Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.

Clozapine Withdrawal-Induced Malignant Catatonia or Neuroleptic Malignant Syndrome: A Case Report and a Brief Review of the Literature.

ABSTRACT: In our brief literature review, we discuss the changes in the concept of catatonia as well as its various types and symptoms. We also succinctly review the possible symptoms of clozapine withdrawal. In addition, we analyze the main features of the very few published cases of clozapine withdrawal-induced catatonia and the relationship between neuroleptic malignant syndrome and the malignant subtype of catatonia. Furthermore, we present the case of a 29-year-old male patient with schizophrenia in whom a malignant catatonic episode/neuroleptic malignant syndrome (with negativism, stupor, mutism, autonomic signs [eg, fever, hyperhidrosis], and elevated creatine kinase levels) began 5 days after the patient decided arbitrarily to cease his clozapine treatment. His catatonic symptoms quickly (ie, within a few days) resolved after the reinstitution of clozapine. Finally, we attempt to provide a theoretical explanation for the surprising finding in the literature that the withdrawal of clozapine, unlike the withdrawal of any other antipsychotics, may be associated with catatonia (frequently its malignant subtype). The take-home message of our case is that clinicians should bear in mind the risk of catatonia (especially the malignant subtype of it) after the prompt withdrawal of clozapine therapy.

Cancer and depression: a concise review / Daganatos megbetegedések és a depresszió: Rövid irodalmi áttekintés

Both depressive and malignant disorders are endemic, furthermore, they are also frequently comorbid. In this narrative review, we briefly discuss the epidemiological aspects of the association between depression and cancer, including the following: 1) the prevalence of depression among patients with cancer is higher than that of the general population; 2) the incidence of cancer is higher among subjects with depression; 3) depression is associated with elevated cancer-specific mortality; and 4) the suicide mortality among cancer patients. Furthermore, we also discuss the possible etiological explanations of the frequent co-occurrence of depression and malignancies, including those biological and psychological factors that may explain how depression (and/or its treatment) may lead to the development of malignancies and vice versa. Finally, some aspects of screening and treatment of depression in cancer patients are also considered. Related to this, we may state that, taking into consideration that depression is frequently underdiagnosed in cancer patients, screening is recommended in this population. However, screening for depression is valueable only if the screened patients found depressed have access to psychiatric services where the final diagnosis can be made and some kind of antidepressive treatment is available.

Natural health products, dietary minerals and over-the-counter medications as add-on therapies to antidepressants in the treatment of major depressive disorder: a review.

Given the moderate efficacy of the currently available antidepressants (ADs) in the treatment of major depressive disorder (MDD), the identification of agents that are both able to enhance the effectiveness of ADs and have a good safety profile is a reasonable task for current psychopharmacology. In addition to the well-known drugs (second-generation antipsychotics, levothyroxine, dopaminergic agents, etc.) for augmentation, investigations suggest that several nutraceuticals and over-the-counter (OTC) drugs may be effective and safe as adjunct therapeutic agents to conventional ADs. To identify such active ingredients we first performed a systematic literature search using PubMed and then conducted both backward and forward citation searches. For the PubMed search, we used the following combinations of keywords: 1) "adjunctive" + "therapy" + "antidepressant"; 2) "add-on" + "therapy" + "antidepressant"; 3) "supplementation" + "therapy" + "antidepressant". As a result of those efforts, we found more than 20 agents (e.g. S-Adenosyl-L-Methionine; folate; ω-3 fatty acids; curcumin; N-acetylcysteine; saffron; 5-hydroxytryptophan; NSAIDs) that are supposedly effective in the augmentation of standard AD treatment. We discussed the possible mechanisms of the antidepressant actions of those agents, as well as the preclinical and clinical evidence for their efficacy as stand-alone and adjunct treatments for MDD.

[Vascular endothelial growth factor (VEGF) as a potential biomarker in major depressive disorder]. / Vaszkuláris endoteliális növekedési faktor (VEGF) mint potenciális biomarker major depresszióval összefüggésben.

