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Are suicide attempts associated with polymorphisms in serotonergic genes?
R6 Other topics
~ A m
Mismatch negativity (MMN) is modulated by dopamlne D2 receptors. Combined EEG and MEG study
suicide attempts associated with polymorphisms in semtonsrgic genes?
D. Rujescu, M. Schgfer, I. Giegling, G. Scheerer, A. Gietl, E Mfdler-Siecheneder, B. Bondy, H.-J. M611er. Department of
Psychiatry, Ludwig-Maximilians-University, Munich, Germany Introduction: Twin studies show a cumulative concordance for completed suicide of 11.3% for monozygotes and 1.8% for dizygores. The estimated heritability is 40% under the assumption of a multifactorial inheritance. During the last 25 years an immense body of evidence points toward the involvement of the serotonergic system in suicidal behavior. Hence, variations in serotonergic genes might contribute to the interindividual vulnerabilityfor this behavior. Until recently, only few studies addressed this question and the results are inconsistent. In this study, we attempted to investigate the role of a comprehensive set of serotonergic candidate genes. Their selection was driven by results from post mortem and genetic studies. Post mortem studies show decreased density of presynaptic serotonin binding sites (partially identical with the serotonin transporter) in the frontal cortex of suicide victims whereas the density ofpostsynaptic 5-HT2A bindingsites is increased. Genetic studies demonstrate an association of a polymorphism in the TPH-gene with suicidal behavior. A functional polymorphism in the promoter of the serotonin transporter gene was found to be associated with completed, mostly aggressive suicide. 5-HT1B knock-out mice show increased aggressive behavior which might parallel the increased level of impulsive aggression found in suicide attempters. In this study we test the hypothesis that suicidal behavior is associated with variations in serotonergic genes. Methods: 18-65 year old Caucasian inpatients, with a current or past history of suicide attempts and various psychiatric disorders (n = 90) were included. The diagnosis was established by the Structured Clinical Interview for DSM-IV (SCID I and SCID II). Exclusion criteria included any serious medical condition, mood disorders due to a general medical condition or substance abuse, dementia, and also schizophrenia and related psychotic disorders. 18-65 year old Caucasians were randomly selected from the general population of Munich and contacted by marl. Subjects who responded were first screened by phone. They subsequently filled out a detailed medical history form both for themselves and their relatives. Psychiatric disorders of the subjects were excluded by SCID I and SCID II and a psychiatric diagnosis in first and second-degree relatives was excluded using the Family History Assessment Module (FHAM). 140 healthy control subjects without relevant somatic and with no psychiatric disorder were included. After written informed consent had been obtained from all subjects, blood samples were collected and the distribution of a genetic potymorphisms in the 5HT1B, 5-HT2A, TPH and SERT genes were examined. Results and Discussion: We found no difference in the distribution of genetic polymorphisms in the 5HT1B and SERT genes between groups. In contrast, there was an association of polymorphisms in the 5-HT2A & TPH genes with suicidal behavior. This study further supports and extends the hypothesis that variations in serotonergic genes contribute to this complex behavior. R m s
[I] D. Rujescu is supportedby the StanleyFoundation
$401
S. IOhk6nan1,2, j. A h v e n i n e n 2 ' E. Pekkonen 1,2,3, S. Kaakkola 3, J. Huttunen3, R. N~t§nan2, LP. J~i~skelftinen2 . IBioMag Lab.,
Medical Engineering Centre, Helsinki University Central Hospital; 2CBRU, Dept. of Psychology, University of Helsinki; 3Dept. of Clinical Neuroscience, Helsinki University Central Hospital, Finland Introduction: Pre-attentive auditory sensory processing can be studied with auditory evoked potentials (AEP) and magnetic fields (AEF) using the mismatch negativity (MMN and MMNm, respectively), which is evoked by infrequent deviant sounds embedded in a sequence of standard sounds (1). Previous studies have shown that the MMN amplitude decreases in schizophrenia (2), the neurochemical abnormality has, however, remained ambiguous. Methods: We investigated MMN in healthy volunteers in a double-blind, placebo-controlled, cross-over design study. Dopamine D2 receptor antagonist haloperidol (2 rag) was given orally to 12 fight-handed healthy volunteers (aged 20-28 years; 6 females) 3 hours before the recording. Subjects were presented, dichotically through earphones, with standard (700 Hz to the left ear, 1100 I-Iz, to the right ear, p = 0.44 for each), and deviant (770 and 1210 Hz respectively, p = 0.06 for each) 60ms pure tones at 60 dB above individually measured hearing threshold. Interstimnlus interval was random at 210--410 ins. Subjects were to attend to tones presented to one ear and to count silently the number of deviants, while ignoring tones presented to the other ear. The AEPs/AEFs were recorded with 122-channel maguetoencephalogram (MEG) and 64-channel electroencephalogram (EEG). The peak amplitudes and latencies for MMN were
obtained from FCz and for MMNm
from the channel pair showing
the highest-amplitude responses, separately for the left and right temporal areas.
