Biomedical subjects
Publications and source records attributed to J M Kane.
Diabetes mellitus has been identified as a possible risk factor for tardive dyskinesia. The authors examined 160 elderly individuals who were beginning neuroleptic treatment; 24 had diabetes and 136 did not. After 43 weeks of neuroleptic exposure, the cumulative incidence rates of tardive dyskinesia were 54.1% (SE = 5.6%) for the diabetics and 25.6% (SE = 16.1%) for the nondiabetics.
Two studies have been performed to evaluate the effect of activation tasks on neuroleptic-induced akathisia (NIA). In the first sample (30 patients) we found a consistent increase of symptoms during mental activation while motor activation led to a decrease. In a second study 34 patients with the same diagnosis were evaluated, using slightly different statistical procedures: while the effects of motor activation were corroborated, mental activation did not change NIA. Since mental and motor activation are usually considered to increase tardive dyskinesia and Parkinsonism, these measures might be helpful in differentiating NIA from other antipsychotic-induced movement disorders.
Despite the enormous benefits provided by antipsychotic medication in the management of schizophrenia, available compounds have serious limitations. Firstly, they are not always effective. Secondly, positive psychopathological symptoms may benefit more than negative or deficit symptoms. Thirdly, antipsychotics are generally associated with a variety of neurological adverse effects. Three drugs have recently been or are close to being introduced into widespread clinical use: clozapine, risperidone and remoxipride. Each of these compounds appears to have some advantages over traditional antipsychotic agents, particularly in terms of reduced propensity to induce adverse neurological effects. All three drugs have been shown to be clinically effective in large scale trials. Future clinical trials are required to establish their relative merits in comparison with one another.
Human brainstem frequency-following responses (FFRs) and cortical event-related potentials (ERPs) were evoked by a low-frequency (230 Hz) tone during directed attention. ERPs showed significant amplitude differences consistent with expected attention effects, viz., largest to attended stimuli and smallest to ignored stimuli. The ERP data thereby confirm that attention effectively modulated cortical responses. The FFR, however, did not differ between conditions. The present results agree with one earlier FFR study and a majority of studies using click stimuli to elicit the brainstem auditory evoked response (BAER). However, several BAER studies and two recent FFR studies have shown that attention can influence human brainstem responses. The present results are therefore interpreted in the context of specific task requirements that optimize early selective attention effects.
Preliminary findings are reported for a study of the relative efficacy of conventional treatment alternatives routinely used to treat acutely relapsed schizophrenic patients who fail an initial course of standard neuroleptic therapy. A sample of 156 acutely ill schizophrenic, schizoaffective, and schizophreniform patients who had been hospitalized recently in an acute-care inpatient facility were treated openly with fluphenazine (FPZ) 20 mg/day and with prophylactic benztropine for 4 weeks. Those subjects who failed to meet a priori criteria for substantial therapeutic response at the end of Week 4 were randomized to receive double-blind treatment for an additional 4 weeks with one of the following: (1) the same dose of neuroleptic (FPZ 20 mg/day); (2) an increased dose of neuroleptic (FPZ 80 mg/day); or (3) a different class of neuroleptic (haloperidol 20 mg/day). Of the 115 subjects who completed the open phase of study, 32 percent were identified as responders. Higher negative symptom scores and increased acute extrapyramidal side effect ratings appeared to distinguish the nonresponder from the responder group. Of the nonresponders who went on to randomized treatment, only 4 of 47 subjects (9%) subsequently responded. No superior efficacy was associated with any of the specific alternative treatments studied.
The relative efficacy of conventional treatment alternatives that are routinely used to treat acutely relapsed schizophrenic patients who have failed an initial course of standard neuroleptic therapy has not been adequately studied, nor have predictors of poor treatment response been reliably identified. We have recently reported preliminary findings that suggest that these patients may subsequently fail to respond to such conventional alternative treatments as (1) maintaining the same dose of the neuroleptic over an extended trial, (2) significantly increasing the dose of the same neuroleptic, or (3) switching to a different class of neuroleptic. Negative symptoms and acute extrapyramidal side effects (EPS) evident during the initial treatment trial were associated with a less favorable clinical response to neuroleptic treatment. We now report on the association between clinical response and negative symptoms and acute EPS. Present findings suggest that a particular degree of negative symptoms apparent prior to treatment may be associated with a poor subsequent treatment response and that negative symptom scores and EPS ratings demonstrate a significant correlation with severity of psychiatric ratings during the treatment trial. The relationship among neuroleptic resistance, negative symptoms, and acute EPS requires further study.
