Neurocognition and psychogenetic vulnerability in depression.

The clinical symptoms of major depression are paralleled by typical neurocognitive deficits. The relation of STin2 - one of the polymorphisms of the serotonin transporter gene - to major depressive disorder (MDD) is less widely investigated. The aim of the present study was to measure the neurocognitive functions of major depressive patients and healthy controls, and identify vulnerability markers of the disease. The frequency of STin2 polymorphism and its effect on neurocognition was investigated in major depression. The gender differences in neurocognitive impairment in patients with major depressive disorder were also studied. Relative to controls, patients with depression showed significant impairment on most neurocognitive tasks, but not in tasks measuring visuo-spatial function, which may suggest intact hippocampal function in depression. We found a significantly higher frequency of the STin2 10/10 genotype in the MDD patient group compared to controls. Our results suggest that the presence of STin2.10 and absence of STin2.12 may be considered a possible genetic endophenotype for cognitive dysfunction detected in major depressive disorder. Depressed women performed significantly worse on tests of cognitive interference and visual recall threshold compared to depressed men. In the light of neuroimaging studies our results suggest that the lateralisation of hippocampal function may play an important role in the background of gender differences.

Intramuscular olanzapine versus short-acting typical intramuscular antipsychotics: comparison of real-life effectiveness in the treatment of agitation.

OBJECTIVE: To compare the effectiveness of intramuscular (IM) olanzapine and typical IM antipsychotics in naturalistically treated acutely agitated patients with schizophrenia or acute mania. METHODS: During the acute phase, 2011 inpatients (including emergency settings) were assessed at 2, 24 and 72 h, and 7 days following initial injection and on oral antipsychotic transition. Mean change in agitation was assessed via Positive and Negative Symptom Scale-Excited Component (PANSS-EC) and Clinical Global Impressions-Severity (CGI-S) scores. Response (> or = 40% reduction in baseline PANSS-EC score) was analysed using logistic regression. RESULTS: Significantly greater decreases in PANSS-EC and CGI-S scores were observed in patients receiving IM olanzapine (n = 1294) as their first injection compared with patients receiving other IM antipsychotics (n = 717) (P<0.05; 2 h: effect size 0.1); IM haloperidol treatment (all assessments, P<0.05); and IM zuclopenthixol treatment (2 h, P<0.001). Higher response rates were observed with IM olanzapine compared with other IM antipsychotics at 24 and 72 h, and 7 days (P<0.05). IM olanzapine was associated with fewer extrapyramidal side effects compared with other assessed IM antipsychotics. CONCLUSIONS: IM olanzapine provided somewhat more effective control of acute agitation than other assessed IM antipsychotics.

Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach.

The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a novel candidate gene for major depressive disorder (MDD) and bipolar disorder (BPD). The proposed risk allele (G-allele) of the rs2230912 polymorphism results in an amino acid change at the 460th position, marking this genetic variation a possibly functional one. Here we present a case-control analysis of 171 patients diagnosed with MDD or BPD and 178 controls, as well as a dimensional approach using the Hospital Anxiety and Depression Scale (HADS) for studying the Gln460Arg polymorphism of the P2RX7 gene as a genetic risk factor in depression. While case-control analysis did not show significant difference between the groups, a significant association was found between the P2RX7 polymorphism and the HADS scales in the clinical group (MANOVA P = 0.001). Both anxiety and depression scores increased as the number of G-allele increased in the genotype groups (ANOVA for HADS-anxiety: P = 0.01, HADS-depression: P < 0.001). A significant interaction of clinical status and the P2RX7 polymorphism was also found for the depression scale (MANOVA P = 0.025, subsequent ANOVA for anxiety: P = 0.252; depression: P = 0.002). Whereas patients with G-allele-present genotypes showed more elevated depression scores, level of depression in the control group was not affected by the P2RX7 genotype. In conclusion, case-control analysis did not reveal significant results, but using a symptom severity scale we could support the association between depressive disorder and the G-allele of the Gln460Arg polymorphism in the P2RX7 gene.

Association of the STin2 polymorphism of the serotonin transporter gene with a neurocognitive endophenotype in major depressive disorder.