Results:Haloperidol increased MMN and MMNm amplitudes for frequency change, however, the latter effect failed to reach statistical significance. No effects were observed on the peak latencies (Table I). Table 1. Effects of haloperidol on mismatchnegativity(MMN) Haloperidol
Placebo
Amplitude MMNmLatency(ms) (fr/cm) Contra Ipsi ContraIpsi 186± 180± 41 + 22 25 20
MMN
Ampfitude Latency (ms) (fr/cm) ContraIpsi ContraIpsi
34 4- 183± 179 4- 31 ± 30 39 41 14
21 417
Latency(ms) Amplitude Latency(ms) Amplitude (t~v) (~v) 190 + 52
-2.08 41.02
149 4- 55
-1.03 4- 0.81 (,p = .02)
Conclusions: The present results suggest that pre-attentive auditory processing is modulated by dopamine D2 receptors. The differing sensitivities of EEG and MEG to detect the effects of
~ A m
Mismatch negativity (MMN) is modulated by dopamlne D2 receptors. Combined EEG and MEG study
suicide attempts associated with polymorphisms in semtonsrgic genes?
D. Rujescu, M. Schgfer, I. Giegling, G. Scheerer, A. Gietl, E Mfdler-Siecheneder, B. Bondy, H.-J. M611er. Department of
Psychiatry, Ludwig-Maximilians-University, Munich, Germany Introduction: Twin studies show a cumulative concordance for completed suicide of 11.3% for monozygotes and 1.8% for dizygores. The estimated heritability is 40% under the assumption of a multifactorial inheritance. During the last 25 years an immense body of evidence points toward the involvement of the serotonergic system in suicidal behavior. Hence, variations in serotonergic genes might contribute to the interindividual vulnerabilityfor this behavior. Until recently, only few studies addressed this question and the results are inconsistent. In this study, we attempted to investigate the role of a comprehensive set of serotonergic candidate genes. Their selection was driven by results from post mortem and genetic studies. Post mortem studies show decreased density of presynaptic serotonin binding sites (partially identical with the serotonin transporter) in the frontal cortex of suicide victims whereas the density ofpostsynaptic 5-HT2A bindingsites is increased. Genetic studies demonstrate an association of a polymorphism in the TPH-gene with suicidal behavior. A functional polymorphism in the promoter of the serotonin transporter gene was found to be associated with completed, mostly aggressive suicide. 5-HT1B knock-out mice show increased aggressive behavior which might parallel the increased level of impulsive aggression found in suicide attempters. In this study we test the hypothesis that suicidal behavior is associated with variations in serotonergic genes. Methods: 18-65 year old Caucasian inpatients, with a current or past history of suicide attempts and various psychiatric disorders (n = 90) were included. The diagnosis was established by the Structured Clinical Interview for DSM-IV (SCID I and SCID II). Exclusion criteria included any serious medical condition, mood disorders due to a general medical condition or substance abuse, dementia, and also schizophrenia and related psychotic disorders. 18-65 year old Caucasians were randomly selected from the general population of Munich and contacted by marl. Subjects who responded were first screened by phone. They subsequently filled out a detailed medical history form both for themselves and their relatives. Psychiatric disorders of the subjects were excluded by SCID I and SCID II and a psychiatric diagnosis in first and second-degree relatives was excluded using the Family History Assessment Module (FHAM). 