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BACKGROUND In recent decades, a series of ecological studies from various countries have attempted to reveal whether there is an association between trace amounts of lithium in drinking water and suicide mortality. With some notable exceptions, results have indicated that there is an inverse association between these two variables. Since Hungary had extremely high rates of suicide with a persistent spatial pattern, we consider that our country is ideal to investigate this research question. METHODS We carried out our research on Hungarian data at the level of districts (n = 197). The dependent variable was the age- and gender-standardized mortality ratio for suicide (sSMR). Our main explanatory variable was the tap water lithium level (Li) from public drinking water supply systems using their own water source (n = 1 325). Those data, which give full national coverage, were aggregated to the level of districts. Confounding factors were religiosity, alcohol consumption and income. Various regression models were used for statistical calculations. RESULTS Findings from our most appropriate regression model - adjusted for relevant confounding variables and able to handle spatial autocorrelation and heteroscedasticity - suggest a significant (p < 0.05) and a trend-like (p < 0.1) negative association between Li and sSMR in the total population and among males, respectively. However, such an association was not found between these two variables among females. CONCLUSION In line with the majority of findings from other countries, our results indicate that the intake of lithium with drinking water may have a gender-dependent suicide-protective effect.

Összefoglaló. Bevezetés: Az öngyilkosság fő rizikófaktorának a pszichiátriai zavarokat tekintjük. A COVID–19 többek között neuropszichiátriai kórképek kialakulásához is vezethet. Ezen túl a pandémia egyéb velejárói, mint például az izoláció vagy a munkahelyvesztés, a társadalom egészséges tagjaiban is stresszhez, végül pszichiátriai zavarokhoz vezethetnek. Célkitűzés: Vizsgálatunk célja annak a teóriának a tesztelése volt, hogy a fenti tényezők miatt együtt járt-e a járvány a hazai suicid halálozás csökkenő trendjének irányváltásával. Módszer: Vizsgálatunkban a megszakított idősorok elemzésének módszerét használtuk, a becslésekhez kvázi-Poisson-regressziót alkalmazva, hogy összehasonlítsuk a 2010 és 2020 közötti időszak havi bontású adataiból kirajzolódó trendek alapján a járvány időszakában (2020. március–december) „elvárt” öngyilkossági esetszámokat a ténylegesen bekövetkezett esetek számával. Eredmények: A COVID–19-hónapok alatt a férfiak által elkövetett öngyilkosságok száma szignifikánsan, 18%-kal nőtt, ahhoz a trendhez képest, amely a COVID–19 hiányában állt volna elő. A teljes populációban szintén szignifikáns, 16%-os emelkedést lehetett megfigyelni, míg a nők által elkövetett öngyilkosságok száma nem tért el szignifikánsan a pre-COVID–19-időszak trendje alapján elvárt értéktől. Megbeszélés és következtetés: A járvány kitörése utáni időszakban a magyar férfiak szignifikánsan gyakrabban követtek el öngyilkosságot, míg a nőknél az adatok nem tükröztek lényegi változást. A más országokban kivitelezett vizsgálatok eredményei érdekes módon inkább csökkenést vagy nem szignifikáns változást jeleztek, amikor a COVID–19-éra suicid számait az azt megelőző időszakok számaival hasonlították össze. A hazai és a nemzetközi eredmények közti eltérések magyarázata egyelőre még nem ismert, így a téma mindenképpen további vizsgálatokat igényel. Orv Hetil. 2021; 162(41): 1631–1636. Summary. Introduction: Psychiatric disorders are the main risk factors for suicide. COVID-19 may result in the appearance of neuropsychiatric syndromes. Moreover, other corollaries of the pandemic (e.g., isolation, job loss) may lead to increasing stress and, ultimately, psychiatric disorders even among the non-infected population. Objective: We aimed to test the theory of whether the pandemic, due to the aforementioned factors, was associated with the reversal of the declining suicide rate trend in Hungary. Method: To compare the observed number of suicides during the COVID-19 months (March–December 2020) with the expected numbers, we used an interrupted time series model and, for the estimations, quasi-Poisson regression. Expected numbers were calculated based on trends derived from monthly data between 2010 and 2020. Results: During the months of the pandemic, the number of suicides among males rose significantly by 18% compared to the hypothetical trend that would have occurred in the absence of COVID-19. A significant increase (16%) was also observed in the total population. By contrast, the number of female suicides did not differ significantly from the number expected based on the pre-COVID-19 trend. Discussion and conclusion: After the outbreak of the epidemic, Hungarian males committed significantly more suicides, while no relevant changes were observed among females. Interestingly, studies from other countries found either no change or decrease when comparing suicide numbers from the COVID-19 period with the corresponding numbers from the pre-COVID-19 period. The explanation for this discrepancy is still lacking, so further investigations are needed. Orv Hetil. 2021; 162(41): 1631–1636.

