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Effects of nicotinic stimulation on cognitive performance.

Recent advances in studies of nicotinic agents in humans have begun to more carefully define cognitive operations that can be influenced by nicotinic stimulation and/or blockade. Careful separation of the cognitive domains affected by nicotinic stimulation has identified attentional performance as the most likely candidate to be positively influenced by nicotinic receptor activation. Studies of the effects of nicotinic systems and/or nicotinic receptor stimulation in pathological disease states such as Alzheimer's disease, Parkinson's disease, attention deficit/hyperactivity disorder and schizophrenia show the potential for therapeutic utility of nicotinic drugs. In contrast to studies in pathological states, studies of nicotine in normal-non-smokers tend to show deleterious effects. This contradiction can be resolved by consideration of cognitive and biological baseline dependency differences between study populations in terms of the relationship of optimal cognitive performance to nicotinic receptor activity. Although normal individuals are unlikely to show cognitive benefits after nicotinic stimulation except under extreme task conditions, individuals with a variety of disease states can benefit from nicotinic drugs. Attentional function/dysfunction may serve as an endophenotypic therapeutic target for nicotinic drug development.

Attention↗

Stress-reactivity in psychosis: evidence for an affective pathway to psychosis.

This paper will review a series of studies using the Experience Sampling Method that suggest that altered sensitivity to stress is an endophenotype for psychosis. The Experience Sampling Method is a structured diary technique allowing the assessment of emotional reactivity to stressors occurring in normal daily life. Elevated emotional reactivity to stress was found in subjects vulnerable to psychosis, suggesting that affective responses to stressors in the flow of daily life are an indicator of genetic and/or environmental liability to psychosis. Indeed, the small stressors in daily life associated with affective responses also predict more intense moment-to-moment variation of subtle positive psychotic experiences. Increased emotional reactivity was found to be independent from cognitive impairments, and argued to constitute evidence of an affective pathway to psychosis that may underlie a more episodic, reactive, good-outcome type of psychosis. Evidence for this hypothesis was found in data suggesting that the experience of stressful life events and early trauma were associated with increased stress-sensitivity, and that women were more likely to display elevated stress-reactivity. These findings are discussed in the light of recent biological and psychological mechanisms.

Affect↗

Behavioural screening in mutagenised mice--in search for novel animal models of psychiatric disorders.

Complementary to the 'gene-driven' analysis of gene function, 'phenotype-driven' approaches can be performed and may be equally important. Despite the current availability of a long list of mouse mutants, there remains an appreciable need for behavioural phenotypes in mouse models permitting to learn more about the aetiology of psychiatric disorders. This lack can be compensated by phenotype-driven ethyl-nitrosourea (ENU)-mutagenesis programs which aim at identifying novel phenotypes without any a priori assumptions, thus, representing a unique possibility to create novel animal models which approximate the underlying genetic aetiology. The power of mouse mutagenesis critically depends on the phenotyping procedures performed. In the case of ENU-mutants, behavioural phenotyping is especially challenging, as behavioural profiles have to be identified in single individuals. For high-throughput screening, approaches have been made to establish standardised screening protocols including a combination of well-validated, easy to perform behavioural tests. Different strategies are being introduced, which are used in ENU-mutagenesis screens to identify behavioural mutants representing possible endophenotypes of psychiatric diseases.

Animals↗

Alcohol dependence and gene x environment interaction in emotion regulation: Is serotonin the link?

Alcohol dependence is characterized by frequent, compulsive and uncontrolled consumption of alcohol associated with behavior of maladaption and destruction. It is an etiologically and clinically heterogeneous syndrome, moderately to highly heritable, and caused by interaction of genes and environment. Alcohol dependence is related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioral control as well as anxiety and stress response. Alcohol induces adaptive changes in brain function providing the basis for tolerance, craving, withdrawal, and emotional disturbance. The differentiation of psychobiological traits of addictive behavior reflecting neurobiological processes is therefore of particular importance for the dissection of the complex genetic susceptibility to alcohol dependence. A central serotonin (5-HT) deficit is thought to be involved in the pathogenesis of alcohol dependence by modulating motivational behavior, neuroadaptive processes, and resulting emotional disturbance. 5-HT-related impulsive, aggressive, and suicidal behavior has been linked to a primordial personality that is susceptible to alcohol dependence. Although variations in many of the genes that encode receptors, enzymes, and transporters of the 5-HT system have been tested as risk factors for alcohol dependence, genetic analyses of 5-HT signaling in alcohol dependence have mainly been focused on the 5-HT transporter (5-HTT) gene. Due to its central role in the fine-tuning serotonergic neurotransmission, a regulatory variant of the 5-HTT, which is associated with anxiety related traits, is not only a key player in the neurobiological mechanism of gene x environment interaction in the etiology of depression, but also contributes to the risk to develop alcohol dependence with antisocial behavior and suicidality. Evidence for a modulatory effect of allelic variation of 5-HTT function on limbic circuit responses to emotional stimuli suggests that genotype-endophenotype correlations may be accessible to molecular functional imaging of the brain. These new developments have broad implications for our understanding how genetic vulnerability to alcohol dependence is manifested in the brain's response to emotional stimuli.