BACKGROUND: There is growing evidence that vascular endothelial growth factor (VEGF) plays a crucial role in neurodevelopment and regeneration. Several data support that intact VEGF pathway is indispensable for therapeutic effect of antidepressants, any disruption of VEGF signaling can result treatment resistance. In our study we investigated the peripherial blood VEGF level before and 4-week after antidepressant treatment in patients with major depressive episode and we compared VEGF levels between responders and non-responders. METHODS: We recruited 34 patients diagnosed with major depression disorder rom our department. Depressive symptoms were followed by the Montgomery Asberg Depression Scale. Level of VEGF was measured from peripheral plasma by ELISA technic. For comparisons we performed general linear models and Mann-Whitney U tests. RESULTS: Baseline VEGF level was significantly higher in the non-responder subgroup compared to responders (p=0.017). In regression analyses the baseline and end-point VEGF levels were correlated with end-point MADRS (p=0.03; p=0.02, respectively). In our sample the higher baseline VEGF level was correlated with 2.75 times greater chance for treatment resistance in non-responders compared to responders. CONCLUSION: Our results confirm the significant role of VEGF signaling in the pathomechanism of major depression disorder. These data suggest that high baseline VEGF level can be a predictor for lack of therapy response, thus VEGF can be regarded as a potential biomarker for treatment resistance in major depression disorder.

[Maternal bonding style, cholinergic receptor gene polymorphisms in association with smoking-related depressive symptoms]. / Az anyai bánásmód, az acetilkolinerg receptor gén polimorfizmusok és a dohányzáshoz társuló pszichés tünetek vizsgálata.

Backgorund: There is accumulating evidence on the association between the cholinergic system and nicotine dependence (ND) in the literature and the bidirectional relationship of ND and depression. However, the molecular background of the development of ND and related affective phenotype is not clear. METHODS: We recruited 255 tretament-seeking smokers into our study. For phenotyping assessments we used the Fagerstrom Nicotine Dependence Test; The Minnessotta Nicotine Withdrawal Scale; the Zung Self-Rating Depression Scale and the Parental Bonding Instrument. DNA was isolated from buccal mucosa sample and CHRNA4 and CHRNB2 gene SNPs were genotyped with MassArray Sequenom techniques. For statistical analyses ANOVA test, Mann-Whitney U test, linear regression, two-step cluster analyses and hapscore tests were performed. RESULTS: Two-step cluster analysis revealed 3 well-differentiated subgroups among smokers based on phenotypic characteristics. One subgroup was associated with the highest withdrawal and depressive scores. Frequency of the risk haplotype of CHRNA4 was significantly higher in this subgroup (p=0.019). Further, lifetime prevalence of major depression was also significantly higher in this subgroup. Besides, CHRNB2 gén variants showed a significant interacting effect with maternal bonding style on suicide thoughts (p=0.005). CONCLUSIONS: Our results confirmed the genetic effect of CHRNA4 and CHRNB2 on smoking-related depression. These findings suggest that a genetically vulnerable subgroup can be distinguished among smokers and this subphenotype is more prone to withdrawal and depressive symptoms. Our data suggest that suicidal risk depends on both CHRNB2 gene variants and maternal bonding style. Pharmacogenetic concerns of CHRNA4 and CHRNB2 genes might be significant considering suicide as side effect of quitting therapy. Further pharmacogenetic investigations are requierd to clarify this possibility.

Maternal bonding styles in smokers and non-smokers: a comparative study.

BACKGROUND: Parental bonding has been implicated in smoking behavior, and the quality of maternal bonding (MB) has been associated with poor mental health and substance use. However, little is known about the association of MB and the smoking of the offspring. METHODS: In our study, 129 smokers and 610 non-smoker medical students completed the parental bonding instrument, which measures MB along two dimensions: care and overprotection. Four categories can be created by high and low scores on care and overprotection: optimal parenting (OP; high care/low overprotection); affectionless control (ALC; low care/high overprotection); affectionate constraint (AC; high care/high overprotection), and neglectful parenting (NP; low care/low overprotection). Nicotine dependence was assessed by the Fagerstrom Nicotine Dependence Test, exhaled CO level, and daily cigarette consumption (CPD). RESULTS: Higher CPD was significantly associated with lower overprotection (p = 0.016) and higher care (p = 0.023) scores. The odds for being a smoker were significantly higher in the neglectful maternal bonding style compared to the other rearing styles (p = 0.022). Besides, smokers showed significantly higher care and lower overprotection scores with the Mann-Whitney U-test than non-smokers, although these associations did not remain significant in multiple regression models. CONCLUSION: Our results indicate that focusing on early life relationship between patient and mother can be important in psychotherapeutic interventions for smoking. Registration trials retrospectively registered.

