Tero Hallikainen

Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour

Abstract.Several studies have shown that impulsive violent and suicidal behaviour is associated with a central serotonin deficit, but until now it has not been possible to use laboratory tests with high sensitivity and specificity to study this kind of deficit or to localize the sites of serotonergic abnormalities in the living human brain. The aim of this study was to test the hypothesis that monoamine transporter density in brain is decreased in subjects with impulsive violent behaviour. We studied serotonin (5-HT) and dopamine (DA) transporter specific binding in 52 subjects (21 impulsive violent offenders, 21 age- and sex-matched healthy controls, and ten non-violent alcoholic controls) with single-photon emission tomography (SPET) using iodine-123-labelled 2β-carbomethoxy-3β(4-iodophenyl)tropane ([123I]β-CIT) as the tracer. The blind quantitative analysis revealed that the 5-HT specific binding of [123I]β-CIT in the midbrain of violent offenders was lower than that in the healthy control subjects (P<0.005; t test) or the non-violent alcoholics (P<0.05). The results imply that habitual impulsive aggressive behaviour in man is associated with a decrease in the 5-HT transporter density.

Lamotrigine in treatment-resistant schizophrenia: A randomized placebo-controlled crossover trial

BACKGROUND There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine. METHODS Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period. RESULTS In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms. CONCLUSIONS These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.

Increase in cerebral blood flow of right prefrontal cortex in man during orgasm

The functional anatomy of human emotional responses has remained poorly understood, mainly because invasive experiments in humans are unacceptable due to ethical reasons. The new functional imaging techniques such as positron emission tomography and single photon emission computed tomography have made it possible to study the neurophysiology of living humans noninvasively. We studied the regional cerebral blood flow with semi-quantitative 99mTc-HMPAO single photon emission computed tomography in eight healthy right-handed heterosexual males during organism. The results showed decrease of cerebral blood flow during orgasm in all other cortical areas except in right prefrontal cortex, where the cerebral blood flow increased significantly (P < 0.005).

Acute Ethanol-Induced Changes in Cerebral Blood Flow

Using high-resolution single photon emission computed tomography, the authors studied changes in cerebral blood flow (CBF) in six healthy men after the men rapidly consumed intoxicating amounts of ethanol. When the subjects were given intravenous placebo before ethanol intake, regional CBF was significantly increased over baseline in the right prefrontal cortex, but no significant change in CBF was observed when the subjects received intravenous naloxone before ethanol intake. The results indicate that euphoria occurring during acute ethanol intake is associated with activation of the right prefrontal cortex and mediated through the endogenous opioid system.

Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior

Addictive drugs, including ethanol, increase the brains dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (chi(2) = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1-8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior.

Ethanol Consumption and DRD2 Gene TaqI A Polymorphism Among Socially Drinking Males

The dopaminergic system in the human brain is thought to play a major role in the development of alcohol consumption habits and alcoholism. It has been reported that homozygous D2−/− knock‐out mice lacking D2 receptors consume about 50% to 60% less ethanol than wild‐type D2+/+ mice, and heterozygous mice have an intermediate level of alcohol consumption. The DRD2 gene TaqI A polymorphism has been suggested to associate with a low D2 receptor density in post mortem and in vivo measurements. Numerous association studies on this polymorphism and alcoholism have shown most controversial results. We studied whether DRD2 TaqI A genotype affects alcohol consumption in an ethnically homogenous, representative sample of 1,019 Finnish Caucasian males. After excluding the abstainers from the study, the self‐reported alcohol consumption among the remaining 884 non‐abstainers was compared in the TaqI A genotype groups (A1/A1, A1/A2, A2/A2). The alcohol consumption of the homozygous A1/A1 group was about 30% lower than in A1/A2 group, and 40% lower than in A2/A2 group (P = 0.042 and 0.041 in a sociodemographic variable‐adjusted multivariate model). The results indicate an association between DRD2 genotype and alcohol consumption habits in humans. These results in the large sample of non‐alcoholic males are also opposite to some previous findings on the higher A1 allele frequency among alcoholic populations.

Imaging the structure of the striatum: a fractal approach to SPECT image interpretation

The spatial pattern of striatal dopamine transporter density in the living human brain was tested by duplicate SPECT scans with [123I]PE2I, [123I]beta-CIT or [123I]beta-CIT-FP and striatal phantom measurements. The resolution-dependent spatial variation was calculated by the fractal analysis of SPECT images. This variation, which depends on the size of the region of interest, was described by the spatial dispersion i.e. the standard deviation of the count densities divided by the mean density. In each sub-region, the observed and methodological dispersions were computed, and the resulting spatial dispersion was calculated. The methodological dispersion is caused by the imaging resolution, flood field non-uniformity, count density, scatter, reconstruction errors and partial volume effects, whereas the spatial dispersion is based on the cerebral heterogeneity of the dopamine transporter density. Recognition of the normal variation in heterogeneity is important in evaluation of the striatal dopamine transporter density between controls and patients suffering from various neuropsychiatric disorders.

Effects of Venlafaxine Treatment on Clozapine Plasma Levels in Schizophrenic Patients

Depressive symptoms are found at any stage of schizophrenia, and antidepressant medication may be beneficial. Selective serotonin reuptake inhibitor antidepressants have been considered safe in schizophrenia but in combination with clozapine, that is widely used in chronic treatment-resistant schizophrenia, remarkable pharmacokinetic interactions can occur causing an elevation in clozapine plasma levels. To investigate this further, the plasma levels of clozapine were measured in 11 schizophrenic male patients with depressive symptoms who were administered both clozapine and venlafaxine. Low to moderate doses of venlafaxine did not seem to have any significant effect on clozapine plasma levels.