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PubMed2004

Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders.

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.

Adolescent↗
PubMed2006

Changes in oxygen uptake, shoulder muscles activity, and propulsion cycle timing during strenuous wheelchair exercise.

STUDY DESIGN: Cross-over study. OBJECTIVE: To determine the effect of strenuous wheelchair exercise on oxygen uptake (VO2 ), muscle activity and propulsion cycle timing (including the push time and recovery time during one full arm cycle). SETTING: Laboratory of Sport Sciences at the University of France-Comte in France. METHODS: Two exercise bouts of 6-min duration were performed at a constant workload: (1) non-fatigable exercise (moderate workload) and (2) fatigable exercise (heavy workload). Measurement of VO2, surface electromyographic activity (EMG) from shoulder muscles, and temporal parameters of wheelchair ergometer propulsion were collected from eight able-bodied men (26+/-4 years). RESULTS: A progressive increase in VO2 associated with EMG alterations (P<0.05), and a decrease of the cycle and recovery time (P<0.05) during the heavy exercise. Whereas the push time remained constant, an increased muscle activation time (P<0.05) was found during heavy exercise. CONCLUSION: Observations during wheelchair ergometry indicate the development of fatigue and inefficient muscle coordination, which may contribute to deleterious stress distributions at the shoulder joint, increasing susceptibility to injury.

Adult↗
PubMed2005

Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status.

Endogenous and exogenous sex steroid hormones have multiple effects on lipid and lipoprotein metabolism. It is also known that estrogen has antiatherogenic actions, therefore we considered examining whether there was any association between polymorphisms in estrogen-metabolizing genes and lipid levels in women. We investigated the association between variants in genes related to estrogen biosynthesis (CYP19-TTTA(n)) and estrogen catabolism (CYP1A1*2A, CYP1A1*2C, CYP1A2-Asn516Asn, CYP3A4*1B, and COMT-Val158Met) with serum lipid levels in a cross-sectional study with 472 Brazilian women of European descent. They were divided into three subgroups according to their hormonal status: premenopausal women (n=187), postmenopausal women exposed to hormonal replacement therapy (HRT) (n=118), and postmenopausal women unexposed to HRT (n=167). The postmenopausal women receiving HRT who were carriers of the CYP3A4*1B variant showed lower low-density lipoprotein cholesterol levels than wild-type homozygotes. Premenopausal women homozygous for the CYP1A1*2C allele had higher high-density lipoprotein cholesterol levels than heterozygotes. While the CYP1A1*2C variant probably has a higher catalytic activity, the functional implications of the CYP3A4 polymorphism are still uncertain. These data are the first attempt to associate estrogen metabolism genes to lipid levels in women.

Adolescent↗
PubMed2000

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies.

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.

Adult↗
PubMed2002

Entacapone improves the availability of L-dopa in plasma by decreasing its peripheral metabolism independent of L-dopa/carbidopa dose.

