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)

L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.
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PMID:Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. 1521 Mar 7

Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronic neuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calcium channels or by promoting inhibition mediated by gamma-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerve injury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predispose neurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs may counteract this abnormal activity by selectively affecting pain-specific firing; for example, many AEDs suppress high-frequency action potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specifically target pathological channels; for example, gabapentin is a ligand of alpha2delta voltage-activated calcium channel subunits that are overexpressed in sensory neurons after nerve injury. Emerging evidence suggests that effects on signaling pathways that regulate neuronal plasticity and survival may be a factor in the delayed clinical efficacy of AEDs in some neuropsychiatric conditions, including bipolar affective disorder.
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PMID:The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. 1522 16

The objective of this study was to assess the pharmacokinetics of the antipsychotic aripiprazole when coadministered with lithium or valproate. Two open-label, sequential treatment design studies were conducted in chronically institutionalized patients with schizophrenia or schizoaffective disorder requiring treatment with lithium (n = 12) or valproate (divalproex sodium) (n = 10). Patients received aripiprazole 30 mg/day on days 1 to 14 and aripiprazole with concomitant therapy on days 15 to 36. Lithium was titrated from 900 mg until serum concentrations reached 1.0 to 1.4 mEq/L for at least 5 days. Valproate was titrated to 50 to 125 mg/L. Coadministration with lithium increased mean Cmax and AUC values of aripiprazole by about 19% and 15%, respectively, whereas the apparent oral clearance decreased by 15%. There was no effect on the steady-state pharmacokinetics of the active metabolite of aripiprazole. Coadministration with valproate decreased the AUC and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite. Therapeutic doses of lithium and divalproex had no clinically significant effects on the pharmacokinetics of aripiprazole in patients with schizophrenia or schizoaffective disorder.
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PMID:Pharmacokinetics of aripiprazole and concomitant lithium and valproate. 1560 9

We describe a case of clozapine-induced seizures in a patient with treatment-resistant schizophrenia. She had previously been treated unsuccessfully with a number of atypical antipsychotic medications, before she was eventually started on clozapine. She experienced two separate episodes of observed fits whilst on an initial daily dose of 125 mg and, subsequently, on a daily dose of 237.5 mg. Following discontinuation of clozapine, she was rechallenged and again was observed to have seizures. Appropriate investigations ruled out any organic cause of the fits and clozapine was successfully restarted, together with sodium valproate. By the time of treatment stabilization, the patient had not experienced any further fits. These findings suggest that clozapine-induced seizures can be successfully treated, that gradual dose titration can reduce the likelihood of further episodes of seizures and that concomitant use of a suitable mood stabilizer/anti-epileptic medication can improve the outcome of treatment-resistant schizophrenia. Furthermore, the concomitant use of fluoxetine and clozapine is discouraged, with citalopram suggested as a suitable antidepressant in those depressed patients receiving clozapine.
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PMID:A case of clozapine-induced tonic-clonic seizures managed with valproate: implications for clinical care. 1567 Nov 34

The neuronal nicotinic acetylcholine receptor alpha7 (nAChR alpha7) may be involved in cognitive deficits in Schizophrenia and Alzheimer's disease. A fast pharmacological characterization of homomeric alpha7 receptors is mostly hampered by their low functional expression levels in heterologous expression systems. In the present study expression of homomeric nAChR alpha7 was achieved in GH3 rat pituitary cells. Alpha7 subunits were heterologously expressed as components of [125I]-labeled alpha-bungarotoxin binding nAChRs (Bmax: 1.2 pmol/mg protein). Function of the expressed alpha7 ion channels was assessed by patch-clamp recording and calcium imaging. While acetylcholine-induced currents desensitized within much less than 1 s, calcium-sensitive fluorescence transients peaked after 5-10 s and returned to background levels within 30 s only. The fluorescence signal was blocked by isradipine and removal of extracellular sodium indicated that in these cells opening of rapidly desensitizing alpha7 nAChR triggers calcium influx via voltage-gated, DHP-sensitive calcium channels. In this cellular system, agonists revealed the following rank order of potency: epibatidine>anatoxin A>AAR17779>ABT-594>DMPP>nicotine>GTS-21>cytisine>ABT-418>acetylcholine>choline>ABT-089. All of the signals were inhibited by the alpha7 antagonists alpha-bungarotoxin (pIC50: 7.4) and methyllycaconitine (pIC50: 7.8). Further, marketed antidepressants showed antagonistic activity with the following rank order of potency: fluoxetine>imipramine>paroxetine>sertraline. These data illustrate that coupling to voltage-gated calcium channels allows a rapid and reliable functional examination of nAChR alpha7.
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PMID:Coupling of human nicotinic acetylcholine receptors alpha 7 to calcium channels in GH3 cells. 1569 60

