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Biomedical subjects

G Remington

Publications and source records attributed to G Remington.

At least 55 records · Page 3Linked to original sources
PubMed1997

The relationship between D2 receptor occupancy and plasma levels on low dose oral haloperidol: a PET study.

The purpose of this study was to determine the relationship between dopamine D2 receptor occupancy and plasma haloperidol. Twelve patients treated with 1-5 mg/day of haloperidol had their D2 occupancy measured using [11C]-raclopride and positron emission tomography and haloperidol plasma levels measured using gas chromatograph mass spectrophotometer. The patients exhibited haloperidol plasma levels ranging from 0.5 to 5.8 ng/ml and D2 occupancy from 53 to 88%. The D2 occupancy was related to the plasma level as a saturating rectangular hyperbola relationship (r2 = 0.84) and it showed that, on average, 50% D2 occupancy was achieved with 0.51 ng/ml and 80% D2 occupancy with 2.0 ng/ml. Our findings demonstrate that 2-5 mg/day of haloperidol, which usually leads to plasma levels of 1-2 ng/ml, would be expected to induce 60-80% dopamine D2 receptor occupancy. If, as has been claimed, 70% D2 occupancy is adequate for typical neuroleptic response, then the conventional use of > 10 mg/day may have been too high, since 70% occupancy can be achieved in most patients by 2-5 mg/day. On the other hand, if as others have suggested, 8-12 ng/ml of haloperidol is the correct therapeutic window for plasma levels, then the required therapeutic D2 occupancy is closer to 90%, not 70%. The implications of the D2 occupancy findings for the optimal dosing of neuroleptics are discussed.

Administration, Oral↗
PubMed1997

PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.

OBJECTIVE: Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses. METHOD: Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively. RESULTS: The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors. CONCLUSIONS: Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not "atypical" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.

Adult↗
PubMed1996

Depression in schizophrenia: a comparison of three measures.

Depression, as a feature of schizophrenia, is well established. However, clarifying the exact nature of this relationship has been problematic. The clinical measures routinely utilized to evaluate depression have not been specifically designed for use in schizophrenia, and it is well recognized that a variety of depressive symptoms overlap with other features common to this illness, e.g. negative symptoms, neuroleptic induced side effects. The present study compared three commonly used measures of depression (Hamilton Depression Rating Scale (Ham-D), Calgary Depression Scale (CDS) and the depression subscale of the Positive and Negative Syndrome scale (PANSS-D) in a group of outpatients with schizophrenia, evaluating the degree of association between the scales. Additionally, the relationship between each of the depression measures, negative symptoms and extrapyramidal symptoms (EPS) was calculated. Results revealed that all three measures of depression were significantly correlated, although the CDS was unique in its ability to distinguish between depression, negative symptoms and EPS. It is concluded that the CDS, when compared with the HAM-D and the PANSS-D, is the most suitable measure of depression in schizophrenia.

Adult↗
PubMed1996

Serotonin-dopamine interaction and its relevance to schizophrenia.

OBJECTIVE: The therapeutic success of clozapine and risperidone has focused attention on the interaction between serotonin and dopamine systems as an avenue for superior therapeutics in schizophrenia. The authors review the neurobiological basis for this interaction and its clinical relevance. METHOD: The authors synthesized information from more than 100 published articles obtained through electronic and bibliography-directed searches. FINDINGS: The serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain. Serotonergic antagonists release the dopamine system from this inhibition. This disinhibition of the dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms, and a similar disinhibition in the prefrontal cortex may ameliorate negative symptoms. However, the benefits of combined serotonergic-dopaminergic blockade may be observed in only a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic blockade. CONCLUSIONS: Serotonergic modulation of dopaminergic function provides a viable mechanism for enhancing therapeutics in schizophrenia, but much remains unclear. Future research will have to establish the existence of this interaction in humans in vivo, specify the conditions under which it leads to optimal therapeutic benefits, and explore the possibility of using specific serotonergic treatments as flexible adjuncts to typical neuroleptics, rather than the present trend toward using single drugs with combined actions.