In their recently published systematic "umbrella" review, Moncrieff and colleagues conclude that there is no consistent evidence that depression is caused by decreased serotonin activity in the central nervous system (CNS). However, this paper - which was extensively publicized and received a lot of attention on the social media - can cause misunderstandings, since the serotonin hypothesis of depression in its original form (i.e. reduced serotonin activity in the CNS = depression) formulated more than 50 years ago has been considered outdated for several decades. It has long been known that depression is a heterogeneous disorder not only genetically, clinically and biologically but also from a pharmacotherapeutic perspective. The decreased activity of serotonin, which undoubtedly plays an essential role in the pathogenesis of depression, is characteristic of only a subgroup of depressed subjects whose clinical picture is mostly dominated by intensified negative emotions, agitation, anxiety, insomnia, decreased appetite, self-blame and suicidality and these individuals are primarily responsive to SSRIs. By contrast, depression cases with reduced positive affects (characterized by anhedonia, anergia, inhibition and reduced cognitive functions) are mainly caused by a disturbance in the metabolism of dopamine and/or noradrenaline. These patients are primarily responsive to dual-action (e.g. SNRI) antidepressants. Results of serotonin and catecholamine (dopamine, noradrenaline) depletion studies also suggest that that the dysregulation of serotonin and dopamine/noradrenaline in the CNS is characteristic of different subgroups of depressed patients. In addition to the serotonergic, dopaminergic and noradrenergic systems, many other neurotransmitter systems (e.g. cholinergic, glutamatergic, GABAergic) and other mechanisms (e.g. neuroinfl ammation) have also been proven to play a role in the development of the disorder. Knowledge of the data presented in our publication is important since the simplistic interpretation by Moncrieffetal. of the role of serotonin in the pathogenesis of depression may undermine confidence in SSRIs in many patients. (Neuropsychopharmacol Hung 2022; 24(3): 120-125).

Treatment of major depressive disorder (MDD) including treatment-resistant depression (TRD) remains a major unmet need. Although there are several classes of dissimilar antidepressant drugs approved for MDD, the current drugs have either limited efficacy or are associated with undesirable side effects and withdrawal symptoms. The efficacy and side effects of antidepressant drugs are mainly attributed to their actions on different monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). Development of new antidepressants with novel targets beyond the monoamine pathways may fill the unmet need in treatment of MDD and TRD. The recent approval of intranasal Esketamine (glutamatergic agent) in conjunction with an oral antidepressant for the treatment of adult TRD patients was the first step toward expanding beyond the monoamine targets. Several other glutamatergic (AXS-05, REL-1017, AV-101, SLS-002, AGN24175, and PCN-101) and GABAergic (brexanolone, zuranolone, and ganaxolone) drugs are currently in different stages of clinical development for MDD, TRD and other indications. The renaissance of psychedelic drugs and the emergence of preliminary positive clinical trial results with psilocybin, Ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and lysergic acid diethylamide (LSD) may pave the way towards establishing this class of drugs as effective therapies for MDD, TRD and other neuropsychiatric disorders. Going beyond the monoamine targets appears to be an effective strategy to develop novel antidepressant drugs with superior efficacy, safety, and tolerability for the improved treatment of MDD and TRD.