Alcoholism↗

Photosensitivity, visually sensitive seizures and epilepsies.

Although many observations in patients with this intriguing type of epilepsy have been described and detailed studies have been performed, only a few meet the current criteria of class 1 or 2 evidence-based studies. In general, the selection bias is due to studying a referral population instead of the general population, and to different age and sex distributions of the subjects under study. Comparing the various studies is often difficult, because of differences in the populations studied (single seizures, epilepsy centre population, etc.), but also because of different methods (photic stimulator, flash frequencies, eye conditions, etc.) and the terminology used. Finally, and most crucial, in many studies there is often no information on how the data were actually obtained (EEG or clinical data or both?). The popular term "photosensitive" is used widely and applied to patients with a history of visually induced seizures, with and without a photoparoxysmal response (PPR), and to those with only a PPR. An overview of the "hard" data is given with future needs for a better understanding of this type of epilepsy and for improving the endophenotype for genetic research. It is important to standardise the studies as much as possible and describe in detail the methodology of the study, taking at least the above variables into account.

Electroencephalography↗

Genetics and personality traits in patients with social anxiety disorder: a case-control study in South Africa.

BACKGROUND: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. METHODS: Sixty-three patients (n=63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores >18, and age-matched control participants (n=150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/character). DNA was extracted and genotyped to investigate the role of select candidate genes encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls (n=88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). RESULTS: Patients scored significantly higher on harm avoidance (p<0.001) but lower on novelty seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT(2A)T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T/T+T/C] vs. [C/C]) (chi2=7.55; p=0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT(2A)T102C polymorphism in SAD patients. CONCLUSIONS: The results suggest a possible role for the 5-HT(2A)T102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.

Adolescent↗

Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies.

Multiple lines of evidence including recent imaging studies suggest that schizophrenia is associated with an imbalance of the dopaminergic system, entailing hyperstimulation of striatal dopamine (DA) D2 receptors and understimulation of cortical DA D1 receptors. This DA endophenotype presumably emerges from the background of a more general synaptic dysconnectivity, involving alterations in N-methyl-d-aspartate (NMDA) and glutamatergic (GLU) functions. Equally important is the fact that this DA dysregulation might further impair NMDA transmission. The first generation antipsychotic (FGA) drugs are characterized by high affinity to and generally high occupancy of D2 receptors. The efficacy of FGAs is limited by a high incidence of extrapyramidal side-effects (EPS). Second generation antipsychotic (SGA) drugs display reduced EPS liability and modest but clinically significant enhanced therapeutic efficacy. Compared to FGAs, the improved therapeutic action of SGAs probably derives from a more moderate D2 receptor blockade. We will review the effects of SGAs on other neurotransmitter systems and conclude by highlighting the importance of therapeutic strategies aimed at directly increasing prefrontal DA, D1 receptor transmission or NMDA transmission to enhance the therapeutic effect of moderate D2 receptor antagonism.

Antipsychotic Agents↗

Sustained and selective attention deficits as vulnerability markers to psychosis.

The first descriptions of schizophrenia emphasized attention problems patients with schizophrenia have but recent results evidence that other psychotic disorders share them. We compared the performance in sustained and selective attention between psychotic patients (P), their healthy first degree relatives (R) and healthy volunteers (C) to prove whether these alterations could be an endophenotype of vulnerability to psychosis. We also compared the performance of schizophrenic patients (SZP) and that of patients with other functional psychoses (OP) in order to prove whether these alterations are specific of any psychotic disorder. Seventy-six P, 70 R and 39 C were included in the study. A selective attention index, comprising TMT A and B and Stroop Test, and a sustained attention index comprising the Continuous Performance Test were calculated. We conducted an univariant general linear model to compare three group performances in these indexes, with age, sex and years of education as a covariables. We found significant differences between the indexes when we compared P, R and C. No differences in performance were found between SZP and OP. Our data showed that sustained and selective attention alterations could be a vulnerability factor to psychotic disorders in general, but they were not specific of schizophrenia.

