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Biomedical subjects

Gary Remington

Publications and source records attributed to Gary Remington.

At least 37 records · Page 2Linked to original sources
PubMed2005

Rational pharmacotherapy in early psychosis.

BACKGROUND: An increased focus in research specific to first-episode schizophrenia has provided a rapidly growing body of evidence that can be directly translated to clinical practice. AIMS: To provide clinical recommendations specific to effective pharmacotherapy of first-episode schizophrenia. METHOD: Evidence from clinical trials focused on the first-episode population is combined with data from other areas of investigation. RESULTS: In first-episode psychosis, when to initiate treatment is not always clear, being intimately linked to challenges regarding early detection and diagnosis. There may be differences in antipsychotic dosing, patterns of response and sensitivity to side-effects. Adherence appears to be even more problematic at this stage. CONCLUSIONS: Clinicians currently treating early psychosis have considerably more information to guide their decision-making. However, the speed at which the field is growing is a reminder to treat this knowledge as a work in progress.

Antipsychotic Agents↗
PubMed2005

Augmentation strategies in clozapine-resistant schizophrenia.

The introduction of antipsychotics in the 1950s revolutionised the treatment of schizophrenia, but it soon became apparent that a substantial number of patients demonstrated a suboptimal response to these antipsychotics. Clozapine proved to be beneficial in patients whose symptoms were treatment resistant, but it too had limitations, with as many as 40-70% of those treated with clozapine demonstrating inadequate response to this drug as well. The availability of other 'atypical' antipsychotics offers options, but clozapine appears to remain the most effective option in treatment-resistant schizophrenia. This, of course, raises the question of what to do when clozapine is only partially effective. To address the issue of treatment in patients who have demonstrated a suboptimal response to clozapine, efforts have focused on a variety of augmentation strategies, including numerous medications and electroconvulsive therapy. The current body of evidence consists largely of data from smaller open trials and case series/reports, although data from a limited number of controlled studies are now available. Not surprisingly, the evidence drawn from the former is more supportive of augmentation strategies, although the controlled trials are not without positive findings. The available information is certainly not so overwhelming as to endorse any single augmentation approach. Indeed, it argues for more controlled data and cautions us regarding the cost-benefit ratio in adopting this strategy. Over and above the added adverse effects of another treatment, there is evidence to indicate that actual clinical worsening can occur. Without compelling evidence, clinicians must resort to guiding principles. The potential benefits of augmentation cannot be ruled out, but it should be approached with caution and in a systematic fashion. Factors compromising clozapine response should first be ruled out, and any augmentation trials should be guided by existing evidence and a treatment plan that incorporates a clear understanding of target symptoms. A means of evaluating outcome effectively needs to be in place, and the trial should be circumscribed to prevent needless polypharmacy. A priori, an endpoint needs to be established and the trial discontinued unless results firmly support added benefits.

Animals↗
PubMed2004

Effect of acute antipsychotic administration on dopamine synthesis in rodents and human subjects using 6-[18F]-L-m-tyrosine.

Clinical effects of antipsychotic drugs are thought to be mediated primarily through antagonism of the dopamine D2 receptors. Recent studies have demonstrated increased aromatic decarboxylase activity following acute administration of dopamine D2 receptor antagonists both in vivo and ex vivo. However, this effect has never been demonstrated in human subjects. We studied the effect of acute antipsychotic administration on dopamine synthesis in rodents and healthy human subjects using 6-[18F]-L-m-tyrosine. In rats, we studied the effect of a single subcutaneous injection of haloperidol and risperidone on dopamine synthesis using 6-[18F]-L-m-tyrosine. In our human study, six healthy volunteers underwent two 6-[18F]-L-m-tyrosine PET scans, before and after 3 mg risperidone to measure the rate of accumulation of radioactivity in the striatum as an index of dopamine synthesis. The striatal/cerebellar radioactivity count ratio and the ratio of dopamine metabolites to dopamine concentration was significantly higher in all rodent treatment groups compared to controls. In the PET study we found no significant change in the rate of uptake in the striatum. Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects.

Adult↗
PubMed2004

The use of pharmacotherapy in the prodrome of schizophrenia.

In treating schizophrenia there has been a shift in focus, with more attention being paid to early intervention based on the notion that effective treatment at this point can improve outcome. Most of this work has centred on pharmacotherapeutic interventions during the first psychotic break. More recently, attention has turned to the potential value of intervening even earlier, that is during the so-called "prodrome" that has been identified as predating the first psychotic break by as much as 4-5 years. We now have a limited number of published reports addressing this topic and these are reviewed here.

Adolescent↗
PubMed2004

A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone.

OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT(2) receptors compared with dopamine D(2) receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D(2) occupancy (using [(11)C]raclopride) and 5-HT(2) occupancy (using [(18)F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose. RESULTS: The mean 5-HT(2) receptor occupancy was significantly higher than the mean D(2) receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT(2) receptor occupancy was almost four times lower than that for D(2) receptor occupancy. CONCLUSIONS: These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT(2) than D(2) receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D(2) receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.

Adult↗
PubMed2004

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics.

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

Adolescent↗
PubMed2004

Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome.

OBJECTIVE: To determine the prevalence and characteristics of coronary heart disease (CHD) risk factors in patients with chronic schizophrenia or schizoaffective disorder. METHOD: We compared individual CHD risk factors and Framingham risk predictions in a group of 240 patients with a large national sample (Canadian Heart Health Survey) matched for age and sex. In addition, we compared rates of the metabolic syndrome (syndrome X) with recently published rates in the US adult population. RESULTS: Compared with the reference population, Framingham 10-year risk of myocardial infarction was greater in the male patients (t3091 = 4.35, P < 0.001) but not in the female patients. Prevalence rates of the metabolic syndrome in the patients (42.6% of men and 48.5% of women) were approximately 2 times published rates in the US adult population. Further, the syndrome appears to occur at a younger age than in the general population. CONCLUSIONS: These long-term patients have increased CHD risks best captured by the metabolic syndrome conceptualization coupled with a high rate of cigarette smoking. This characterization is consistent with increased cardiovascular morbidity and decreased life expectancy in both men and women. We underscore the importance of both screening for and treating potentially reversible CHD risk factors in schizophrenia patients.

Adolescent↗
PubMed2003

Direct activation of the ventral striatum in anticipation of aversive stimuli.

The brain "reward" system, centered on the limbic ventral striatum, plays a critical role in the response to pleasure and pain. The ventral striatum is activated in animal and human studies during anticipation of appetitive/pleasurable events, but its role in aversive/painful events is less clear. Here we present data from three human fMRI studies based on aversive conditioning using unpleasant cutaneous electrical stimulation and show that the ventral striatum is reliably activated. This activation is observed during anticipation and is not a consequence of relief after the aversive event. Further, the ventral striatum is activated in anticipation regardless of whether there is an opportunity to avoid the aversive stimulus or not. Our data suggest that the ventral striatum, a crucial element of the brain "reward" system, is directly activated in anticipation of aversive stimuli.

Adult↗
PubMed2003

Apathy in schizophrenia: clinical correlates and association with functional outcome.

Apathy is considered one of the negative symptoms of schizophrenia, but its natural history and relationship to other clinical characteristics have not been systematically studied. The purpose of this cross-sectional study was to measure the level of apathy in schizophrenia and its relation to other symptoms and functional outcome. Twenty-eight patients with schizophrenia, and receiving antipsychotic treatment, were assessed with the Apathy Evaluation Scale (AES). The mean level of apathy of patients with schizophrenia, as rated by the AES, was significantly higher than that of matched healthy control subjects. In the patients, apathy was not significantly correlated with positive symptoms or depressive symptoms. It was significantly correlated with the item "emotional withdrawal" on the negative subscale of the Positive and Negative Syndrome Scale (PANSS), but was not correlated with the overall negative subscale score. Apathy was more highly associated with functional outcome than were other symptom measures, and it was independently associated with functional outcome above and beyond other negative symptoms. It was not associated with observed interest in playing a video game or performance on a simulated clerical task.

Activities of Daily Living↗
PubMed2003

Differential effects of within-day continuous vs. transient dopamine D2 receptor occupancy in the development of vacuous chewing movements (VCMs) in rats.

Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D(2) receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D(2) receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D(2) receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n=36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D(2) occupancy levels were measured in vivo using [(3)H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D(2) occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dose-dependent D(2) occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D(2) occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.

Animals↗
PubMed2003

Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic.

BACKGROUND: The long-term safety and efficacy of long-acting injectable risperidone, the first long-acting second-generation antipsychotic, were evaluated in stable patients with schizophrenia. METHOD: After a 2-week run-in period during which patients with DSM-IV schizophrenia received flexible doses of 1 to 6 mg of oral risperidone, patients received injections of 25 mg, 50 mg, or 75 mg of long-acting risperidone every 2 weeks for 12 months. Severity of extrapyramidal symptoms was assessed with the Extrapyramidal Symptom Rating Scale (ESRS), and efficacy was assessed with the Positive and Negative Syndrome Scale (PANSS). This study was conducted from March 29, 1999 to July 19, 2000. RESULTS: The subjects were 615 patients with schizophrenia who received at least 1 injection of long-acting risperidone. The 12-month trial was completed by 65% of patients. Treatment was discontinued because of adverse events in 5% of patients. Extrapyramidal symptoms as adverse events were reported by 25% of the patients. Severity of extrapyramidal symptoms (according to ESRS scores) was low at baseline and decreased in each of the groups during the 12 months. The other most common adverse events were anxiety in 24%, insomnia in 21%, psychosis in 17%, and depression in 14% of the patients. Little pain was associated with the injections. Severity of symptoms of schizophrenia was improved in each group, with significant reductions in PANSS total scores (p <.01) and positive (p <.01) and negative (p <.001) factor scores. CONCLUSION: In terms of both safety and efficacy, symptomatically stable patients with schizophrenia benefit from being switched to long-acting injectable risperidone.

