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)

It has been hypothesized that the negative symptoms of schizophrenia are related to structural brain abnormalities and respond poorly to treatment with neuroleptics and other drugs since they are persistent, if not irreversible. Because this issue has important clinical and theoretical implications, the authors reviewed the relevant literature on the effect of neuroleptics, L-dopa, and other psychotropic agents on these symptoms. Contrary to the above conclusions, several large scale, controlled studies of the therapeutic effects of conventional neuroleptics have reported clinically relevant improvement in negative symptoms in a significant proportion of schizophrenics. The improvement tended to occur early in the course of treatment and was most notable in those patients with relatively shorter durations of illness. A specific class of neuroleptic drugs not studied in these earlier large scale trials, the diphenylbutylpiperidines, has been suggested to be particularly likely to ameliorate negative symptoms, possibly because of their significant calcium channel blocking action. A review of the clinical studies comparing this group of neuroleptics with those from different classes supports the suggestion that they can produce greater improvement in anergia and emotional withdrawal. Six open and four controlled trials of L-dopa treatment of negative symptoms with L-dopa alone or in combination with neuroleptics. As with neuroleptics alone, improvement tended to be greater in those with a shorter duration of illness. The available evidence suggests that negative symptoms, at least in less chronic schizophrenic patients, may be partially responsive to currently available pharmacological intervention in a significant proportion of schizophrenics.
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PMID:The effect of neuroleptics and other psychotropic drugs on negative symptoms in schizophrenia. 287 56

Reports over the last 20 years suggest that pimozide, a neuroleptic of the diphenylbutylpiperidine (DPBP) group, might be helpful in the treatment of negative symptoms of schizophrenia, which are considered less responsive to standard neuroleptics than are positive symptoms. Research suggests that neuroleptic drugs of the DPBP group possess a unique property--potent calcium channel antagonism--which could explain their ability to relieve negative symptoms. Earlier reports, however, used measures not specifically designed to assess the negative syndrome. The Positive and Negative Syndrome Scale (PANSS) was developed and standardized to measure the negative syndrome in schizophrenia. The authors used the PANSS to study the effects of pimozide in a 6-week, open clinical trial with 10 neuroleptic-resistant schizophrenic inpatients who had prominent deficit features. Negative but not positive symptoms improved significantly, suggesting that the drug might target the negative profile. The authors discuss possible pharmacologic mechanisms for pimozide's potentially distinct clinical properties.
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PMID:Pimozide treatment of the negative schizophrenic syndrome: an open trial. 328 15

Verapamil, a papaverine calcium channel blocker, has been used effectively and safely in the treatment of angina pectoris and auricular arrhythmias, and more recently in the treatment of mania. Many antipsychotic drugs show calcium channel blocking effects similar to verapamil's. A 41 year old male schizophrenic, only partially responsive to haloperidol decanoate and oral haloperidol, was given increasing doses of verapamil concomitantly, and monitored clinically and by the BPRS, electrocardiogramme, and other laboratory measures. The patient's total BPRS score dropped from 79 to 41 and remained stable, after initial worsening at lower doses, at verapamil 80 mg po qid. Mild fatigue was the only side effect. Further investigation of verapamil in the treatment of schizophrenia is warranted.
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PMID:Verapamil in refractory schizophrenia: a case report. 362 27

Antischizophrenic neuroleptic drugs of the diphenylbutylpiperidine class, which includes pimozide, fluspirilene, penfluridol, and clopimozide, inhibit [3H]nitrendipine binding with IC50 values of 13-30 nM. This inhibition involves receptors for the verapamil/prenylamine class of calcium channel antagonists. These diphenylbutylpiperidines also inhibit potassium-induced calcium-dependent contractions of rat vas deferens at concentrations of 40-350 nM. Other phenothiazine and butyrophenone neuroleptics lack such potent calcium-antagonist actions. Diphenylbutylpiperidines also differ from other neuroleptics in their ability to relieve negative symptoms of schizophrenia, such as emotional withdrawal, as well as the positive symptoms which respond to all neuroleptics. We suggest that these unique antischizophrenic actions are related to a blockade by diphenylbutylpiperidines of voltage-operated calcium channels.
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PMID:Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists. 613 40

Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression because they resemble depressed humans in that they have elevated REM sleep, reduced activity, and increased immobility and anhedonia after exposure to stressors. The present paper reviews experiments on the drug treatment of FSL and control Flinders Resistant Line (FRL) rats related to their utility as an animal model of depression, and presents new information. FSL rats exhibited exaggerated immobility in the forced swim test which is counteracted by the tricyclic antidepressants imipramine and desipramine and the serotonin reuptake blocker sertraline; the low immobility exhibited by the FRL rats is generally unaffected by these compounds. In contrast to these "therapeutic" effects of well recognized antidepressants, lithium and bright light treatment did not alter the exaggerated immobility of FSL rats. Novel data indicated that neither FSL nor FRL rats exhibited alterations in swim test immobility following chronic administration of the psychomotor stimulant amphetamine (2 mg/kg) and the anticholinergic scopolamine (2 mg/kg), which typically reduce immobility after acute administration. However, it was found that the calcium channel blockers verapamil (5 and 15 mg/kg) and nicardipine (10 mg/kg) did reduce the exaggerated immobility in FSL rats following chronic administration, suggesting that these compounds need to be evaluated further in humans. Previous studies have indicated no differences between FSL and FRL rats evaluated in the elevated plus maze, either at baseline or after the administration of diazepam, suggesting that the FSL rat may not differ from controls in anxiety-related behavior. Another recently published study showed that the FSL rat also did not differ from normal Sprague-Dawley rats in startle tests, indicating that the FSL rats do not exhibit behaviors shown in animal models of schizophrenia. These findings confirm the utility of FSL rats as an animal model of depression because the FSL rats do not appear to exhibit behaviors analogous to anxiety or schizophrenia and because they respond "therapeutically" to antidepressants and not psychomotor stimulants.
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PMID:Administration of antidepressants, diazepam and psychomotor stimulants further confirms the utility of Flinders Sensitive Line rats as an animal model of depression. 853 39