Összefoglaló. Bevezetés: Az öngyilkosság régóta jelentős probléma hazánkban. Célkitűzés: Az elmúlt 20 év során elkövetett, befejezett öngyilkosságok elemzése három időintervallumban (2000–2006, 2006–2010, 2010–2019) nemek, korcsoportok, az elkövetési mód, a családi állapot és a munkanélküliség szempontjából. További célunk volt a pszichiátriai ellátást negatívan érintő, 2007. évi egészségügyi reform suicid halálozással való összefüggéseinek vizsgálata. Módszer: A suicid halálozást a Központi Statisztikai Hivatal adatainak felhasználásával elemeztük. Az évenkénti suicid rátát 100 000 lakosra adtuk meg. Az adatok statisztikai feldolgozásához az Excel 2011-es, az SPSS 23-as és az amerikai NIH Jointpoint programjának 4.8.0.1-as verzióját használtuk. Eredmények: 2000 és 2019 között 51,4%-kal csökkent a suicid halálozás (nők: 15,57 vs. 7,69/100 000 fő; férfiak: 51,5 vs. 24,73/100 000 fő, összlakosság: 32,61 vs. 15,85/100 000 fő). A legnagyobb mértékben a férfiak és a középkorúak körében csökkent a mortalitási ráta, a legkevésbé a fiatal, egyedülálló nőknél. A leggyakoribb elkövetési mód változatlanul az akasztás (58,4%). A 20 évig tartó rátacsökkenés 2006 után több évre megtorpant, és egészen 2010-ig nagyjából konstans maradt (24,43 vs. 24,88/100 000 fő). Azt feltételezzük, hogy ennek hátterében jelentős részben a pszichiátriai ellátórendszert negatívan érintő, 2007-ben bevezetett egészségügyi reform állt. Ez a megtörés kimutatható volt szinte minden korcsoportnál, a leggyakoribb elkövetési módoknál, és egyaránt érintette a hajadonokat/nőtleneket, a házasokat, az özvegyeket és az elváltakat. Csak 2010 után kezdődött újra a suicid mortalitás szignifikáns csökkenése. Az utolsó 10 év alatt 36,3%-kal csökkent a suicid mortalitás (24,88 vs. 15,85/100 000 fő), ami kiemelkedő eredmény az európai országok körében. Következtetés: Egy elhibázott, a pszichiátriai ellátórendszert sújtó egészségügyi reform következményeként az addig egyenletesen csökkenő suicid halálozás üteme 2006 után megtört, és néhány évig stagnált. Több évig tartott, mire bizonyos mértékig rendeződött a pszichiátriai ellátórendszer, és ennek köszönhetően 2010 után ismét folyamatosan és szignifikánsan csökkent a suicid mortalitás. Orv Hetil. 2021; 162(32): 1283–1296. Summary. Introduction: In Hungary, suicide has been a major public health issue for a long time. Objective: Our objective was to examine data on completed suicide cases in Hungary from a 20-year period divided into three intervals (2000–2006; 2006–2010; 2010–2019) grouped by sex, age, methods of commitment, marital and employment statuses. An auxiliary aim was to assess the associations between the healthcare reform in 2007 (with unfavourable impacts on the psychiatric care system) and suicide mortality. Method: Data on suicide were provided by the Hungarian Central Statistical Office. In all cases, the yearly suicide rates were given for 100 000 inhabitants. For statistical calculations, we used Excel 2011, SPSS v. 23 and NIH Joinpoint Regression Program v. 4.8.0.1. Results: Between 2000 and 2019, there was a 51.4% reduction in the suicide mortality (females: 15.57 vs. 7.69/100 000; males: 51.5 vs. 24.73/100 000; total population: 32.61 vs. 15.85/100 000). The greatest declines occurred among males and middle-aged. At the same time, the rate of young single females declined only slightly. The most common method of commitment remained hanging (58.4%). During the 20-year-long period investigated, there was a temporary halt between 2006 (24.43/100 000) and 2010 (24.88/100 000) in the otherwise steadily declining trend of the rate. One of the major underlying causes of this plateau is presumed to be the healthcare reform commenced in 2007 with negative impacts on psychiatric services. This plateau was observable in almost all subpopulations irrespective of their age, marital status and the suicide method they used. The decline of the rate restarted only after 2010. In the last 10 years, suicide mortality has decreased by 36.3% (from 24.88 to 15.85/100 000) in Hungary, which is a very good result in a European comparison. Conclusion: Due to an unsound health reform threatening the psychiatric care, the previously experienced declining trend of the suicide rate halted in 2006 and has remained almost unchanged for a few years during which psychiatric services could be restored in some degree. From 2010, as a consequence of this restoration, the marked decline of the suicide rate restarted and has been remained stable. Orv Hetil. 2021; 162(32): 1283–1296.

Inadequate adherence to long-term therapies significantly affects the course and outcome of the disease, and therefore poses a serious threat to both the effectiveness and success of treatment and the long-term well-being of patients. Therapeutic adherence is an extremely complex process, with a number of risk and protective factors identified, many of which underlie the psychological characteristics of the patient. A number of medication adherence models have been developed to take into account the psychological characteristics of patients, and recent research has examined the relationship between different personality models and adherence to therapeutic recommendations. In this review we aim to summarize current knowledge, adherence models, research findings on the relationship between personality and adherence, including implications for future research.

A sharp increase in the prevalence of neuropsychiatric disorders, including major depression, anxiety, substance use disorders and posttraumatic stress disorder (PTSD) has occurred due to the traumatic nature of the persisting COVID-19 global pandemic. PTSD is estimated to occur in up to 25% of individuals following exposure to acute or chronic trauma, and the pandemic has inflicted both forms of trauma on much of the population through both direct physiological attack as well as an inherent upheaval to our sense of safety. However, despite significant advances in our ability to define and apprehend the effects of traumatic events, the neurobiology and neuroanatomical circuitry of PTSD, one of the most severe consequences of traumatic exposure, remains poorly understood. Furthermore, the current psychotherapies or pharmacological options for treatment have limited efficacy, durability, and low adherence rates. Consequently, there is a great need to better understand the neurobiology and neuroanatomy of PTSD and develop novel therapies that extend beyond the current limited treatments. This review summarizes the neurobiological and neuroanatomical underpinnings of PTSD and discusses the conventional and emerging psychotherapies, pharmacological and combined psychopharmacological therapies, including the use of psychedelic-assisted psychotherapies and neuromodulatory interventions, for the improved treatment of PTSD and the potential for their wider applications in other neuropsychiatric disorders resulting from traumatic exposure.

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. Orv Hetil. 2020; 161(22): 908-916.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. Orv Hetil. 2020; 161(22): 908-916.

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.

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.

