Volume 18, Issue 4, December 2016

Editoral in Hungarian

János Réthelyi

Abstract

Molekuláris pszichiátriai kutatások Magyarországon

Réthelyi János


A Neuropsychopharmacologia Hungarica legújabb száma bepillantást nyújt a Magyarországon zajló molekuláris pszichiátriai kutatások jelenlegi állásába. A molekuláris pszichiátria fogalmának meghatározása nem könnyű feladat. Túl egyszerű lenne a kérdést azzal elintézni, hogy a pszichiátriai zavarok molekuláris mechanizmusaival, betegségútvonalaival foglalkozó tudományos megközelítés. Ide soroljuk a pszichiátriai genetikai és epigenetikai kutatásokat, és a biomarkerekre irányuló génexpressziós és proteomikai vizsgálatokat egyaránt. Ide tartoznak továbbá az állatkísérletes és farmakológiai megközelítések is a pszichiátriában.
Angyal Nóra és szerzőtársai eredeti adatokon alapuló munkájukban azt vizsgálták, hogy a kortizol mellett a nyál alfa-amiláz szintje is alkalmazható-e biomarkerként externalizáló viselkedési problémákkal küzdő serdülő fiúk csoportjában. Benkovits Judit és munkatársai a Magyar SCHIZOBANK Konzorcium eredményeit mutatják be. A közlemény alapjául szolgáló genetikai vizsgálatban öt hazai pszichiátriai ellátó egységben bevont szkizofrén páciensek DNS mintáit dolgozták fel. Hathy Edit és munkatársai egy új in vitro módszert, az indukált pluripotens őssejt alapú betegségmodellezést mutatják be és ennek pszichiátriai relevanciáját. Hermán Levente és szerzőtársainak munkája teljes mértékben klinikai indíttatású, egy először 10 évvel ezelőtt leírt új nozológiai egységről, a gyakran pszichiátriai tünetek formájában jelentkező anti-NMDAR enkefalitiszről szól. Klein Izabella és munkatársai egy genetikai szindróma, a 22q11.2 kromoszómarégió deléciójának (22Q11DS) pszichiátriai vonatkozásairól írtak összefoglaló közleményt, melyben saját adataikat is bemutatják.
A konkrét eredmények mellett a közlemények számos egyéb kérdést is felvetnek. Milyen módon érdemes ezeket az eredendően klinikai kutatásokat a pszichiátriai osztályok működéséhez kapcsolni? Hogyan valósítható meg optimálisan a vizsgálatokhoz szükséges betegek bevonása? Érdemes-e multicentrikus módon az osztályok és a kapcsolt laboratóriumok erőforrásait koncentrálni? Ezekről a kérdésekről érdemes lenne közösen gondolkodni, a megfelelő fórumokon végigbeszélni őket, és ha szükséges, a gyakorlatunkat ennek megfelelően módosítani. A különszámban összegyűjtött munkák, a nemzetközi lapokban megjelenő számos közlemény, a sikeresen működő hazai kutatócsoportok munkája alapján pozitív érzésekkel tekinthetünk a hazai molekuláris pszichiátriai kutatás jelen állására. A laphoz jó olvasást kívánok.

Potential salivary biomarkers and their genetic effects in a pilot study of adolescent boys with externalizing problems

Nóra Angyal, József Halász, Gergely Mészáros, Judit Krisztina Kovács, Emese Kruk and Zsófia Nemoda