Adult↗

Why genetic investigation of psychiatric disorders is so difficult.

Genetic investigations of psychiatric disease have historically relied on subjectively assessed disease diagnoses to define phenotypes. Recent developments in several areas have provided various new approaches to behavioral disorder phenotyping that promise to advance our understanding of the genetic and environmental etiologies of these traits. Such developments include re-evaluation of the boundaries between different psychiatric categories, implementation of quantitative neurobiological assessments that may serve as endophenotypes, generation of increasingly sophisticated animal behavioral models, and investigation of explicit environmental covariates. At the same time, movement toward large-scale, collaborative efforts is increasing the effectiveness of traditional genetic mapping approaches.

Animals↗

Resting EEG in offspring of male alcoholics: beta frequencies.

This study examines the differences in beta (12-28 Hz) band power in offspring of male alcoholics from densely affected alcoholic families. We have attempted to investigate if the increase in beta power is a 'state' or 'trait' marker for alcoholism. This study also explores the gender differences in the expression of this potential risk marker. Absolute beta power in three bands-beta 1(12-16 Hz), beta 2 (16-20 Hz), and beta 3 (20-28 Hz)-in the eyes closed EEG of 171 high risk (HR) subjects who were offspring of male alcoholics and 204 low risk (LR) subjects with no family history of alcoholism, were compared for each gender separately using a repeated measures analysis of variance design. Alcoholic and non-alcoholic subjects within the high risk group were compared using a repeated measures design as a follow-up analysis. The present study demonstrated increased beta power in the resting EEG of offspring of male alcoholics. Male HR subjects had higher beta 1 (12-16 Hz) power and female HR subjects had increased power in beta 2 (16-20 Hz) and beta 3 (20-28 Hz) as compared with low risk participants. Female HR subjects also showed significantly increased beta 2 and beta 3 power if they had two or more alcoholic first-degree relatives when compared with HR females having only an affected father. Risk characteristics are expressed differentially in males and females and may be an index of differential vulnerability to alcoholism. The results indicate that increased EEG beta power can be considered as a likely marker of risk for developing alcoholism and may be used as a predictive endophenotype.

Adolescent↗

The role of brain oscillations as functional correlates of cognitive systems: a study of frontal inhibitory control in alcoholism.

Event-related oscillations play a key role in understanding the brain dynamics and human information processing. In the present study, the Go/No-Go paradigm has been used to examine whether alcoholics have poor inhibitory control as compared to control subjects in terms of different oscillatory brain responses. The matching pursuit algorithm was used to decompose the event-related electroencephalogram into oscillations of different frequencies. It was found that alcoholics (n=58) showed significant reduction in delta (1.0-3.0 Hz) and theta (3.5-7.0 Hz) power during No-Go trials as compared to controls (n=29). This reduction was prominent at the frontal region. The decreased delta and theta power associated with No-Go processing perhaps suggests a deficient inhibitory control and information-processing mechanism. A neuro-cognitive model has been provided to explain the findings. It is suggested that the oscillatory correlates during cognitive processing can be an endophenotypic marker in alcoholism.

Adolescent↗

Evoked gamma band response in male adolescent subjects at high risk for alcoholism during a visual oddball task.

This study investigates early evoked gamma band activity in male adolescent subjects at high risk for alcoholism (HR; n=68) and normal controls (LR; n=27) during a visual oddball task. A time-frequency representation method was applied to EEG data in order to obtain stimulus related early evoked (phase-locked) gamma band activity (29-45 Hz) and was analyzed within a 0-150 ms time window range. Significant reduction of the early evoked gamma band response in the frontal and parietal regions during target stimulus processing was observed in HR subjects compared to LR subjects. Additionally, the HR group showed less differentiation between target and non-target stimuli in both frontal and parietal regions compared to the LR group, indicating difficulty in early stimulus processing, probably due to a dysfunctional frontoparietal attentional network. The results indicate that the deficient early evoked gamma band response may precede the development of alcoholism and could be a potential endophenotypic marker of alcoholism risk.

Adolescent↗

Delta and theta oscillations as risk markers in adolescent offspring of alcoholics.