AIMS: Entacapone is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor. To improve the benefits of oral L-dopa in the treatment of Parkinson's disease (PD), entacapone is administered as a 200 mg dose with each daily dose of L-dopa. This study evaluated the effects of entacapone 200 mg on the pharmacokinetics and metabolism of L-dopa given as standard release L-dopa/carbidopa. METHODS: Six different doses of l-dopa/carbidopa were investigated in this placebo-controlled, double-blind (regarding entacapone), randomized, single-dose study in 46 young healthy males. The subjects were divided into three groups (n = 14-16). Two different L-dopa/carbidopa doses were administered to each subject (50/12.5 mg and 150/37.5 mg, or 100/10 mg and 100/25 mg, or 200/50 mg and 250/25 mg). Each dose was given on two occasions; simultaneously with entacapone or with placebo, in random order, on two consecutive study visits, separated by a washout period of at least 3 weeks (four-way crossover design). Serial blood samples were drawn before dosing and up to 24 h after the dose and pharmacokinetic parameters of L-dopa, its metabolites, carbidopa, and entacapone were determined. RESULTS: Entacapone increased the AUC(0,12 h) of L-dopa to a similar extent at all doses of L-dopa/carbidopa, that is by about 30-40% compared with placebo (P < 0.001, 95% CI 0.15, 0.40). When evaluated as the ratio of geometric means, entacapone slightly decreased the mean C(max) values for L-dopa at all L-dopa/carbidopa doses compared with placebo. When given with entacapone, higher plasma concentrations of L-dopa were maintained for a longer period at all doses of L-dopa/carbidopa. Entacapone also decreased the peripheral formation of 3-O-methyldopa (3-OMD) to about 55-60% of the placebo treatment level (P < 0.001, 95% CI -0.72, -0.35) and increased the mean AUC(0,12 h) of 3,4-dihydroxy-phenylacetic acid (DOPAC) 2-2.6-fold compared with placebo (P < 0.001, 95% CI 0.60, 1.10). The mean AUC(0,12 h) of 3-methoxy-4-hydroxy-phenylacetic acid (HVA) following entacapone was approximately 65-75% of that observed with placebo (P < 0.001-0.05, 95% CI -0.76, -0.01) at each L-dopa/carbidopa dose except the 50/12.5 mg dose (P > 0.05, 95% CI -0.59, 0.05). The metabolic ratios (MR, AUC metabolite/AUC L-dopa) also confirmed that entacapone significantly decreased the proportion of 3-OMD (P < 0.001, 95% CI -0.85, -0.68) and HVA (P < 0.001, 95% CI -1.01, -0.18) in plasma at each L-dopa/carbidopa dose, whereas the AUC DOPAC/AUC L-dopa ratio was increased again at all doses (P < 0.001, 95% CI 0.26, 0.90). Entacapone did not significantly affect the pharmacokinetics of carbidopa at any of the doses, nor did L-dopa/carbidopa affect the pharmacokinetics of entacapone. CONCLUSIONS: The 200 mg dose of entacapone similarly and significantly increases the AUC of L-dopa by changing the metabolic balance of L-dopa independent of the L-dopa/carbidopa dose and therefore entacapone is likely to have a similar L-dopa potentiating effect independent of L-dopa dose.

Adult↗
PubMed2000

Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences.

In mice lacking the dopamine transporter (DAT), the amplitude of dopamine (DA) release and the kinetics of dopamine elimination were measured in vivo using carbon fibre electrodes combined with amperometry. DA release was evoked by electrical stimulation of the medial forebrain bundle. The amplitude of DA release per pulse was lower (7% in striatum and 21% in nucleus accumbens) than in wild-type mice. Inhibition of monoamine oxidases (MAOs) by pargyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowed down DA elimination in knockout mice. As DA half-life was two orders of magnitude higher in these mice, the DA diffusion distance was 10-times higher than in wild-types (100 and 10 microm, respectively). In knockout mice, alpha-methyl-p-tyrosine induced a much faster decline of DA release and haloperidol was less effective in potentiating DA release. Therefore, DA release was more dependent on DA synthesis than in normal animals but was less influenced by D2 autoregulation. Dopaminergic neurons exhibit two kinds of discharge activity, i.e. single spikes and bursts of 2-6 action potentials. In wild-type mice, stimuli mimicking bursts evoked significant increases in extracellular DA over its basal level sustained by tonic activity. However, in mice lacking the DAT, low frequency firing resulted in consistently high extracellular DA levels that could not be distinguished from DA levels achieved by high frequency firing. Therefore, the burst firing activity cannot be specifically translated into phasic changes in extracellular DA. This deficit might contribute to the difficulties of these mice in spatial cognitive function.

Animals↗
PubMed2000

Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA.

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Animals↗
PubMed1999

Motor fluctuations in Parkinson's disease: pathophysiology and treatment.

