A kis „n”, nagy „P” probléma a neuropszichofarmakológiában, avagy hogyan kontrolláljuk a hamis felfedezések arányát

Számos korszerű neuropszichofarmakológiai vizsgálati módszer jellegzetessége, hogy aránylag kevés vizsgálati egyénről (n) nagyon sok adatot (paramétert, P) gyűjt. Példaképpen említhetjük a képalkotó módszereket (pl. funkcionális mágneses rezonancia és egyéb képalkotó eljárásokat), az elektroenkefalográfiát (EEG), vagy a genomikai vizsgálatokat. Egyetlen microarray chip például több ezer próbát tartalmazhat, azaz a P ezres nagyságrendekkel haladhatja meg az n-t. Az ilyen elrendezésű vizsgálatok elemzése komoly statisztikai problémákat vet fel, amit a statisztikai szakirodalomban kis "n" nagy "P" problémának neveznek. A többszörös tesztelés problémája akkor lép fel, ha két vagy több csoportba tartozó egyéneket hasonlítunk össze a mért P számú jellemző alapján. Amennyiben az összehasonlítás az egyes jellemzők alapján történik, akkor akár több ezer statisztikai hipotézisvizsgálat elvégzése is szükségessé válhat. Amennyiben a többszörös tesztelés okozta megnövekedett klasszifikációs hibát nem vesszük figyelembe, akkor számos statisztikailag szignifikáns különbséget fedezhetünk fel a vizsgálati csoportok között. Azonban ezeknek a felfedezéseknek egy része valójában a véletlen műve és ezek a kísérleti eredmények általában nem reprodukálhatóak. A problémára több megoldás is született. Ezek közül cikkünkben a klaszter szintű összehasonlítást, valamint a hamis találati arányon alapuló statisztikai tesztet mutatjuk be

Az ecstasy hatása a kognitív funkciókra

Az ecstasy főleg entaktogén és eufóriát okozó hatásai miatt közkedvelt kábítószer a fiatalok körében. Akutan az ecstasy a visszavételi mechanizmusok megfordításával megemeli az agyi monoaminok koncentrációját és ezen keresztül fokozza az ébrenlétet, emeli a testhőmérsékletet, valamint csökkenti az agyi vérátáramlást és a táplálékfelvételt. Hosszú távon ugyanakkor az agyi szerotonin koncentrációk és szerotonerg markerek mennyiségének csökkenése figyelhető meg a felhasználókban. Ezzel párhuzamosan funkcionális károsodások is megjelenhetnek, mint például az alvás- és hangulatzavarok, valamint a szorongás és az agresszivitás fokozódása. Mindemellett az ecstasy egyik legjellemzőbb hosszú távú mellékhatása a kognitív deficit. Különösen a szert rendszeresen fogyasztó felhasználók esetén csökkent retro- és prospektív memória, valamint károsodott végrehajtó funkciók figyelhetők meg. Számos tanulmány a szerotonerg károsodás mellett felvetette az endokannabinoid rendszer, az alvásszabályzás és a hypothalamus-hypophysis-mellékvesekéreg tengely szerepét e folyamatban. Ugyanakkor ismert, hogy a fenti rendszerek egymás működését is képesek befolyásolni. Jelen tanulmányunkban a szerotonerg károsodás, az endokannabinoid rendszer és a fenti szabályozó mechanizmusok hatásait külön-külön, valamint egymásra gyakorolt lehetséges interakcióikat is tárgyaljuk, amelyek magyarázhatják az ecstasy által okozott hosszan tartó kognitív funkciócsökkenést

Acute 5-HT 2C Receptor Antagonist SB-242084 Treatment Affects EEG Gamma Band Activity Similarly to Chronic Escitalopram

Serotonin 2C receptors (5-HT2CRs) are implicated in the pathomechanism and treatment of anxiety and depression. Recently, as a new biomarker of depression, alterations in the gamma power of the electroencephalogram (EEG) have been suggested. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram has been shown to cause sleep-wake stage-dependent alterations in gamma power. However, despite the antidepressant potency of 5-HT2CR-antagonists, there is no data available regarding the effects of selective 5-HT2CR-antagonists on gamma activity. Therefore, we investigate the acute effect of the 5-HT2CR-antagonist SB-242084 on gamma power in different vigilance stages when given in monotherapy, or in combination with chronic escitalopram treatment. We administered SB-242084 (1 mg/kg, intraperitoneally) or vehicle to EEG-equipped rats after a 21-day-long pretreatment with escitalopram (10 mg/kg/day, via osmotic minipumps) or vehicle. Frontoparietal EEG, electromyogram, and motor activity were recorded during the first 3 h of passive phase, after the administration of SB-242084. Quantitative EEG analysis revealed that acute SB-242084 increased gamma power (30–60 Hz) in light and deep slow-wave sleep, and passive wakefulness. However, in active wakefulness, rapid eye movement sleep, and intermediate stage, no change was observed in gamma power. The profile of the effect of SB-242084 on gamma power was similar to that produced by chronic escitalopram. Moreover, SB-242084 did not alter chronic escitalopram-induced effects on gamma. In conclusion, the similarity in the effect of the 5-HT2CR-antagonist and chronic SSRI on gamma power provides further evidence for the therapeutic potential of 5-HT2CR-antagonists in the treatment of depression and/or anxiety

