A UK consensus on the administration of aripiprazole for the treatment of mania.

Aripiprazole has recently received approval for the treatment of moderate to severe manic episodes in bipolar I disorder and prevention of new manic episodes in aripiprazole-responsive patients. Aripiprazole differs from other antipsychotics in its pharmacology, and the need for prescribing guidance in the UK was recently identified. A UK multidisciplinary panel was convened in November 2007. This report describes the consensus agreed during the meeting on the optimal approach to prescribing aripiprazole: how best to approach initiation of, and switching to, treatment with aripiprazole and management strategies for side effects. A literature review of the randomised controlled clinical trials of aripiprazole in mania supports these recommendations. Aripiprazole should be initiated at 15 mg/day (range 5-20 mg/day). If necessary, adjunctive medication should be used in early treatment to manage side effects or assist in management of symptoms such as agitation. When switching to aripiprazole, the therapeutic dose of current treatment should be maintained while adding aripiprazole 15 (5-20) mg/day. Only once an effective dose of aripiprazole is reached should previous medication be reduced. Nausea, insomnia and agitation typically resolve within days. Some principles for dosing and switching are provided to assist with a successful treatment outcome with aripiprazole in mania.

The levels of telomere-binding proteins in human tumours and therapeutic implications.

Tumours require telomeric integrity to maintain viability, conferred by adequate length of telomeric DNA replenished by telomerase, and binding of telomere-binding proteins (TBPs), thus telomeres have received attention as an anticancer target. Levels of TBPs in tumour tissue may have implications for drug development if they render some cancers relatively more sensitive or resistant to telomere targeted agents. This review gives an overview of the studies examining the levels of TBPs in tumours and discusses possible reasons for differences in the findings, given the interplay between various factors determining telomere stability. Whether cancers with lower levels of TBPs will be more susceptible to therapies targeting telomere maintenance will require clinical trials of these novel therapies.

Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism.

The pentacyclic acridinium methosulfate salt RHPS4 induces the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase to the telomere and thus G-quadruplex ligands can effectively inhibit both the catalytic and capping functions of telomerase. In this study, we examined mechanisms underlying telomere uncapping by RHPS4 in uterus carcinoma cells (UXF1138L) with short telomeres and compared the susceptibility of bulk and clonogenic cancer cells to the G-quadruplex ligand. We show that treatment of UXF1138L cells with RHPS4 leads to the displacement of the telomerase catalytic subunit (hTERT) from the nucleus, induction of telomere-initiated DNA-damage signalling and chromosome fusions. We further report that RHPS4 is more potent against cancer cells that grow as colonies in soft agar than cells growing as monolayers. Human cord blood and HEK293T embryonic kidney cell colony forming units, however, were more resistant to RHPS4. RHPS4-treated UXF1138L xenografts had a decreased clonogenicity, showed loss of nuclear hTERT expression and an induction of mitotic abnormalities compared with controls. Although single-agent RHPS4 had limited in vivo efficacy, a combination of RHPS4 with the mitotic spindle poison Taxol caused tumour remissions and further enhancement of telomere dysfunction.

Use of antipsychotic drugs and lithium in mania.

BACKGROUND: Studies highlighting the difficulties associated with lithium suggest that the role of antipsychotic drugs and mood stabilizers in bipolar disorder should be reconsidered. AIMS: To review the efficacy and mode of action of antipsychotic drugs in mania, and to consider the differences between official guidelines and routine clinical practice in the use of these agents for mania. METHOD: Review of research, guideline- and practice-based literature. RESULTS: Guidelines recommend lithium or valproate as first-line treatments for mania, and antipsychotic agents only as 'adjuncts' for agitation, dangerous behaviour or psychosis. However, in routine practice, antipsychotic drugs are often prescribed. The effectiveness of these agents in mania has been established by several studies; newer atypical compounds demonstrate antimanic efficacy with a reduced incidence of neurological side-effects. CONCLUSION: Antipsychotic drugs are important in the treatment of bipolar disorder and mania. Future studies should evaluate the long-term efficacy and safety of newer atypical antipsychotic agents, and the place of anticonvulsants in combination with antipsychotics in bipolar disorder.