BACKGROUND: The aim of our study was to investigate the association of STin2 polymorphism and cognitive dysfunction in major depression. METHODS: 71 patients with major depression and 99 controls were genotyped for STin2. All depressive subjects and 30 controls also completed tests measuring neurocognitive performance. RESULTS: We found a significantly higher frequency of the STin2.10/Stin2.10 homozygous genotype in the depressed group compared to controls. In the depressed group subjects with at least one copy of the 10-repeat allele showed decreased interference threshold in Stroop III compared to patients without the 10-repeat allele. Average performance of the depressed group without the 12-repeat allele was significantly weaker in the Rey Auditory Verbal Learning Test working memory and recall tasks compared to patients having at least one copy of the 12-repeat allele. CONCLUSION: Our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be related to a possible genetic endophenotype for characteristic cognitive dysfunctions detected in MDD.

[Validation of a new mood questionnaire on healthy sample]. / Egy új hangulati kérdoív validálása egészséges mintán.

Depression is a frequent, wide spectrum disease causing substantial suffering. Quantitative tools for measuring depression are rather important both at the clinical and non-clinical state. BDI (Beck Depression Inventory) the HADS (Hospital Anxiety and Depression Scale) and the BHS (Beck Hopelessness Scale) are used both in clinical practice and research. Primary aim of these questionnaires is the diagnosis of clinical depression, however, screening for less severe stages of depression, and realization of predisposition to depression is also important. Based on results from recent twin-studies genetic factors of depression are significant. Moreover, discovering genetic risk factors of depression is a challenging task of psychogenetic association studies. Creating new endophenotypes, those units of our phenotypic makeup which can be objectively measured and are linked to certain genetic components, is an important step in completion of this challenge. The primary goal of the present study was to characterize predisposition to depression with endophenotypes suitable for genetic association analysis. To achieve this goal 170 participants filled out the BDI and HADS questionnaires in the first stage of the study (99 were diagnosed with clinical depression, and 71 were healthy adults). Psychometric properties of these questionnaires were assessed, reliability of the Hungarian version of both scales proved to be satisfactory. Using items from these tools we derived a common factor structure in order to create a new, short measure (the DS1K) of the depression construct ready to be used as endophenotype in psychogenetic association studies. Usability of the DS1K was assessed based on data from 144 healthy adults. The measure proved to be highly reliable (Cronbach-alpha = 0.88) and valid (correlation with the BDI and HADS scales were high and significant).

[Gender differences in the neurocognitive components of depression]. / A depresszió neurokognitív összetevoinek és nemi külonbségeinek vizsgálata.

UNLABELLED: The clinical symptoms of major depression are paralleled by typical neurocognitive deficits. Our aim was to investigate the gender differences in neurocognitive impairment in patients with major depressive disorder. METHODS: 96 patients with acute major depressive disorder meeting DSM-IV criteria participated in our study. Depression was assessed by the Montgomery-Asberg Depression Rating Scale, the Hamilton Depression Scale and the Beck Depression Inventory. We measured neurocognitive functions associated with verbal learning and memory (Rey Auditive Verbal Learning Test), visual reconstruction and recall (Rey-Osterreith Complex Figure Test), selective attention, executive functions and inhibitory control (Trail Making Test, Stroop Test). RESULTS: Depressive patients performed significantly worse than controls in all tests. We found no gender differences in any of the tests in the control group. Depressed women performed significantly worse on tests of cognitive interference threshold compared to depressed men (Stroop III). Depressed women performed significantly worse compared to depressed men in the test of visual recall (Rey-Osterreith Complex Figure Test). CONCLUSION: Depressed patients performed worse in all tests of neurocognitive function compared to healthy controls. Depressed women performed significantly worse compared to depressed men in tests of visuospatial recall and cognitive interference. In the light of neuroimaging studies our results suggest that in the background of gender differences we observed in depressed patients lateralisation of hippocampal function may play an important role.

Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims.