Antidepressant treatment response is modulated by genetic and environmental factors and their interactions

Although there is a wide variety of antidepressants with different mechanisms of action available, the efficacy of treatment is not satisfactory. Genetic factors are presumed to play a role in differences in medication response; however, available evidence is controversial. Even genome-wide association studies failed to identify genes or regions which would consequently influence treatment response. We conducted a literature review in order to uncover possible mechanisms concealing the direct effects of genetic variants, focusing mainly on reports from large-scale studies including STAR*D or GENDEP. We observed that inclusion of environmental factors, gene-environment and gene-gene interactions in the model improves the probability of identifying genetic modulator effects of antidepressant response. It could be difficult to determine which allele of a polymorphism is the risk factor for poor treatment outcome because depending on the acting environmental factors different alleles could be advantageous to improve treatment response. Moreover, genetic variants tend to show better association with certain intermediate phenotypes linked to depression because these are more objective and detectable than traditional treatment outcomes. Thus, detailed modeling of environmental factors and their interactions with different genetic pathways could significantly improve our understanding of antidepressant efficacy. In addition, the complexity of depression itself demands a more comprehensive analysis of symptom trajectories if we are to extract useful information which could be used in the personalization of antidepressant treatment

The UKB envirome of depression

Major depressive disorder is a result of the complex interplay between a large number of environmental and genetic factors but the comprehensive analysis of contributing environmental factors is still an open challenge. The primary aim of this work was to create a Bayesian dependency map of environmental factors of depression, including life stress, social and lifestyle factors, using the UK Biobank data to determine direct dependencies and to characterize mediating or interacting effects of other mental health, metabolic or pain conditions. As a complementary approach, we also investigated the non-linear, synergistic multi-factorial risk of the UKB envirome on depression using deep neural network architectures. Our results showed that a surprisingly small number of core factors mediate the effects of the envirome on lifetime depression: neuroticism, current depressive symptoms, parental depression, body fat, while life stress and household income have weak direct effects. Current depressive symptom showed strong or moderate direct relationships with life stress, pain conditions, falls, age, insomnia, weight change, satisfaction, confiding in someone, exercise, sports and Townsend index. In conclusion, the majority of envirome exerts their effects in a dynamic network via transitive, interactive and synergistic relationships explaining why environmental effects may be obscured in studies which consider them individually

Blockade of Serotonin 2C Receptors with SB-242084 Moderates Reduced Locomotor Activity and Rearing by Cannabinoid 1 Receptor Antagonist AM-251

The endocannabinoid and serotonin (5-HT) systems have key roles in the regulation of several physiological functions such as motor activity and food intake but also in the development of psychiatric disorders. Here we tested the hypothesis, whether blockade of serotonin 2C (5-HT 2C ) receptors prevents the reduced locomotor activity and other behavioral effects caused by a cannabinoid 1 receptor antagonist. As a pretreatment, we administered SB-242084 (1 mg/kg, ip.), a 5-HT 2C receptor antagonist or vehicle (VEH) followed by the treatment with AM-251 (5 or 10 mg/kg, ip.), a CB 1 receptor antagonist or VEH. The effects of the 2 drugs alone or in co-administration were investigated in social interaction (SI) and elevated plus maze (EPM) tests in male Wistar rats. Our results show that AM-251 decreased the time spent with rearing in the SI test and decreased locomotor activity in EPM test. In contrast, SB-242084 produced increased locomotor activity in SI test and evoked anxiolytic-like effect in both SI and EPM tests. When applied the drugs in combination, these behavioral effects of AM-251 were moderated by SB-242084. Based on these findings, we conclude that certain unwanted behavioral effects of CB 1 receptor antagonists could be prevented by pretreatment with 5-HT 2C receptor antagonists

Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression

Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development

Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress

Interleukin-1b is one of the main mediators in the cross-talk between the immune system and the central nervous system. Higher interleukin-1b levels are found in mood spectrum disorders, and the stressinduced expression rate of the interleukin-1b gene (IL1B) is altered by polymorphisms in the region. Therefore we examined the effects of rs16944 and rs1143643 single nucleotide polymorphisms (SNPs) within the IL1B gene on depressive and anxiety symptoms, as measured by the Brief Symptom Inventory, in a Hungarian population sample of 1053 persons. Distal and proximal environmental stress factors were also included in our analysis, namely childhood adversity and recent negative life-events. We found that rs16944 minor (A) allele specifically interacted with childhood adversity increasing depressive and anxiety symptoms, while rs1143643’s minor (A) allele showed protective effect against depressive symptoms after recent life stress. The genetic main effects of the two SNPs were not significant in the main analysis, but the interaction effects remained significant after correction for multiple testing. In addition, the effect of rs16944 A allele was reversed in a subsample with low-exposure to life stress, suggesting a protective effect against depressive symptoms, in the post hoc analysis. In summary, both of the two IL1B SNPs showed specific environmental stressor-dependent effects on mood disorder symptoms. We also demonstrated that the presence of exposure to childhood adversity changed the direction of the rs16944 effect on depression phenotype. Therefore our results suggest that it is advisable to include environmental factors in genetic association studies when examining the effect of the IL1B gene