BACKGROUND: Visual P300 is consistently lower in alcohol-dependent individuals, their offspring and subjects at risk. Delta and theta event-related oscillations (ERO) are the major contributors to the P300 signal. The total and evoked power in delta and theta bands in the 300 to 700 ms post-stimulus window (corresponding to the zone of P300 maxima) was compared between adolescent offspring of alcoholics (high-risk) and age-matched normal controls (low-risk), to assess the utility of the risk markers. METHODS: EEG was recorded during the performance of a visual oddball task. The S-transform algorithm decomposed the EEG signals into different frequency bands and the group differences in total and evoked power in the oscillatory responses during the P300 time window (300 to 700 ms) were analyzed using a multivariate design. Similar analysis was performed on P300 peak amplitude for the target. RESULTS: The high-risk group showed significantly lower parietal post-stimulus evoked and total power in the delta band for targets. A decrease in total power was seen centrally and parietally in the theta band. The P300 peak amplitude in the parietal electrodes was also significantly lower in the high-risk group. CONCLUSIONS: The decreased total theta power and total and evoked delta power for visual targets in high risk individuals may serve as an endophenotypic marker in the development of alcoholism and other disinhibitory disorders. The differences seen between the offspring of alcoholics and controls may have a cholinergic basis. The ERO measures appear to be more robust than the P300 amplitude in differentiating the groups.

Adolescent↗

TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament.

OBJECTIVE: To validate a short English-language version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), a self-report questionnaire designed to measure temperamental variations in psychiatric patients and healthy volunteers. Its constituent subscales and items were formulated on the basis of the diagnostic criteria for affective temperaments (cyclothymic, dysthymic, irritable, hyperthymic, and anxious), originally developed by the first author and his former collaborators. Further item wording and selection were achieved at a later stage through an iterative process that incorporated feedback from clinicians, researchers, and research volunteers. METHOD: A total of 510 volunteers (284 patients with mood disorders, 131 relatives of bipolar probands, and 95 normal controls) were recruited by advertisement in the newspapers, announcements on radio and television, flyers and newsletters, and word of mouth. All participants were interviewed using the Structured Clinical Interview for DSM-III-R, and completed the 110-item TEMPS-A and the Temperament and Character Inventory (TCI-125). The factorial structure, the alpha coefficients, and the item-total correlations coefficients of the TEMPS-A and the correlation coefficients between the dimensions of the TCI and the TEMPS-A subscales were then determined. RESULTS: A principal components analysis with a Varimax rotation found that 39 out of the 110 original items of the TEMPS-A loaded on five factors that were interpreted as representing the cyclothymic, depressive, irritable, hyperthymic, and anxious factors. Coefficients alpha for internal consistency were 0.91 (cyclothymic), 0.81 (depressive), 0.77 (irritable), 0.76 (hyperthymic), and 0.67 (anxious) subscales. We found statistically significant positive correlations between all-but the hyperthymic-subscales and harm avoidance. Positive correlations with the hyperthymic and cyclothymic, and novelty seeking and negative correlations with the remaining subscales were also recorded. Other major findings included positive correlations between the hyperthymic and reward dependence, persistence and self-directedness; positive correlation between the self-transcendence and the cyclothymic, hyperthymic and the anxious; and negative correlations between the depressive, cyclothymic, irritable, anxious and cooperativeness. LIMITATION: As the full-scale anxious temperament was added after the four scales of the TEMPS-A were developed, it has only been evaluated in 345 subjects. CONCLUSIONS: These data indicate that the TEMPS-A in its shortened version is a psychometrically valid scale with good internal consistency. The proposed five subscale structure is upheld. Concurrent validity against the TCI is shown. Most importantly, for each of the temperaments, we were able to show positive attributes which are meaningful in an evolutionary context, along with traits which make a person vulnerable to mood shifts. This hypothesized dual nature of temperament, which is upheld by our data, is a desirable characteristic for a putative behavioral endophenotype in an oligogenic model of inheritance for bipolar disorder.

Adult↗

Subthreshold depression is linked to the functional polymorphism of the 5HT transporter gene.

BACKGROUND: The functional polymorphism of the serotonin transporter gene (5HTTLPR) has been earlier associated with affective disorders. No research has however been carried out to identify the relationship between this polymorphism and depressive traits and subclinical depressive symptoms within a psychiatrically healthy population. METHODS: One hundred and twenty-eight female subjects with no lifetime or current history of DSM-IV Axis I disorders participated in the study. All subjects completed the Zung Self-Rating Depression Scale and were genotyped for the 5HTTLPR polymorphism. RESULTS: Significant differences were found on the Zung SDS and also on the physical-vegetative subscale of the Zung SDS according to both phenotype and genotype. Subjects carrying the s allele scored significantly higher on the Zung SDS and had also significantly higher scores on the physical-vegetative symptom subscale. Furthermore, subjects carrying the ss genotype scored highest and subjects carrying the ll genotype scored the lowest on both scales. CONCLUSION: Subclinical depressive symptoms (i.e. DSM-IV subthreshold depression) are associated with the functional polymorphism of the serotonin transporter gene. The main association between this polymorphism and subclinical depression is primarily carried by the physical symptoms of depression. The s allele of the 5HTTLPR gene is associated with a "low mood endophenotype".

