Jarmo Hietala

Comparison of the Transient Equilibrium and Continuous Infusion Method for Quantitative PET Analysis of [11C]Raclopride Binding

Several approaches have been applied for quantification of D2 dopamine receptors in positron emission tomography studies using [11C]raclopride. Initial approaches were based on analyses of data obtained after rapid bolus injection of [11C]raclopride. A continuous infusion paradigm has more recently been applied. The current study compares these approaches in healthy men. Two positron emission tomography measurements were performed in each of six healthy men, the first with rapid bolus injection and the second with continuous infusion of [11C]raclopride. In rapid bolus injection, the binding potential was calculated by the following methods. One approach is the kinetic analysis using the standard three-compartment model. Another is to define a transient equilibrium at the moment when the specific binding reaches its maximum. In continuous infusion, binding potential was calculated by using time-activity data at equilibrium condition. All methods gave almost identical binding potential, representing cross-validation of these methods. The continuous infusion method can provide “true” equilibrium condition. The kinetic analysis is a sophisticated approach but requires determination of an arterial input function. The transient equilibrium method thus is suitable for routine clinical research, since it does not require determination of an arterial input function.

Extrastriatal dopamine D2 and D3 receptors in early and advanced Parkinson's disease

Objective: To investigate whether dopamine D2 and D3 receptor subtypes (D2/3Rs) outside the caudate-putamen are affected in PD. Background: Alterations in striatal D2-like dopamine receptors in PD have been extensively demonstrated using PET, but there are no studies focusing on extrastriatal D2/3Rs. Methods: Fourteen unmedicated patients with idiopathic early PD with predominantly left-sided symptoms, 14 levodopa-medicated patients with advanced PD, and 20 normal age-matched controls were examined using PET. PET scanning was performed with a novel high-affinity D2/3R radioligand ([11C]FLB 457) and a PET scanner in three-dimensional mode. Results: In advanced PD, the binding potential of [11C]FLB 457 in the dorsolateral prefrontal cortex was decreased by 40% (p < 0.01), in the anterior cingulate cortex by 20% (p < 0.01), and in the medial thalamus by 17% (p < 0.05) compared with healthy controls. In early PD, the extrastriatal [11C]FLB 457 binding potentials were not significantly different compared with the control group. However, the binding potential in the anterior cingulate cortex (29%; p < 0.05) was higher in early PD compared with advanced PD. Conclusions: These results imply that the D2/3 receptor subtypes outside the striatum are affected in advanced PD but not in the early stages of the disease, and that this receptor decline is present in the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus.

Sevoflurane and propofol increase 11C-flumazenil binding to gamma-aminobutyric acidA receptors in humans.

Based on in vitro studies and animal data, most anesthetics are supposed to act via &ggr;-aminobutyric acid type A (GABAA) receptors. However, this fundamental characteristic has not been extensively investigated in humans. We studied 11C-flumazenil binding to GABAA receptors during sevoflurane and propofol anesthesia in the living human brain using positron emission tomography (PET). Fourteen healthy male subjects underwent 2 60-min dynamic PET studies with 11C-labeled flumazenil, awake and during anesthesia. Anesthesia was maintained with 2% end-tidal sevoflurane (n = 7) or propofol at a target plasma concentration of 9.0 ± 3.0 (mean ± sd) &mgr;g/mL (n = 7). The depth of anesthesia was measured with bispectral index (BIS). Values of regional distribution volumes (DV) of 11C-flumazenil were calculated in several brain areas using metabolite-corrected arterial plasma curves and a two-compartment model. Separate voxel-based statistical analysis using parametric DV images was performed for detailed visualization. The average BIS index was 35 ± 6 in the sevoflurane group and 28 ± 8 in the propofol group (P = 0.02). Sevoflurane increased the DV of 11C-flumazenil significantly (P < 0.05) in all brain areas studied except the pons and the white matter. In the propofol group the increases were significant (P < 0.05) in the caudatus, putamen, cerebellum, thalamus and the frontal, temporal, and parietal cortices. Furthermore, the DV increases in the frontal, occipital, parietal, and temporal cortical areas and in the putamen were statistically significantly larger in the sevoflurane than in the propofol group. Our findings support the involvement of GABAA receptors in the mechanism of action of both anesthetics in humans.