Background and Objectives: The role of affective temperament in the genesis and outcome of major mood disorders is well studied, but there are only a few reports on the relationship between panic disorder (PD) and affective temperaments. Accordingly, we aimed to study the distribution of affective temperaments (depressive (DE), cyclothymic (CT), irritable (IRR), hyperthymic (HT) and anxious (ANX)) among outpatients with PD. Materials and Methods: Affective temperaments of 118 PD outpatients (80 females and 38 males) with or without agoraphobia but without any other psychiatric disorder at the time of inclusion were evaluated using the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) and compared with the affective temperament scores of control subjects. All patients were followed up for at least 1.5 years in order to detect the onset of any major affective disorders, substance use disorders and suicide attempts. Results: Among females, the dominant ANX and DE temperaments were four and three times as common as in a large normative Hungarian sample (for both cases p &lt, 0.01). Among male PD patients, only the dominant DE temperament was slightly overrepresented in a non-significant manner. Females with PD obtained significantly higher scores on ANX, DE and CT subscales of the TEMPS-A, whereas males with PD showed significantly higher scores on ANX, DE and HT temperament subscales compared with the members of a large normative Hungarian sample and also with a gender- and age-matched control group. During the follow-up, newly developed unipolar major depression and bipolar spectrum (bipolar I or II and cyclothymic) disorders appeared in 64% and 22% of subjects, respectively. Conclusions: Our preliminary findings suggest that a specific, ANX-DE-CT affective temperament profile is characteristic primarily for female patients, and an ANX-DE-HT affective temperament profile is characteristic for male patients with PD, respectively. These findings are in line with expectations because PD is an anxiety disorder par excellence on the one hand, whereas, on the other hand, it is quite frequently comorbid with mood (including bipolar) disorders.

Purpose Treatment-resistant depression (TRD) is associated with a poor quality of life and high economic burden. This observational retrospective epidemiological study aimed to estimate the proportion of patients with TRD within a cohort of patients with major depressive disorder (MDD) in Hungary and examine the mortality and comorbidities of patients with and without TRD. Patients and methods This study included patients with MDD who experienced onset of a new depressive episode between 01 January 2009 and 31 August 2015, using data from a nationwide, longitudinal database. Results Overall, 99,531 patients were included in the MDD cohort, of which 8,268 (8.3%) also met the criteria for TRD. The overall survival of non-TRD patients was longer than in TRD patients; the risk of mortality for TRD patients was significantly higher than of non-TRD patients (HR [CI] 1.381 [1.212–1.571]; p Discussion To our best knowledge, this is the first study to assess the frequency of TRD in Hungary. In a cohort of Hungarian MDD patients, we have found that the proportion of TRD (~8.3%) is comparable to those reported in previous studies with similar methodology from other countries. The majority of our other main findings (e.g. more frequent self-harming behaviour, increased risk of “Neurotic, stress-related and somatoform disordersˮ and higher overall mortality in TRD subjects) are also in line with previous results from other countries. Taking the substantial proportion of patients with TRD into consideration, a more comprehensive and targeted treatment strategy would be required for these individuals.

Backgorund Increasing experimental data confirm the crucial role of the endocannabinoid (eCB) system in the regulation of stress response and emotional processes. Despite of the fact, that genetically determined vulnerability for stress is a widely accepted concept in the pathomechanism of affective disorders, replicable human genetic results with interaction analyses of early life trauma and eCB genes are rare. The aim of this study is to test the associations between genetic variants of the eCB pathway, childhood trauma and affective phenotypes. Methods We selected 18,897 SNPs in the eCB pathway of a GWAS dataset in two general population cohorts (BP sample N = 837; MN sample N = 988). Association analyses were performed on the anxious and depressive subscales of the Brief Symptom Inventory (BSI-ANX and BSI-DEP, respectively). Childhood trauma was assessed by the Childhood Adversity Questionnaire (CAQ). Association analyses were performed in the R 2.0. statistical program using the SNPassoc package. Reults Genetic effect was more robust in the BP sample than in the MN sample. The most comprehensive results showed that SNPs in the CACNA1C gene associated with depressive phenotype in interaction with CAQ in both BP (p = 1.2 × 10−4) and MN samples (p = 1.6 × 10−4). Direct association analyses (without interaction) provided significant associations between SNPs in different genesets of the two study populations. SNPs in KCNJ3 and GNB5 genes on the BSI-DEP (p = 6.1 × 10−5; p = 7.1 × 10−4) and GNG12 gene on the BSI-ANX (p = 7.4 × 10−6) in the BP sample, while GABAergic, ADCY1 and HTR2A gene variants can be outlined from results of MN sample with less strong p-values. Conclusion Our results confirmed the prominent role of CACNA1C gene in the pathogenic effect of early life stress in the development of affective vulnerability in two different study populations using GxE interaction analysis. CACNA1C gene, as it encodes for L-type voltage-gated calcium channel, contributes to neuronal excitability, plasticity and neurogenesis being a crucial effector of both eCB signaling and the BDNF-CREB pathway as well. Our findings suggest that childhood trauma related depression may have more robust genetically determined basis than without early life stress.