Neurotensin is a linear tridecapeptide that elicits a variety of physiological responses in the brain, including hypothermia and antinociception, and reduced levels have been linked to schizophrenia. Previously in our laboratory we developed a truncated neurotensin derivative, KK13. This hexapeptide exhibited key pharmacokinetic and behavioural characteristics of an antipsychotic and elicited central effects after oral administration. To examine the potential mechanism(s) of uptake, a radioactive analogue of KK13 (*KK13) was synthesized, characterized, and evaluated in the Caco-2 cell model of the human intestinal epithelium. Results suggested that uptake of *KK13 was a time-dependent passive process. A general linear trend in uptake was demonstrated over the concentration range (10 microM-1 m M) tested, and uptake was neither pH- nor sodium-dependent. Finally, after 60 min, intact *KK13 was identified associated with the cell components, providing further evidence for uptake and stability of the peptide.
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PMID:Cellular uptake of a radiolabelled analogue of neurotensin in the Caco-2 cell model. 1580 88

A 19-year-old woman with a 3-year history of schizophrenia suddenly began to vomit, and rapidly developed a coma an hour after the onset of vomiting. A brain CT scan showed diffuse brain edema with compression of the ventricles. Laboratory tests showed a low serum sodium concentration of 117 mmol/L. She died 67 h after the onset of the first symptom. A postmortem examination showed diffuse swelling of the brain with bilateral uncal and tonsillar herniations. Histologically, no necrotic, hemorrhagic or encephalitic changes were seen. However, microvacuolar changes with lymphocytic infiltration were found in the venous walls (media and adventitia) mainly in the basal ganglia, thalamus and brainstem. To our knowledge, this is the first demonstration of venous alterations in fatal hyponatremic brain edema. These changes may have participated in the exacerbation of the brain edema due to functional disturbance of venous drainage.
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PMID:Peculiar venous lesions in fatal hyponatremic brain edema. 1582 24

A 54-year-old woman with schizophrenia presented to hospital with unconsciousness, fever and marked muscle rigidity. She had been given fluphenazine decanoete 20 mg intramuscularly 15 days before the admission and she had continued taking haloperidol 20 mg daily and oral biperiden 2-4 mg. She was extremely rigid and unresponsive. On laboratory investigations revealed: serum sodium 120 mEq/l, creatinine phosphokinase 12,980 IU/l (normal up to 170), lactate dehydrogenase 1544 IU/l (150-500), free trioidothyronine < 1.00 pg/ml (1.5-4.5), free throxyine 0.76 ng/dl (0.8-1.9), thyroid stimulating hormone 1.14 microU/ml (0.4-4), cortisol (at 8.00 a.m.) 9 microg/dl (5-25). Antipsychotic drugs were withdrawn after admission. A diagnosis of secondary adrenal insufficiency and secondary hypothyroidism was made. Hormonal substitution with hydrocortisone and levothyroxine and correction of hyponatremia with intravenous hypertonic saline solution resulted in rapid improvement of symptoms and signs. It seems that the symptoms and signs of hypothyroidism and hyponatremia were attributed to acute psychosis in this patient. As a conclusion failure to recognize the endocrinopathy may not only produce recovery difficulties but also psychiatric and endocrine repercussions if psychotropic medications are given in such masked cases.
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PMID:Possible malignant neuroleptic syndrome that associated with hypothyroidism. 1592 37

Voltage-gated sodium channels are encoded by a family of ten structurally-related genes that are expressed in spatially and temporally distinct patterns, mainly in excitable tissues. They underlie electrical signalling in nerve and muscle. It has long been known that sodium channel blockers are anaesthetics as well as powerful analgesics when delivered at low concentrations. In addition, cardiac arrhythmias and epileptic activity can be treated with sodium channel blockers. As we have learned more about the sub-types of sodium channels and their distribution, new therapeutic opportunities have suggested themselves. There are indications that sodium channel blockers may also be useful in affective disorders and schizophrenia. The production of tissue-specific and eventually inducible knock out mice as well as genetic studies has proved useful in understanding the specialised role of individual types of sodium channels. The development of sub-type specific blockers has proved slower than anticipated, although the properties of naturally occurring toxin blockers suggest that subtype-specific blockers of sodium channels could be very useful clinically in the treatment of pain.
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PMID:Voltage-gated sodium channel blockers; target validation and therapeutic potential. 1602 75

Dopamine is an important endogenous catecholamine which exerts widespread effects both in neuronal (as a neurotransmitter) and non-neuronal tissues (as an autocrine or paracrine agent). Within the central nervous system, dopamine binds to specific membrane receptors presented by neurons and it plays the key role in the control of locomotion, learning, working memory, cognition, and emotion. The brain dopamine system is involved in various neurological and psychiatric disturbances such as Parkinson's Disease, schizophrenia, and amphetamine and cocaine addiction. Thus, this system is the major target of powerful drugs applied in the treatment of neuropsychiatric diseases. Physiological functions of the brain dopamine system are well recognized. However, dopamine biosynthesis does not only occur in neurons, but also in peripheral tissues. Dopamine receptors have been described in the kidney, pancreas, lungs, and in numerous blood vessels outside the central nervous system. Renal dopamine is now recognized as an important regulator of sodium extraction and electrolyte balance, while defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of human and animal hypertension. This article gives a brief overview of the importance of dopamine acting as a neurotransmitter and peripheral hormone. Special consideration is given to: (i) biochemical disturbances occurring in both brain and kidneys in various diseases and (ii) current therapy correcting disturbances in dopamine systems.
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PMID:[Dopamine: not just a neurotransmitter]. 1610 42


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