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.     

Quetiapine: efficacy, tolerability and safety in schizophrenia

Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic, multireceptor antagonist that has a preclinical profile similar to clozapine. Randomized studies have demonstrated the efficacy of quetiapine relative to placebo in the treatment of acute relapse and the long-term management of schizophrenia. Quetiapine is generally well tolerated relative to other antipsychotic medications, although side effects include sedation, orthostatic hypotension, anticholinergic and metabolic side effects. The purpose of this article is to critically review the current literature on quetiapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of schizophrenia. There are also continued efforts to understand, predict and manage the side-effect risk with quetiapine.     

Aripiprazole: pharmacology, efficacy, safety and tolerability

Aripiprazole is a recently released antipsychotic medication which differs from other atypical antipsychotic agents by its partial agonist activity at postsynaptic D2 receptors. It is administered orally and is distinguished by a long elimination phase half-life relative to other antipsychotic medications. Randomized studies have demonstrated the efficacy of aripiprazole relative to placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, and treatment of acute bipolar mania. Aripiprazole is generally well tolerated relative to other antipsychotic medications, although commonly reported side effects include worsening extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information about the comparative safety, efficacy and tolerability of aripiprazole.     

Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability

The authors report a retrospective analysis of the use of mycophenolate mofetil (MyM) in 85 patients with autoimmune myasthenia gravis. The Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) was used to characterize the treatment response in each patient. Sixty-two patients (73%) achieved a PIS status indicating improvement. Quantitative strength testing performed on the majority of patients before and after treatment also improved. Side effects to MyM were observed in 27% of patients but required discontinuation in only 6%.     

The efficacy and tolerability of divalproex sodium in elderly demented patients with behavioral disturbances

Behavioral disturbances are commonly encountered in elderly demented patients. The records of all patients admitted to a geropsychiatric inpatient unit within a 2-year period who had a primary diagnosis of dementia and an accompanying behavioral disturbance treated with divalproex sodium were reviewed. Of the 13 patients identified, all tolerated divalproex sodium without significant side-effects. General psychiatric symptoms, overall agitation, physical aggression and non-aggressive physical agitation decreased significantly, but verbal agitation did not. Divalproex sodium is well tolerated and may be effective in ameliorating certain behavioral disturbances in elderly demented patients with agitation. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics, safety, and tolerability of the new antiepileptic carisbamate in the elderly

PURPOSE: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation. METHODS: The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18-55, 65-74, and >or= 75 years (N=48). Subjects received single (100mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study. RESULTS: After either single or repeated IR administration, no apparent differences were observed between the two elderly and the non-elderly groups. Following single-dose CR administration, the two elderly age groups had higher exposure compared with non-elderly subjects, but the difference decreased for all doses tested after repeated administration. There was no effect of age on plasma protein binding of carisbamate. Renal clearance decreased with age for both formulations, but this decrease had no effect on the total clearance of the drug because of its limited renal elimination. CONCLUSION: Age had no effect on pharmacokinetics of carisbamate IR formulation. The small effect observed after single-dose CR carisbamate diminished after repeated dosing. The drug was generally safe and well tolerated.     

Clozapine efficacy in tardive dyskinesia in schizophrenic patients

Tardive dyskinesia (TD) is a long-term severe complication of antipsychotic treatment, with mean prevalence of 20–35%. The aim of this study was to evaluate effects of clozapine in severe TD. In an open trial seven patients with schizophrenia and severe TD were given clozapine for 6 months. Tardive dyskinesia severity was evaluated with AIMS and ESRS and schizophrenic psychopathology with PANSS. Clozapine mean dose at the end of the study was 392.86 mg/day. A mean reduction of 52% was observed in ESRS scores for TD. Two patients also had dystonic movements, and there was 50% reduction in one of them and complete remission in the other. There was also a 27% mean reduction in PANSS scores. Clozapine seems to be an alternative in the treatment of schizophrenic patients with severe TD. Received: 27 November 1997 / Accepted: 13 February 1998     

Galantamine demonstrates efficacy and safety in elderly patients with Alzheimer disease

Alzheimer disease (AD) treatment guidelines state that cholinergic agents are not cost-effective in patients with more severe disease. Because many physicians may deem an older patient unlikely to respond to treatment, older AD patients may remain untreated. Galantamine (Reminyl), a novel cholinergic agent, is effective in mild to moderate AD. This post hoc analysis of pooled phase III galantamine clinical trials was designed to assess whether older (> or =80 years) and younger (< or =79 years) AD patients experience similar benefits with galantamine based on changes in the ADAS-cog and CIBIC-plus. Mean ADAS-cog scores for older patients treated with galantamine 24 mg/day significantly improved versus baseline and versus placebo at month 3. Cognitive improvement was maintained versus placebo at month 6; the ADAS-cog score for placebo patients dropped below baseline at month 6. Change in CIBIC-plus for galantamine was significantly different from placebo at months 5 to 6. Mean ADAS-cog score in older patients taking galantamine for 12 months remained above baseline. The score for patients taking placebo for 6 months before switching to galantamine did not differ significantly from baseline at 12 months but was lower than in patients receiving galantamine for 12 months. Incidence of adverse events in patients > 80 years was similar to that in the overall study population. Galantamine maintained cognitive and global function in patients > 80 years with mild to moderate AD for at least 5 to 6 months and cognitive efficacy for 12 months. Prescribing approved therapies such as galantamine for older patients with AD is recommended.     

