Tamara Arenovich

Autoimmune hepatitis: Effect of symptoms and cirrhosis on natural history and outcome

Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten‐year survival was 80.0% (62.5%‐97.5%) in the asymptomatic group and 83.8% (75.1%‐92.6%) in the symptomatic patients (P = NS). Survival to liver‐related endpoints at 10 years was similar in both groups: 89.5% (75.7%‐100%) asymptomatic and 83.8% (75.1%‐92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10‐year survival (61.9% [CI 44.9%‐78.9%]) than those without cirrhosis at presentation (94.0% [CI 87.4%‐100%]) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH. (HEPATOLOGY 2005.)

Baseline Ductopenia and Treatment Response Predict Long-Term Histological Progression in Primary Biliary Cirrhosis

OBJECTIVES:Laboratory and pathological predictors of future histological progression in primary biliary cirrhosis (PBC) are needed for routine practice and clinical trials. We sought to develop clinically meaningful markers for those with predominantly early disease at risk of progressive liver damage.METHODS:Patients with PBC (n=69) with a follow-up liver biopsy performed approximately 10 years after initial histological diagnosis were identified and reviewed.RESULTS:Histological progression in the stage of fibrosis observed in paired liver biopsies from the same patient was associated with the absence of biochemical response to ursodeoxycholic acid (UDCA) at 2 years: alkaline phosphatase (ALP) >1.67 × ULN (upper limit of normal) (P=0.001, odds ratio (OR) 12.14, 95% confidence interval (CI) 2.69–54.74) when defined as an increase in one stage and ALP > 1.76 × ULN (P=0.03, OR 5.07, 95% CI 1.17–21.95) when defined as an increase in two stages. Ductopenia (>50% loss), as formally evaluated through blinded biopsy review of liver tissue obtained at initial diagnosis in a subset of 34 patients, predicted histological progression (P=0.012), along with biochemical response to UDCA (P=0.002). The presence of interface hepatitis in the same biopsies did not.CONCLUSIONS:Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.

An Algorithm-Based Approach to First-Episode Schizophrenia: Response Rates Over 3 Prospective Antipsychotic Trials With a Retrospective Data Analysis

OBJECTIVEnEarly, effective treatment in first-episode schizophrenia is advocated, although evidence based on a systematic approach over multiple antipsychotic trials is lacking. Employing a naturalistic design, we examined response rates over 3 circumscribed antipsychotic trials.nnnMETHODnBetween June 2003 and December 2008, 244 individuals with first-episode schizophrenia or schizoaffective disorder according to DSM-IV criteria were treated at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, following an algorithm that moved them through 2 antipsychotic trials, followed by a trial with clozapine. For the first 2 trials, treatment consisted of risperidone followed by olanzapine, or vice versa; each trial consisted of 3 stages (low-, full-, or high-dose) lasting up to 4 weeks at each level and adjusted according to response/tolerability. Clinical response was defined as a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved) and/or a Brief Psychiatric Rating Scale Thought Disorder subscale score ≤ 6. Data were analyzed retrospectively, and publication of anonymized clinical data was approved by the Research Ethics Board of the Centre for Addiction and Mental Health in May 2003.nnnRESULTSnIn trial 1, 74.5% of individuals responded, with rates significantly higher for olanzapine (82.1%, 115/140) versus risperidone (66.3%, 69/104; P = .005). With trial 2, response rate dropped dramatically to 16.6% but again was significantly higher for olanzapine (25.7%, 9/35) compared to risperidone (4.0%, 1/25; P = .04). Response rate climbed above 70% once more, specifically 75.0% (21/28), in those individuals who agreed to a third trial with clozapine.nnnCONCLUSIONSnResults confirm a high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia. A considerably lower response rate (< 20%) occurs with a second antipsychotic trial. Results here were specific to olanzapine and risperidone, suggesting clinical differences (ie, olanzapine more effective than risperidone). A subsequent trial with clozapine is clearly warranted, although it remains unclear whether outcome would be further enhanced if it were used earlier in the treatment algorithm.

Early use of clozapine for poorly responding first-episode psychosis.

Although most patients treated for first-episode schizophrenia will experience considerable improvement with initial antipsychotic therapy, a subgroup experiences significant ongoing positive symptoms. Clozapine has unique efficacy in improving treatment-resistant patients with chronic schizophrenia, but its role in the treatment of first-episode patients remains unclear. A standardized treatment algorithm was implemented in our First Episode Psychosis Program, with patients receiving 2 trials with 2 second-generation antipsychotics (olanzapine, quetiapine, or risperidone at low, medium, and high doses), followed by a trial of clozapine as early as 25 weeks into the start of their treatment. Patients progress along the algorithm according to their response as defined by clinical rating scales. To date, 123 patients with first-episode schizophrenia have been treated according to the algorithm. Of these, 93 (76%) responded to the first trial of an antipsychotic. Only 7 (23%) of the remaining 30 patients responded to a second antipsychotic trial; 13 of the remaining 23 individuals agreed to a trial of clozapine. We compared the clozapine-treated group with a group of 9 patients who refused clozapine and chose to continue the same antipsychotic treatment as before. Subjects who received clozapine experienced a mean Brief Psychiatric Rating Scale change of 19 points (from 53.5 to 34.5) and a change in the Clinical Global Inventory severity rating from 5.4 to 3.5 (from severely ill to mildly ill); those who refused clozapine had a 2-point increase in mean Brief Psychiatric Rating Scale (from 53 to 55) and a 0.6-point increase in the mean Clinical Global Inventory severity rating from 5.4 to 6 (remaining markedly to severely ill). In clinical practice, there is a hesitancy to switch individuals to clozapine given its side effect profile and position as treatment of last resort. The present findings suggest that clozapine may have an important role in the early treatment of first-episode patients whose psychosis does not remit with other second-generation antipsychotics during the first months of treatment.

