Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular prion protein (PrP(C)) has been involved in several neurodegenerative disorders however it has been proposed that it is also be implicated in psychotic disorders. We investigated the effect of three psychotropic drugs in locomotor activity of PrP(C) knockout (Prnp(O/O)) and wild-type mice. The NMDA receptor channel blocker MK-801 (0.25 mg/kg), the indirect dopamine agonist amphetamine (1 mg/kg) and the adenosine receptor antagonist caffeine (10 mg/kg) were administered i.p. after 60 min of habituation and locomotion was monitored for 3 h. Prnp(O/O) mice presented a diminished hyperlocomotor response to MK-801 treatment but normal response to amphetamine and caffeine compared to wild type mice. These results suggest that lack of PrP(C) leads to a functional alteration in the glutamatergic system, whereas the regulation of both dopaminergic and adenosinergic systems are preserved. Finally, lack of PrP(C) seems not to exacerbate the response to these psychotropic drugs, which modulate neurotransmitter systems possibly involved in schizophrenia and psychotic disorders.
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PMID:Decreased hyperlocomotion induced by MK-801, but not amphetamine and caffeine in mice lacking cellular prion protein (PrP(C)). 1242 47

In the article, the author develops an analysis of external and intrapsychic factors related to adults' insomnia. First she undertakes a literature review to describe semiological, evolutive and etiological levels of insomnia. From a semiological point of view, it is usual to differenciate initial insomnia (associated to the first phase of sleeping), intermittent insomnia (related to frequent awakenings) and final insomnia (related to early morning awakenings). From an evolutive point of view, we can identify transitory insomnia (characterized by frequent awakenings) and chronic insomnia. On the other hand, we are allowed to distinguish organic insomnia (disorder where an organic cerebral injury is demonstrated or suspected) from insomnias related to psychiatric or somatic disease or idiopathic one. Then, the author makes a literary review to identify various insomnia causes and points out. Social factors: insomnia rates are higher by divorced, separated or widowed people. Percentages are higher when scholastic level is weak, domestic income is less then 915 O a month, or by unemployed people. Besides, sleep quality is deteriorated by ageing. Sleeping and waking rhythm is able to loose its synchronization. Complaints about insomnia occur far frequently from women than men. Environmental factors: working constraints increase sleep disorders. It is possible to make the same conclusion when we have to face overcharge of external events, deep intrapsychic conflicts (related to grief, unemployment, damage or hospitalization) or interpersonal conflicts' situations where we are confronted to stress related to socio-affective environment, lack of social support or conjugal difficulties. Medical and physiologic causes: legs impatience syndrome, recurrent limbs shakings syndrome, breathe stop during sleep, narcolepsy, excessive medicine or hypnotic drugs use, some central nervous system injuries, every nocturnal awakening (related to aches.), surgical operation. Chronobiological factors: night working or day-night shift produce insomnia by desynchronization. It is the same for time lag related to jet-lag flights. Significant gaps between the internal biological clock and environmental synchronizators, such as phase delay sleep, phase advance sleep, sleep-waking cycle longer than 24 (25) hours, or variations in sleep-awakening cycle, are of less importance. Toxic factors are numerous: amphetamines, antidepressors, medication against anorexia and tubercular disease, caffeine and alcohol excessive use, chronic alcoholism. Behavioral factors: enduring insomnias are related to poor nightroutines (to go to sleep too early, to read or to look at T.V. when going to bed). The same effect is produced by regular intellectual activities close to bedtime or by a late meal in the evening, by an noisy or unhealthy environment, by physical hyperactivity or sleeping after each lunch. Psychiatric factors: insomnia often appears with psychiatric disorders such as a major depressive episode, an anxiety disorder or schizophrenia. Insomnia also is able to open a delirious disorganization or a manic access. Psychological factors: overstimulation of waking system (related to stress overdose or intellectual hyperactivity), conditioning phenomena, fear of not falling asleep, intrapsychic and interpersonal conflicts. Third, the author put hypothesis about psychodynamic etiology of chronic insomnia. Following a first assumption, insomnia should be a result of anguish excess related to intrapsychic (and not interpersonal) conflicts which can't lead to a mental elaboration. These conflicts run over dream protective function, generating a breakdown of dream symbolization function. At a clinical level, we are in some cases in front of people enduring sleeping insomnia but more often, we are confronted with an intermittent or early waking insomnia sometimes associated with nightmares. Following a second assumption, insomnia should be a result of psychic functioning invalidation. Here, failure of dream protective and symbolization function is related to anguish excess associated with an amount of external conflicts. Overwhelmed by concretude, insomniac patients present an alexythimic intrapsychic functioning forbiding dream realization. These persons have no possibility to elaborate conflicts especially external overcharge, using dreams or imagination to escape from an intrusive reality and regress to sleeping. Here we are in front of initial sleep insomnia. Following a third hypothesis, some insomnias are related to wakings associated with repetitive nightmares. This type of insomnia should be related to a past traumatic event or activated by actual existential context and produces a too important anguish charge to follow a mental elaboration process and lead to mental symbolic representation. Following a fourth hypothesis, some insomnias are in relation with an impossibility to accept passive position. The last one will expose to a danger consisting either of castration or loneliness and death. To conclude, the author suggests some preventive perspective to face insomnia. Especially, she points out limits of pharmalogical treatments. She underlines the necessity to promote no medical methods to facilitate sleep induction and maintenance, including sleep hygiene measures, relaxation, psychotherapic approach and behavioral methods. She emphasizes the danger of a reductive approach of insomnia which would be focused on a single medical, psychological or environmental dimension. Last but not least, she makes methodological propositions to test from a clinical point of view the four psychodynamic exposed hypotheses.
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PMID:[Etiology of adult insomnia]. 1250 61