Use of antipsychotic drugs and lithium in mania.

Background Studies highlighting the difficulties associated with lithium suggest that the role of antipsychotic drugs and mood stabilisers in bipolar disorder should be reconsidered. Aims To review the efficacy and mode of action of antipsychotic drugs in mania, and to consider the differences between official guidelines and routine clinical practice in the use of these agents for mania. Method Review of research, guideline-and practice-based literature. Results Guidelines recommend lithium or valproate as first-line treatments for mania, and antipsychotic agents only as 'adjuncts' for agitation, dangerous behaviour or psychosis. However, in routine practice, antipsychotic drugs are often prescribed. The effectiveness of these agents in mania has been established by several studies; newer atypical compounds demonstrate antimanic efficacy with a reduced incidence of neurological side-effects. Conclusion Antipsychotic drugs are important in the treatment of bipolar disorder and mania. Future studies should evaluate the long-term efficacy and safety of newer atypical antipsychotic agents, and the place of anticonvulsants in combination with antipsychotics in bipolar disorder.

The face validity of a final professional clinical examination.

OBJECTIVE: To develop new methods of evaluating face validity in the context of a revised final professional examination for medical undergraduates, organized on three sites, over 2 days. METHODS: The opinion of the students and examiners was surveyed by Likert-style questionnaires, with additional open comments. Expert opinion was gathered from external examiner reports and a recent Quality Assurance Agency (QAA) Subject Review Report. RESULTS: The questionnaires had an overall response rate of 84%. Internal reliability, assessed by comparing responses to appropriate questions, was good with an equivalence of 45% (weighted kappa 0.54) for the students and 33% (weighted kappa 0.41) for the assessors. There was little evidence of inconsistency between days or sites. The majority of the opinions from the students, examiners and external experts were positive. Negative comments related to time pressure and case mix. CONCLUSION: The measurement of face validity proved feasible and valuable and will assist in the further development of the course and the examination.

The efficacy of lamotrigine in rapid cycling and non-rapid cycling patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) who have rapid cycling features are often treatment refractory. Clear and conclusive evidence regarding effective treatments for this group is not available. METHODS: Patients with diagnoses of refractory bipolar disorder who were currently experiencing manic, mixed, depressive, or hypomanic episodes were treated with lamotrigine as add-on therapy (60 patients) or monotherapy (15 patients). We compared the efficacy of lamotrigine in the 41 rapid cycling and 34 non-rapid cycling patients with BD. RESULTS: Improvement from baseline to last visit was significant among both rapid cycling and non-rapid cycling patients for both depressive and manic symptomatology. For patients entering the study in a depressive episode, improvement in depressive symptomatology was equivalent in the two groups. Among patients entering the study in a manic, mixed, or hypomanic episode, those with rapid cycling improved less in manic symptomatology than did non-rapid cycling patients. Among rapid cycling patients with initial mild-to-moderate manic symptom severity, improvement was comparable to that in non-rapid cycling subjects; however, the subset of rapid cycling patients with severe initial manic symptomatology had little improvement in mania. Rapid cycling patients had earlier onset and more lifetime episodes of mania, depression, and mixed mania. CONCLUSIONS: Lamotrigine was generally effective and well tolerated in this group of previously non-responsive, rapid cycling bipolar patients.

Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.

OBJECTIVE: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. METHOD: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. RESULTS: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. CONCLUSIONS: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Fluoxetine: therapeutic and undesirable effects.

The place of fluoxetine as a prototypical selective serotonin reuptake inhibitor and its marketing success have enabled extensive research on its clinical applications. This article summarizes the evidence concerning its efficacy, side-effects and toxicity.