Gender differences in brain serotonin transporter availability in panic disorder

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP ND) in male and female patients with PD. The SERT BP ND was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [11C]MADAM tracer. SERT BP ND were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP ND were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT1A receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation

&NA; The 957C>T polymorphism of the dopamine D2 receptor gene acts as an independent determinant of thermal pain sensitivity and susceptibility to neuropathic pain. &NA; We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n = 29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n = 16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol‐O‐methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P = .0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P = .0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P = .0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain.

Effects of lorazepam administration on striatal dopamine D2 receptor binding characteristics in man--a positron emission tomography study.

Abstract Lorazepam is a widely used benzodiazepine class anxiolytic drug. It is known to enhance GABAergic neurotransmission in the brain, but the actions of benzodiazepines on other neurotransmitter systems are largely unknown. We studied the effects of 1u2005week’s administration with lorazepam (2u2005mg daily, PO) or placebo on striatal D2 dopamine receptors in four healthy male volunteers using a double-blind randomized cross-over design. D2 receptor density and affinity as well as binding potential (Bmax/Kd) were measured with [11C]-raclopride and positron emission tomography. Although the individual responses varied, lorazepam did not significantly affect D2 receptor binding characteristics, nor did the average effect sizes exceed test-retest variability of the method. In conclusion, the results suggest that striatal D2 dopamine receptor characteristics are not affected by the clinically relevant lorazepam treatment regimen used.

Noradrenergic and dopaminergic effects of nomifensine in healthy volunteers.

Intravenous doses (100 mg in 20 minutes) of the antidepressant drug nomifensine, administered to male volunteers, increased heart rate and blood pressure, elevated the plasma levels of norepinephrine and its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), and powerfully stimulated growth hormone release and inhibited the secretion of prolactin. Oral nomifensine, either as a single 100 mg dose or as a similar dose after 2 weeks treatment with the drug (150 mg/day), caused none of the above effects. This was in line with the limited (less than 30%) oral bioavailability of the active, unconjugated form of the drug, estimated in the same subjects. MHPG in plasma was slightly but consistently reduced by the 2 weeks treatment, suggesting reduced turnover of norepinephrine. The observed clinical effects of nomifensine are compatible with uptake inhibition and augmented release of norepinephrine and dopamine and possibly direct agonistic effects on dopamine receptors. Although nomifensine was withdrawn from the market because of immunologic complications, it serves as a model compound of a new pharmacologic class of antidepressants, devoid of many of the disturbing side effects of the tricyclic drugs.

Brain neurokinin-1 receptor availability in never-medicated patients with major depression - A pilot study.

BACKGROUNDnNeurotransmitter substance P (SP) and its preferred neurokinin-1 receptor (NK1R) have been implicated in the treatment of affective and addiction disorders. Despite promising preclinical data on antidepressant action, the clinical trials of NK1R antagonists in major depression have been disappointing. There are no direct in vivo imaging studies on NK1R characteristics in patients with a major depressive disorder (MDD).nnnMETHODSnIn this cross-sectional case-control study, we recruited nine never-medicated patients with moderate to severe MDD and nine matched healthy controls. NK1R availability (NK1R binding potential, BPND) was measured with in vivo 3-D positron emission tomography and a specific NK1 receptor tracer [18F]SPA-RQ. Clinical symptoms were assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D17).nnnRESULTSnNK1R-BPND did not differ statistically significantly between patients with MDD and healthy controls. HAM-D17 total scores (range 21-32) correlated positively with NK1R-BPND in cortical and limbic areas. HAM-D17 subscale score for anxiety symptoms correlated positively with NK1R-BPND in specific brain areas implicated in fear and anxiety.nnnLIMITATIONSnSmall sample size. Low variability in the clinical HAM-D subscale ratings may affect the observed correlations.nnnCONCLUSIONSnOur preliminary results do not support a different baseline expression of NK1Rs in a representative sample of never-medicated patients with MDD during a current moderate/severe depressive episode. The modulatory effect of NK1Rs on affective symptoms is in line with early positive results on antidepressant action of NK1 antagonists. However, the effect is likely to be too weak for treatment of MDD with NK1R antagonists alone in clinical practice.