The role of calcium in the etiology of anxiety has been proposed for several decades. Calcium channel blockers profoundly influence calcium metabolism and the transport of calcium. Even though the evidence for the role of calcium remains weak, drugs affecting calcium might be useful in the treatment of anxiety disorders. One of these compounds, verapamil, has been used to treat mood disorders. Calcium channel blockers have also been tried in other indications such as premenstrual syndrome, irritable bowel syndrome, schizophrenia, tardive dyskinesia, and Tourette's syndrome. However, the number of articles on the use of calcium channel blockers in the treatment of anxiety disorders is low. Three reports (two open, one double-blind) described some success in the treatment of panic disorder with verapamil, diltiazem, or nimodipine and one open-label study described unsuccessful treatment of anxiety and phobia with nifedipine in patients with various anxiety disorders. Further double-blind placebo-controlled studies of calcium channel blockers in the treatment of anxiety disorders are warranted to determine a possible role of these compounds in the armamentarium of antianxiety drugs.
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PMID:Calcium channel blockers for anxiety disorders? 898 18

Phencyclidine (PCP) can result in schizophrenia-like behavior. It binds at the PCP site on the NMDA-receptor calcium channel and at the sigma receptor. PCP also induces the heat shock gene hsp7O in retrosplenial cortex neurons. An antipsychotic drug, rimcazole, inhibits PCP hsp7O induction. Rimcazole binds predominantly to sigma-2 sites. It is hypothesized that sigma ligands without antipsychotic properties and with some sigma-2 affinity should partially reverse the effects of rimcazole. (+)-3-PPP, (+)-cyclazocine, and (+)-pentazocine bind predominantly to sigma-I sites. (+)-3-PPP is also a modest sigma-2 ligand. Female Sprague-Dawley rats (200-260 g) were injected intraperitoneally (IP) with (+)-3-PPP (50 mg/kg), rimcazole (60 mg/kg) and, after 5 min, with PCP (40 mg/kg). Brains were sectioned (100 mu m) and presence of the hsp7O gene protein product, HSP7O, was determined immunocytochemically. (+)-3-PPP significantly (0 <0.05) diminished the ability of rimcazole to inhibit PCP hsp7O induction in the retrosplenial cortex. (+)-Cyclazocine (15mg/kg, IP) and (+)-pentazocine (8Omg/kg, IP) given in an analogous manner did not diminish the ability of rimcazole to inhibit PCP hsp7O induction.
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PMID:Effects of sigma ligands on the ability of rimcazole to inhibit PCP hsp70 induction. 913 45

Nilvadipine is a calcium channel inhibitor used commonly for the treatment of cerebrovascular insufficiency. We observed two patients with schizophrenia whose psychiatric symptoms and tardive dyskinesia improved after the addition of nilvadipine to their antipsychotic drug regimen. The total score of the brief psychiatric rating scale (BPRS) in case 1 fell from 56 to 42 after 8 weeks on nilvadipine; while that of case 2 fell from 44 to 32. The total score of the abnormal involuntary movement scale (AIMS) in case 2 decreased from 12 to 7. No adverse effects occurred during treatment. Nilvadipine may thus offer a new approach to the adjunctive treatment of schizophrenia.
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PMID:Effectiveness of nilvadipine in two cases of chronic schizophrenia. 917 44

We herein report the findings of an autopsy case of spinocerebellar ataxia type 6 (SCA6) which revealed a mild CAG-repeat expansion in the alpha1A voltage-dependent calcium channel (CACNL1A4) gene on chromosome 19p13. A 39-year-old man who showed slowly progressive mental disorders and gait ataxia was clinically diagnosed to have cortical cerebellar atrophy (CCA) and schizophrenia. None of his relatives revealed any symptoms such as spinocerebellar disease, however, his younger brother had shown some mental disorders. The patient eventually died at 52 years of age, and an autopsy was thus performed. The main histopathological findings included a severe neuronal cell loss of Purkinje cells and inferior olivary nuclei. The number of Purkinje cells in our case had decreased severely in comparison to that in either OPCA or age-matched control cases, and the Purkinje cells in the cerebellar hemisphere were more affected than those in the cerebellar vermis. The neurons of the dentate nucleus and pontine nuclei were well-preserved, and no pathological changes were seen in cerebral cortices or basal ganglia. The clinicopathological findings were similar to those of late cortical cerebellar atrophy (LCCA), Holmes' cortical cerebellar atrophy (Holmes type) or SCA6 cases reported previously. Using genomic DNA extracted from archival paraffin-embedded sections in the frontal lobe, cerebral basal ganglia and cerebellum, the identical mild CAG-repeat expansions in the CACNL1A4/SCA6 gene were revealed in all samples examined. These findings suggest that in cases with LCCA or Holmes type atrophy, we should thus examine the CAG-repeat expansions in the SCA6 gene, and the genomic DNA extracted from paraffin-embedded sections was thus found to be useful in diagnosing SCA6 retrospectively.
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PMID:An autopsy case of spinocerebellar ataxia type 6 with mental symptoms of schizophrenia and dementia. 1044 62

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.
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PMID:Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists. 1175 Jan 86


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