At the initial stages of Parkinson's disease (PD), levodopa (LD) is able to reduce most motor symptoms and to significantly improve the patient's quality of life. However, in the vast majority of patients with prolonged LD usage, some decline in efficacy occurs and motor complications eventually begin to appear. These complications consist not only of daily fluctuations in the voluntary motor performance often accompanied by involuntary movements, but also of fluctuations in cognitive, autonomic, and sensory functions. Several recent studies on LD complications in PD have led to a better understanding of their pathophysiology and of the possible therapeutic interventions, and a summary of these findings is presented in this review. Different observations now suggest that postsynaptic pharmacodynamic factors play a major role in determining fluctuations in PD. Two explanations are given: chronic intermittent dopaminergic therapy may lead to postsynaptic receptor downregulation in PD; or, receptor changes in the striatum may occur independently of treatment as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of the nigrostriatal pathway. The hypothesis of reversible postsynaptic changes as the main mechanism underlying a fluctuating response to LD lends itself to a possible pharmacological manipulation of the dopaminergic response to reverse, or even avoid, motor fluctuations (initial monotherapy with dopamine agonists and early combination LD/dopamine agonists). The role of peripheral pharmacokinetics factors is also critical and the use of controlled release LD formulations, of monoamine oxidase (MAO)-B and of catechol-O-methyltransferase (COMT) inhibitors may all, to a different degree, improve such phenomena. In the last decade, there has been a resurgence in surgical therapies in advanced PD, due to higher levels of accuracy and safety provided by the new surgical devices, and to a more precise localization of the target areas allowed by the neurophysiological mapping techniques. The surgical procedures currently used in advanced PD are stereotactic brain lesions (internal globus pallidus and subthalamic nucleus), chronic brain stimulation (of the same nuclei) and striatal grafting of dopamine-producing cells. All these procedures have already shown their efficacy in the management of severe fluctuations in PD, but their indications, and relative advantages and disadvantages, are still the subject of considerable debate and controversy.

Catechol O-Methyltransferase Inhibitors↗
PubMed2003

The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease.

The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P < 0.05). The patients' global assessment indicated that 69% of patients improved when given entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of entacapone. In conclusion, entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

Aged↗
PubMed2001

Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties.

The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine-stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA, (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)-dependent catabolic pathway and significantly activated the catechol-O-methyltransferase (COMT)-dependent O-methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Urinary excretion of olive oil phenols and their metabolites in humans.

We have recently demonstrated, in humans, the bioavailability of hydroxytyrosol (3,4-dihydroxyphenylethanol; HT), one of the major antioxidant components of virgin olive oil. In particular, we reported that this compound is present in lipoproteins involved in atherosclerotic processes and is excreted in the urine mainly as glucuronide-conjugate. The aim of the present study was to elucidate, in humans, the metabolic fate of HT after ingestion of virgin olive oil. After administration of virgin olive oil, 24-hour urine collections of healthy volunteers were prepared for gas chromatography-mass spectrometry analyses in order to identify and quantify HT and its metabolites homovanillic alcohol (HVA1c) and homovanillic acid (HVA). The results indicate that this compound undergoes the action of catechol-O-methyl transferase (COMT), enzymes involved in the catecholamine catabolism, resulting in an enhanced excretion of HVA1c. We also found a significant increase of HVA, indicating an oxidation of the ethanolic residue of HT and/or of HVA1c in humans. The excretion of both metabolites significantly correlated with the dose of administered HT.

Biological Availability↗
PubMed2001

[Clinical relevance and treatment possibilities of rapid cycling in patients with bipolar disorder].

In the actual version of the WHO diagnostic guidelines, the ICD-10, subtypes of bipolar disorder are not specified, in contrast to the American DSM-IV, where bipolar disorder has already been differentiated in bipolar I (severe manic and depressive episodes) and bipolar II disorder (depressive and hypomanic episodes). Furthermore, aspects of the longitudinal course of the illness, like rapid cycling (RC), are reflected as well. Rapid cycling is defined as four or more affective episodes within one year of the illness. It has been postulated that rapid cycling is related with a poor response to lithium, to the same extent as mixed episodes or an atypical onset (depressive episode first) of the disease. Here, the current status of alternative pharmacological and supportive therapy of rapid cycling is presented and discussed. Furthermore, the article also displays biological parameters associated with rapid cycling like higher prevalence in women, hypothyreoidism, subtype of bipolar disorder, COMT-allele, influence of sleep or risk of antidepressant induced cycling.

