Novel antidepressant drugs: Beyond monoamine targets.

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.

[Fortification of drinking water with lithium to reduce suicide in the population].

Antimanic and phase-prophylactic features of lithium (Li) in subjects with affective disorders has been known for a long while. Furthermore, it has also been proven for decades that - partially due to its aforementioned effects - Li has marked antisuicide properties in subjects with mood disorders. Intriguingly, consistent findings from several studies conducted in the last 15 years suggest that the antisuicide effect of Li can also be detected in those members of the population who consume drinking water with high Li contents (in connection with this, we must note that the level of Li in tap water is several orders of magnitude less than the therapeutic dose of Li). Based on these results, and also taking into the consideration the long-known anti-goiter effect of iodized table salt, some experts suggest considering the enrichment of tap water with microdose Li. This paper paper briefly summarizes our current knowledge on this topic as well as the related clinical and ethical dilemmas.

Serotonin and depression - a riposte to Moncrieff et al. (2022).

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).

The relationship between therapeutic adherence and personality.

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.

Affective Temperaments, Panic Disorder and Their Bipolar Connections.

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 < 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.

[The use of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder: theoretical and practical considerations].

In the last 2 decades, a growing body of evidence documented the efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) in the treatment of psychiatric diseases, especially of major depressive disorder (a.k.a. unipolar depression). In our paper, we discuss briefly the historical aspects of TMS, its position among neurostimulatory methods and its mechanism of action. Then we review in details the practical aspects of the application of rTMS (e.g. stimulation parameters, contraindicatitions, side-effects) as well as the evidences of its efficacy in the treatment of depression. We also outline the possibilities of the use of rTMS in other psychiatric disorders than MDD. In our opinion, more than 10 years after receiving the FDA clearence, rTMS should be added to the Hungarian treatment guideline of MDD. Furthermore, the elaboration of the details of the insurance coverage of the rTMS treatment by the Hungarian National Health Insurance Fund would also be required.

Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid ß peptide (Aß) and tau protein are among the major pathological hallmarks of AD. Aß 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.

Associations between untreated depression and secondary health care utilization in patients with hypertension and/or diabetes.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Suicide Risk in Bipolar Disorder: A Brief Review.

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.

[Investigation of the acute effect of bilateral repetitive transcranial magnetic stimulation (rTMS) in therapy resistant major depression patients]. / Bilaterális repetitív transzkraniális mágneses stimuláció (rTMS) akut hatásának vizsgálata terápia rezisztens major depresszióban szenvedok körében.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[The role of nutritional factors in the adjuvant treatment of major depressive disorder].

A growing body of data has accumulated in the past decades about the possible role of nutritional factors in influencing the initiation and course of mental disorders as well as in the treatment of these disorders. As a result of the aggregation of this data a new field emerged - "nutritional psychiatry". In our current review paper we discuss some of those natural agents that supposedly have antidepressive properties and, accordingly, may play a role in the stand-alone and/or adjuvant treatment of major depressive disorder.

[The practical considerations of antidepressant use during pregnancy and breastfeeding]. / Az antidepresszívumhasználat gyakorlati szempontjai a várandósság és az anyatejes táplálás idoszakában.

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.

[Assessing suicide risk using the Brief Suicide Questionnaire - preliminary results]. / Az öngyilkossági veszély felmérése a Rövid Szuicid Kérdoív segítségével ­ elozetes eredmények.

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.

The development of a short version of TEMPS-A in Hungarian non-clinical samples.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Differences in clinical characteristics between bipolar patients with current psychotic symptoms and those who have never been psychotic.

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.

Suicid risk in mood disorders - can we better prevent suicide than predict it?

The risk of suicidal behaviour in major mood disorders is an inherent phenomenon and it strongly relates to the presence and severity of depressive episode. However, since the majority of mood disorder patients never commit or attempt suicide, special clinical characteristics of the illness as well as some personality, familial, psycho-social and demographic factors should also play a contributory role. Considering the clinically explorable suicide risk factors - discussed in this paper - in patients with major mood disorders, suicidal behaviour is predictable with a relatively good chance. As suicidal behaviour frequently develops later in the course of mood disorders, successful treatment of initially nonsuicidal major depressives and bipolar patients can prevent the later developing suicidal behaviour. This phenomenon could be called as "hidden suicide prevention". It means that preventing suicide is more easy than to predict it.

[About the association between antipsychotic medication and cardiovascular morbidity: epidemiology and possible background mechanisms]. / Az antipszichotikum kezelés és a kardiovaszkuláris morbiditás közötti kapcsolatról: epidemiológiai összefüggések és azok lehetséges magyarázatai.

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.

[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.

[Similarities and differences between bipolar disorder and hypertension: may be mania is the hypertension of the mood?] / A mánia a hangulat hipertóniája? Hasonlóságok és különbségek a bipoláris betegség és a hipertónia között.

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.

[Assessing suicide risk based on a hierarchical classification of risk factors]. / Az öngyilkossági veszély felmérése a rizikófaktorok hierarchikus osztályozása alapján.

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.