There is a 20-year history of rTMS treatment, however, is not available in Hungary in routine clinical practice for therapy resistant depression (TRD). In this study we analysed the change of symptom profile of a Hungarian cohort with TRD using bilateral rTMS treatment.A cohort of 22 patients suffering from TRD was enrolled in the study. For assessment of the phenotypic profile the Beck Depression Inventory (BDI), The Beck Anxiety Inventory (BAI), The Montgomery-Asberg Depression Rating Scale (MADRS), the Snaith-Hamilton Pleasure Scale (SHAPS), the Insomnia Severity Index (ISI), and the Trail Making Test were applied. Differences of mean scores of scales were compared between the day 1 (before treatment) and the day 14 (after conclusion of treatment). Furthermore, we performed phenotypic comparisons between the gender subgroups.In the total sample significant reduction of symptom scores was found on the depression (pMADRS=0,022; pBDI=0,001) and the anxiety scales (pBAI=0,020) and in case of the TMT-A test (pTMT-A=0,019) at the end of the treatment. The mean scores of the SHAPS, the ISI and the TMT-B did not change up to the day 14. In the sex-specific analysis we found that in men only sleep disorder was improved (p=0,015), while in women both depression scores and TMT-A score decreased significantly (MADRSp=0,015; BDIp=0,005; TMT-Ap=0,036). There were no adverse events during the rTMS treatment.2x5 sessions of bilateral rTMS treatment is an effective, safety applicable intervention in patients with TRD. Our results suggest that significant improvement of depressive, anxious and attention symptoms can be observed already after 10th session. Our findings highlighted that different symptoms evolve in women and men due to the acute effect of the rTMS treatment. Further follow-up study is required to evaluate the long-term effect of rTMS concerning the maintenance of symptom reduction and potential change of anhedonia and insomnia.

Background Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid β peptide (Aβ) and tau protein are among the major pathological hallmarks of AD. Aβ and tau burden follows predictable spatial patterns during the progression of AD. Nevertheless, it remains obscure why certain brain regions are more vulnerable than others; to investigate this and dysregulated pathways during AD progression, a mass spectrometry-based proteomics study was performed. Methods In total 103 tissue samples from regions early (entorhinal and parahippocampal cortices - medial temporal lobe (MTL)) and late affected (temporal and frontal cortices - neocortex) by tau pathology were subjected to label-free quantitative proteomics analysis. Results Considering dysregulated proteins during AD progression, the majority (625 out of 737 proteins) was region specific, while some proteins were shared between regions (101 proteins altered in two areas and 11 proteins altered in three areas). Analogously, many dysregulated pathways during disease progression were exclusive to certain regions, but a few pathways altered in two or more areas. Changes in protein expression indicate that synapse loss occurred in all analyzed regions, while translation dysregulation was preponderant in entorhinal, parahippocampal and frontal cortices. Oxidative phosphorylation impairment was prominent in MTL. Differential proteomic analysis of brain areas in health state (controls) showed higher metabolism and increased expression of AD-related proteins in the MTL compared to the neocortex. In addition, several proteins that differentiate brain regions in control tissue were dysregulated in AD. Conclusions This work provides the comparison of proteomic changes in brain regions affected by tau pathology at different stages of AD. Although we identified commonly regulated proteins and pathways during disease advancement, we found that the dysregulated processes are predominantly region specific. In addition, a distinct proteomic signature was found between MTL and neocortex in healthy subjects that might be related to AD vulnerability. These findings highlight the need for investigating AD's cascade of events throughout the whole brain and studies spanning more brain areas are required to better understand AD etiology and region vulnerability to disease.

We determined the prevalence of untreated depression in patients with hypertension (HT) and/or diabetes (DM) and estimated the extra health care use and expenditures associated with this comorbidity in a rural Hungarian adult population. We also assessed the potential workload of systematic screening for depression in this patient group. General health check database from a primary care programme containing survey data of 2027 patients with HT and/or DM was linked to the outpatient secondary care use database of National Institute of Health Insurance Fund Management. Depression was ascertained by Beck Depression Inventory score and antidepressant drug use. The association between untreated depression and secondary healthcare utilization indicated by number of visits and expenses was evaluated by multiple logistic regression analysis controlled for socioeconomic/lifestyle factors and comorbidity. The age-, sex- and education-specific observations were used to estimate the screening workload for an average general medical practice. The frequency of untreated depression was 27.08%. The untreated severe depression (7.45%) was associated with increased number of visits (OR 1.60, 95% CI 1.11–2.31) and related expenses (OR 2.20, 95% CI 1.50–3.22) in a socioeconomic status-independent manner. To identify untreated depression cases among patients with HT and/or DM, an average GP has to screen 42 subjects a month. It seems to be reasonable and feasible to screen for depression in patients with HT and/or DM in the primary care, in order to detect cases without treatment (which may be associated with increase of secondary care visits and expenditures) and to initiate the adequate treatment of them.

Beyond both being biphasic/bidirectional disorders (hypo)mania and essential hypertension share a surprising number of similarities and an overlap between their genetics, biological background, underlying personality and temperamental factors, precipitating factors, comorbidity and response to treatment, indicating a possibly partially shared biological background. Based on theoretical knowledge, similarities related to characteristics, manifestation and course, and the results of pharmacological studies related to the effects and side effects of pharmacotherapies used in the treatment of these two distinct disorders, the authors outline a hypothesis discussing the similar origins of these two phenomena and thus mania being the hypertension of mood in memory of Athanasios Koukopoulos, one of the greatest researchers and theoreticists of mania of all time.