Inherited prothrombotic states and ischaemic stroke in childhood.

OBJECTIVE: To investigate the prevalence of currently recognised inherited prothrombotic states in a population of children with arterial stroke. METHODS: Children with arterial stroke presenting to a tertiary level paediatric neurology centre between 1990 and 1996 were investigated for inherited prothrombotic states. RESULTS: Sixty seven children with arterial stroke were investigated. Abnormalities were initially identified in 16 patients; however, only eight children (12%) had an inherited prothrombotic state. This was type 1 protein S deficiency in one patient, the factor V Leiden mutation in six, and activated protein C resistance (without the factor V Leiden mutation) in one. The prevalence of the factor V Leiden mutation was not significantly higher in children with arterial stroke (12%) than in a control population of children without thrombosis attending the same institution (5.2%; Fisher's exact test, p=0.19; difference in prevalence between patients and controls (95% confidence interval)=6.8% (-2.78% to 16.8%)). CONCLUSIONS: Currently recognised inherited prothrombotic tendencies were rarely associated with stroke in this group of children, although larger numbers of patients would be needed to confirm this. Age appropriate normal values should be used when interpreting the results of a prothrombotic screen. Prothrombotic abnormalities seen acutely are as often transient as inherited. Longitudinal assessment and family studies are required before low concentrations of an anticoagulant protein found acutely can be attributed to an inherited abnormality.

Long-term outcome with clozapine: comparison of patients continuing and discontinuing treatment.

The aim of this naturalistic study was to compare the outcome of patients who continued on clozapine with that of those who discontinued treatment with this drug. Data from 113 patients who commenced clozapine between January 1990 and June 1995 were available for analysis. The main outcome measures were hospitalization status at each anniversary since starting treatment, and the proportion of time spent in hospital by the survey endpoint. On average, patients had been ill for 11.8 years (SD 7.9) and had spent a total of 3.5 years (SD 5.3) in hospital, before treatment with clozapine. The mean duration of follow-up was 2.5 years (SD 1.25, range: 0.32-5.5), by which time 39 patients (35%) had discontinued clozapine. Patients who remained on clozapine (n = 74) were no more likely to have been discharged from hospital than those who discontinued it (n = 39) by the end of the first, second or third year of treatment (p < 0.05). Recent reports of the cost-effectiveness of clozapine treatment should be interpreted with caution.

Quantitative assessment of the rheumatoid synovial microvascular bed by gadolinium-DTPA enhanced magnetic resonance imaging.

OBJECTIVE: To examine the relation between rate of synovial membrane enhancement, intra-articular pressure (IAP), and histologically determined synovial vascularity in rheumatoid arthritis, using gadolinium-DTPA enhanced magnetic resonance imaging (MRI). METHODS: Dynamic gadolinium-DTPA enhanced MRI was performed in 31 patients with knee synovitis (10 patients IAP study, 21 patients vascular morphometry study). Rate of synovial membrane enhancement was quantified by line profile analysis using the image processing package ANALYZE. IAP was measured using an intra-compartmental pressure monitor system. Multiple synovial biopsy specimens were obtained by a blind biopsy technique. Blood vessels were identified immunohistochemically using the endothelial cell marker QBend30 and quantified (blood vessel numerical density and fractional area). RESULTS: Median blood vessel numerical density and fractional area were 77.5/mm2 (IQR; 69.3-110.7) and 5.6% (IQR; 3.4-8.5) respectively. The rate of synovial membrane enhancement (median 2.74 signal intensity units/s, IQR 2.0-3.8) correlated with both blood vessel numerical density (r = 0.46, p < 0.05) and blood vessel fractional area (r = 0.55, p < 0.02). IAP did not influence the rate of enhancement. CONCLUSIONS: Gadolinium-DTPA enhanced MRI may prove to be a valuable technique for evaluating drugs that influence angiogenesis.

Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion.

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.