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Biomedical subjects

Michael H Allen

Publications and source records attributed to Michael H Allen.

At least 19 recordsLinked to original sources
PubMed2006

Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania.

OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.

Acute Disease↗
PubMed2006

Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

OBJECTIVE: Depressive episodes are common in bipolar disorder, and the disorder is characterized by high suicide rates. Recent analyses indicate a possible association of antidepressant treatment and suicidality in children and adults with depressive or anxiety disorders. However, few data are available to inform the suicidality risk assessment of antidepressant use specifically in bipolar disorder. METHOD: Of the first 2000 participants followed for 18 months in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 425 experienced a prospectively observed, new-onset major depressive episode without initial suicidal ideation. Standardized ratings of suicidality and antidepressant exposure at index depressive episode and next evaluation were used to investigate the primary hypothesis that new-onset suicidality was associated with increased antidepressant exposure (antidepressant initiation or dose increase). Secondary analysis investigated correlates of new-onset suicidality and antidepressant exposure. Data were collected from November 8, 1999, to April 24, 2002. RESULTS: Twenty-four participants (5.6%) developed new-onset suicidality at follow-up, including 2 suicide attempts. There was no association of new-onset suicidality with increased antidepressant exposure or any change in antidepressant exposure, and no association with initiation of antidepressant treatment. New-onset suicidality was associated with neuroticism, prior attempt, and higher depressive or manic symptom ratings at index episode. Increased antidepressant exposure was negatively associated with higher manic symptom rating at index episode; control for this sole empirically identified confound did not alter the primary results. CONCLUSIONS: Although careful monitoring for suicidality is always warranted in bipolar disorder, this cohort study provides no evidence that increased antidepressant exposure is associated with new-onset suicidality in this already high-risk population. Correlates of both suicidality and antidepressant exposure indicate directions for further research.

Adult↗
PubMed2005

Best clinical practice with ziprasidone IM: update after 2 years of experience.

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.

Administration, Oral↗
PubMed2005

The expert consensus guideline series. Treatment of behavioral emergencies 2005.

OBJECTIVES: Due to inherent dangers and barriers to research in emergency settings, few data are available to guide clinicians about how best to manage behavioral emergencies. Key constructs such as agitation are poorly defined. This lack of empirical data led us to undertake a survey of expert opinion, results of which were published in the 2001 Expert Consensus Guidelines on the Treatment of Behavioral Emergencies. Several second-generation (atypical) antipsychotics (SGAs) are now available in new formulations for treating behavioral emergencies (e.g., intramuscular [i.m.] olanzapine and ziprasidone; rapidly dissolving tablets of olanzapine and risperidone). Critical questions face the field. The SGAs are significantly different from the FGAs and from each other and have not been studied in unselected patients as were the FGAs. Can the SGAs can be thought of as a class, do all antipsychotics have similar anti-agitation effects in different conditions, and, if equally effective, what limits might their safety profiles impose? Should antipsychotics be used more specifically to treat psychotic conditions, while benzodiazepines (BNZs) alone are used nonspecifically? Few data are available concerning combinations of SGAs and BNZs, and findings concerning the traditional combination of haloperidol plus a BNZ may not be relevant to combinations with SGAs. The culture is also evolving with more emphasis on patient involvement in treatment decisions. An international consensus has been developing that calming rather than sedation is the appropriate endpoint of behavioral emergency interventions. We undertook a new survey of expert opinion to update recommendations from the earlier survey. METHOD: A written survey of 61 questions (1,020 options) was mailed to 50 experts in the field, 48 (96%) of whom completed it. The survey sought to define level of agitation at which emergency interventions are appropriate, scope of assessment depending on urgency and patients' ability to cooperate, guiding principles for selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence for a variety of provisional diagnoses and complicating conditions. A modified version of the RAND Corporation's 9-point scale for rating appropriateness of medical decisions was used to score most options. Consensus was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean. Ratings were used to develop guidelines for preferred strategies in key clinical situations. This study received financial support from multiple sponsors, with the panel kept blind to sponsorship to reduce possible bias. Medication ratings were based on responses of only those respondents with direct experience with each drug. In reporting practice patterns, the panel was asked to respond based on actual data rather than estimates. RESULTS: The expert panel reached consensus on 78% of the options rated on the 9-point scale. The responses suggest that physicians can make provisional diagnoses with some confidence and that pharmacological and nonpharmacological interventions are selected differentially based on diagnosis and other salient demographic and medical features. BNZs are recommended when no data are available, when there is no specific treatment (e.g., personality disorder), or when they may have specific benefits (e.g., intoxication). No single SGA emerges as a nonspecific replacement for haloperidol; instead, different SGAs are preferred in various circumstances consistent with current evidence. To the degree that haloperidol is recommended, it is almost always in combination with a BNZ; haloperidol alone is preferred only in the medically compromised. In contrast, the SGAs are more often recommended for use alone, and the panel would avoid combining BNZs with some SGAs. Oral risperidone alone or combined with a BNZ receives strong support in a variety of situations. Oral olanzapine was rated very similarly to risperidone, with slightly higher ratings than risperidone in situations where it has been studied (e.g., schizophrenia, mania) and slightly lower ratings where it has not been studied or safety may be a concern; there was less support for combining oral olanzapine with a BNZ. For oral treatment of agitation related to schizophrenia or mania, olanzapine alone, risperidone alone or combined with a BNZ, and haloperidol plus a BNZ are first line, with strong support also for combining divalproex with the antipsychotic for presumed mania. Oral ziprasidone and quetiapine generally received similar second-line ratings in most situations. If a parenteral agent is needed, i.m. olanzapine alone received somewhat more support than i.m. ziprasidone alone; however, there was more support for i.m. ziprasidone alone or combined with a BNZ than for i.m. olanzapine plus a BNZ, probably reflecting safety concerns. For example, for a provisional diagnosis of schizophrenia, first-line parenteral options are i.m. olanzapine or ziprasidone alone or i.m. haloperidol or ziprasidone combined with a BNZ. Neither of the new parenteral formulations received as much support as traditional agents (i.m. BNZs, i.m. haloperidol) when no data are available or the diagnosis involves medical comorbidity or intoxication. When initial intervention with risperidone, ziprasidone, or haloperidol is unsuccessful, the panel recommended adding a BZD to the antipsychotic. However, when initial treatment with olanzapine or quetiapine is unsuccessful, increasing the dosage is recommended. Perphenazine was consistently rated second line and droperidol and chlorpromazine received third-line ratings throughout. CONCLUSIONS: Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines suggest that the SGAs are now preferred for agitation in the setting of primary psychiatric illnesses but that BNZs are preferred in other situations.