[Antidepressant-resistant depression and the bipolar spectrum -- diagnostic and therapeutic considerations]. / Antidepresszívum-rezisztens depresszióés a bipoláris spektrum kapcsolata -- diagnosztikaiés terápiás szempontok.

According to the results of epidemiological studies mood disorders with unipolar (major and minor depressive disorder; dysthymia) or bipolar features are among the most prevalent psychiatric disorders. These disorders with their frequent comorbidities (alcohol and/or drug use disorders, smoking, suicide, cardiovascular disorders) pose great public health challenge and cause substantial individual and familar burdens as well. Since SSRIs and other new antidepressant agents entered the market the possibilities to treat depression improved substantially but 25-35 percent of major depressives do not respond even to the second antidepressant trial but the rate of patients who are resistant after the third and fourth adequate antidepressant trial are around only 15-25 and 10 percent, respectively. Pharmacotherapy-resistant depression is a multicausal phenomenon. Along with its well-known risk-factors investigations of the past decade have revealed that unrecognised or hidden (subsyndromal or subthreshold) bipolarity is one of the most frequent causes of treatment resistance. In the case of bipolar depression (either as a part of syndromal bipolar I or II disorder or a subsyndromal manifestation) antidepressant monotherapy should be avoided and, instead of it, the administration of a mood stabilizer (primarily lithium and lamotrigine) or some atypical antipsychotics (preferably quetiapine) are recommended. If antidepressant is inevitably necessary in bipolar depression, we should use it always in combination with mood stabilizers or atypical antipsychotics.

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC).

BACKGROUNDS: Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit. METHODS: Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified. RESULTS: There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828-2.525; p <0.001). CONCLUSIONS: Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies.

[30 years against suicide: a summary of our research on depression and suicide prevention between 1985 and 2015]. / 30 év az öngyilkosság ellen: Munkacsoportunk depresszió- és szuicidprevenciós kutatásainak összefoglalása - 1985-2015.

In this paper we gather and discuss the results of our workgroup on depression and suicide prevention published between 1985 and 2015. We hope that this summary will focus the interest of the scientific community on suicidology and turn the attention of decision-makers on the fact that despite of its marked decrease in the past three decades, the suicide rate in Hungary is still the second highest in the EU. So, based on expert opinion, joint action is needed in order to achieve a further decrease of suicide rate in Hungary.

The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype.

OBJECTIVES: Neuronal nicotinic acetylcholinergic receptors (nAChR) and especially α4ß2 nAChRs are the major targets for cessation medications and also for some promising antidepressant agents. Furthermore, depressive symptoms pose multifacet difficulties during cessation therapy. However, gene encoding for the ß2 subunit of nAChRs has been poorly investigated in association with depression. Since both nicotine dependence (ND) and depressive phenotype are complex disorders, we investigated the effects of a significant early life experience, maternal bonding style (MB) and CHRNB2 gene SNPs on smoking-related depression. METHODS: We recruited two hundred and thirty-two treatment-seeking smokers in our study. Phenotypic variants were evaluated using the Fagerstrom Test for Nicotine Dependence (FTND), the Zung Self-Rating Depression Scale (ZSDS) and the Parental Bonding Instrument (PBI). Besides the total score (TS) of ZSDS, impulsivity (ZSDS-I) and suicidal ideation (ZSDS-S) were distinguished as phenotypic variable. DNAs were extracted from buccal mucosa samples and one SNP in promoter and two SNPs in 3' UTR of CHRNB2 gene were genotyped. GLM and ANOVA tests were performed for genotype associations and interaction analyses. RESULTS: Maternal bonding had a significant impact on depressive phenotypes. Low care, high protection and affectionless control (ALC) were associated with ZSDS-TS and all subphenotypes of ZSDS. One SNP, the rs2072660 in 3' UTR, had a significant effect on the FTND score (p=0.010). Direct association of CHRNB2 variants and depressive phenotypes were not significant. However, in interaction with ALC, rs2072660 was significantly associated with ZSDS-S (p=0.005). MB had no significant effect on smoking-related phenotype. CONCLUSIONS: Our results highlight the important role of 3' UTR in the CHRNB2 gene in the shared molecular background of ND and depressive phenotype. Parental bonding style can be suggested as a significant environmental factor in further GxE studies of depression. The presented significant GxE interaction on smoking-related suicidal subphenotype may help establish further investigations on development of more effective and safer smoking cessation and antidepressant agents.