140 healthy control subjects without relevant somatic and with no psychiatric disorder were included. After written informed consent had been obtained from all subjects, blood samples were collected and the distribution of a genetic potymorphisms in the 5HT1B, 5-HT2A, TPH and SERT genes were examined. Results and Discussion: We found no difference in the distribution of genetic polymorphisms in the 5HT1B and SERT genes between groups. In contrast, there was an association of polymorphisms in the 5-HT2A & TPH genes with suicidal behavior. This study further supports and extends the hypothesis that variations in serotonergic genes contribute to this complex behavior. R m s
[I] D. Rujescu is supportedby the StanleyFoundation
$401
S. IOhk6nan1,2, j. A h v e n i n e n 2 ' E. Pekkonen 1,2,3, S. Kaakkola 3, J. Huttunen3, R. N~t§nan2, LP. J~i~skelftinen2 . IBioMag Lab.,
Medical Engineering Centre, Helsinki University Central Hospital; 2CBRU, Dept. of Psychology, University of Helsinki; 3Dept. of Clinical Neuroscience, Helsinki University Central Hospital, Finland Introduction: Pre-attentive auditory sensory processing can be studied with auditory evoked potentials (AEP) and magnetic fields (AEF) using the mismatch negativity (MMN and MMNm, respectively), which is evoked by infrequent deviant sounds embedded in a sequence of standard sounds (1). Previous studies have shown that the MMN amplitude decreases in schizophrenia (2), the neurochemical abnormality has, however, remained ambiguous. Methods: We investigated MMN in healthy volunteers in a double-blind, placebo-controlled, cross-over design study. Dopamine D2 receptor antagonist haloperidol (2 rag) was given orally to 12 fight-handed healthy volunteers (aged 20-28 years; 6 females) 3 hours before the recording. Subjects were presented, dichotically through earphones, with standard (700 Hz to the left ear, 1100 I-Iz, to the right ear, p = 0.44 for each), and deviant (770 and 1210 Hz respectively, p = 0.06 for each) 60ms pure tones at 60 dB above individually measured hearing threshold. Interstimnlus interval was random at 210--410 ins. Subjects were to attend to tones presented to one ear and to count silently the number of deviants, while ignoring tones presented to the other ear. The AEPs/AEFs were recorded with 122-channel maguetoencephalogram (MEG) and 64-channel electroencephalogram (EEG). The peak amplitudes and latencies for MMN were
obtained from FCz and for MMNm
from the channel pair showing
the highest-amplitude responses, separately for the left and right temporal areas.
Results:Haloperidol increased MMN and MMNm amplitudes for frequency change, however, the latter effect failed to reach statistical significance. No effects were observed on the peak latencies (Table I). Table 1. Effects of haloperidol on mismatchnegativity(MMN) Haloperidol
Placebo
Amplitude MMNmLatency(ms) (fr/cm) Contra Ipsi ContraIpsi 186± 180± 41 + 22 25 20
MMN
Ampfitude Latency (ms) (fr/cm) ContraIpsi ContraIpsi
34 4- 183± 179 4- 31 ± 30 39 41 14
21 417
Latency(ms) Amplitude Latency(ms) Amplitude (t~v) (~v) 190 + 52
-2.08 41.02
149 4- 55
-1.03 4- 0.81 (,p = .02)
Conclusions: The present results suggest that pre-attentive auditory processing is modulated by dopamine D2 receptors. The differing sensitivities of EEG and MEG to detect the effects of