[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To conduct a systematic review examining the relationships between olanzapine dose, clinical outcome, dopamine occupancy, and plasma concentration; and to evaluate the potential for therapeutic drug monitoring. METHODS: A search using Embase, Medline, and Pubmed was conducted; and the literature was systematically reviewed. Studies meeting inclusion criteria were examined. The relationships between olanzapine dose, response, dopamine occupancy, and concentration were analyzed using statistical regression. RESULTS: Ten studies were included in the analysis for dose-response. The effect size-dose relationship showed a typical dose-response curve with minimal rise in slope for doses higher than 10 mg/d. For the dose-occupancy relationship, 6 studies were included. Doses more than approximately 12 mg/d were sufficient to block 65% of striatal D2 receptors. Doses higher than 20 mg led to minimally higher receptor occupancies. Fifteen studies were included in the meta-regression of olanzapine mean concentrations. A linear relationship between mean plasma concentration and mean dose was observed. CONCLUSIONS: Our review suggests that the likelihood of a favorable response with olanzapine is maximized at doses of 10 to 15 mg/d (perhaps lower in nonsmoking females). Higher doses may be considered if 15 mg is ineffective and if plasma level is less than 20 ng/mL on that dose. There is a direct linear relationship between olanzapine dose and plasma concentration. Therapeutic drug monitoring may be useful in patients who are suspected of nonadherence, where there is potential for a drug interaction, and in patients taking 15 mg/d or more and who have not reached clinical response.
Journal of clinical psychopharmacology 04/2013; 33:329-335. · 5.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Seizures are more common during the initiation phase of clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the clozapine plasma level exceeds 500 μg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of clozapine-induced seizures are valproate (particularly where there is mood disturbance) and lamotrigine (where there is resistance to clozapine).
Therapeutic advances in psychopharmacology. 04/2011; 1(2):47-66.
[show abstract][hide abstract] ABSTRACT: Paliperidone palmitate is a new long-acting antipsychotic injection for the treatment of acute and maintenance therapy in schizophrenia. Paliperidone (9-hydroxyrisperidone) is the major active metabolite of risperidone and acts at dopamine D(2) and serotonin 5HT(2A) receptors. As with other atypical antipsychotics, it exhibits a high 5HT(2A):D(2) affinity ratio. It also has binding activity as an antagonist at α(1)-and α(2) adrenergic receptors and H(1) histaminergic receptors, but has virtually no affinity for cholinergic receptors. Paliperidone palmitate has been shown to be effective in reducing Positive and Negative Syndrome Scale total scores in four short-term trials in acute schizophrenia. It was also effective as maintenance therapy in a long-term trial in which time to recurrence of symptoms was significantly longer in paliperidone-treated patients compared with placebo. In addition, paliperidone was shown to be noninferior to risperidone long-acting injection in one study, but this noninferiority was not established in another longer study comparing the two drugs. Treatment should be initiated with 234 mg on day 1 and 156 mg on day 8, followed by a recommended monthly maintenance dose of 39-234 mg based on efficacy and tolerability. Paliperidone palmitate is generally well tolerated, although it can cause weight gain and a rise in prolactin levels, which is generally greater in women than in men. Overall, paliperidone palmitate may have advantages over other currently available long-acting injections, and therefore may be a useful alternative for the treatment of schizophrenia, although further long-term trials comparing it with active treatments are warranted.
Neuropsychiatric Disease and Treatment 01/2010; 6:561-72. · 2.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: The management of Behavioural and Psychological Symptoms of Dementia (BPSD) has been the subject of considerable debate over the last few years in view of the poor evidence base for pharmacological agents and concerns about their safety.
This study sought to obtain expert opinion on the management of BPSD and to investigate current prescribing practices in the UK.
A total of 166 expert opinion surveys were emailed to UK consultants in Old Age Psychiatry asking them to rate the appropriateness of psychotropics in different aspects of BPSD. A service evaluation was also carried out in 8 UK centres to investigate prescribing patterns.
Overall, 59 consultants returned completed questionnaires, a response rate of 35%. Results revealed that experts rated quetiapine as the most appropriate agent for all BPSD followed by acetylcholinesterase inhibitors for psychotic symptoms, benzodiazepines for agitation or aggression and trazodone for behavioural symptoms such as disinhibition. The service evaluations showed that benzodiazepines were most frequently prescribed for BPSD.
Although quetiapine was judged by experts to be the most appropriate agent for BPSD, it appears that in clinical practice benzodiazepines are most often used to manage these symptoms. Evidence from both studies show wide inconsistencies in prescribing trends.