Administration, Oral↗
PubMed2003

Understanding antipsychotic "atypicality": a clinical and pharmacological moving target.

The introduction of a number of new antipsychotics in the last decade has generated considerable excitement regarding the treatment of schizophrenia and related psychotic conditions. Clinically, it has produced changing expectations regarding treatment outcome, while academically it has encouraged a re-evaluation and expansion of theories of the pathophysiology of schizophrenia and antipsychotic activity. In this review, the development of antipsychotics is traced, beginning with chlorpromazine's introduction in the early 1950s, and followed to the present. Despite 50 years of use and a plethora of antipsychotics available worldwide, our conceptualization of their major mode of action remains essentially unchanged. It was shortly after their development that attention turned to the importance of dopamine, and in particular the dopamine D2 receptor. Current thinking has elaborated on this model, with serotonin and glutamate receiving the greatest attention most recently, but D2 antagonism remains the sine qua non of antipsychotic activity. Although the notion of "atypical" remains somewhat of a moving target, we do have at our disposal a new generation of antipsychotics that reflect a different clinical profile from their conventional counterparts. The precise degree of these differences and the underlying mechanisms remain unclear, however. The direction new antipsychotic development takes will undoubtedly hinge on answers to these questions.

Animals↗
PubMed2003

Actigraphic measurement of the effects of single-dose haloperidol and olanzapine on spontaneous motor activity in normal subjects.

OBJECTIVE: To quantitatively examine the effects of haloperidol and olanzapine on spontaneous motor activity in normal subjects. DESIGN: Randomized, double-blind, placebo-controlled medication study. PARTICIPANTS: Normal volunteers (n = 30). INTERVENTIONS: Subjects received 1 dose of either haloperidol 2 mg (n = 9), olanzapine 10 mg (n = 10) or placebo (n = 10) and were admitted to hospital for the next 24 hours. OUTCOME MEASURES: Subjects wore an actigraphic monitor, which recorded movement in 15-second epochs. The Simpson-Angus Extrapyramidal Side Effect Scale (SAS) and the Barnes Akathisia Scale (BAS) were administered before and 7 and 24 hours after medication was given. RESULTS: Compared with placebo, total motor activity was decreased by 41% with olanzapine (p = 0.004) and by 12% with haloperidol (NS). There were significantly more epochs with zero movement with olanzapine than with haloperidol or placebo. For non-zero epochs, the mean activity count and the distribution of activity counts did not differ significantly among groups. There were no positive findings on the SAS or the BAS. CONCLUSIONS: Olanzapine decreased total motor activity by increasing the amount of time during which subjects were immobile, rather than by affecting the magnitude of movement during periods in which there was activity. This effect occurred at a dose of olanzapine low enough not to cause clinically observed extrapyramidal side effects. Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity.

Adolescent↗
PubMed2002

The relationship between dopamine D2 receptor occupancy and the vacuous chewing movement syndrome in rats.

RATIONALE: A dose-response relationship between dopamine D(2) occupancy and acute extrapyramidal symptoms (EPS) has been well established. However, the link with the induction of tardive dyskinesia (TD) is less clear. OBJECTIVES: To ascertain the nature and extent of D(2) receptor occupancy effects on haloperidol-induced vacuous chewing movements (VCMs) in a rat model of TD. METHODS: Groups of eight rats received haloperidol decanoate injections corresponding to daily doses of 0, 0.08, 0.17, 0.33, or 1 mg/kg for 10-12 weeks. VCMs were measured on a weekly basis and D(2) occupancy levels were measured in vivo using [(3)H]-raclopride at the end of the experiment. RESULTS: Final VCM scores were significantly different between haloperidol doses ( P=0.001). Moderate but significant correlations were found between dose and average VCM scores (r=0.69, P<0.001) and between D(2) occupancy and average VCM scores (r=0.65, P<0.001). The rats that developed the VCM syndrome (>/=8 VCMs) had higher occupancies than rats that did not. Of the rats with an occupancy above 70%, 63% developed VCMs, compared with 37% of the rats with D(2) occupancy below that. CONCLUSIONS: These results indicate that chronic haloperidol induces VCMs in a dose-dependent manner, with doses leading to high D(2) occupancy increasing the likelihood of emergence of the VCM syndrome. While a certain level of D(2) occupancy may be necessary for inducing VCMs, it is not sufficient in and of itself to induce the VCM syndrome.