The association of affective temperaments with smoking initiation and maintenance in adult primary care patients.

BACKGROUND: Smoking behaviour and its course is influenced by personality factors. Affective temperaments could allow a more specific framework of the role trait affectivity plays in this seriously harmful health-behaviour. The aim of our study was to investigate if such an association exists in an ageing population with a special emphasis on gender differences. METHODS: 459 primary care patients completed the TEMPS-A, Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Subjects were characterized according to their smoking behaviour as current, former or never smokers. Univariate analysis ANOVA and logistic regression were performed to analyse differences in the three smoking subgroups to predict smoking initiation and maintenance. RESULTS: Current smokers were younger and less educated than former or never smokers. Males were more likely to try tobacco during their lifetime and were more successful in cessation. Depressive, cyclothymic and irritable temperament scores showed significant differences between the three smoking subgroups. Irritable temperament was a predictor of smoking initiation in females whereas depressive temperament predicted smoking maintenance in males with a small, opposite effect of HAM-A scores independent of age, education, lifetime depression and BDI scores. Whereas smoking initiation was exclusively predicted by a higher BDI score in males, smoking maintenance was predicted by younger age and lower education in females. LIMITATIONS: The cross-sectional nature of the study design may lead to selective survival bias and hinder drawing causal relationships. CONCLUSIONS: Affective temperaments contribute to smoking initiation and maintenance independently of age, education, and depression. The significant contribution of depressive temperament in males and irritable temperament in females may highlight the role of gender-discordant temperaments in vulnerable subgroups.

Massive withdrawal symptoms and affective vulnerability are associated with variants of the CHRNA4 gene in a subgroup of smokers.

Heterogeneous phenotypes of complex disorders pose a great challenge for genetic association studies and for the development of personalized treatment strategies. Cluster analysis of phenotypic data has been recently proposed as a reliable auxiliary method for such studies. A cohort of 236 treatment-seeking smokers was investigated after overnight nicotine abstinence. Alpha4 nicotinic acetylcholine receptor (nAChR) subunit-related phenotypes were assessed by the Fagerström Test for Nicotine Dependence (FTND), exhaled carbon monoxide (CO) measurements, the Minnesota Nicotine Withdrawal Scale (MNWS) and the Zung Self-Rating Depression Scale (ZSDS). Seven tag SNPs (single-nucleotide polymorphisms) across CHRNA4 (the gene encoding alpha4 subunit of the nicotinic acetylcholine receptor) were genotyped and two-step cluster analysis was used for phenotypic cluster characterization. Haplotype estimation was determined by HapStat module of R 2.0 software. Three different phenotypic clusters were identified and the C3 cluster was characterized by the highest ZSDS and MNWS scores compared to others. Furthermore, lifetime prevalence of major depression was significantly higher in the C3 cluster (p = 0.019). In genetic association tests, this cluster was also significantly associated with rs3787138 genotypes (p = 0.004) while haplotype analyses of three SNPs (rs3787138, rs1044396, rs3787140) revealed that the risk for C3 phenotype was almost three times higher in GCC haplotype carriers compared to others (pperm = 0.013). This is the first report on a significant association between CHRNA4 variants and a subgroup of smokers characterized by massive withdrawal symptoms and affective vulnerability. Identification of such a phenotypic cluster can be a pivotal step for further pharmacogenetic studies on ligands of the alpha4 nAChR subunit. Our results suggest that performing cluster analysis in genetic association studies can be proposed for complex disorders.

Suicide in Hungary-epidemiological and clinical perspectives.