Animals↗
PubMed2005

[Genetic risk factors in schizophrenia].

The high pathogenetic relevance of genetic factors in schizophrenia is beyond doubt based on the findings of epidemiological studies. By means of a complex mode of transmission, it is likely that several genes with weak to moderate effect jointly constitute a genetic basis for a vulnerability to schizophrenia that may well vary for different individuals. Other organic and psychosocial factors also play an individually different -- in some cases significant -- role in terms of pathogenesis, as a result of which an oligogenic/polygenic multifactor model is assumed from the standpoint of aetiopathogenetics. Molecular genetic methods consist in linkage analyses and association analyses. Positive linkage findings accumulate particularly for the chromosomes 1q, 6p, 8p, 13q and 22q. By themselves, individual mutations contribute little to the range of schizophrenic feature characteristics, it was not possible -- irrespective of some subtypes -- to replicate genes of major effect. From the large number of possible candidate genes, although studies on DRD3, DRD2 and HTR2A produced positive results, the magnitudes of effect were low. The findings for alleles of dysbindin, neuregulin 1, DAO, COMT, PRODH, ZDHHC and DISC are less clear. The search for schizophrenia-relevant mutations is hampered by the possibility of a heterogeneous phenotype of schizophrenia in case of a homogeneous genotype as much as by the possibility of inter-individually homogeneous phenotypical characteristics in case of schizophrenia-relevant heterotype in the genome. With the aid of the concept of endo-phenotypes, based on neurobiological phenomena, it might be possible to take a more direct approach that leads from relevant mutations to the risk of schizophrenias. However, replacing schizophrenic alienation with neurobiological aspects leads to difficulties in explaining these complex disorder profiles. Schizophrenic diseases require an explanatory approach that also incorporates personality and developmental psychological aspects from the outset, if the aim is not to restrict type of schizophrenic disease exclusively to loci of molecular genetic changes.

Genetic Linkage↗
PubMed2005

[Neuroimaging in schizophrenia].

This overview is focused on functional neuroimaging including functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). Recent evidence for the "dopamine hypothesis of schizophrenia" is summarized including alterations of presynaptic dopamine metabolism and postsynaptic receptor binding potential. Emphasis is given to dopaminergic challenge studies using amphetamine and AMPT. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release as well as decrease of AMPT-induced dopamine depletion in drug-naive schizophrenic patients, indicating a dysregulation of dopaminergic neurotransmission. Results of studies combining amphetamine challenge and the NMDA receptor antagonist ketamine are related to glutaminergic dysfunction and neurotransmitter interactions. FMRI and PET results demonstrating alterations in task-specific functional connectivity between brain areas are discussed with a focus on the prefrontal cortex and temporal structures. Increase of serotonin-1A receptor binding potential in prefrontal and mesotemporal cortex is related to the serotonin-dopamine interaction. Genetic neuroimaging techniques, including voxel-based morphometry (VBM) and fMRI, revealing significant effects of the dopamine metabolizing enzyme COMT on functional activation in prefrontal areas are also discussed. Functional neuroimaging based on challenge-paradigms in PET as well as task-specific state- or trait-dependent alterations of activation patterns in fMRI, seems to be a promising candidate for the development of biological marker tests for schizophrenia.

Brain↗
PubMed1983

Clinical and biological parameters as predictors for antidepressant drug responses in depressed patients.