Animals↗
PubMed2002

How much are atypical antipsychotic agents being used, and do they reach the populations who need them? A Canadian experience.

BACKGROUND: The introduction of new antipsychotic agents in the past decade has helped alter the treatments available to 2 vulnerable populations-those with schizophrenia and related psychotic conditions and elderly individuals with dementia. OBJECTIVE: After examining overall trends in antipsychotic use, this analysis reviews patterns of atypical antipsychotic use in the elderly and financially disadvantaged populations of Ontario. It identifies affected subpopulations and offers several interpretations of how observed patterns of use reflect outpatient prescribing practices. METHODS: This study used drug claims data from the Ontario Drug Benefit (ODB) program for the years 1992 to 1998. The use of antipsychotic agents was followed for 2 years in a subpopulation of ODB participants identified as consistent users of these agents (ie, those with evidence of > 1-time use). RESULTS: During the study period, the total number of ODB claimants grew by 1%, the number of claimants using antipsychotic agents increased by approximately 25%, and the expenditure per claimant in this group increased by nearly 250%. Much of this growth in expenditures was associated with use of the newer atypical antipsychotic agents olanzapine, risperidone, and quetiapine. Compared with patients aged > or = 65 years, those aged < 65 years were more likely to receive an initial prescription for an atypical antipsychotic or be switched to an atypical antipsychotic. However, the proportion of patients aged > 85 years consistently using antipsychotic agents was greater than predicted based on the proportion of the ODB population they represent. These patients were more likely to use conventional antipsychotic agents exclusively. CONCLUSIONS: The introduction of the atypical antipsychotic agents was paralleled by a striking increase in ODB expenditures for antipsychotic drugs, although use of these agents was not consistent across age groups. There was more switching to atypical antipsychotics, as well as greater use in general, among younger compared with older patients, despite evidence that the atypical antipsychotics may be safer in the elderly than conventional antipsychotics. Guideline dissemination may be an important way of familiarizing clinicians with the atypical agents. Health care systems should be aware of the potential for a substantial increase in health care costs with more widespread adoption of these medications.

Adolescent↗
PubMed2002

The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: is there a relationship to dopamine D(2) receptor occupancy?

Tardive dyskinesia (TD) is a late side effect of long-term antipsychotic use in humans, and the vacuous chewing movement (VCM) model has been used routinely to study this movement disorder in rats. Recent receptor occupancy studies in humans and rats have found that antipsychotics given in doses which lead to moderate levels of D(2) receptor blockade can achieve optimal clinical response while minimizing the emergence of acute motor side effects. This suggests that clinicians may have been using inappropriately high doses of antipsychotics. A review of the existing VCM literature indicates that most animal studies have similarly employed antipsychotic doses that are high, i.e. doses that lead to near complete D(2) receptor saturation. To verify whether the incidence or severity of VCMs would decrease with lower antipsychotic doses, we conducted initial experiments with different doses of haloperidol (HAL) given either as repeated daily injections or as depot injections over the course of several weeks. Our results demonstrate that (1) the incidence of VCMs is significantly related to HAL dose, and (2) significant levels of VCMs only emerge when haloperidol is continually present. These findings are consistent with the possibility that total D(2) occupancy, as well as 'transience' of receptor occupation, may be important in the development of late-onset antipsychotic-induced dyskinetic syndromes.

Animals↗
PubMed2002

Double-blind, placebo-controlled comparison of the efficacy of sertraline as treatment for a major depressive episode in patients with remitted schizophrenia.

The effectiveness of selective serotonin reuptake inhibitors for depression in remitted schizophrenia has not been clearly demonstrated. A randomized, double-blind, prospective placebo-controlled study was performed of 48 subjects meeting DSM-IV criteria for both schizophrenia in remission and for a major depressive episode. Twenty-seven patients were randomized to placebo and 21 to sertraline. All subjects had a 1-week anticholinergic phase before randomization. The treatment duration was 6 weeks. Sertraline was started at 50 mg/day; this could be increased to 100 mg after 4 weeks for an inadequate response. There were no statistically significant differences in symptoms between the two groups at randomization. There were no differences in outcome between treatment groups. In both groups, between 40% and 50% of subjects showed a 50% reduction in depression score. This study does not provide support for the efficacy of sertraline in the treatment of depression in remitted schizophrenia. The small sample size limits the strength of the conclusions that can be drawn from this study. The study design called for a sample size of 96 on the basis of an expected placebo response rate of 30%. Recruitment for the study was difficult because of the placebo design. The placebo response was 50%. Clinicians and patients underestimate the strength of the placebo response and may overestimate the risk of participating in such a study. Testing the efficacy of widely accepted but poorly evaluated treatments should be a research priority. Future studies require a larger sample size and longer duration of treatment.

Adolescent↗