Annual suicide rates of Hungary were unexpectedly high in the previous century. In our narrative review, we try to depict, with presentation of the raw data, the main descriptive epidemiological features of the Hungarian suicide scene of the past decades. Accordingly, we present the annual suicide rates of the period mentioned and also data on how they varied by gender, age, urban vs. rural living, seasons, marital status, etc. Furthermore, the overview of trends of other factors that may have influenced suicidal behavior (e.g., alcohol and tobacco consumption, antidepressant prescription, unemployment rate) in the past decades is appended as well. Based on raw data and also on results of the relevant papers of Hungarian suicidology we tried to explain the observable trends of the Hungarian suicide rate. Eventually, we discuss the results, the possibilities, and the future tasks of suicide prevention in Hungary.

Peripheral vascular endothelial growth factor level is associated with antidepressant treatment response: results of a preliminary study.

BACKGROUND: Recent investigations have revealed multiple actions of vascular endothelial growth factor (VEGF) in the nervous system. The role of VEGF in the molecular background of mood disorders has also been proposed. In this study we were interested in investigating a possible association between VEGF levels and treatment response in patients with a current episode of major depression (MDE). METHODS: 34 patients with MDE were enrolled in our study. Depressive symptoms were monitored by the Montgomery-Åsberg Depression Rating Scale at baseline (V(1)) and after a 4-week treatment period (V(2)). Patients with less than a 50% improvement in MADRS total scores during this period were regarded as non-responders. RESULTS: Plasma VEGF levels did not change during the treatment period in either the total sample or in the responder and non-responder subsamples. There was a strong trend for higher baseline VEGF levels in the non-responder group than in the responder group (p=0.055) and this difference-as a weak trend-was still detectable at the end of the treatment period (p=0.097). Regression analysis revealed that the baseline VEGF level was a significant predictor for the endpoint MADRS score (p=0.02). LIMITATIONS: Sample size was relatively small; sample consists of both patients with MDD and bipolar disorder. CONCLUSIONS: Our preliminary results raise the possibility that baseline levels of peripheral VEGF may predict treatment response in patients with mood disorders. Considering the limitations of our study, further investigations should resolve whether VEGF is a useful biomarker for treatment response in depression in clinical practice.

Investigation of circulating endothelial progenitor cells and angiogenic and inflammatory cytokines during recovery from an episode of major depression.

BACKGROUND: Epidemiological studies strongly suggest a bidirectional positive relationship between mood and cardiovascular disorders (CVD). Reduced numbers of circulating endothelial progenitor cells (cEPCs) are associated with elevated risks of CVD. Previously we demonstrated that patients with a current episode of major depression (MDE) have a decreased number of cEPCs. The role of vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF) has been demonstrated in the etiopathogenesis of depression. In addition these cytokines are also involved in regulation of the vascular system. This suggests that VEGF and/or TNF may also mediate the elevated risk of CVD associated with mood disorders. METHODS: In the current investigation, which has a self-controlled study design, we examined changes in VEGF and TNF levels and--for the first time--changes in cEPC number during recovery from MDE. RESULTS: Twenty-four patients with MDE were enrolled. The severity of their depressive symptoms improved significantly during the one-month treatment period (~50% decrease in MADRS score; P≤0.001). We did not find significant differences between baseline and end-point levels of VEGF, TNF and the number of cEPCs. CONCLUSION: Our negative result for alteration in the number of cEPCs in the course of recovery from MDE raises several questions. Before discarding the number of cEPCs as a possible marker of depression--and/or elevated CV risk associated with it--our results would require confirmation in larger samples. Our results for TNF and VEGF do not contradict the findings of prior studies, since these were controversial.

Over-the-counter nicotine replacement therapy for everyone: is it the best solution?

The persistent use of different forms of nicotine replacement therapy (NRT) is an under-investigated issue in medical research. While the data concerning the proportion of long-term users in the population of total NRT users seems reassuring at first glance, we must recognize that the small relative numbers (proportions) conceal a population of persistent NRT users with a considerable absolute number of members. Furthermore, only a small amount of data is available concerning the safety of persistent NRT use. At the present time we therefore have no basis for declaring that the population of long-term users are under cover (we are only able to state that persistent use of NRT is undoubtedly safer than the continuation of smoking). Consequently, there is a need to conduct large-scale studies with the primary aim of monitoring for misuse of OTC NRT and assessing the possible physical and mental health risks of persistent NRT use.