Abstract

Aims: Beside the well-known stress response marker cortisol, salivary alpha-amylase is receiving
increasing attention. Numerous studies have investigated the potential biomarker properties
of cortisol mirroring abnormal hypothalamic-pituitary-adrenal axis activity in connection to
both internalizing and externalizing behavior problems. The other major physiological system
involved in stress reactivity, the sympathetic nervous system activity can be also measured by
the surrogate marker of salivary alpha-amylase. Most of the studies applied a stressful situation
to obtain inter-individual differences in stress-reactivity, although differences in the baseline
level of cortisol have been also shown in relation to externalizing problems. To test the relevance of another (easier) biomarker, we selected to study baseline circadian salivary cortisol
and alpha-amylase levels among adolescent boys with externalizing problems. Methods:
Saliva samples were collected at 3 time-points (morning, noon, evening) during 3 consecutive days from 37 inpatient boys (mean age 12.4±1.0). Cortisol and alpha-amylase levels were
measured by enzyme-linked immunosorbent and kinetic enzyme assays, respectively. Genetic
variants in the hypothalamic-pituitary-adrenal axis and the norepinephrine transporter or
catecholamine metabolizing enzymes were tested for potential moderating effects at these
salivary biomarkers. Results: Saliva cortisol showed the classical diurnal fluctuation in boys
with externalizing problems (possibly from a lower morning level), but it was not modified
by the presence of either conduct, oppositional defiant or attention-deficit/hyperactivity
disorder. The diurnal fluctuation of the salivary alpha-amylase levels was also typical, but the
presence of conduct disorder was associated with significantly lower alpha-amylase activity (p=0.024) among boys with externalizing problems. The catechol-O-methyltransferase
Val158Met (rs4680) polymorphism had an additional effect on salivary alpha-amylase: boys
with homozygote genotypes had lower alpha-amylase activity at all 3 time-points compared
to Val/Met heterozygotes (p=0.045). Conclusions: Our preliminary data suggest that salivary
alpha-amylase might be used to further characterize subgroups within externalizing problems,
however, this biomarker might be modified by certain genetic polymorphisms.
(Neuropsychopharmacol Hung 2016; 18(4): 173–179)

Keywords: alpha-amylase, conduct disorder, cortisol, externalizing behavior, stress

Investigation of CNTF, COMT, DDR1, DISC1, DRD2, DRD3, and DTNBP1 candidate genes in schizophrenia: Results from the Hungarian SCHIZOBANK Consortium

Judit Benkovits, Szilvia Magyarósi, Attila Pulay, Zoltán Makkos, Anikó Égerházi, Nóra Balogh, Péter Álmos, István Likó, Hungarian SCHIZOBANK Konzorcium, György Németh, Mária JuditMolnár, László Nagy and János Réthelyi

Abstract

Schizophrenia is a chronic, debilitating psychiatric disorder characterized by heterogeneous clinical symptoms. Although the pathogenesis of this disorder is poorly understood, several lines of evidence support the role of both common and rare genetic variants in the etiology of schizophrenia. Common variants, single nucleotide polymorphisms can be investigated by candidate gene association studies or genome-wide association studies, while rare variants, single nucleotide variants are assessable by means of candidate gene resequencing or wholeexome and genome sequencing using next generation sequencing. In this study we investigated polymorphisms of 7 candidate genes in a Hungarian schizophrenia cohort. Candidate genes were chosen on the basis of previous results and biological plausibility. 390 patients were recruited in 5 centers in the framework of the Hungarian SCHIZOBANK Consortium, the schizophrenia sample was contrasted to 1069 healthy control individuals. In this sample SNPs of DDR1 and DRD2 genes demonstrated significant association with schizophrenia. The role of DDR1 and DRD2 genes in the etiology of schizophrenia warrant further investigation, based
on their genomic localization and biological functions.

Keywords: schizophrenia, single nucleotide polymorphism, association study, candidate
gene, DDR1, DRD2