Adolescent↗

The 5HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A.

BACKGROUND: Increasing evidence supports the notion of a continuum between affective temperaments and major mood disorders, suggesting that these temperament types represent the subclinical manifestations of affective disorders and often present an increased vulnerability for these diseases. METHODS: The Hungarian rendition of the full-scale 110-item version of the TEMPS-A questionnaire and 5HTTLPR genotype was investigated in a sample of 139 unrelated Caucasian females with no current or lifetime Axis I psychiatric disorders. RESULTS: A significant association was found between the s allele and the TEMPS scores of the depressive, anxious, irritable, and particularly the cyclothymic temperaments; no such association emerged with respect to the hyperthymic temperament. LIMITATION: The database is entirely female. Given that the hyperthymic type predominates in males, our results could have been different if men were included in our sample. CONCLUSIONS: Our results are in good agreement with earlier studies reporting a strong association between the s allele of the 5HTTLPR and major as well as subthreshold forms of depression, and extend this association to the normative temperament level. Indeed, these temperaments might best be regarded as proximate behavioural endophenotypes. Our data raise the provocative possibility that the genetic potential for mood episodes lies in these temperaments. Further studies are needed to delineate the role of gender in the associations under consideration, as well as to investigate the genetic background of the hyperthymia-mania part of the affective spectrum. Given that affective temperaments are widely distributed in the general population, the strategy employed by us is of potential public health significance in terms of detecting individuals in the community at risk for affective spectrum disorders.

Adolescent↗

Typus melancholicus: personality structure and the characteristics of major unipolar depressive episode.

BACKGROUND: The melancholic type of personality (TM) has long been considered in continental and Japanese psychopathology as a relevant vulnerability trait constellation for the development of depression. METHOD: The symptom presentation in an outpatient population of 116 subjects suffering from a DSM-IV major depressive episode was rated according to the standardized documentation system of the Association for Methodology and Documentation in Psychiatry (AMDP). Personality features were explored by means of the Criteria for Typus Melancholicus (CTM). RESULTS: Statistically significant differences in depression-related psychopathological scores (i.e. higher level of guilt feelings, feeling of the loss of feelings, loss of vital drive and lower degrees of irritability and dysphoria) were found between TM and non-TM subjects, supporting the phenomenic specificity of TM depression at both symptom and subsyndromal level. LIMITATION AND CONCLUSIONS: Although our results were obtained in a selected sample of outpatients at an University Mental Health Center, they are indicative of psychopathological differences between TM and NTM in the core symptoms of depression. These differences highlight the importance of including TM criteria for phenotypic characterization of depressive disorder, suggesting that it may improve diagnostic and therapeutic practice and might be a reasonable psychopathologic endophenotype in investigating affective-spectrum vulnerability in at-risk populations.

Adult↗

The assessment of anhedonia in clinical and non-clinical populations: further validation of the Snaith-Hamilton Pleasure Scale (SHAPS).

BACKGROUND: Anhedonia, the inability to experience pleasure, is a major endophenotype of depression. In addition to this, it is an important clinical feature of schizophrenia and substance abuse disorders. Valid instruments to measure anhedonia are sparse. METHODS: In the present study, a short, 14-item instrument, the Snaith-Hamilton Pleasure Scale (SHAPS) to measure anhedonia in normal and clinical samples was further validated. Various aspects of the reliability and validity of the SHAPS that have not been addressed before, were examined in three separate studies. First, we assessed the internal consistency, convergent and discriminative validity of the SHAPS in a non-clinical sample. Second, the test-retest reliability of the SHAPS was investigated in another sample. In the third study, the internal consistency, convergent and discriminative validity of the SHAPS was tested by administering the scale in three clinical samples of psychiatric inpatients. RESULTS: The SHAPS was found to be highly reliable in terms of internal consistency and test-retest stability. Further, the SHAPS correlated in a theoretically meaningful way with other measures of affect and personality. Patients with a depression, psychosis or substance dependence scored significantly higher on the SHAPS than non-patient controls. Patients with a depression displayed the highest SHAPS-score. LIMITATIONS: The absence of structured assessment data to validate the clinical diagnoses. CONCLUSIONS: The current study shows that the SHAPS is a reliable and valid questionnaire to assess hedonic tone in patient and non-patient populations. Because it is a brief scale it seems to be a very useful instrument for measuring anhedonia in clinical and research settings.

Adolescent↗