CONTEXT: Depression is a major public health problem. Despite many years of research, the molecular mechanisms associated with depression remain unclear. Rap-1, activated in response to many extracellular stimuli, is one of the major substrates of protein kinase A, which participates in myriad physiologic functions in the brain, including cell survival and synaptic plasticity. Rap-1 is also activated directly by cyclic adenosine monophosphate through Epac, and thus participates in mediating physiologic functions independent of protein kinase A. OBJECTIVE: To examine whether the pathogenesis of depression is associated with altered activation and expression of Rap-1, as well as expression of Epac, in depressed suicide victims. DESIGN: Postmortem study. SETTING: Tissues were obtained from the Lenhossek Human Brain Program, Semmelweis University, Budapest, Hungary, and the Brain Collection Program of the Maryland Psychiatric Research Center, Baltimore. PARTICIPANTS: Postmortem brains of 28 depressed suicide victims and 28 nonpsychiatric control subjects. INTERVENTION: Examination of brain tissues. MAIN OUTCOME MEASURES: Rap-1 activation as well as messenger RNA and protein levels of Rap-1 and Epac in prefrontal cortex, hippocampus, and cerebellum. RESULTS: Rap-1 activation was significantly reduced (P<.001) in prefrontal cortex and hippocampus in the suicide group. This was associated with significant reductions in Rap-1 messenger RNA and protein levels (P<.001). In contrast, protein level of only Epac-2 (P<.001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects. These changes were present whether the 2 cohorts were analyzed together or separately. None of the measures showed any significant change in cerebellum in the suicide group. CONCLUSION: Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.

[Markers of cognitive vulnerability in major depression]. / Kognitív vulnerabilitás markerek major depresszióban.

Neuropsychological deficits have been reported in patients with major depressive disorder in a lot of lectures. The aim of the present study was to measure the neurocognitive functions of major depressive patients and healthy controls, and identify some vulnerability marker of the disease. Seventy-one patients with major depressive disorder were compared to thirty healthy control subjects on tasks from Trail Making Test, Stroop Test, Rey Verbal Auditory Learning Test and Rey-Osterreich Figure Test. Patients with depression relative to controls were significantly impaired on tasks of attention, executive function, memory and psychomotor speed, but not in visuo-spatial function. These findings suggest deficits in cognitive function as, attention, visual and verbal memory and learning, as vulnerability marker for major depressive disorder. The second important finding, the better result of the visual perception and short memory in depressed patient, was caused by intact hippocampal function. The functional importance of this result is the connection of the neuronal network and signs of depression.

[Association of neurocognitive endophenotype and STin2 polymorphism in major depressive disorder]. / Neurokognitív endofenotípus és STin2 polimorfizmus asszociáció vizsgálata major depresszióban.

Two well known polymorphic regions of the serotonin transporter gene (SLC6A4) are the 5HT-TLPR which consists of a 44-bp insertion or deletion in the promoter region and the STin2 consisting of variable number of tandem repeats in the second intron. Several studies focused on the association of the 5HTTLPR and behavioral or clinical factors of depression; on the other hand, the relation of the STin2 to major depressive disorder (MDD) is less widely investigated. We carried out a case-control study of 71 MDD patients and 99 healthy control subjects comparing frequencies of the STin2 allele- and genotype variants in the two populations. We found a significantly higher frequency of the STin2 10/10 homozygous genotype in the MDD patients' group compared to controls (chi2 = 6,01, df = 2, p < 0.05). To further explore possible endophenotypes of neurocognitive functioning in the background of this disorder we measured performance of 71 cases and 30 matched controls using several tests of neurocognitive functioning. Our results indicated cognitive dysfunctions of the MDD patients in all tests as compared to control individuals. The clinical subgroup with at least one copy of the 10-repeat allele showed a decreased interference threshold in Stroop III as compared to patients without the 10-repeat allele. Average performance of the clinical subgroup without the 12-repat allele proved to be significantly weaker in the working memory and recall tasks (RAVLT) compared to patients having at least one copy of the 12-repeat allele. After further confirmation our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be defined as a possible genetic endophenotype for cognitive dysfunctions detected in MDD.

[Maintenance pharmacotherapy of schizophrenia: remission and the effectiveness of long-acting risperidone therapy]. / A szkizofrénia hosszú távú farmakoterápiája: fókuszban a remisszió és a tartós hatású risperidon kezelés eredményei.

UNLABELLED: Schizophrenia is a severe and devastating psychiatric disorder affecting about 1 percent of the world's population, is characterized by psychotic episodes, negative symptoms and cognitive deficits. New advances in the understanding of schizophrenia etiology, course, treatment have increased interest in the development of consensus-defined standards for clinical status, improvement, remission and recovery. The introduction of standardized remission criteria may offer significant opportunities for clinical practice and clinical trials. Risperidone is the first atypical antipsychotic available in a long-acting injectable formulation. Clinical studies have demonstrated that long-acting risperidone is effective and well tolerated in patient with schizophrenia. Significant clinical improvement has been reported in patients switched to long-acting risperidone from other antipsychotic agents. Several patient groups (young, first episode, schizoaffective patients) have been shown significant benefit from long-acting risperidone. Special patient groups, including, the insufficient efficacy, the partial compliance, the suffering from side effect may benefit from treatment with long-acting risperidone. This treatment should improve the compliance and achieve remission and functional recovery. KEYWORDS: schizophrenia, remission, long-acting atypical antipsychotic.