Long-term safety,tolerability, and clinical efficacy of quetiapine in adolescents: an open-label extension trial

Quetiapine is a novel, atypical antipsychotic agent that has been shown to provide long-term efficacy without serious adverse effects in adults. This is the first study of the extended use of quetiapine in adolescents. Five boys and 5 girls, ages 12.3 to 15.9 years, with diagnoses of schizoaffective disorder (n = 7) or bipolar disorder with psychotic features (n = 3) were eligible for entry into this single-site, 88-week, open-label trial. Subjects had completed a pharmacokinetic study over 23 days, during which the dosage of quetiapine was increased sequentially from 25 mg bid to a maximum of 400 mg bid (800 mg/day) (McConville et al. 2000). In the open-label extension of this trial, which followed directly after this trial, a physician's choice design allowed for flexible dose titration of quetiapine by the study physician to an optimal dose for each patient, with ending doses ranging from 300 mg/day to 800 mg/day. Concomitant medications, especially for anxiety and/or manic symptoms, were allowed as deemed necessary. Tolerability and safety were assessed using clinical laboratory tests, physical examinations, measurements of vital signs, interviews for selective symptomatology, and electrocardiograms. Psychiatric measurements included the 18-item Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and the modified Scale for the Assessment of Negative Symptoms (SANS). Neurologic symptom ratings included the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Mean BPRS, CGI, and SANS scores improved significantly during the trial (p < 0.05). No extrapyramidal symptoms or evidence of tardive dyskinesia was seen. Clinically, there was a nonsignificant increase in mean weight and body mass index at week 64. This long-term study suggests that quetiapine is a well-tolerated antipsychotic agent that is efficacious for the treatment of symptoms of selected psychotic disorders in adolescents.     

Clozapine: its impact on aggressive behavior among patients in a state psychiatric hospital.

Clozapine has shown consistent efficacy against positive symptoms of psychoses, and emerging reports indicate improvements in aggression and suicidality. This study evaluated the impact of clozapine aggression in a psychiatric hospital. Over a three year period, 137 subjects with schizophrenia or schizoaffective disorder received clozapine, of whom nearly 50% (n=69) experienced seclusion or restraint. Using a mirror-image study design, seclusion and restraint rates were computed per patient-month pre-clozapine and compared during clozapine treatment to a maximum of 12 months in either direction. The rest of the hospital not receiving clozapine served as a comparator group. Statistically significant reductions occurred in both seclusion (0.44+/-0.46 vs. 0.16+/-0.32, z=-3.91, p=0.0003) and restraint (0.34+/-0.47 vs. 0.08+/-0.23, z=-2.27, p=0.032) during clozapine treatment as compared with the pre-clozapine period. The comparator group experienced a low rate of seclusion and restraint throughout. While there are limitations to a mirror-image design, this study supports the emerging data on the benefits of clozapine for aggressive and violent patients with psychoses. Preliminary data suggests other second generation antipsychotic agents may have similar effects.     

Quetiapine versus risperidone in elderly patients with behavioural and psychological symptoms of dementia: efficacy, safety and cognitive function.

OBJECTIVE: In this study we directly compared the efficacy and tolerability of the atypical antipsychotics quetiapine and risperidone in elderly patients with dementia and symptoms of disturbed perception, thought content, mood or behaviour (behavioural and psychological symptoms of dementia-BPSD). METHODS: We conducted an 8-week, rater-blinded, randomised study of 72 outpatients (55-85 years) with BPSD (assessed by NPI baseline score), who received flexibly-dosed quetiapine (50-400 mg/day) or risperidone (0.5-2 mg/day). Primary efficacy measure: Neuropsychiatric Inventory (NPI) Parts 1 and 2; secondary efficacy measures: Clinical Global Impression (CGI), Cohen-Mansfield Agitation Inventory (CMAI), Mini-Mental State Examination (MMSE), Age-adjusted concentration test (AKT). Safety evaluations included the incidence of extrapyramidal symptoms (EPS) and adverse events (AEs). RESULTS: Sixty-nine of 72 patients were evaluable for efficacy (72 were evaluated for safety), 4 patients discontinued (3 due to AEs: quetiapine 2, risperidone 1; 1 lost to follow-up). Sixty-five patients received quetiapine (n=34; mean dose 77+/-40 mg/day) or risperidone (n=31; mean dose 0.9+/-0.3 mg/day). There was no significant difference between treatments on NPI scores; within treatment groups, NPI scores decreased significantly from baseline to Week 8 (P相似文献   