Abstract
Abstract

Anti-NMDAR (N-methyl-D-aspartic acid receptor) encephalitis, first described in 2007, is a rare, autoimmune limbic encephalitis. In half of the cases anti-NMDAR antibodies are paraneoplastic manifestations of an underlying tumor (mostly ovarian teratoma). In the early stage of the disease psychiatric symptoms are prominent, therefore 60-70% of the patients are first treated in a psychiatric department. In most of the cases, typical neurological symptoms appear later. Besides the clinical picture and typical symptoms, verifying presence of IgG antibodies in the serum or CSF is necessary to set up the diagnosis. Other diagnostic tools, including laboratory
tests, MRI, lumbar puncture or EEG are neither specific, nor sensitive enough. Therapy is based on supportive care, plasma exchange and immune suppression, intensive care administration can be necessary. If there is an underlying tumor, tumor removal is the first-line treatment. The disease can cause fatal complications in the acute phase but with adequate therapy long-term prognosis is good, although rehabilitation can last for months. In the past few years besides the typical clinical picture and illness course an increasing number of case reports described no
typical neurological symptoms, only psychiatric symptoms, including psychosis, disorganized behavior, and catatonic symptoms. Immune suppressive treatment was still effective in most of these cases. Such cases present a difficult diagnostic challenge. These patients may receive unnecessary antipsychotic treatment because of the suspected schizophrenia, although they often suffer from serious extrapyramidal side effects. A few years ago there was a hypothesis that a small part of the patients who are treated with therapy-resistant schizophrenia may suffer from anti-NMDAR encephalitis, so they require a different kind of medication. Evidence
from the latest publications did not confirm this hypothesis, although the connection between anti-NMDAR antibodies and disorders with psychotic symptoms is still not clear. After reviewing the most important studies regarding the psychiatric aspects of anti-NMDAR encephalitis, we present a case report of a patient with a pure sychiatric manifestation of this disease. We conclude with a short outline of the design and plan of our future study.

Keywords: NMDA, encephalitis, psychosis, schizophrenia, autoimmune

Abstract
Abstract

Schizophrenia is a severe debilitating psychiatric disorder, with a typical onset in adolescence or early adulthood. This condition is characterized by heterogeneous symptoms (hallucinations, delusions, disorganized behaviour, affective flattening, and social isolation) and a lifetime prevalence of 0.5-1.2%. In spite of the efforts to uncover the etiology of the disorder, its pathogenesis and neurobiological background are poorly understood. Given the high heritability in schizophrenia, genetic research remains an important area of focus. Besides the common variations of low penetrance – single nucleotid polymorphisms (SNPs) –, rare variants, mainly copy number variations (CNVs) play a role in the genetic architecture of the disorder.
The most frequent CNV associated with schizophrenia is the hemizygous deletion of the 22q11.2 region. According to previous research this genetic variant occurs in 1% of the patients and conversely, 25% of the carriers of the 22q11.2 microdeletion will develop schizophrenia. The 22q11.2 deletion syndrome (22Q11DS, velocardiofacial (VCFS) syndrome, DiGeorgesyndrome) is usually a childhood diagnosis. Its prevalence is 1:2000–4000 considering all births. Patients can demonstrate heart developmental disorders, craniofacial (elongated face, hypertelorism), immunological (thymus-hypoplasia), endocrinological (hypocalcaemia) abnormalities, and  eurodevelopmental alterations, but only a proportion will have
these abnormalities due to incomplete penetrance. The variable symptoms complicate the recognition of the syndrome in the day to day medical practice. 25% of the known 22Q11DS patients develop schizophrenia but the risk of neuropsychiatric problems, like autism, ADHD and childhood conduct disorder is also increased, while early onset Parkinson’s disease in also more frequent in adults. The schizophrenia phenotype is not distinguishable at the moment in patients with or without the 22q11 deletion. But emerging evidence suggests that early onset Parkinson’s disease is more frequent in 22Q11DS and the effects of clozapine treatment could be different in schizophrenia with 22Q11DS. The question arises what is the incidence rate of the 22q11.2 microdeletion among our Hungarian DNA samples with schizophrenia. To answer the question, we utilized a new method used in routine genetic diagnostics, multiplex ligation-based probe amplification (MLPA). Although we genotyped the DNA of 315 Hungarian schizophrenia patients, we found no 22Q11DS in this cohort. The findings are discussed in terms of basic research and their translation into everyday clinical practice.

Keywords: schizophrenia, CNV, 22Q11DS, MLPA, clinical screening