Animals↗
PubMed1996

High levels of dopamine D2 receptor occupancy with low-dose haloperidol treatment: a PET study.

OBJECTIVE: The purpose of this study was to determine the dopamine D2 receptor occupancy induced by low-dose haloperidol treatment in a prospective trial. METHOD: Seven patients with schizophrenia were treated with 2 mg/day of haloperidol for 2 weeks, and D2 receptor occupancy was measured by [11C]raclopride and positron emission tomography. RESULTS: The patients showed high levels of D2 occupancy (53%-74%); five of them showed substantial clinical improvement, and none showed important side effects. CONCLUSIONS: The findings demonstrate that low doses of haloperidol induce D2 receptor occupancies that are in the putative therapeutic range. In combination with recent empirical trials, these findings should encourage clinicians to initiate treatment of psychotic episodes with low (2-4 mg haloperidol equivalent) doses of typical neuroleptics, particularly for first-episode patients.

Adult↗
PubMed1995

The D2 dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study.

Risperidone is a recently introduced neuroleptic distinguished by a decreased incidence of extrapyramidal side effects (EPS). The mechanism of its low EPS is unclear. Since it has been shown that EPS is related to the level of D2 receptor occupancy, we studied nine patients receiving 2-6 mg/day of risperidone using [11C]-raclopride PET scans in order to determine the in vivo D2 receptor binding characteristics of risperidone. The mean level of receptor occupancy was 66% at 2 mg; 73% at 4 mg; and 79% at 6 mg. Three patients, those with the highest receptor occupancies, exhibited mild EPS, though none required anitparkinsonian medications. Our results suggest that at doses of 4-6 mg the in vivo D2 receptor occupancy of risperidone is similar to that of typical neuroleptics and higher than that of clozapine. This would suggest that the EPS benefits of risperidone cannot be explained by a low D2 binding but may be related to its high 5-HT2 affinity. However, the emergence of EPS at higher levels of D2 receptor occupancy, in this study and in previous clinical trials, would suggest that risperidone's high 5-HT2 affinity provides only a relative protection from EPS. And once the D2 occupancy exceeds a certain threshold this 'relative' 5-HT2-mediated protection from EPS may be lost.

Adult↗
PubMed1993

Haloperidol and loxapine but not clozapine increase synaptic responses in the hippocampus.

Effects of two typical neuroleptics haloperidol and loxapine, and an atypical antipsychotic clozapine on excitatory synaptic transmission were examined in the CA1 area of rat hippocampal slices. Haloperidol (10 mumol) and loxapine (10 mumol) increased extracelllar evoked field potentials by an average of 57 and 125% of the control level respectively. Clozapine (50 mumol) induced a transient depression (21% of control) of the response followed by a small augmentation (10%). Examination of haloperidol actions using the whole cell clamp technique showed an increase in the amplitude of the excitatory postsynaptic current (e.p.s.c.) in response to the drug without any apparent changes in the resting membrane current. These data suggest that haloperidol and loxapine may act by enhancing excitatory synaptic transmission in some areas of the brain, and that novel antipsychotic clozapine differs in its mechanism of action.

Animals↗
PubMed1993

Placebo response in refractory tardive akathisia.

A double-blind, crossover drug trial with a patient with treatment-resistant tardive akathisia is described. The finding of a placebo response was unexpected, but emphasizes the value of such an approach in refractory cases.

Akathisia, Drug-Induced↗
PubMed1993

A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients.

