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G Remington

Publications and source records attributed to G Remington.

At least 37 records · Page 2Linked to original sources
PubMed2000

Clozapine augmentation: safety and efficacy.

While clozapine has been demonstrated to be efficacious in refractory schizophrenia and possibly schizoaffective as well as bipolar disorders, a substantial number of patients still remain unresponsive. One strategy in treating these refractory patients is to augment clozapine with other somatic treatments. This article reviews the efficacy and safety of the combination of clozapine with other somatic treatments. A total of 70 articles were obtained from a manual, as well as computerized (Medline), search of the English language literature from 1978 to March 1998. Few controlled studies exist; most were case reports/series. From these data, the greatest risk of adverse effects seems to be associated with clozapine combined with benzodiazepines, valproate, or lithium, but no currently evaluated combination is absolutely unsafe. In terms of efficacy, the data suggest a number of potential augmentation strategies, although controlled data are few. Combination therapies with clozapine are common in clinical practice, despite a lack of empirical data, and the benefits and risks of these combinations need to be systematically reviewed.

Antipsychotic Agents↗
PubMed2000

Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia.

OBJECTIVE: Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. METHOD: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. RESULTS: The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively. CONCLUSIONS: The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.

Adolescent↗
PubMed2000

Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench.

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D2 occupancy in rats using a method similar in principle to the [11C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models.

Animals↗
PubMed1999

Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia.

OBJECTIVE: Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.

Adult↗
PubMed1999

D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET.

The advent of a number of new antipsychotics has been paralleled by efforts to better delineate their mechanisms of action and, in doing so, further our understanding of schizophrenia and its pathophysiology. Technological advances, such as positron emission tomography (PET), have proven to be powerful tools in this process, allowing us to evaluate in vivo models based primarily on in vitro evidence. Combined serotonin-2/dopamine-2 (5-HT2/D2) antagonism represents one such model, and we now have PET evidence available that can be extrapolated to our understanding and clinical use of both conventional and novel antipsychotics.

Amoxapine↗
PubMed1999

Conventional versus novel antipsychotics: changing concepts and clinical implications.

Novel antipsychotics represent a significant advance in the treatment of schizophrenia after many years of few developments. The conventional antipsychotics are potent D2 antagonists, but fail to achieve a response in about 30% of cases. They are also associated with a high rate of extrapyramidal side effects. The greater and broader spectrum of efficacy combined with the reduced short- and long-term side effects of the new drugs such as quetiapine, risperidone, olanzapine and ziprasidone, contribute to a fresh optimism for the pharmacotherapy of schizophrenia. These novel agents are now driving further advances in schizophrenia research through a growing understanding of their pharmacological and clinical profiles. Clozapine, the first novel antipsychotic, has relatively low activity at D2 receptors, a high affinity for D4 receptors and a greater 5-HT2 (serotonin) than D2 antagonism. Hence, clozapine and other novel antipsychotics can be classified as such by this latter characteristic. However, some of these drugs have D2 occupancy greater than 60% (the clinical response threshold), while others have a lower D2 occupancy. The novel antipsychotics according have also been classified according to their activity on different neurotransmitter systems. While more effective, novel antipsychotics are not a panacea; they have limitations and side effects. In clinical practice, the American Psychiatric Association recommends either a conventional or novel antipsychotic for initial treatment of schizophrenia, whereas Canadian guidelines recommend novel agents. These agents should also be considered for treatment of refractory schizophrenia. Patients whose schizophrenia does not respond to one of these agents may respond to another. Future research should involve longer clinical trials, given the long periods needed to establish efficacy, and should address many remaining questions about the novel agents.

Antipsychotic Agents↗
PubMed1998

5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. CONCLUSIONS: Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.

Adult↗
PubMed1998

Pharmacotherapy of first-episode schizophrenia.

BACKGROUND: A growing interest in first-episode schizophrenia reflects the belief that this line of investigation will lead to further developments regarding schizophrenia's aetiology, course and outcome. METHOD: Evidence from more recent clinical trials involving first-episode schizophrenia is integrated with neuroimaging data, specifically positron emission tomography, to provide direction regarding pharmacotherapy. RESULTS: Individuals with a first episode of schizophrenia appear particularly responsive to pharmacotherapy, as well as quite sensitive to side-effects. At the same time, current clinical and receptor-binding data support the efficacy of low-dose neuroleptic treatment. CONCLUSIONS: Early and effective treatment of schizophrenia has been associated with better long-term outcome. Low-dose neuroleptic therapy is an effective treatment strategy and the diminished risk of side-effects with this approach may further enhance compliance and outcome.

Antipsychotic Agents↗
PubMed1997

Relationship between negative symptoms in chronic schizophrenia and neuroleptic dose, plasma levels and side effects.

The negative symptoms of schizophrenia are often difficult to distinguish from the side effects of antipsychotic medication. In this study, we tried to clarify this issue by studying a group of patients in a clinic setting where a wide range of antipsychotic doses were being prescribed. Thirty-one patients meeting DSM-III-R criteria for schizophrenia or schizoaffective disorder were studied. Clinical ratings were carried out to assess the positive and negative symptoms of schizophrenia, parkinsonism, akathisia and tardive dyskinesia. Plasma levels were also measured for the majority of patients. Antipsychotic plasma levels were found to be highly correlated with dose. Antipsychotic dose and plasma levels were not correlated with the severity of negative symptoms, akathisia or parkinsonism. However, the severity of positive symptoms and tardive dyskinesia were positively correlated with both dose and plasma level. These findings do not support the hypothesis that higher doses of antipsychotic medication are associated with more severe negative symptoms.

Adult↗