A review of the literature concerning the use of oral and depot antipsychotic medication has high-lighted some important considerations in the treatment of chronic schizophrenic patients. All patients not treated with any form of antipsychotic drug will relapse within 3 years. These relapses will be more clinically significant and will occur at greater frequency than in patients who receive medication on a regular basis. Careful consideration should be given to each patient when choosing between oral or depot medication and inpatient or outpatient therapy. In addition, the clinician should consider the dosage schedule of each medication and balance this against the probability of extrapyramidal side effects and noncompliance. One option for the prevention of relapse without an increase in adverse side effects is the administration of depot haloperidol. For all therapeutic options, medication should be given on a regular basis, since intermittent dosing strategies do not work, and psychosocial rehabilitation should be initiated.
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BACKGROUND: The authors attempted to determine if chronic exposure to clozapine can cause tardive dyskinesia. METHOD: Twenty-eight schizophrenic or schizoaffective patients with no prior history of definite tardive dyskinesia were treated with clozapine for at least 1 year, and their ongoing modified Simpson Dyskinesia Scale ratings were analyzed. These data were then compared with those of another group of similarly diagnosed patients who were treated with a conventional neuroleptic for at least 1 year. RESULTS: Two patients in the clozapine-treated group (both of whom had ratings of questionable tardive dyskinesia at baseline) were later rated by the modified Simpson Dyskinesia Scale as having mild tardive dyskinesia on at least two consecutive ratings 3 months apart. Although there was uncertainty about whether clozapine definitely caused the tardive dyskinesia in those two patients, a survival analysis comparing the clozapine-treated group with the neuroleptic-treated group showed a lower risk of tardive dyskinesia developing in the clozapine-treated group. CONCLUSION: This study was unable to definitively conclude whether clozapine causes tardive dyskinesia. However, if cases do develop, the risk of tardive dyskinesia is likely to be less with clozapine than with typical neuroleptics.
Disrupted glycinergic inhibition in the brainstem and spinal cord may contribute to some of the alterations in reflex control seen in patients with spastic disorders. MDL 27,531, which acts functionally like a glycine agonist in its capacity to selectively reverse seizures produced by the glycine antagonist strychnine, was evaluated in a model of spinal injury-induced reflex dysfunction. Rats recovering chronically from complete spinal cord transections exhibited intermittent contractions of the paralyzed hindlimbs, as measured with an automated apparatus. MDL 27,531 selectively decreased these hindlimb contractions, as did the clinically demonstrated antispastic agent clonidine. In its therapeutic dose range, clonidine, but not MDL 27,531, produced ataxia in non-transected rats. These data suggest that MDL 27,531 may be a useful therapeutic agent for the treatment of dysfunctions of reflex control seen in spastic disorders of spinal origin, with potentially fewer side effects than are seen with existing drug therapies.
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MDL 26,479, a novel triazole compound with action at the GABAA receptor complex, was examined in 2 models of working memory deficit in the rat. MDL 26,479 attenuated a scopolamine-induced acquisition deficit in a T-maze reinforced alternation task. MDL 26,479 also reversed a performance deficit induced by increased delay between sample and choice trials in the same task, suggesting that the compound may have memory enhancing potential. This finding further supports claims that drugs acting at the GABAA receptor complex are of potential use in the treatment of memory disorder.
Ninety-four patients with bipolar disorder participating in a random-assignment, double-blind, prospective maintenance trial of standard- (0.8 to 1.0 mmol/L) vs low-range (0.4 to 0.6 mmol/L) serum lithium levels were assessed to determine the presence and significance of subsyndromal symptoms during periods of remission and recovery. A significant relationship was found between prescribed serum lithium level and the probability of major affective relapse and the occurrence of subsyndromal symptoms. Patients given lithium carbonate to achieve low-range levels had 2.6 times the risk of major affective relapse as those given lithium for standard-range levels and nearly twice the risk of developing subsyndromal symptoms. Patients given the low-range therapy showed a greater variance in weekly Psychiatric Status Rating measures, and their symptoms were more likely to worsen at any time than were symptoms in their standard-level group counterparts. The first occurrence of subsyndromal symptoms increased the risk of major affective relapse fourfold. Following the onset of subsyndromal symptoms, the patients originally randomized to receive standard-range lithium therapy were still better protected from relapse than were patients randomized to receive low-range lithium treatment. Patients were two times more likely to develop depressive than hypomanic symptoms between acute episodes of illness. However, onset of hypomanic symptoms predicted subsequent major affective relapse twice as strongly as did depressive symptoms. Seventy-six percent of patients who became hypomanic had a major affective relapse, compared with 39% of patients who were subclinically depressed.