International Journal of Geriatric Psychiatry 01/2009; 24(9):944-54. · 2.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Asenapine is a new atypical antipsychotic agent currently under development for the treatment of schizophrenia and bipolar disorder. It has high affinity for various receptors including antagonism at 5HT(2A), 5HT(2B), 5HT(2C), 5HT(6) and 5HT(7) serotonergic receptor subtypes, alpha(1A), alpha(2A), alpha(2B) and alpha(2C) adrenergic and D(3) and D(4) dopaminergic receptors. As with other atypicals, asenapine exhibits a high 5HT(2A):D(2) affinity ratio. Although similar to clozapine in its multi-target profile, it shows no appreciable affinity for muscarinic receptors. Asenapine has shown efficacy in alleviating both positive and negative symptoms of schizophrenia compared with placebo. Although promising, further studies are required in order to determine whether it has advantages over placebo and other antipsychotics in alleviating cognitive impairment associated with schizophrenia. It has also shown long-term efficacy comparable with olanzapine in bipolar I disorder. Asenapine is generally well tolerated and appears to be metabolically neutral. It has low propensity to cause weight gain and prolactin elevation. There were no concerns in the studies about its effects on the cardiovascular system and QTc prolongation. The incidence of extrapyramidal symptoms with asenapine however has been found to be higher than that with olanzapine. It may be a useful alternative to aripiprazole in schizophrenia and bipolar disorder in patients who are at high risk of metabolic abnormalities.
Neuropsychiatric Disease and Treatment 01/2009; 5:483-90. · 2.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate outcomes of clinical use of risperidone long-acting injection (RLAI) and determine factors predicting continuation with treatment.
This prospective, 3-year follow-up of consecutive patients started on treatment with RLAI in normal clinical practice between August 2002 and September 2003 obtained demographic and clinical data from case notes, prescription charts, and hospital computer records. To determine predictors of continuation, a proportional hazards regression (Cox) model was constructed.
The study included 211 evaluable patients. Over 3 years, 84% of subjects discontinued RLAI; 27.7% of these switched to oral risperidone. The Cox model showed that younger age (p = .001), longer duration of illness (p = .001), inpatient status at initiation (p = .002), and an RLAI dose of 25 mg/2 weeks (p < .001) predicted greater probability of discontinuation.
A small proportion of patients initiated on treatment with RLAI continued for 3 years. Outcome is likely to be improved by targeting RLAI treatment at specific patient groups and by using a dose of more than 25 mg/2 weeks.
The Journal of Clinical Psychiatry 12/2008; 70(2):196-200. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since the introduction of a group of atypical antipsychotics in the 1990s, there has been a decline in the rate of new antipsychotics being introduced into clinical practice. However, with increasing safety and efficacy concerns over currently available drugs and a dearth of options available for atypical depot formulations, there is a considerable need for the development of new formulations and agents. This review examines the profile of seven antipsychotic drugs currently in the premarketing stage of development and summarizes their mechanism of action, clinical potential and safety.Asenapine is an antipsychotic with activity for multiple receptors and has potential to improve negative and cognitive symptoms of schizophrenia. Bifeprunox is a partial dopamine D2 and serotonin 5-HT(1A) receptor agonist showing a less than convincing efficacy profile, but which may offer safety advantages over available agents by means of a reduced risk of metabolic complications. Iloperidone is a D2 and 5-HT(2A) receptor antagonist requiring further studies to establish its effectiveness. It has a high affinity for alpha(1)-adrenoceptors, which can lead to associated haemodynamic adverse effects. Nemonapride is essentially a typical antipsychotic drug, similar in structure to sulpiride, which has been available for some time in Japan. It has efficacy against positive symptoms and has shown some antidepressant and anxiolytic properties, although efficacy data for it are somewhat limited. Norclozapine (N-desmethylclozapine) is a major metabolite of clozapine formed by its demethylation. Its partial agonist activity at D2 receptors has raised interest in it as an antipsychotic in its own right. In addition, it appears to have muscarinic agonist activity, which is believed to be responsible for the observed positive effects it has on cognition. It was envisaged to be effective as an adjunct to other agents or at high doses in the treatment of refractory schizophrenia, although a recent randomized, controlled study showed that it was no more effective than placebo in patients with schizophrenia experiencing an acute psychotic episode. Olanzapine pamoate depot injection has shown comparable efficacy to oral olanzapine in several studies. However, it has provoked considerable safety concerns by its association with inadvertent intravascular injection events in numerous patients. This accidental intravascular administration of olanzapine pamoate leads to excessive sedation, confusion, dizziness and altered speech. Post-injection observation periods and postmarketing surveillance are planned following the introduction of the depot. Paliperidone palmitate is the palmitate ester of paliperidone, the major metabolite of risperidone, and is formulated as a long-acting injection for intramuscular use. Its pharmacology is comparable to risperidone, having D2 and 5-HT(2A) receptor antagonist activity. Efficacy studies have shown positive results, and because paliperidone has no antagonistic activity at cholinergic receptors, it has low potential for anticholinergic adverse effects, including cognitive dysfunction. However, with higher doses, the frequency of extrapyramidal side effects and orthostatic hypotension have been shown to be greater than with placebo.