[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

Altered white matter integrity in adults with autism spectrum disorder and an IQ >100: a diffusion tensor imaging study.

OBJECTIVE: White matter (WM) alterations have been reported in children and adults with autism spectrum disorder (ASD). In particular, impaired connectivity of limbic structures may be related to social deficits. Heterogeneous findings could be explained in terms of differences in sample characteristics and methodology. In this context, non-syndromic forms might differ substantially in WM structure from secondary ASD forms. METHOD: In an attempt to recruit a homogeneous study sample, we included adults with high-functioning ASD and an IQ > 100 to decrease the influence of syndromic forms being often associated with cognitive deficits. Diffusion tensor imaging (DTI) was performed in 30 participants with ASD and 30 pairwise-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) as surrogate imaging markers for WM integrity were calculated. RESULTS: We found a significant FA decrease in the ASD group in the genu and body of the corpus callosum (CC). Increased MD was detected in the subgenual anterior cingulate cortex (sACC). CONCLUSION: The finding of decreased WM integrity in the genu of the CC is in line with earlier studies reporting a decreased number of interhemispheric fibers in the frontal lobe of ASD. Alterations in the sACC might be associated with 'Theory of mind' deficits.

Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis.

Over the last few years, awareness of autism spectrum disorder (ASD) in adults has increased. The precise etiology of ASD is still unresolved. Animal research, genetic and postmortem studies suggest that the glutamate (Glu) system has an important role, possibly related to a cybernetic imbalance between neuronal excitation and inhibition. To clarify the possible disruption of Glu metabolism in adults with high-functioning autism, we performed a magnetic resonance spectroscopy (MRS) study investigating the anterior cingulate cortex (ACC) and the cerebellum in adults with high-functioning ASD. Twenty-nine adult patients with high-functioning ASD and 29 carefully matched healthy volunteers underwent MRS scanning of the pregenual ACC and the left cerebellar hemisphere. Metabolic data were compared between groups and were correlated with psychometric measures of autistic features. We found a significant decrease in the cingulate N-acetyl-aspartate (NAA) and the combined Glu and glutamine (Glx) signals in adults with ASD, whereas we did not find other metabolic abnormalities in the ACC or the cerebellum. The Glx signal correlated significantly with psychometric measures of autism, particularly with communication deficits. Our data support the hypothesis that there is a link between disturbances of the cingulate NAA and Glx metabolism, and autism. The findings are discussed in the context of the hypothesis of excitatory/inhibitory imbalance in autism. Further research should clarify the specificity and dynamics of these findings regarding other neuropsychiatric disorders and other brain areas.

Altered cingulate and amygdala response towards threat and safe cues in attention deficit hyperactivity disorder.

BACKGROUND: Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). METHOD: In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS- were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS- during testing. No UCS was presented. RESULTS: Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. CONCLUSIONS: During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS--related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

[High-functioning autism spectrum disorders in adulthood]. / Autismusspektrumstörungen mit hohem Funktionsniveau im Erwachsenenalter.

The prevalence of autism spectrum disorders in the general population is approximately 1 %. Some individuals with high-functioning autism graduate from regular schools without autism having been diagnosed and problems only occur when the demands for social competence increase. Then patients often present with secondary psychiatric symptoms, such as depression, anxiety or interpersonal problems. At this time, typical autistic features, such as social interaction deficits, restricted interests and stereotypic behavior can be camouflaged by high compensatory skills, particularly in highly intelligent patients. Therefore, missed or wrong diagnoses are frequent. Interviews, questionnaires and neuropsychological tests might be used to support the diagnosis. In cases where there is evidence for a secondary cause of autistic symptoms, somatic disorders should be excluded. Pharmacological treatment should be symptom-oriented. Individualized psychotherapeutic approaches are becoming increasingly more available; however, pragmatic solutions often need to be deployed.

Toward the development of a supported employment program for individuals with high-functioning autism in Germany.