1. Strychnine-sensitive glycine receptors are primarily localized in the brainstem and spinal cord where they are the major mediators of postsynaptic inhibition. A compound which acts functionally like a glycine receptor agonist would be potentially useful as a pharmacological tool and as a therapeutic agent for treating disorders of glycinergic transmission. 2. MDL 27,531 (4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole) blocked strychnine-induced tonic extensor seizures in mice following either intraperitoneal (ED50 = 12.8 mg kg-1; 30 min) or oral (ED50 = 7.3 mg kg-1; 30 min) administration. Time course studies revealed a maximal effect at 30-60 min, though significant activity was still seen after 24 h. 3. MDL 27,531 was selective in antagonizing strychnine seizures and little or no activity was seen against seizures produced by other chemical convulsants (bicuculline; quinolinic acid; mercaptopropionic acid); by electrical stimuli (maximal electroshock); or by sensory stimuli (audiogenic seizure susceptible mice). MDL 27,531 blocked pentylenetetrazol-induced seizures with an ED50 = 55 mg kg-1. This profile differed from those of the anticonvulsants diazepam, valproic acid, and diphenylhydantoin. 4. The antagonism of strychnine seizures by MDL 27,531 occurred at doses that did not produce signs of sedation (suppression of spontaneous motor activity), motor ataxia (disruption of rotarod performance), muscle relaxation (inhibition of morphine-induced Straub tail), or CNS depression (potentiation of hexobarbitone sleep time). MDL 27,531 had less side effect potential (as derived from ratios obtained from the above measures) relative to those of the known muscle relaxants diazepam and baclofen. 5. Although MDL 27,531 behaved functionally like a selective agonist at the strychnine-sensitive glycine receptor, the compound did not alter the in vitro binding of [3H]-strychnine to mice brainstem/spinal cord membranes at concentrations of up to 100 microM. In further in vitro binding assays, MDL 27,531 at concentrations of up to 100 microM, did not displace the binding of [3H]-muscimol, [3H]-flunitrazepam, or["S]-t-butylbicyclophosphorthionate to rat cortical membranes. These ligands bind to the 7y-aminobutyric acid (GABA), benzodiazepine, and picrotoxin-convulsant binding sites, respectively.6. MDL 27,531 (10-100mgkg-', i.p.) enhanced binding of the benzodiazepine antagonist [3H]-Ro15-1788 to mouse cerebral cortex in vivo without directly affecting GABA levels.7. Ro 15-1788 (16, 32 mg kg-') significantly blocked the MDL 27,531 antagonism of strychnineinduced seizures, though this antagonism was not competitive. The same doses of Ro 15-1788 produced parallel rightward shifts in the dose-response curves for diazepam inhibition of pentylenetetrazol-induced seizures, consistent with a competitive antagonism.8. Thus, MDL 27,531 acts functionally like an agonist at the strychnine-sensitive glycine receptor in its capacity to reverse selectively strychnine-induced seizures. Though the precise mechanism of action of MDL 27,531 is unknown, MDL 27,531 may act at an allosteric site on the strychnine-sensitive receptor which produces agonist-like activity.
1. The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione). 2. The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22 +/- 0.05 mg kg-1) inhibited [3H]-flumazenil (Ro15-1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3. Parenteral administration of MDL 26,479 (1 mg kg-1) or the benzodiazepine (BZD) inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg kg-1) increased cortical ex vivo binding of [3H]-hemicholinium-3 ([3H]-HC-3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg-1). 4. MDL 26,479 (20 microM) and DMCM (1 microM) increased excitation in the hippocampal long-term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5. In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6. Previous work showed that MDL 26,479 enhances learning acquisition in animal models.The present study suggests that at least some of the cognition enhancing properties are due to the enhancement of cortical and hippocampal cholinergic function and LTP.
The ability to use pharmacological treatment for schizophrenia is progressing in a most efficacious fashion, while the risk of adverse effects is declining. An important reevaluation of minimal effective antipsychotic drug dosages for both acute and extended treatment has taken place. Clozapine has provided clinical practitioners with a useful new alternative for treatment-refractory patients, and new research has helped clarify the role of different maintenance and prophylactic medication strategies. The author summarizes recent progress in these areas.
Neuroleptic drugs remain a critical modality in the treatment of schizophrenia. Numerous variables influence response to neuroleptic drugs including biologic, pharmacologic, and psychosocial factors. This review cites some examples of how such factors have been examined.
BACKGROUND: Depot neuroleptics are effective as long-term maintenance therapy in chronic schizophrenia and are widely used in Europe. In the United States, however, physicians have been reluctant to use them. They assume that depot neuroleptics present an increased risk of major side effects, that patients do not accept or tolerate them as well as oral agents, and that prescribing depot neuroleptics increases the possibility of medicolegal problems. METHOD: We analyzed the published data on neuroleptic malignant syndrome, tardive dyskinesia, extrapyramidal symptoms, perceptions of depot therapy, and medicolegal concerns. Whenever possible, we used the Mantel-Haenszel test to compare the outcome of oral versus depot neuroleptic medication treatment. RESULTS: Depot neuroleptics are not associated with an increase in any of the negative outcomes assessed. CONCLUSION: Depot neuroleptics represent a valuable treatment option for many patients and merit wider use.