Adenosine A (2A) receptors have been implicated in the pathophysiology of schizophrenia by clinical, anatomical, biochemical and genetic studies. We hypothesized that a genetically determined low number of adenosine A (2A) receptors could be a vulnerability factor for the development of the disease. The density of adenosine A (2A) receptors was investigated in human postmortem striatum of patients with schizophrenia (n = 9) and matched controls ( n= 9) using [ H)CGS 21680 as a radioligand probe. The maximum number of binding sites (B) (max) was 70% higher in patients with schizophrenia than in matched controls (609.4 +/- 259.1 354.0 +/- 156.4 fmol/mg protein, p=0.04). No significant difference could be discerned for the affinity of caffeine for adenosine A receptors between patients and controls. The increase in receptor density correlated with the dose of antipsychotic medication in chlorpromazine equivalents (r =0.61, = 0.014). We failed to provide evidence for a genetically determined reduction of adenosine A 2(A) receptors in schizophrenia. Instead, consistent with findings from animal experiments, our observation supports a role of adenosine A (2A) receptors in the molecular effects of antipsychotic drugs.
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PMID:Up-regulation of striatal adenosine A(2A) receptors in schizophrenia. 1263 74

To understand the elevated smoking rates among psychiatric patients, the authors investigated whether psychiatric diagnosis, illness severity, and other substance use predicted smoking status in a diverse sample (N=2774) of psychiatric outpatients. Results indicated that 61% smoked daily and that 18% smoked heavily. Smoking was related to psychiatric diagnosis and illness severity as well as caffeine consumption and substance abuse. Diagnoses of bipolar disorder, schizoaffective disorder, and schizophrenia were independently related to smoking status, an association that was most pronounced among persons treated at clinics serving more impaired patients. Thus, diagnosis and illness severity contribute to elevated smoking rates, even after controlling for other substance use. Cessation programs are needed to reduce tobacco use in this vulnerable population.
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PMID:Smoking among psychiatric outpatients: relationship to substance use, diagnosis, and illness severity. 1464 Aug 21

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients. In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05). We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.
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PMID:CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. 1465 89

