud, vähendavad nende kasutamisvõimalusi ravimiinteraktsioonid, eriti etüülalkoholiga, samuti üldine pärssiv toime ja sõltuvuse väljakujunemine. Bensodiasepiinide tarbimine on vähenenud tänu valikuvõimalusele, mida pakuvad antidepressandid (valikuliselt serotoniini tagasihaaret pärssivad ning serotoniini ja noradrenaliini tagasihaaret pärssivad ravimid), mis ongi kujunenud esmavalikuks ärevushäirete puhul. 2013. aasta Oswald Schmiedebergi loengus kirjeldati viimasel paaril aastakümnel tehtud katseid luua põhimõtteliselt uusi anksiolüütikume, keskendudes eriti neuropeptiidisüsteemidele. Paljulubavad uurimissuunad on selles vallas GABA-, glutamaadi- ja endokannabinoidsüsteemide valikulise toimega modulaatorid, aga ka neuropeptiidiretseptorite antagonistid ja mitme molekulaarse sihtmärgiga ravimid, mis loodetavasti juhatavad sisse senisest rohkem personaliseeritud ravimravi ajastu.Eesti Arst 2013; 92(10):565–57

Sõltuvuse neurobioloogia

Farmakonid, mis tekitavad füüsilise, psüühilise või käitumusliku sõltuvuse, on erinevate esmaste molekulaarsete toimemehhanismidega. Neil kõigil on võime suurendada dopaminergilist neurotransmissiooni keskaju-eesaju teljel ning korduval uimastite tarvitamisel kujunevadventraalses tegmentum’is ja naalduvas tuumas, aga ka paljudes teistes ajupiirkondades välja püsivad komplekssed muutused geeniekspressioonis ja närvirakkude morfoloogias. Eesti Arst 2006; 85 (10): 697–70

Farmakoloogia vanaisa Rudolf Buchheim 200

Eesti Arst 2022; 101(2):122–12

Reward sensitivity, affective neuroscience personality, symptoms of attentiondeficit/hyperactivity disorder, and TPH2-703G/T (rs4570625) genotype

Objective: Reward sensitivity is an increasingly used construct in psychiatry, yet its possible inner structure and relationship with other affective variables are not well known. Methods: A reward sensitivity measurement scale was constructed on the basis of large item pool collected from birth cohort representative samples (the Estonian Children Personality Behaviour and Health Study; original n = 1238). Affective Neuroscience Personality Scale (ANPS) and the Adult Attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS) were administered in young adulthood. A variant (rs4570625) of the gene encoding tryptophan hydroxylase 2 (TPH2) that is responsible for the synthesis of central serotonin was genotyped. Results: Reward sensitivity consisted of two orthogonal components, operationally defined as Openness to Rewards and Insatiability by Reward, that respectively characterise the striving towards multiple rewards and the strong pursuit and fixation to a particular reward. While SEEKING and PLAY (and to lower extent CARE) of the ANPS co-varied with Openness to Rewards, FEAR, SADNESS, and ANGER were related to Insatiability by Reward. The total score of ASRS was moderately correlated with Insatiability by Reward, while the association with Openness to Rewards was negligible. However, ASRS Inattention had some negative relationship with the Social Experience facet of Openness to Rewards. The T/T homozygotes for the TPH2 promoter polymorphism had lower Insatiability by Reward but not Openness to Rewards. Conclusions: Behaviours sensitive to rewards are separable to the components of variability and fixation, and these components are differentially related to affective aspects of personality, attention, and hyperactivity as well as to TPH2 genotype

Efficacy of intervention at traffic schools reducing impulsive action, and association with candidate gene variants

OBJECTIVE: Road traffic injuries are the leading cause of death among young people. Recognition of the contribution of impulsive behaviour may help novice drivers to behave more safely. Previously a brief intervention focusing on impulsive traffic behaviour conducted by psychologists in driving schools had been effective. The aim of this study was an independent re-evaluation of the effect of the intervention, as conducted by driving school teachers, and assessment of the potential associations with candidate genotypes. METHODS: Driving school students (mean age 22.5, SD=7.9) were divided into intervention (n=704) and control (n=737) groups. Driving school teachers were trained to administer the intervention which consisted of a lecture and group work (1.5 h in total) on impulsivity. Traffic offences and crashes were monitored during 3 years, using police and traffic insurance fund databases. Functional polymorphisms of the dopamine transporter (DAT) and serotonin transporter genes (DAT1 VNTR and 5-HTTLPR) were assessed. RESULTS: The intervention significantly lowered general traffic risk and prevalence of traffic accidents. DAT1 VNTR 9R carriers, particularly males, had higher general traffic risk in the whole sample. Female 5-HTTLPR s' allele carriers of the intervention group had the lowest general traffic risk. Intervention was most effective in female DAT1 VNTR 10R/10R homozygotes. CONCLUSIONS: Brief impulsivity-centred intervention appears as a promising strategy for preventing risk-taking behaviour in novice drivers and can be fully integrated to driving school curriculum

Neuropeptide Y gene variants in obesity, dietary intake, blood pressure, lipid and glucose metabolism: a longitudinal birth cohort study