The selective effect of antipsychotics on the different dimensions of the experience of psychosis in schizophrenia spectrum disorders

While most standard symptom scales regard the psychotic or positive dimension of schizophrenia as a single factor, several lines of evidence suggest that psychosis itself is a multidimensional phenomenon. The foregoing literature suggested at least five distinct dimensions to psychosis; to test this, we developed, validated and applied an instrument to measure these dimensions and then applied it to examine the effect of antipsychotics on the different dimensions of the psychotic experience. The Dimensions of Psychosis Instrument (DIPI) was administered to 91 psychotic patients with schizophrenia spectrum disorders and a confirmatory factor analyses (CFA) was carried out to examine the five dimensions: cognitive preoccupation (CP) with the psychotic experience; emotional involvement (EM); behavioural impact (BI) of the experience; conviction (CO) in it; emotional; and external perspective (EP) about the experience. In a separate cohort of 17 prospectively treated patients, the impact of antipsychotics on these dimensions was assessed. BI showed the greatest improvement (32%) at 2 weeks, while CP and emotional improved somewhat less (22% and 14%, respectively). Improvement in CO was limited (6%) while EP showed no change. These results suggest that over the first few weeks of treatment, antipsychotics rapidly reduce the behavioural impact of the principal psychotic symptom and decrease cognitive and emotional preoccupation with it, without greatly altering the patients conviction in or perspective about their psychotic experience.

Obesity comorbidity in unipolar major depressive disorder: refining the core phenotype.

OBJECTIVEnWhile a significant body of research has demonstrated high comorbidity rates between depression and obesity, the vast majority of this work has considered depression as a unitary diagnosis. Given that increased appetite and weight gain are highly characteristic of the atypical subtype of depression, while classic depression is characterized by decreased appetite and weight loss, it would be important to examine whether increased obesity risk is consistent across the major vegetative subtypes of depression or is limited to the atypical subtype.nnnMETHODnUsing data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we identified 5,092 US adults with past or current major depression based on DSM-IV-TR criteria and 1,500 gender-matched controls. Each depressed subject was designated as having classic, atypical, or undifferentiated depression based on core vegetative symptoms. Logistic regression models examined rates of current obesity (defined as a current body mass index [kg/m2] > 30) across the 3 depressive subgroups and nondepressed controls, adjusting for demographic differences. To limit the possible effect of current depressive symptoms on observed obesity rates, secondary analyses were completed in individuals with past depression only.nnnRESULTSnSubjects with atypical depression had markedly elevated obesity rates compared to population controls and to other depressed subjects, with corresponding pairwise odds ratios consistently greater than 2.0 (P < .001). In contrast, obesity rates were not significantly different in subjects with classic depression and nondepressed controls. These results were manifest in individuals with either current or past depression and were independent of gender and age.nnnCONCLUSIONSnWhile many individuals with classic depression will present with obesity due to the high prevalence of both disorders, only atypical depression is associated with an elevated risk of obesity relative to the population at large. Refining the target phenotype(s) for future work on depression and obesity might improve our understanding, prevention, and treatment of this complex clinical problem.

Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

Abstract Atypical antipsychotics may “directly” influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor &agr;). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: An animal model

The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 μg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia: a randomized, double-blind, placebo-controlled study.

OBJECTIVEnAntipsychotic polypharmacy (APP) is employed routinely, although it remains controversial because robust evidence supporting its efficacy is lacking. In addition, it is associated with increased costs, higher antipsychotic dosing, and greater risk of side effects. Surprisingly, no prospective, randomized, double-blind studies have addressed this issue; the present investigation set out to fill this gap in knowledge.nnnMETHODnA 12-week, double-blind, randomized, placebo-controlled, single-site study was carried out in individuals with schizophrenia or schizoaffective disorder (DSM-IV) receiving a designated primary antipsychotic plus a secondary antipsychotic, with doses stabilized for each. Individuals were randomly assigned to APP (N = 17), reflecting current treatment, or antipsychotic monotherapy (APM) (N = 18), in which the secondary antipsychotic was discontinued. Assessments occurred weekly during month 1 and every 2 weeks during months 2 and 3; the primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Other measures included the Clinical Global Impressions (CGI) scale, Simpson-Angus Scale, and Barnes Akathisia Scale. The study was carried out between August 2006 and March 2011.nnnRESULTSnWithdrawal due to clinical deterioration occurred in 1 individual receiving APP (5.8%) and in 4 individuals in the APM group (22.2%). Overall, however, there was no indication of clinical worsening with APM, as measured using BPRS and CGI scale.nnnCONCLUSIONSnAlmost 80% (n = 14) of individuals with schizophrenia or schizoaffective disorder currently receiving APP could be safely transitioned to APM with no clinical deterioration. For those who do deteriorate, risk appears greatest in the first several months. From another perspective, results also indicate that a minority of individuals benefit from APP, and research focusing on identifying this group may represent the best strategy to curb excessive use of APP.nnnTRIAL REGISTRATIONnClinicalTrials.gov identifier: NCT00493233.