F135. BODY MASS INDEX TRAJECTORIES IN CHILDHOOD AND RISK FOR NON-AFFECTIVE PSYCHOSIS – A GENERAL POPULATION COHORT STUDY

Abstract Background It is well known that underweight in adolescence and early adulthood predicts later schizophrenia.1 Some studies have shown an association between future schizophrenia or psychosis and underweight in children, starting at the age of 7.2 There are very few previous studies concerning underweight in early childhood and the risk of psychosis as well as other psychiatric outcomes. Our aim was to study whether deviation from normal weight, i.e. underweight or overweight, in early childhood and adolescence predicts later development of non-affective psychosis. And if so, whether the mechanism is specific to psychosis or also predicts other psychiatric disorders. Methods The participants were derived from a general population cohort study ‘Cardiovascular Risk of Young Finns’, which was started in 1980 with 3596 children and adolescents participating from six different age groups (3–18 years), with a continued follow-up. BMI was recorded before the first hospitalization due to a psychiatric disorder (≤18 years of age) and categorized as underweight, normal weight or overweight using the BMI classification for children and adolescents provided by Cole et al.3,4 All psychiatric diagnoses of the participants were acquired from the Finnish Hospital Discharge Register. We formed DSM-IV diagnostic groups of non-affective psychosis (n=70, including a schizophrenia subgroup, n=41), personality disorders (n=44), affective disorders (mood- and anxiety disorders, n=115), and substance-related disorders (n=53). Participants in the diagnostic groups were compared with subjects with no psychiatric diagnoses (n=3313). Sex, age, low birth weight and mother’s mental disorders were used as potential confounders in the analyses. Results Underweight, but not overweight, during the age of 3 to 18 years independently predicted later development of non-affective psychosis. Underweight in childhood and/or adolescence increased the risk of psychosis over two-fold (relative risk (RR) [95% CI] 2.31 [1.2–4.4]). Results were similar for schizophrenia; underweight was associated with nearly 2.5-fold risk of schizophrenia (RR 2.44 [1.03–5.8]). Underweight or overweight in childhood and adolescence was not significantly associated with any other studied psychiatric disorder with a more severe clinical phenotype that required hospital treatment. Discussion Underweight in childhood and adolescence is an independent risk factor for later non-affective psychosis. The mechanism behind underweight in premorbid phase of psychosis is not known but e.g. low level of insulin-like growth factor-I (IGF-I) may be involved. These results support the hypothesis of schizophrenia as a neurodevelopmental disorder with somatic aspects appearing already in early childhood and psychosis as a late stage of illness. References 1.Weiser M, Knobler H, Lubin G, et al. Body mass index and future schizophrenia in Israeli male adolescents. J Clin Psychiatry. 2004;65(11):1546–1549. doi:10.4088/JCP.v65n1117. 2.Wahlbeck K, Forsén T, Osmond C, Barker DJP, Eriksson JG. Association of Schizophrenia With Low Maternal Body Mass Index, Small Size at Birth, and Thinness During Childhood. Arch Gen Psychiatry. 2001;58(1):48. doi:10.1001/archpsyc.58.1.48. 3.Cole TJ. Establishing a standard definition for child overweight and obesity worldwide: international survey. Bmj. 2000;320(7244):1240-1240. doi:10.1136/bmj.320.7244.1240. 4.Cole TJ, Flegal KM, Nicholls D, Jackson AA. Body mass index cut offs to define thinness in children and adolescents: international survey. Bmj. 2007;335(7612):194-194. doi:10.1136/bmj.39238.399444.55.

Trends in the long-term use of benzodiazepine anxiolytics and hypnotics: A national register study for 2006 to 2014

Long‐term benzodiazepine (BZD) treatment continues to be a debated topic. Because individual BZDs have different clinical profiles, we assessed the nationwide trends of long‐term BZD use at active substance level during years 2006 to 2014.