Clinical and biological variables were investigated for their predictive value with respect to an antidepressant drug treatment. Thirty patients received clomipramine and thirty patients maprotiline. Characteristic features of the biography, the family anamnesis and the previous course of illness (apart from intermittent course) have no predictive value. The psychopathological symptoms before the start of treatment are also not suitable for prediction (except vegetative syndrome). The activity of the enzymes MAO, COMT and DBH before the start of treatment have no predictive value. The serum level of maprotiline on the seventh day of treatment does not correlate with the outcome of treatment. It is possible that patients, who have relatives with suicidal tendencies, are more likely to be clomipramine non-responders; patients with relatives who have a psychiatric history but without suicidal tendencies, are more likely to be maprotiline responders; i.a., relatives of the first degree manifesting psychiatric problems speak against a response to clomipramine and indicate a response to maprotiline. Patients with diurnal variations before the start of treatment are possibly more likely to respond to maprotiline than to clomipramine. There are statistically established findings for only the following variables: Diurnal variations during treatment speak in favour of an antidepressant response. A positive SD reaction indicates clomipramine response. A serum level of more than 75 ng clomipramine and more than 30 ng desmethyl-clomipramine/ml serum on the 7th day of treatment clearly predict a response to clomipramine.

Adult↗
PubMed1980

Genetic studies of manic-depressive illness.

The Unipolar (UP) and Bipolar (BP) forms of affective illness appear not to be genetically and physiologically identical, although the degree of overlap in family and biologic pharmacologic studies is considerable. It appears likely that at least a subgroup of UP illness shares its genetic diathesis with BP illness. The hypothesis of monoamine alterations associated with the affective illnesses has led to studies of genetics of enzymes of monoamine metabolism as observed in peripheral blood, erythrocyte catechol-O-methyl-transferase (COMT), platelet monoamine oxidase (MAO), and plasma dopamine-beta-hydroxylase (DBH). These are under genetic control and show some differences between patients with affective illness and controls, but these differences have not been consistently propagated through families along with the disorder. Linkage of BP illness to markers on the X-chromosome has been reported, but the evidence has internal inconsistencies which must be resolved before the phenomenon can be accepted. Association of BP illness with specific HLA types has also been reported, but efforts at replication have been unsuccessful. Mathematical models of transmission applied to family study data do not consistently support the same mode of transmission when applied to data collected at different centers.

Bipolar Disorder↗
PubMed2005

Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis.

Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts of Dbh (dopamine beta-hydroxylase), Drd4 receptors, Gprk6 (G protein-coupled receptor kinase 6), Comt (catechol-O-methyltransferase), or Th-/-, DbhTh/+ (tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2High were found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2High states, it suggests that there are many pathways to psychosis, any one of which can be disrupted.

Animals↗
PubMed2002

Entacapone does not induce conformational changes in liver mitochondria or skeletal muscle in vivo.

Entacapone and tolcapone, novel catechol-O-methyl-transferase (COMT) inhibitors, have been developed for the treatment of Parkinson's disease in combination with levodopa. Three fatal cases of drug-induced hepatitis, one with hepatic necrosis and mitochondrial changes have been reported in clinical use of tolcapone. In vitro tolcapone has been shown to induce uncoupling of oxidative phosphorylation. Liver and skeletal muscle tissues from an oral rat toxicity study were used to investigate the influence of entacapone, tolcapone (300 and 500 mg/kg/day) or a known uncoupling agent, 2,4-dinitrophenol (DNP), (20 mg/kg/ day) on the cell morphology. Centrolobular hypertrophy was revealed in the histopathology of the liver in tolcapone-treated rats. Transmission electron microscopy (TEM) of the liver and skeletal muscle tissue, revealed mitochondrial swelling and reduced matrix density with deformation of cristae in the tolcapone and DNP groups. Intermyofibrillar edema was characteristic of the skeletal muscle tissue of DNP- and tolcapone-exposed animals. In the tolcapone group, also the sarcomeres were prominent. Treatment-related light microscopic or TEM findings were not observed either in entacapone-treated or control animals. The similarity of structural damages induced by both tolcapone- and DNP suggests that uncoupling of oxidative phosphorylation may contribute to the toxicity of tolcapone in the rat.

2,4-Dinitrophenol↗