Objective: Neuropeptide Y affects several physiological functions, notably appetite regulation. We analysed the association between four single nucleotide polymorphisms (SNP) in the NPY gene (rs5574, rs16147, rs16139, rs17149106) and measures of obesity, dietary intake, physical activity, blood pressure, glucose and lipid metabolism from adolescence to young adulthood. Methods: The sample included both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n = 1075 with available complete data), 18 (n = 913) and 25 (n = 926) years. Linear mixed-effects regression models were used for longitudinal association between NPY SNP-s and variables of interest. Associations at ages 15, 18 and 25 were analysed by ANOVA. Results: Rs5574 CC-homozygotes had a greater increase per year in waist-to-hip ratio (WHR) and a smaller decrease in daily energy intake and carbohydrate intake from age 15 to 25 years; fasting glucose and cholesterol were higher in rs5574 CC-homozygotes. Rs16147 TT homozygotes had higher body weight and a greater increase in sum of 5 skinfolds, waist circumference, WHR and waist-to-height ratio; however, they had lower carbohydrate intake throughout the observation period. Rs16147 TT-homozygotes and both rs16139 and rs17149106 heterozygotes had higher triglyceride levels. All NPY SNP-s were associated with blood pressure: rs5574 TT-and rs16147 CC-homozygotes had a smaller increase in diastolic blood pressure, while rs16139 and rs17149106 heterozygous had lower blood pressure throughout the study. Conclusion: Variants of the NPY gene were associated with measures of obesity, dietary intake, glucose and lipid metabolism and blood pressure from adolescence to young adulthood

Low cholesterol levels in children predict impulsivity in young adulthood

Objective: Severe behavioural issues such as impulsive action and suicide have since long been associated with low levels of cholesterol. While it is known that cholesterol plays a role in neural development and hence low levels of serum lipids could have long-term effects on behaviour, there are no longitudinal studies showing association of serum lipids levels with impulsivity. We aimed to examine the prognostic properties of serum lipid levels during childhood and adolescence on measures of impulsivity during early adulthood in a representative birth cohort sample. Methods: We have investigated whether serum lipid levels measured at 9, 15, 18 and 25 years of age have an association with impulsivity in 25 years old young adults. This analysis was based on data of the birth cohort representative samples of the Estonian Children Personality Behaviour and Health Study (original n=1238). Impulsivity was self-reported with the Adaptive and Maladaptive Impulsivity Scale. Results: Total and LDL cholesterol measured in 9, 15 and 18 years old boys predicted Disinhibition and Thoughtlessness in 25 years old young adults. High scores of Disinhibition were associated with low total and LDL cholesterol levels in males but, while less consistently, with high total and LDL cholesterol levels in females. Cross-sectional analysis did not result in systematic outcomes. Conclusions: Serum lipid levels could have an impact on development of maladaptive impulsivity starting from an early age. This effect of cholesterol continues throughout adolescence into young adulthood

Nice guys: Homozygocity for the TPH2 -703G/T (rs4570625) minor allele promotes low aggressiveness and low anxiety

Background: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. We examined whether the TPH2 polymorphism -703G/T (rs4570625) is associated with aggressiveness and impulsivity, and the prevalence of psychiatric disorders, in a population-representative sample. Methods: We used self and proxy reports on aggressive behaviour in the younger birth cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study collected at age 25, and earlier collected impulsivity and related data of both ECPBHS cohorts. Results: The TT homozygous males reported less aggressive behaviour in the Life History of Aggression interview at age 25. They also had significantly lower scores in Illinois Bully Scale peer reports, and less ADHD symptoms rated by teachers both at ages 9 and 15. The TT homozygotes of both sexes had the lowest Maladaptive Impulsivity at ages 18 and 25, and the highest Adaptive Impulsivity at age 25. The TT homozygotes also had low depressiveness and trait anxiety by age 25, and the odds ratio for the prevalence of anxiety disorders was 9.38 for the G-allele carriers. Limitations: The main limitation of the study is the naturally occurring low number of subjects with the TT genotype. Conclusions: Subjects with the TPH2 rs4570625 TT genotype, especially males, exhibit less aggression and a favourable impulsivity profile, and develop anxiety disorders by young adulthood less often

The role of reward sensitivity in obesity and its association with Transcription Factor AP2B: a longitudinal birth cohort study

Objective One factor potentially contributing to obesity is reward sensitivity. We investigated the association between reward sensitivity and measures of obesity from 9–33 years of age, paying attention to the inner structure of reward sensitivity. Methods The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between reward sensitivity and measures of obesity was assessed using mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, 25 and 33 (older cohort) years were analyzed by one-way ANOVA. The indirect effect of the gene encoding transcription factor 2 beta (TFAP2B) on obesity through reward sensitivity was tested using mediation analysis. Results According to linear mixed effects regression models, an increase in scores of Insatiability by Reward and both of its components, Excessive Spending and Giving in to Cravings, significantly increased body weight, body mass index, sum of five skinfolds, waist circumference, hip circumference and waist-to-height ratio from 15 to 25 years of age. Findings were similar at age 9 and 33 years. In contrast, no association between obesity and Openness to Rewards or its facets was observed. The TFAP2B genotype was also associated with fixation to rewards in females, but not with striving towards reward multiplicity. Conclusion Our results suggest that reward sensitivity is associated with obesity by its reward fixation component. The heterogeneity of the reward sensitivity construct should be taken into account in studies on body composition