From the end of the 1980s, the Hungarian suicide rate, which had been until that point the highest in the world for decades, has decreased drastically. The reason behind this decrease was probably due to the changes in numerous and often interlinked risk factors. Studies on this topic have mostly ignored to interrogate to what extent the change of the population composition, for example the improvement of educational level, contributed to the decrease of the rate in the given period? Our aim was to assess the contribution of changes in some sociodemographic factors to the decrease of the suicide rate in Hungary. During the analysis, data from 1990 were compared with data from 2011. For the statistical calculations, the method of “Standardization and Decomposition (SDA)” was used, which according to our best knowledge, has not yet been applied in Hungarian suicide studies. The results show that the improvement of educational level helped to decrease the rate for men by about a third, while for women only by about a tenth. However, the benefit of the improvement in educational attainment during the period investigated was significantly offset by the changes primarily in marital status (the ratios of unmarried and divorced subjects increased for both genders) and in age distribution (the ratio of the elderly persons increased for both genders). The results of our study emphasise the inverse relationship between suicide and educational level and support the hypothesis that we can regard educational policy as indirect health policy.

Oxytocin (OT) is a neurohypophysial hormone and neuropeptide produced by the hypothalamus and released by the pituitary gland. It has multiple physiological roles including stimulation of parturition and lactation, and promotion of pro-adaptive social behaviors necessary for mammalian survival. OT interacts with one receptor subtype: the OT receptor (OTR) which, upon stimulation, triggers different intracellular signal transduction cascades to mediate its physiological actions. Preclinical studies show that OT regulates social behaviors such as pair bonding, recognition and social interaction. It also coordinates the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of corticotrophin-releasing hormone. Further evidence suggests that OT plays an important role in regulating caloric intake and metabolism, and in maintaining electrolyte and cardiovascular homeostasis. OT is also involved in attenuating the neurophysiological and neurochemical effects of trauma on the brain and body by facilitating both physical attachment such as wound healing, and psychological/social attachment, thereby increasing resilience to subsequent traumatic events. Clinical trials have reported that intranasal administration of OT provides therapeutic benefits for patients diagnosed with traumatic stress-related diseases such as major depressive disorders and post-traumatic stress disorder. OT's therapeutic benefits may result from context-dependent interactions with key neural pathways (social, cognitive, and reward), neurotransmitters (dopamine, norepinephrine, serotonin, and endogenous opioids), and biomarkers (adrenocorticotropic hormone, cortisol, and dehydroepiandrosterone sulfate), that lead to a decrease in stress -associated behaviors, and facilitate post-traumatic growth, ultimately leading to increased resilience, through improved social cohesion and attachment. OT induced-augmentation of physical and cognitive resilience may play a significant role in both the prevention of, and improved clinical outcomes for, traumatic stress-related disorders following either acute or enduring traumatic experiences.

The Temperament Evaluation of Memphis, Pisa and San Diego Autoquestionnaire (TEMPS-A) is a widely used measure of affective temperaments. Affective temperaments refer to people's prevailing moods and are important precursors of affective disorders. With the two studies presented in this paper, we aimed to develop a short version of the Hungarian TEMPS-A.A total number of 1857 university students participated in two studies. The original 110-item version and the newly developed short version of TEMPS-A, the anger, depression, and anxiety scales of the PROMIS Emotional Distress item bank, the Altman Self-Rating Mania Scale, the Satisfaction With Life Scale, and the Well-Being Index were administered to participants.Out of the original 110 items, 40 items of TEMPS-A loaded on five factors that represented the five affective temperaments. Factors of the short version showed moderate to strong correlations with their original counterparts. All factors had good to excellent internal reliability. Factors of the newly developed short version of TEMPSA showed meaningful correlations with measures of emotional distress, mania, and indices of psychological well-being.The short version of the Hungarian TEMPS-A is a promising instrument both in clinical fields and for academic research. The newly developed short version proved to be a valid and reliable measure of affective temperaments.

Main indications of antidepressants (ADs) as major depressive disorder (MDD) and different kinds of anxiety disorders are quite prevalent during pregnancy and the postpartum period. Due to the possible hazards of in utero and breast milk exposition of ADs, both psychiatrists and mothers frequently have concerns about the use of ADs during the periods of pregnancy and breastfeeding. However, we should also bear in mind that affective disorders left untreated during these periods are also associated with health risks for the mother and the baby as well. Accordingly, the treatment of affective disorders during these periods is essential. For mild cases of affective disorders the recommended treatment modality is typically psychotherapy while for the severe cases pharmacotherapy (including AD treatment) is recommended. Unfortunately, due to the lack of well-designed prospective studies, only sparse information is available on the efficacy and safety of AD treatment in pregnant and breastfeeding women. In this review we try to provide some practical advice in terms of the use of ADs during the periods in question.

The authors tested the clinical applicability of a self-developed, 6-item, clinician-rated questionnaire evaluating suicide risk in suicidal and non-suicidal psychiatric inpatients and healthy controls. Results have shown that the questionnaires able to detect marked suicide risk in psychiatric inpatients with a high sensitivity and specificity which indicates its usefulness and good applicability in clinical practice.