In a double-blind study, 135 inpatients with a diagnosis of chronic schizophrenia were randomly assigned to 8 weeks of treatment with one of six parallel treatments: risperidone (a new central 5-hydroxytryptamine2 and dopamine D2 antagonist), 2, 6, 10, 16 mg/day; haloperidol, 20 mg/day; or placebo, after a single-blind placebo washout period. Doses were increased in fixed increments up to a fixed maintenance dose reached after 1 week. On the Clinical Global Impression-Severity of Illness and Improvement, all active medications were superior to placebo except for risperidone (2 mg) on the Clinical Global Impression-Improvement. On the total Positive and Negative Syndrome Scale (PANSS) score and positive subscale, superiority to placebo was observed for all treatment groups except for haloperidol and risperidone (2 mg), which tended to be superior to placebo on total PANSS and the positive subscale, respectively. On the PANSS negative subscale, only risperidone (6 mg/day) was significantly better than placebo. Risperidone (6 mg) was superior to haloperidol on the total PANSS, General Psychopathology, and Brief Psychiatric Rating Scale subscales. Although there was a linear increase in parkinsonism with increasing risperidone dosage, there were no statistically significant differences between risperidone (2, 6, and 16 mg/day) and placebo. At doses of 6 to 16 mg, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. By contrast, haloperidol produced significantly more parkinsonism than placebo and risperidone (2, 6 and 16 mg), with no effect on tardive dyskinesia. These data suggest that risperidone, at the optimal therapeutic dose of 6 mg/day, produced significant improvement in both positive and negative symptoms without an increase in drug-induced parkinsonian symptoms and with a significant beneficial effect on tardive dyskinesia.

Adult↗
PubMed1993

Acutely psychotic patients receiving high-dose haloperidol therapy.

Despite the trend towards lower neuroleptic dosing in the treatment of psychosis, there continue to be patients who are administered doses that are higher than recommended. Thirty-six acutely psychotic patients receiving parenteral haloperidol were evaluated by the Brief Psychiatric Rating Scale, the Schedule for Affective Disorders and Schizophrenia-Change Version, and the Nurses' Observation Scale for Inpatient Evaluation, as well as by drug levels in plasma. Patients were compared on the basis of total haloperidol dose in the first 24 hours: regular dose (RD: 10-30 mg) and high dose (HD: 40-80 mg). At baseline, patients in the HD group scored significantly higher on the Brief Psychiatric Rating Scale factor Hostile-Suspiciousness and the Nurses' Observation Scale for Inpatient Evaluation factor Irritability. Assignment to regular-dose and HD groups could not be accounted for on the basis of age, gender, weight, or duration of illness. Moreover, drug levels in plasma indicated that the HD patients did not require higher doses on the basis of differences in haloperidol levels.

Acute Disease↗
PubMed1991

Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography.

Loxapine, its N-demethylated metabolite amoxapine, and their 7- and 8-hydroxy metabolites were determined simultaneously in plasma by a simple two-step extraction procedure followed by reversed-phase liquid chromatography. Baseline separation was achieved by a 5-microns Spherisorb C6 column. The mobile phase consisted of 5 mM phosphate buffer (with 14 mM orthophosphoric acid)-acetonitrile (with 105 microM nonylamine) (77:23, v/v). Assays of the steady-state plasma samples obtained from seventeen patients on loxapine showed substantial amounts of 8-hydroxy metabolites, lesser amounts of loxapine, amoxapine and 7-hydroxyloxapine and trace amounts of 7-hydroxyamoxapine. As 8-hydroxy metabolites possess only weak dopamine-D2 blocking activity, the final neuroleptic property of loxapine may be affected significantly by metabolic polymorphism.

Amoxapine↗
PubMed1991

Rabbit syndrome, antidepressant use, and cerebral perfusion SPECT scan findings.

The rabbit syndrome is an extrapyramidal side effect associated with chronic neuroleptic therapy. Its occurrence in a patient being treated with imipramine is described, representing the first reported case of this syndrome in conjunction with antidepressants. Repeated cerebral perfusion SPECT scans revealed decreased basal ganglia perfusion while the movement disorder was present, and a return to normal perfusion when the rabbit syndrome resolved.

Basal Ganglia Diseases↗