The purpose of the present study was to assess the impact of smoking on the metabolism of psychotropic drugs in a group of patients with schizophrenia, by measuring CYP1A2 activity. This activity was assessed by the molar ratio (MR) of caffeine metabolites in urine [(AFMU+1U+1X)/17U] and saliva (17X/137X). Participants were 40 patients with schizophrenia: 30 current cigarette smokers and 10 nonsmokers. The two groups (smokers and nonsmokers) differed significantly in their ratio of men to women (83% men and 17% women were among smokers compared with 50% men and 50% women nonsmokers). No other group differences were found regarding age, level of education, PANSS, extrapyramidal symptoms, age of symptoms onset, antipsychotic doses (chloropromazine equivalents), and anticholinergic drug used. Smokers had significant higher MR in urine (P<0.001) as well as in saliva (P=0.001) than nonsmokers, suggesting a higher activity of CYP1A2 dependent on smoking. When gender was used as a covariate, the differences between the two groups remained significant for MR. Cigarette smoking may be a factor influencing the plasma levels of antipsychotics that metabolized through CYP1A2. Clinicians should weight the possibility that smoking and the subsequent modulation of antipsychotic metabolism may be the main reason of treatment resistance. Furthermore, any attempt to reduce or cease smoking in patients with schizophrenia necessitates close monitoring of drug doses, because untoward adverse effects may emerge.
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PMID:Smoking impact on CYP1A2 activity in a group of patients with schizophrenia. 1465 85

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.
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PMID:Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. 1520 69

Guanosine has been shown to modulate glutamate system by stimulating astrocytic glutamate uptake. Recent evidence suggest that the locomotor effects of NMDA receptor antagonists, an animal model of schizophrenia, is associated with activation of non-NMDA glutamatergic receptors caused by increased glutamate release. The present work was undertaken to evaluate whether guanosine could have influence on the hyperlocomotion induced in mice by dizocilpine (MK-801), a NMDA antagonist. We also evaluated the effect of guanosine on the hyperlocomotion induced by the indirect dopamine agonist amphetamine, and by the non-selective adenosine receptor antagonist caffeine. Guanosine (7.5 mg/kg) produced an attenuation of about 60% on the hyperlocomotion induced by dizocilpine (0.25 mg/kg), whereas it did not affect the hyperlocomotion induced by amphetamine (5 mg/kg) or caffeine (30 mg/kg). Guanosine pre-treatment did not affect total spontaneous locomotion in all experiments. To test neuronal pathway selectivity, we evaluated MK-801 against guanosine in a working memory paradigm (spontaneous alternation task). Guanosine did not reverted the impairment caused by MK-801 in the spontaneous alternation test, and when administered alone also presented an amnesic effect. The results are discussed based on the current hypothesis of locomotor activation induced by the psychoactive drugs studied. Further studies are necessary to evaluate if guanosine could have clinical utility for the treatment of schizophrenia.
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PMID:Guanosine selectively inhibits locomotor stimulation induced by the NMDA antagonist dizocilpine. 1531 29

In the present study, we examined the relationships between plasma concentrations of risperidone and clinical responses, extrapyramidal symptoms, plasma levels of cotinine and caffeine, or cytochrome (cyp)2D6 genotypes. In addition, we also investigated the relationships between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) or homovanillic (HVA) acid and clinical responses to risperidone. One hundred and 36 patients (male/female: 58/78, age 37+/-13 years) who met DSM-IV criteria for schizophrenia, schizoaffective disorder, delusional disorder and brief psychotic disorder, and who were being treated with risperidone alone, were evaluated regarding their clinical improvement and extrapyramidal symptoms using the Positive and Negative Syndrome Scale (PANSS) and Simpson and Angus (SAS), respectively, and plasma levels of cotinine, caffeine, MHPG and HVA were analysed by high-performance liquid chromatography. The cyp2D6*5 and *10 alleles were identified using the polymerase chain reaction. There was a positive correlation between plasma levels of risperidone plus 9-hydroxyrisperidone (active moiety) and SAS scores, but not the PANSS. Pretreatment HVA levels in responders were higher than those in nonresponders. In addition, there was a negative correlation between changes in HVA levels and improvement in PANSS scores. There was no association between plasma levels of risperidone and plasma levels of cotinine or caffeine. Furthermore, there were no differences in the risperidone/9-hydroxyrisperidone ratio, clinical improvements and extrapyramidal symptoms among cyp2D6 genotypes. These results indicate that pretreatment HVA levels and plasma concentrations of active moiety might play a part in predicting the clinical response and occurrence of extrapyramidal symptoms, respectively, when treating patients with risperidone.
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PMID:Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. 1572 81

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.
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PMID:Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice. 1576 42


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