There are conflicting results concerning risk of violence in schizophrenia. Empathy and mentalization deficits are associated both with schizophrenia and violence, however, there are only a few studies with equivocal results concerning their relationship. 88 violent and nonviolent paranoid schizophrenic and violent and nonviolent control males in psychiatric, forensic psychiatric and correctional institutions completed the Ekman 60 Faces test, Faux Pas Recognition Test, Eysenck IVE test, Interpersonal Reactivity Index, and the Spielberger Anger Expression Scale. Data were analysed with ANOVA and logistic regression models. Significant group differences with a characteristic pattern were detected in mentalization, facial affect recognition, fear and anger recognition, interpersonal distress, and frequency of direction of anger expression. Predictors of violent behaviour were different in the schizophrenic and non-schizophrenic groups. Lack of major differences in empathy and mentalization between violent and nonviolent schizophrenia patients suggests that such deficits are core features of schizophrenia but do not determine emerging violence in this illness. Our results emphasise the importance of distinguishing between violence related to core positive symptoms of schizophrenia and that emerging from independent comorbid antisocial personality traits in order to identify targets for screening, detection, prevention and management of violence risk in different subpopulations of schizophrenia patients.

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.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.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.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.

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.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.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).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.

Suicide risk factors could be organised into a hierarchical order and a questionnaire constructed based on this hierarchical structure may help clinicians assess suicide risk. The paper presents analysis of the clinical utility of a questionnaire developed by the authors, in samples of suicidal and nonsuicidal psychiatric patients as well as among normal control subjects. Based on their results the authors suggest a shorter and expectedly more sensitive, 6-item version instead of the original 12-item version scale.

Background Psychotic symptoms are common in bipolar disorder (BD). Data suggest that BD patients with or without psychotic symptoms may differ from each other with regards to some clinical features of BD (e.g., age at onset, suicidality, psychiatric comorbidity, number of hospitalizations). However, the literature in this area is relatively scarce and not always conclusive. Therefore, the objective of the current study was to investigate whether the presence of psychotic symptoms is associated with clinical characteristics of patients with BD. Subjects and methods We enrolled 365 hospitalized patients who were diagnosed with BD according to the ICD-10 criteria. After we excluded 196 patients without current psychotic symptoms but psychotic mood episodes in their medical history, our final sample consisted of 169 patients (i.e., 89 BD patients presenting with current psychotic symptoms and 80 BD patients who were hospitalized in the same period, but who did not have psychotic symptoms either currently or during their previous hospitalizations). Clinically available data were collected, systematized and statistically processed according to the aims of the study. Results Early age of onset, bipolar-I diagnosis, comorbid personality disorder, number of hospitalizations and suicidality were significantly more common in the psychotic group compared to the never-psychotic group. On the contrary, sedative/hypnotics dependence was more frequent in the never-psychotic group. Conclusions Our results support the notion that the presence of psychotic symptoms in the context of BD may be associated with various other clinical features of this disease.

The aim of the present study was to analyze the relationship between increasing utilization of antidepressants and lithium, and suicide rate of persons less than 20 years of age in Hungary, with particular regard to seasonal patterns.Time trend analysis was carried out to determine the correlation between antidepressant and lithium prescription patterns in Hungarian persons under age of 20 years as well as seasonal variations within the study period from January 1998 to December 2006.There was a significant correlation (P = 0.03) between the eight-fold increase in antidepressant + lithium prescriptions and decreasing suicides in young Hungarian people under 20 years of age within the study period. Lithium, selective serotonin reuptake inhibitors (SSRIs) and the group of "other antidepressant drugs" rather than nonselective monoamine reuptake inhibitors and monoamine oxidase-A inhibitors were responsible for this association. No significant association could be drawn from seasonal variation with boys (P = 0.964), girls (P = 0.140), or both genders (P = 0.997).Ecological study design.Our findings are in good agreement with large-scale ecological studies showing that the beneficial effect of more widely used antidepressants at a given point could appear on the level of suicide rate of the general population even among patients under the age of 20 years.

The history of antipsychotics began with the discovery of chlorpromazine in the 1950s. Since then this group of medications has become one of the most important element of the armamentarium of psychopharmacology. While initially these pharmacons were used in the treatment of psychotic states (including psychotic mania) in the last approximately 10-15 years new indications - such as treatment of depressive, manic and mixed states and also mood-stabilization in bipolar disorder and also the treatment of major depressive disorder - for several second-generation antipsychotic (SGA) agents have been introduced. Taking this fact into consideration it is not surprising that the market of SGAs has been broadened in several countries. At the same time, safety issues have been raised related to some SGAs, mainly because of their adverse cardiometabolic effects (e.g. weight gain; dyslipidemia; disturbances of glucose metabolism). Related to this, it is worthy of note that the lifespan of patients with serious mental illness (SMIs, such as schizophrenia; bipolar disorder; major depression) is shorter than their healthy counterparts and that somatic comorbidities (mainly cardiovascular disorders) of these patients are primarily responsible for this fact. In this paper, firstly we briefly discuss the history and features of APs then we present data on the shorter than expected lifespan of patients with SMIs and also the possible background mechanisms of it (including the supposed role of AP treatment). Then we provide a short discussion on endothelial progenitor cells (EPC), their role in cardiovascular system and related clinical relevance. Eventually, we also discuss our pilot study with the aim to reveal whether there is any effect of AP therapy on the number of CD34/KDR double-positive EPCs.