Human-human interactions are of central relevance for the success in professional and occupational environments, which also substantially influence quality of life. This is especially true in the case of individuals with high-functioning autism (HFA), who experience deficits in social cognition that often lead to social exclusion and unemployment. Despite good education and high motivation, individuals with HFA do not reach employment rates that are substantially higher than 50 %. This is an alarmingly high rate of unemployment considering that the United Nations have recently emphasized the inclusion of handicapped persons as a mandatory human right. To date, the specific needs of autistic persons with respect to their working environment are largely unexplored. It remains moreover an open question how support systems and activities, including newly developed communication devices for professional environments of individuals with HFA, should look like. The German health and social care systems are not adequately prepared for the proper support of this population. This leads us to suggest that supported employment programs should be developed for adults with HFA that specifically address their needs and requirements. Such programs should comprise (1) the adequate assessment of HFA, including a neuropsychological profile and an individual matching of persons' preferences with requirements of the working place, (2) on-the-job coaching activities that include systematic communication and interaction training, and (3) instruction of non-autistic peers, including colleagues and supervisors, about weaknesses and strengths of HFA.

Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder -- a magnet resonance spectroscopy study.

BACKGROUND: The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD. In the present study, we wanted to test the hypothesis that prefrontal glutamate signals indirectly indicate dopaminergic dysfunction in adult patients with ADHD. METHODS: Twenty-eight adult patients with ADHD and 28 group-matched healthy volunteers were studied clinically and using chemical-shift MR spectroscopy (MRS) of the prefrontal cortex covering the anterior cingulate gyrus. RESULTS: A significant reduction of the combined glutamate/glutamine to creatine ratio in the right anterior cingulate cortex in patients with ADHD was found. DISCUSSION: Glutamatergic alterations as measured with MRS might play a role in the pathogenesis of adult patients with ADHD.

Evidence of disturbed amygdalar energy metabolism in patients with borderline personality disorder.

In order to detect possible links between structural and neurochemical brain abnormalities we applied high resolution morphometric imaging and short-echo time absolute-quantification magnetic resonance spectroscopy (MRS) at the left hand side to the amygdala in 12 patients with borderline personality disorder (BPD) and 10 group-matched healthy controls. Confirming earlier reports we found a significant 11-17% reduction of amygdalar volumes in patients with BPD. In addition there was a significant 17% increase of left amygdalar creatine concentrations in BPD patients. Left amygdalar creatine concentration correlated positively with measures of anxiety and negatively with amygdalar volume. This pilot study of simultaneous amygdalar morphometry and spectroscopy in BPD reveals a possible link between amygdalar volume loss, psychopathology and neurochemical abnormalities in terms of creatine signals.

Amygdala enlargement in dysthymia--a volumetric study of patients with temporal lobe epilepsy.

BACKGROUND: Previous studies indicated an important role of the amygdala for emotional information processing. We investigated a possible relationship between amygdala volumes, aggressive behavior, and dysthymia, in patients with temporal lobe epilepsy (TLE). METHODS: Patients with TLE with and without aggression or dysthymia and healthy volunteers were assessed using quantitative MRI. Amygdala volumes were measured in a blinded fashion and corrected for total brain volumes. RESULTS: There was a highly significant enlargement of left and right amygdala volumes in patients with dysthymia (right side, p < .000; left side, p = .001). We found a significant positive correlation between left amygdala volumes (p = .02) and a trend towards positive correlation between right amygdala volumes and depression (p = .06), as measured with the Beck Depression Inventory. Amygdala volumes of females were significantly larger than those of males (left side: p = .005; right side: p = .06). CONCLUSIONS: This is the second report of a relationship between amygdala volumes and depressed mood, confirming an earlier finding in patients with bipolar disease, and the first study reporting a correlation between amygdala volumes and depression. Increased processing of emotional information might increase amygdala blood flow and subsequently, result in amygdala enlargement.

Visual contrast response functions in Parkinson's disease: evidence from electroretinograms, visually evoked potentials and psychophysics.

OBJECTIVES: Visual contrast detection thresholds and suprathreshold contrast discrimination thresholds were compared to luminance and flash/pattern electroretinograms (ERG) and visually evoked potentials (VEP) in patients with Parkinson's disease (n = 31), patients with multiple system atrophy (n = 6), patients with progressive supranuclear palsy (n = 6) and control patients without central nervous disease (n = 33). METHODS: The stimuli were luminance modulated full-field (flash) or horizontally oriented sinewave gratings (pattern), the latter having either a low (0.5 cycles/deg) or medium (4.0 cycles/deg) spatial frequency. Stimulus contrast ranged from 10 to 80% so that contrast response functions could be derived. RESULTS: Contrast thresholds were higher in the patients with Parkinson's disease than in the control patients. Contrast discrimination thresholds were also somewhat elevated in patients with Parkinson's disease. Pattern ERG amplitudes were significantly reduced in patients with Parkinson's disease for the medium spatial frequency stimulus, but less for the low spatial frequency and flash stimuli. CONCLUSIONS: Our results suggest that Parkinson's disease impairs contrast processing in the retina. VEP amplitudes did not significantly differ between the groups for the conditions tested. Patients with progressive supranuclear palsy also showed impaired contrast perception and reduced ERG amplitudes, whereas patients with multiple system atrophy were less impaired.

