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 9,689 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The atypical antipsychotic agent clozapine is associated with a lower propensity for extrapyramidal symptoms than classical antipsychotic agents. The pharmacokinetics of clozapine are affected by wide interpatient variability and a potential for drug interactions. Some studies have shown a relationship between plasma concentrations, duration of treatment and antipsychotic clinical response. Clozapine (mean 274.2 mg/day; n = 490) had a greater preventive effect on suicidality among patients with schizophrenia or schizoaffective disorder at high risk for suicide than olanzapine (mean 16.6 mg/day; n = 490) in a randomised, rater-blinded, multicentre study (p < 0.05; a 22-24% improvement). Other prospective noncomparative trials of the effects of clozapine on suicidal ideation or attempts endorsed these results, while results from retrospective trials are equivocal. Clozapine is commonly associated with sedation, hypersalivation, tachycardia, dizziness, constipation and orthostatic hypotension. Agranulocytosis, diabetes mellitus and weight gain may also occur.
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PMID:Clozapine: in prevention of suicide in patients with schizophrenia or schizoaffective disorder. 1266 98

Risperidone is one of the second-generation antipsychotics (SGAs). Use of SGAs or so-called atypical antipsychotics is becoming more frequent because they are more efficacious and safer than typical antipsychotics. This is due to their ability to occupy some other receptors as well as dopamine type 2 (D(2)) receptors in the brain. Risperidone has more affinity for serotonin type 2 (5-HT(2)) than for D(2) receptors. This accounts for its better treatment of negative symptoms of schizophrenia and fewer extrapyramidal side effects when compared with typical antipsychotics. Common side effects associated with risperidone include extrapyramidal symptoms, dizziness, nausea, weight gain, sleep disturbance, and sexual dysfunction. We describe here a case of risperidone-induced hypothermia. Body temperature is regulated by the preoptic anterior hypothalamus with involvement of dopamine, serotonin, norepinephrine, and alpha-adrenergic receptors. Experimental data suggest that stimulation of 5-HT(2) and dopamine receptors can increase the body temperature. Additional clinical evidence indicates potent antagonists of 5-HT(2) are more likely to cause hypothermia. Risperidone has higher potency for occupying 5-HT(2) than D(2) receptors.
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PMID:A case of risperidone-induced hypothermia. 1513 39

Acute agitation is a common psychiatric emergency often treated with intramuscular (i.m.) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional i.m. antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon) is the first second-generation, or atypical, antipsychotic to become available in an i.m. formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings. In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol i.m. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from i.m. to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical setting are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.
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PMID:Best clinical practice with ziprasidone IM: update after 2 years of experience. 1624 23

This retrospective study examined adjunct divalproex (N = 15) or lithium (N = 9) in treatment-resistant schizophrenia patients added to clozapine and compared to clozapine monotherapy (N = 25). Six month total BPRS scores were similarly improved in all treatment groups, however significantly greater improvements occurred in the first month for those on divalproex (-9) or lithium (-8) vs. clozapine alone (-4.5) (F = 3.32, df = 10.43, p = 0.0003). Rates of sedation, tachycardia, orthostasis, GI disturbances, confusion and dizziness were similar among groups. Mean weight gain was 8.7 pounds for clozapine monotherapy, 3.0 pounds in the adjunct divalproex group and 13.3 pounds in the adjunct lithium group (P = NS). A trend was noted for greater increases in blood glucose levels for those treated with adjunct lithium (F = 2.62, df = 2.28, p = 0.09). The addition of divalproex was significantly more effective in reducing global symptoms (driven by hostility and anxiety) in the first month of adjunct treatment as compared to clozapine monotherapy and to previous clozapine treatment.
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PMID:Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia. 1639 57

The literature related to somatoform disorders in the workplace is very limited, and these disorders need more attention from mental health professionals in the workplace as well as from employers. Over the last decade, major changes have taken place in the work environment in Japan. More stress and less support from supervisors or colleagues in the workplace have made employees stressed out. The number of employees with mental disorders, including somatoform disorders, taking sick leave has significantly increased. In our multi-centre collaborative study, somatoform disorders were the third most prevalent psychiatric disorder in employees, after mood and schizophrenic disorders. Employees with neurotic disorders manifested physical symptoms more frequently than those without. Young employees frequently reported somatic symptoms such as general malaise, nausea, constipation, diarrhoea, headache, stiff shoulder, and dizziness. A rational new approach is needed to tackle this important psychopathology increasingly seen among employees.
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PMID:Somatoform disorders in the workplace in Japan. 1645 78