Protein kinase A in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits.

BACKGROUND: We recently reported reduced [3H]cyclic adenosine monophosphate binding and catalytic activity of protein kinase A in prefrontal cortex of depressed suicide victims. Here we examined the molecular basis of these alterations and whether these findings can be replicated in another cohort. METHODS: Prefrontal cortex from depressed suicide victims and nonpsychiatric controls were obtained from the Lenhossek Human Brain Program, Budapest and the Maryland Brain Collection Program. [3H]cyclic adenosine monophosphate binding and protein kinase A activity were determined by radioligand binding and enzymatic assay, respectively. Expression of catalytic and regulatory subunits was determined by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. RESULTS: [3H]cyclic adenosine monophosphate binding and total and endogenous protein kinase A activity were significantly decreased in membrane and cytosol fractions of prefrontal cortex of depressed suicide victims from the Budapest cohort, with a similar magnitude (33%-40% reduction) as reported for the Maryland cohort. In both cohorts, selective reduction (36%-41%) in mRNA and protein expression of the regulatory RIIbeta and the catalytic Cbeta was observed. CONCLUSIONS: Our results suggest abnormalities in [3H]cyclic adenosine monophosphate binding and catalytic activity kinase A in brain of depressed suicide victims, which could be due to reduced expression of RIIbeta and Cbeta. These abnormalities in PKA may be critical in the pathophysiology of depression.

Interaction of 5-HTTLPR genotype and unipolar major depression in the emergence of aggressive/hostile traits.

OBJECTIVE: The 5-HTTLPR polymorphism has been associated both with depression and aggression/hostility. The multidirectional association between depression, aggression and the s allele may be important, since all these phenomena are related to suicidal behavior. Our aim was to investigate the association between 5-HTTLPR and aggressive/hostile traits in depressed patients and controls. METHODS: 137 depressive and 118 control women completed the Buss-Durkee Hostility Inventory and were genotyped for 5-HTTLPR. BDHI scores in the different groups were investigated by Generalized Linear Model Analysis. Association between dependent and independent variables in the model was tested by the likelihood ratio Chi-square statistic. RESULTS: Diagnosis and genotype showed a significant association with several aggressive/hostile traits. Interaction of the two main effects was also significant in case of several subscales. Post hoc analyses indicated a significant association between BDHI subscales and s allele only in the depressed group. LIMITATION: Only women were studied and since gender differences are present both in aggressive behavior and putatively in the behavioral effects of 5-HTTLPR genotype, our findings pertain only to females. CONCLUSION: Our results indicate a robust relationship between aggression/hostility and 5-HTTLPR genotype, but this association is more marked in the presence of depression. The presence of the s allele thus not only contributes to a higher risk of depression, but in depressives also leads to higher aggression/hostility. Our results have important implications for suicide research, since the s allele is associated with violent suicide, and this association may be mediated through the emergence of increased aggression/hostility in depressed patients carrying the s allele.

Regional distribution and relative abundance of serotonin(2c) receptors in human brain: effect of suicide.

Abnormalities in serotonin receptor subtypes have been observed in the postmortem brain of suicide victims. We examined the regional distribution of serotonin (5HT)(2C) receptor mRNA in several areas of the human brain and also compared its protein and mRNA expression in the prefrontal cortex (PFC), hippocampus, and choroid plexus between suicide victims and normal control subjects. 5HT(2C) receptors were found to be distributed in several areas of the human brain (in order of abundance): highly concentrated and richest in choroid plexus; hypothalamus; nucleus accumbens; with the lowest abundance in PFC and cerebellum. Comparison of 5HT(2C) receptors between suicide victims and control subjects showed higher protein levels in the PFC but not the hippocampus or choroid plexus of suicide victims. However, there were no significant differences in mRNA levels between suicide victims and control subjects in these brain areas. These results suggest that 5HT(2C) receptors are richly distributed throughout the brain with the highest level in the choroid plexus and that abnormalities in protein expression of 5HT(2C) receptors in the PFC may be associated with suicide.