Increased amygdala volumes in female and depressed humans. A quantitative magnetic resonance imaging study.

The amygdala are thought to play an important role in emotional information processing. First studies indicate a link between amygdala atrophy, fear and aggression and between amygdala hypertrophy and depression. To investigate a possible relationship between amygdala volumes, aggression and depression, we measured the amygdala of 62 patients with temporal lobe epilepsy (TLE) with and without aggressive behavior or depression and 20 healthy volunteers using quantitative magnetic resonance imaging (MRI). Amygdala volumes of female patients (n=26) were significantly larger than those of males (n=36) (left side: P=0.001; right side P=0.05). Depressed patients displayed significant enlargement of both amygdala (left side: P=0.008; right side: P=0.001) There was no significant finding relating to the factor aggression neither was there any significant interaction between aggression, dysthymia and gender.

Frontoorbital volume reductions in adult patients with attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood and adolescence and in a considerable number of patients it persists into adulthood. A network of brain regions have been shown to be abnormal in ADHD. In the present study we used magnetic resonance volumetry to investigate a possible role of the orbitofrontal cortex (OFC). Eight never medicated male patients fulfilling diagnostic criteria for ADHD and 17 male healthy controls were investigated. There was a significant reduction of the volume of the left OFC in patients with ADHD. It remains unknown whether small volumes are a primary deficit or a result of dysfunctional activation during childhood in terms of a residual deficit or a specific type of adult outcome of the disease.

Attention-deficit disorder in adults with or without hyperactivity: where is the difference? A study in humans using short echo (1)H-magnetic resonance spectroscopy.

The DSM-IV distinguishes three subtypes of attention deficit hyperactivity disorder: The predominantly inattentive subtype (ADD), the hyperactive-impulsive subtype (ADHD) and the combined subtype. We used short echo time (1)H-magnetic resonance spectroscopy (TE=30 ms, TR=3000 ms) for absolute quantification of neurometabolites using the LC model algorithm to investigate a possible metabolic neuropathology in adult patients with ADD and ADHD and compared their spectra with healthy controls (n=5 in each group). Spectra were acquired in the left dorsolateral prefrontal cortex and the left striatum. There was a significant group difference in N-acetylaspartate (NAA) concentration in the left dorsolateral prefrontal cortex distinguishing patients with the ADHD from patients with pure ADD and healthy controls. The absolute NAA concentration was significantly reduced only in the ADHD group. Since NAA-depletion reflects a state of neuronal dysfunction, this finding indicates evidence of subtle left prefrontal neuropathology in ADHD in adults.

Chronic antidopaminergic medication might affect amygdala structure in patients with schizophrenia.

BACKGROUND: Recently amygdala enlargement has been reported in patients with schizophrenia like psychosis of epilepsy. The effect of antipsychotic medication on amygdala structure has not been investigated so far. There is theoretical evidence to support the assumption that dopaminergic neurotransmission might affect neuronal plasticity. METHODS: In order to analyze the influence of chronic antidopaminergic medication on amygdala structure we compared amygdala volumes in patients with schizophrenia like psychosis of epilepsy (POE) treated with neuroleptic medication (n = 11) to patients with POE not treated with such medication (n = 15), patients with epilepsy alone (n = 24) and healthy control subjects (n = 20). RESULTS: Analyzing our data with a factorial ANOVA approach, we found a significant effect of the factor medication in that patients treated with antipsychotic medication displayed a "normalization" of the increased amygdala volumes observed in the untreated patient group. CONCLUSION: This observation supports the assumption that antidopaminergic medication might affect the amygdala structure.

A psychopathological study into the relationship between attention deficit hyperactivity disorder in adult patients and recurrent brief depression.