Bupropion was initially developed and licensed for the treatment of major depressive disorder in the United States in 1989. It was licensed as a pharmacotherapy for smoking cessation in the United States in 1997 and in the United Kingdom in 2000, and for the prevention of seasonal major depressive episodes in patients with seasonal affective disorder in the United States in 2006. Its main mechanism of action is believed to be via dopamine and noradrenalin reuptake inhibition. In addition to proven clinical efficacy for the treatment of major depression, the prevention of depressive episodes in patients with seasonal affective disorder, and as an aid to smoking cessation treatment, bupropion has demonstrated efficacy for attenuation of symptoms of attention deficit hyperactivity disorder, and more recently it has shown anti-inflammatory action against proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), which may be implicated in a number of inflammatory diseases such as Crohn's disease. The twice-daily sustained-release formulation has been extensively evaluated for smoking cessation and has shown continuous smoking abstinence rates at one year of the order of 20% across many clinical groups including healthy smokers, and smokers with cardiovascular disease, chronic obstructive airways disease, depression and schizophrenia. Bupropion is well tolerated with side effects including insomnia, headache, dry mouth, dizziness and nausea. Bupropion is a cytochrome p450 2D6 inhibitor and care must be taken when coprescribing with drugs cleared by this enzyme and when coprescribing with drugs that lower seizure threshold. Despite the clinical effectiveness and cost-effectiveness of bupropion as an aid to smoking cessation, its uptake for this indication remains low when compared with nicotine replacement therapy.
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PMID:Bupropion. 1713 26

The potential of dopamine D(1) receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D(1) agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D(1)-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.
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PMID:A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia. 1746 56

Iloperidone, a mixed D2/5-HT2 antagonist, is currently in clinical development for the treatment of schizophrenia. This article assesses the short-term safety of iloperidone using a pooled analysis of 3 phase 2, short-term acute schizophrenia studies conducted between 1998 and 2002 (N = 1943). Patients exposed to 3 dose ranges of iloperidone, another antipsychotic, or placebo were compared on rates of serious adverse events (SAEs), adverse events (AEs), extrapyramidal symptoms, akathisia, prolactin, weight and metabolic parameters, QTc, and other standard safety parameters. The most common treatment-related AEs observed with iloperidone were dizziness, headache, dry mouth, nausea, and insomnia. Discontinuation due to AEs was 4.8% for iloperidone, 7.6% for haloperidol, 6.2% for risperidone, and 4.8% for placebo. Iloperidone groups showed better overall performance on the Extrapyramidal Symptom Rating Scale and Barnes Akathisia Scale than risperidone or haloperidol groups. Patients taking iloperidone experienced a mild weight increase (range, 1.5-2.1 kg) similar to that of risperidone (1.5 kg), whereas those on haloperidol and placebo showed mean weight loss (-0.1 kg and -0.3 kg, respectively). QTc interval significantly increased across all iloperidone groups (least squares mean change from baseline to end point, 2.9-9.1 msec) and for haloperidol (5.0 msec). No significant QTc changes occurred in the risperidone or placebo groups. Iloperidone was associated with no change from baseline in total cholesterol, mild elevation in serum glucose, and slight decrease in triglycerides. Prolactin levels decreased with iloperidone and increased significantly with risperidone and haloperidol. These short-term trials suggest that iloperidone has a reassuring safety profile in many of the areas that are of potential concern, including relatively low dropout rates because of AEs, low extrapyramidal symptoms, akathisia, and prolactin elevation, and a modest short-term effect on weight gain.
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PMID:Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. 1833 8

Iloperidone is a mixed D2/5-HT2 antagonist in development for treatment of schizophrenia. This trial aimed to evaluate the efficacy and safety of a fixed dose of iloperidone in patients with acute exacerbations of schizophrenia. This randomized, placebo-controlled, multicenter study comprised a 1-week titration period and a 3-week double-blind maintenance period. Eligible patients (n = 593) were randomized to iloperidone 24 mg/d, ziprasidone 160 mg/d as an active control, or placebo. Primary efficacy variable was change from baseline in the Positive and Negative Syndrome Scale Total (PANSS-T) score, using a mixed-effects model repeated measures analysis. Iloperidone demonstrated significant reduction versus placebo on the PANSS-T score (P< 0.01). Significant improvement versus placebo was also demonstrated with ziprasidone (P < 0.05). Compared with ziprasidone, iloperidone was associated with lower rates of many adverse events (AEs) that are particularly troublesome with antipsychotics, including sedation, somnolence, extrapyramidal symptoms, akathisia, agitation, and restlessness; iloperidone was associated with higher rates of weight gain, tachycardia, orthostatic hypotension, dizziness, and nasal congestion as reported as an AE. Most AEs were mild to moderate. A similar amount of QT prolongation was observed with both active treatments, although no patient had a treatment-emergent postbaseline corrected QT interval of 500 msec or greater. The incidence of clinically relevant changes in laboratory parameters was comparable between iloperidone and ziprasidone. Iloperidone was associated with a low incidence of extrapyramidal symptoms. Overall, there was improvement in akathisia with iloperidone treatment. Iloperidone treatment was effective, safe, and well tolerated in patients with acute exacerbation of schizophrenia.
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PMID:Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. 1833 9

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.
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PMID:Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. 1897 93


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