文拉法辛缓释剂与氟西汀治疗老年抑郁症首次发病患者的对照研究

目的探讨文拉法辛缓释剂治疗老年抑郁症首次发病（以下简称首发）患者的有效性及安全性。方法采用随机、单盲对照法，将64例年龄大于60岁的抑郁症首发患者分为文拉法辛组[（75～150）mg／d]和氟西汀组[（20～40）mg／d]，疗程均为8周。治疗前后以汉密尔顿抑郁量表（17项，HAMD）评估疗效；记录不良反应及实验室情况。结果实际完成观察63例，其中文拉法辛组31例，氟西汀组32例。治疗第2周末，文拉法辛组的HAMD总分较治疗前明显下降（P〈0．01），减分率高于氟西汀组（t=3．120，P〈0．05）。氟西汀组HAMD总分在治疗第4周末较治疗前明显下降（P〈0．01）。治疗第2，4周末，文拉法辛组有效率分别为16％和55％，氟西汀组分别为3％和25％，组间差异均有统计学意义（χ^2=9．828，P〈0．01；χ^2=18．748，P〈0．01）。治疗第6，8周末，文拉法辛组治愈率分别为39％和61％，氟西汀组分别为22％和47％，组间差异均有统计学意义（χ^2=6．817，P〈0．01；χ^2=3．945，P〈0．05）；而两组有效率的差异无统计学意义（P〉0．05）。两组患者出现药物不良反应者各9例（分别占29％和28％），差异无统计学意义（χ^2=0．221，P〉0．05）。结论文拉法辛缓释剂治疗老年首发抑郁症患者起效较快、安全、疗效肯定，治疗第6，8周末时的治愈率高于氟西汀。     

Efficacy,safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson’s disease

Background: Rasagiline, an MAO‐B inhibitor, is indicated for the treatment of Parkinson’s disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (≥70 years) and younger (<70 years) patients with PD. Methods: Data were pooled from the Parkinson’s Rasagiline: Efficacy and Safety on the Treatment of ‘OFF’ and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double‐blind, placebo‐controlled trials with the primary efficacy end‐point being the reduction from baseline in daily OFF time. Secondary efficacy end‐points included scores for Clinical Global Improvement (CGI)‐Examiner during ON time, Unified Parkinson’s Disease Rating Scale (UPDRS)‐ADL during OFF time, UPDRS‐Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. Results: Rasagiline decreased daily OFF time versus placebo (P < 0.01) and improved CGI‐Examiner score (P = 0.001) and UPDRS‐Motor ON score (P < 0.05). Changes in UPDRS‐ADL OFF score and total daily ON time without dyskinesia also favoured rasagiline but were not significant. Between‐group comparisons (≥70 vs. <70 years) showed that efficacy was unaffected by age for all end‐points (P > 0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P > 0.1). Conclusions: Adjunct rasagiline is efficacious and well tolerated in elderly non‐demented patients (≥70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD.     

Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke. METHODS: This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (100 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period. RESULTS: The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups. CONCLUSIONS: On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remacemide and the desglycinyl metabolite rapidly reach comparable brain concentrations within 1 hour, despite a lower plasma concentration of the metabolite.     

Tardive dyskinesia in elderly psychiatric patients in Singapore.

The prevalence of tardive dyskinesia (TD) in 514 psychiatric patients who were 60 years and above in Singapore was found to be 27.6%. This is low compared with other studies done on elderly psychiatric patients in the West. Among the different ethnic groups, the Eurasians have the highest prevalence of 53.8% compared to the Chinese, Malays or Indians. Inpatients have a higher prevalence (31.5%) than outpatients (10.5%). Higher prevalence was also found in women, who were 2.2 times more common than men. 50% of the mentally retarded patients were found to have TD.     

Apathy, anhedonia, and psychomotor retardation in elderly psychiatric patients and healthy elderly individuals

Normal aging of the brain affects the basal ganglia-thalamocortical circuits. These circuits are implicated in several neuropsychiatric disorders. Normal aging may therefore influence the symptomatology of psychiatric disorders in the elderly. We investigated motivational behavior that is associated with the function of these circuits, such as apathy, anhedonia, and psychomotor retardation in healthy elderly subjects and psychiatric inpatients (age > or = 60 yr). Apathy, anhedonia, and psychomotor retardation were assessed with the Apathy Evaluation Scale, the Snaith-Hamilton Pleasure Scale, and the Widl?cher Retardation Rating Scale. Other measurements included the Comprehensive Psychopathological Rating Scale, the Mini-Mental State Examination, and the assessment of vascular risk factors. We found some evidence for age-related changes in motivational behavior. In the healthy elderly group (n = 64), increasing age was associated with anhedonia, and in the patient group (n = 62), increasing age was associated with psychomotor retardation. Motivational disturbances could be the effect of an interaction between brain aging and the neuropathology of psychiatric disorders in the elderly.