Aggression↗
PubMed2005

Suicidal ideation and pharmacotherapy among STEP-BD patients.

OBJECTIVE: Little is known about the effects of lithium on suicidal ideation or about the possible antisuicidal effects of divalproex, second-generation antipsychotics, or antidepressants among persons with bipolar disorder. METHODS: Using a cross-sectional design, the authors examined patterns of psychotropic drug use relative to suicidal ideation among 1,000 patients with bipolar disorder in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). RESULTS: The presence of suicidal ideation was similar between patients who were taking any lithium and those who were not (22.2 percent and 25.8 percent, respectively) and between those who were taking any divalproex and those who were not (20.3 percent and 21.5 percent). Suicidal ideation was significantly more prevalent among patients who were taking a second-generation antipsychotic than those who were not (26 percent and 17 percent) and those who were taking an antidepressant and those who were not (25 percent and 14 percent). After other variables had been controlled for, lithium prescriptions were significantly more common among patients who had suicidal ideation. CONCLUSIONS: Among patients with bipolar disorder who have suicidal ideation, antidepressants and second-generation antipsychotics appear to be prescribed by community practitioners more often than other medications, with lithium reserved for those with more severe illness characteristics.

Adult↗
PubMed2005

Contributors to suicidal ideation among bipolar patients with and without a history of suicide attempts.

This study was designed to develop models for vulnerability to suicidal ideation in bipolar patients. Logistic regression models examined correlates of suicidal ideation in patients who had versus had not attempted suicide previously. Of 477 patients assessed, complete data on demographic, illness history, and personality variables were available on 243. The regression models achieved positive predictive values of 55% and 59% for the attempter (N = 92) and nonattempter groups (N = 151), respectively. Depression was cross-sectionally associated with suicidal ideation in both the attempter and nonattempter groups but made a smaller contribution among attempters. Poor psychosocial adaptation and the personality factor "openness" were stronger contributors to suicidal ideation among prior attempters while anxiety and extraversion appeared protective against ideation. Among nonattempters, depression, anxiety, and neuroticism were the predominant influences on suicidal ideation. Bipolar patients with suicidal ideation may benefit from different treatment strategies depending on their prior attempt status.

Adult↗
PubMed2004

A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups.