OBJECTIVE: Clinical and epidemiological observations and neurobiological data suggest that there might be an inherent link between attention deficit hyperactivity disorder (ADHD) and recurrent brief depression (RBD). In this psychopathological study, we investigated the comorbidity between these two conditions. METHOD: Using an index patient approach 40 adult out-patients fulfilling the criteria for ADHD were investigated for lifetime history of RBD and another 40 out-patients with the primary diagnosis of RBD were investigated for a lifetime history of ADHD. RESULTS: We found a high prevalence of RBD in patients with ADHD (70%) while the prevalence of ADHD in the index sample with RBD was smaller (about 40%). CONCLUSION: In terms of comorbidity ADHD was the second commonest psychiatric disorder in patients with RBD next to other affective disorders. The psychopathological pattern of lifetime comorbidity might be of clinical relevance in terms of medical treatment.

Contrast detection, discrimination and adaptation in patients with Parkinson's disease and multiple system atrophy.

Visual spatial contrast thresholds and suprathreshold contrast matches were measured before and after adaptation to high-contrast sinewave gratings in patients with Parkinson's disease (n = 27), patients with multiple system atrophy (n = 6) and a group of age-matched control patients without CNS disease (n = 27). Contrast thresholds were higher in the Parkinson's disease patients than in either the multiple system atrophy patients or control patients. The effect of contrast adaptation on both contrast thresholds and matches was approximately equal in the three groups. This suggests that contrast adaptation is not affected by these CNS disorders and is consistent with the hypothesis that the loss in contrast sensitivity in Parkinson's disease is mediated by retinal effects. The results are discussed in terms of the underlying pathology of the visual deficits in Parkinson's disease and the possible diagnostic implications for differentiating Parkinson's disease and multiple system atrophy.

Religiosity is associated with hippocampal but not amygdala volumes in patients with refractory epilepsy.

OBJECTIVE: To assess the relationship between the behavioural triad of hyper-religiosity, hypergraphia and hyposexuality in epilepsy, and volumes of the mesial temporal structures. METHOD: Magnetic resonance images were obtained from 33 patients with refractory epilepsy and mesial temporal structure volumes assessed. Amygdala and hippocampal volumes were then compared in high and low scorers on the religiosity, writing, and sexuality sub-scales of the Neurobehavioural Inventory. RESULTS: Patients with high ratings on the religiosity scale had significantly smaller right hippocampi. Religiosity scores rated by both patient and carer showed a significant negative correlation with right hippocampal volumes in this group. There were no other differences in amygdala or hippocampal volumes between these groups, or between high and low scorers on the writing and sexuality sub-scales. CONCLUSIONS: These findings suggest that right hippocampal volumes are negatively correlated with religiosity in patients with refractory epilepsy.

Amygdala pathology in psychosis of epilepsy: A magnetic resonance imaging study in patients with temporal lobe epilepsy.

Psychosis of epilepsy (POE) has been recognized as a severe complication of chronic intractable epilepsy for more than a century. Most of the clinical symptoms of POE are reminiscent of schizophrenia. Nevertheless, there is general agreement that the phenomenology of POE differs from classical schizophrenia. The temporal lobe hypothesis of schizophrenia put forward in the 1960s notes that episodes with paranoid psychoses are more prevalent in temporal lobe epilepsy (TLE). However, the aetiology and pathogenesis of POE are poorly understood. One of the strongest biological findings in schizophrenia is volume loss of temporal lobe structures and the hippocampus in particular. In order to test the hypothesis that atrophy of the hippocampus and the amygdala is found in patients with TLE and POE, we performed a retrospective study of all patients with TLE who were admitted to the assessment unit of the Chalfont Centre for Epilepsy from 1995 until 1999. Twenty-six (2.6%) of these 1008 patients fulfilled inclusion criteria and were compared with 24 patients with TLE without psychopathology and 20 healthy volunteers. All patients underwent extensive MRI investigations, including volumetric data sets and quantitative T(2 )relaxometry. We found that patients with TLE and POE differed from patients with TLE alone and healthy volunteers in that the total brain volumes were significantly smaller. While there were no differences in hippocampal volumes between the three study groups, there was a significant 16-18% enlargement of the amygdala on both sides in patients with POE. Our findings support the notion that POE is a distinct nosologic entity differing from schizophrenia not only in clinical details but also in neurobiological aspects. The finding of amygdala enlargement agrees with the observation of an association between dysphoric disorders of epilepsy and POE described nearly 100 years ago.