Besides psychological and social effects, biological, biochemical and genetic factors also play a role in the background of suicide. The aim is developing a complex model incorporating all the above factors so that suicide could be predicted and prevented in those at risk. Based on several studies 5-HTTLPR s allele frequency is increased in case of violent completed suicides. The aim of the present study was to validate this association in a sample of completed suicides.During autopsy sample DNA samples were obtained for 5-HTTLPR genotyping from 200 subjects deceased due to suicide and 200 controls deceased due to other causes. Chi square tests and logistic regressions were performed according to additive, dominant and recessive models to analyse the possible association between 5-HTTLPR genotype distribution and suicide.Ratio of violent and non-violent suicides was 81% and 19% respectively. No significant difference was found in the distribution of 5-HTTLPR genotypes between the suicide and controls samples. No difference was found between violent and nonviolent suicides with respect to genotype distribution. A significant association was found between sl genotype and suicide at a younger age.Our pilot study did not support the supposed association between 5-HTTLPR and completed suicides or with violent completed suicides. However we found a significant association between sl genotype and suicide in young suicidals.

A possibly shared pathophysiological background between bipolar disorders and essential hypertension is suggested by the several similarities and overlaps between their genetic background, underlying biological disturbances (including partially shared neuroanatomical and neurochemical correlates), concomitant personality and temperamental characteristics, precipitating factors, comorbidity and treatment response. In this paper we outline and extend our previously published hypothesis discussing the similar origins of these two biphasic/bidirectional phenomena.

Bipolar disorders (BDs) are prevalent mental health illnesses that affect about 1−5% of the total population, have a chronic course and are associated with a markedly elevated premature mortality. One of the contributors for the decreased life expectancy in BD is suicide. Accordingly, the rate of suicide among BD patients is approximately 10−30 times higher than the corresponding rate in the general population. Extant research found that up to 20% of (mostly untreated) BD subjects end their life by suicide, and 20−60% of them attempt suicide at least one in their lifetime. In our paper we briefly recapitulate the current knowledge on the epidemiological aspects of suicide in BD as well as factors associated with suicidal risk in BD. Furthermore, we also discuss concisely the possible means of suicide prevention in BD.

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–Asberg 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.

Background Birth season has well-known effects on neuropsychiatric disorders, and may also influence genotype distribution by possibly influencing chance of conception via parental idiosyncratic conception patterns or survival of foetuses or infants. The 5-HTTLPR is associated with phenomena including affective temperaments or suicide which are also associated with birth season. Our aim was to investigate the association of 5-HTTLPR genotype and birth season in a healthy female population. Methods Birth date and 5-HTTLPR genotype was determined for 327 psychiatrically healthy women. The association between presence of s allele and time of birth was analysed using generalized linear models. Results A significant association between s allele frequency and time of birth was detected. S allele carrier frequency was marginally significantly higher in July borns and significantly lower in autumn borns. Limitations We investigated an adult sample so genotype frequency data do not reflect birth frequencies. Our sample consisted exclusively of females. Conclusions There is no clear explanation for the observed association, although idiosyncratic parental conception patterns, the association of 5-HTTLPR with sudden infant/intrauterine death, or other s allele-mediated behaviours may play a role. Our results are strikingly parallel with earlier data reporting a higher risk of completed suicide in July borns, and higher scores of July borns and lower scores of autumn borns on certain affective temperament scales, both of which are also associated with the s allele of 5-HTTLPR. Thus our results may add to the growing body of evidence regarding the etiological background of affective disorders.

Background It is widely believed that in randomized controlled trials of antidepressants the difference between drug and placebo response rates is rather small (around 20%), leading to a common perception that antidepressants have limited efficacy. Aim The aim of the present paper was to present an alternative calculation and interpretation of antidepressant–placebo difference in the treatment response to antidepressant in drug trials which may shed a new light on the efficacy of antidepressants. Issues We have previously highlighted several controversial points concerning the calculation of antidepressant and placebo response rates in randomised controlled trials, which may influence views concerning the efficacy of drugs, and demonstrated several factors which may lead to overestimation of the placebo effect and underestimation of antidepressant efficacy. The traditional interpretation of antidepressant–placebo difference in randomized controlled trials on major depression has been also challenged previously from at least five points of view but all leading to a conclusion that currently prevailing opinions concerning relative placebo and antidepressant response rates overestimate placebo response, and thereby underestimate efficacy of antidepressant drugs. In our present paper we propose another method for calculating placebo and antidepressant response rates which may shed new light on an overlooked aspect of the efficacy of these drugs. Conclusions We contend that opinions on the effectiveness of antidepressants should be reconsidered, and comparisons with placebo should be more carefully applied. Interpretation of the placebo response is of crucial importance for establishing the efficacy of antidepressive medications, and psychiatry should not become the hostage of placebo.