Psoriasis is a chronic skin disorder with multifactorial aetiology. Genome-wide scans have provided unambiguous evidence for a major disease susceptibility locus on chromosome 6p21 (PSORS1). A minimal PSORS1 interval has been defined which encompasses three genes (HLA-C, HCR and CDSN) carrying psoriasis-associated SNPs. On the basis of this genetic evidence, we have undertaken an assessment of CDSN allele functional impact. A comparison of CDSN intragenic haplotypes showed that SNPs exclusive to disease-associated chromosomes are located in regions implicated in the stabilization of RNA transcripts. As CDSN is over-expressed in psoriatic lesions, we hypothesised that disease-associated intragenic SNPs may alter the rate of its mRNA decay. Here, we demonstrate that mRNAs transcribed from a CDSN risk haplotype present a 2-fold increase in stability, compared with those transcribed from a neutral haplotype (t-test P=0.004). Site-directed mutagenesis revealed that a single synonymous SNP (CDSN*971T) accounts for the observed increase in RNA stability. CDSN*971T maps to a RNA stability motif and UV cross-linking analysis demonstrated that the SNP affects the transcript affinity for a 39 kDa RNA binding protein. Association analyses show that haplotypes bearing CDSN*971T confer psoriasis susceptibility in a wide range of ethnic groups. These results demonstrate the effect of synonymous variation upon allele specific gene expression, a finding of relevance to future studies of the pathogenesis of common and complex traits.

Animals↗
PubMed2004

Intramuscular antipsychotics: clinical experience review.

Acute agitation is a therapeutic dilemma. Rapid control of agitation is necessary to minimize danger both to recipients of care and to caregivers. Although a comprehensive assessment may ultimately be necessary to determine the cause of agitation and to identify or exclude underlying medical illness, it is often imperative to treat agitation immediately. In this imperfect clinical world, it is essential to have treatments that are both safe and effective for patients with a wide variety of causes of agitation.

Antipsychotic Agents↗
PubMed2004

Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program.

OBJECTIVE: This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status. METHOD: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. CONCLUSIONS: Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

Adult↗
PubMed2003

Treatment of behavioral emergencies: a summary of the expert consensus guidelines.

OBJECTIVES: Behavioral emergencies are a common and serious problem for consumers, their communities, and the healthcare settings on which they rely, but there is little research to guide provider responses to this challenge. Key constructs such as agitation have not been adequately operationalized so that the criteria defining a behavioral emergency are vague. A significant number of deaths of patients in restraint has focused government and regulators on these issues, but a consensus about key elements in the management of behavioral emergencies has not yet been articulated by the provider community. The authors assembled a panel of 50 experts to define the following elements: the threshold for emergency interventions, the scope of assessment for varying levels of urgency and cooperation, guiding principles in selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence and for a variety of etiologies and complicating conditions. METHOD: A written survey with 808 decision points was completed by 50 experts. A modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions was used to score options. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/ alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables were constructed describing the preferred strategies in key clinical situations. RESULTS: The expert panel reached consensus on 83% of the options. The relative appropriateness of emergency interventions was ascertained for a continuum of behaviors. When asked about the frequency with which emergency interventions (parenteral medication, restraint, seclusion) were required in their services, 47% of the experts reported that such interventions were necessary for 1%-5% of patients seen in their services and 32% for 6%-20%. In general, the consensus of this panel lends support to many elements of recent regulations from the Health Care Financing Administration (now the Centers for Medicare and Medicaid Services), including the timing of clinician assessment and reassessment and the intensity of nursing care. However, the panel did not endorse the concept of "chemical restraint," instead favoring the idea that medications are treatments for target behaviors in behavioral emergencies even when the causes of these behaviors are not well understood. Control of aggressive behavior emerged as the highest priority during the emergency; however, preserving the physician-patient relationship was rated a close second and became the top priority in the long term. Oral medications, particularly concentrates, were clearly preferred if it is possible to use them. Benzodiazepines alone were top rated in 6 of 12 situations. High-potency conventional antipsychotics used alone never received higher ratings than benzodiazepines used alone. A combination of a benzodiazepine and an antipsychotic was preferred for patients with suspected schizophrenia, mania, or psychotic depression. There was equal support for high-potency conventional or atypical antipsychotics (particularly liquids) in oral combinations with benzodiazepines. Droperidol emerged in fourth place in some situations requiring an injection. CONCLUSIONS: To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in the management of psychiatric emergencies and can be used to inform clinicians in acute care settings regarding the relative merits of various strategies.

Journal Article↗