Associations between season of birth and the risk of lung cancer: epidemiological findings from Hungary.

Lung cancer is the leading cause of cancer deaths worldwide. Both incidence and mortality of lung cancer are especially high in Hungary. Several investigations suggested recently that month of birth (MOB) is associated with the risks of several nonmalignant disorders as well as some malignant disorders. Only a few studies investigated previously the association between MOB and risk of lung cancer, but they provided inconsistent results. We, therefore, decided to investigate this issue in a large sample of individuals who died from lung cancer. Accordingly, we determined the MOB-associated risk of death by lung cancer between the years 1970 and 2009 among all individuals born in Hungary between 1925 and 1934. The final sample included about two million people. A total of 61,904 deaths by lung cancer occurred in this sample during the period investigated. Using analysis of variance (ANOVA), we did not find significant association between MOB and risk of lung cancer death, either in the whole population investigated (F = 1.492; p = .145) or in the female subpopulation (F = 1.535; p = .129). However, those males born in late spring (May-June) had a lower risk of lung cancer development (F = 2.577; p = .006). Results of the Edwards test also did not suggest consistent association between MOB and risk of lung cancer death in the whole investigated period (1925-1934) in any populations (i.e., whole population or male and female subpopulations). In conclusion, we did not find significant association between MOB and risk of lung cancer in our total sample (although results alluded to a weak association between MOB and risk of lung cancer development among males). The possible associations between MOB and the risk of lung cancer development (or smoking) would require confirmation (or refutation) in large studies from other populations.

Genetic and pharmacogenomic data on smoking: the bigger sample size, the less reliable phenotype? A critical review.

Increasing amount of genetic data on nicotine dependence (ND) is available in the literature, sometimes extremely large population size is reported but the study design is not always consequent. Phenotypic measures can vary from a simple 6-item self-rating scale to breath CO or serum cotinine level test but in genetic investigations this is not sophisticated; moreover the population stratification is also usually ignored. In contrast, possibly because of the strict traditions of pharmacological investigations, pharmacogenomic studies on smoking cessation therapy use more reliable phenotypic measures with high quality design consequently involving fewer participants. In spite of the heavy epidemiological data on smoking in Hungary, genetic background of heavy smoking is still not studied in this population. In this review we sum up the most important, replicated results but we also provide some critical remarks about the methodological shortcomings of these studies. Keeping in mind the value of large scale population ND association studies we would also like to emphasize that the clinical implementation of studies with larger samples but with weaker methodology and statistical analyses is limited. Similar to many other psychiatric disorders, ND is a multifactorial condition, therefore the measure of genetic effects requires a more complex study design.

Tobacco consumption and antidepressant use are associated with the rate of completed suicide in Hungary: an ecological study.

The suicide rate of Hungary is the highest in the world averaged over the last century but it has shown a very pronounced decrease since 1987. To explore the background of this decrease we investigated the associations between some known suicide-related factors (i.e. tobacco use, antidepressant use and alcohol consumption at the population level) and the suicide rate between 1985 and 2008. The total number of man-hours worked per year by psychiatrists in the outpatient service system and real GDP growth were also monitored in our study. A time series analysis model was constructed to investigate the associations between the above variables and the suicide rate. In the unadjusted model annual tobacco consumption was significantly associated with the suicide rate in a positive manner, while antidepressant use and man-hours were significantly associated with the suicide rate in a negative manner. After adjustment, the associations remained significant only for tobacco consumption and antidepressant use. Neither alcohol consumption nor real GDP growth was associated with the suicide rate in any models. Our results from group-level data confirmed the role of smoking in suicidal behavior previously suggested mainly by studies using individual-level data and also corroborated the results of previous ecological studies concerning the inverse association between antidepressant use and suicide rate. These findings and the results of previous studies - investigating the relationship between smoking and the risk of suicidal behavior at the individual-level - may suggest that programs to prevent tobacco use or to address the widespread recognition and treatment of depression may also prevent suicidality.