Effects of food on the pharmacokinetics of ponatinib in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high- and low-fat meals by healthy subjects. METHODS: Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (anova) were performed on natural log-transformed PK parameters Cmax and AUC0-∞. RESULTS AND DISCUSSION: Geometric mean maximum plasma concentration (Cmax) values for the fasted, low-fat and high-fat regimens were 54·7, 51·6 and 51·5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h × ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for Cmax and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high- or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. WHAT IS NEW AND CONCLUSION: Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.

SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage.

BACKGROUND: Use of medications with vasoconstrictive or vasodilatory effects can potentially affect the risk for vasospasm after aneurysmal subarachnoid hemorrhage (SAH). METHODS: Using International Classification of Diseases-9 diagnostic codes followed by medical record review, the authors identified 514 patients with SAH admitted between 1995 and 2003 who were evaluated for vasospasm between days 4 and 14. The authors determined risks for vasospasm, symptomatic vasospasm, and poor clinical outcomes in patients with documented pre-hemorrhagic use of calcium channel blockers, beta-receptor blockers, ACE inhibitors, aspirin, selective serotonin reuptake inhibitors (SSRIs), non-SSRI vasoactive antidepressants, or statins. RESULTS: Vasospasm developed in 62%, and symptomatic vasospasm in 29% of the cohort. On univariate analysis, the risk for all vasospasm tended to increase in patients taking SSRIs (p = 0.09) and statins (p = 0.05); SSRI use increased the risk for symptomatic vasospasm (p = 0.028). The Cochran-Armitage trend test showed that the proportion of patients taking SSRIs and statins increased significantly across three worsening categories (none, asymptomatic, symptomatic) of vasospasm. Logistic regression analysis showed that SSRI use tended to predict all vasospasm (O.R. 2.01 [0.91 to 4.45]), and predicted symptomatic vasospasm (O.R. 1.42 [1.06 to 4.33]). Statin exposure increased the risk for vasospasm (O.R. 2.75 [1.16 to 6.50]), perhaps from abrupt statin withdrawal (O.R. 2.54 [0.78 to 8.28]). Age < 50 years, Hunt-Hess grade 4 or 5, and Fisher Group 3 independently predicted all vasospasm, symptomatic vasospasm, poor discharge clinical status, and death. CONCLUSION: Selective serotonin reuptake inhibitor and statin users have a higher risk for subarachnoid hemorrhage-related vasospasm. Whether the underlying disease indication, direct actions, or rebound effects from abrupt drug withdrawal account for the associated risk warrants further investigation.

What predicts suicide attempts in women with eating disorders?

BACKGROUND: Suicide is a common cause of death in anorexia nervosa and suicide attempts occur often in both anorexia nervosa and bulimia nervosa. No studies have examined predictors of suicide attempts in a longitudinal study of eating disorders with frequent follow-up intervals. The objective of this study was to determine predictors of serious suicide attempts in women with eating disorders. METHOD: In a prospective longitudinal study, women diagnosed with either DSM-IV anorexia nervosa (n = 136) or bulimia nervosa (n = 110) were interviewed and assessed for suicide attempts and suicidal intent every 6-12 months over 8.6 years. RESULTS: Fifteen percent of subjects reported at least one prospective suicide attempt over the course of the study. Significantly more anorexic (22.1%) than bulimic subjects (10.9%) made a suicide attempt. Multivariate analyses indicated that the unique predictors of suicide attempts for anorexia nervosa included the severity of both depressive symptoms and drug use over the course of the study. For bulimia nervosa, a history of drug use disorder at intake and the use of laxatives during the study significantly predicted suicide attempts. CONCLUSIONS: Women with anorexia nervosa or bulimia nervosa are at considerable risk to attempt suicide. Clinicians should be aware of this risk, particularly in anorexic patients with substantial co-morbidity.

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis.

Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness.

Mortality in eating disorders: a descriptive study.

OBJECTIVE: We report rates and causes of death for a cohort of 246 eating-disordered women and provide descriptive information on their eating disorder and comorbid diagnoses. METHOD: Data on mortality were collected as part of a longitudinal study of anorexia nervosa and bulimia nervosa, now in its 11th year. Other data sources included death certificates, autopsy reports, relative interviews, and a National Death Index search. RESULTS: Seven deaths have occurred during the study, all among anorexic subjects with a history of binging and purging and with comorbid Axis I disorders. The crude mortality rate was 5.1%. The standardized mortality ratios for death (9.6) and suicide (58.1) were significantly elevated (p <. 001). CONCLUSIONS: Anorexia nervosa is associated with a substantial risk of death and suicide. Features correlated with fatal outcome are longer duration of illness, binging and purging, comorbid substance abuse, and comorbid affective disorders.

Recovery and relapse in anorexia and bulimia nervosa: a 7.5-year follow-up study.

OBJECTIVE: To assess the course and outcome of anorexia nervosa (AN) and bulimia nervosa (BN) at a median of 90 months of follow-up in a large cohort of women with eating disorders. METHOD: A prospective, naturalistic, longitudinal design was used to map the course of AN and BN in 246 women. Follow-up data are presented in terms of full and partial recovery, predictors of time to recovery, and rates and predictors of relapse. RESULTS: The full recovery rate of women with BN was significantly higher than that of women with AN, with 74% of those with BN and 33% of those with AN achieving full recovery by a median of 90 months of follow-up. Intake diagnosis of AN was the strongest predictor of worse outcome. No predictors of recovery emerged among bulimic subjects. Eighty-three percent of women with AN and 99% of those with BN achieved partial recovery. Approximately one third of both women with AN and women with BN relapsed after full recovery. No predictors of relapse emerged. CONCLUSIONS: The findings suggest that the course of AN is characterized by high rates of partial recovery and low rates of full recovery, while the course of BN is characterized by higher rates of both partial and full recovery.

A crossover study of lecithin treatment of tardive dyskinesia.

The authors enrolled 21 patients in a random-order, crossover, double-blind trial of phosphatidylcholine (lecithin) 20 g/day and placebo. Fourteen patients completed at least 6 weeks of the second 8-week trial and were used for efficacy analyses. Side effects were minimal. The lecithin treatment effect--about one half of an Abnormal Involuntary Movement Scale point--was seen as a statistical effect of treatment order, based on differences between patients who took the active compound before or after they took the placebo. Clinically, however, the lecithin effect was negligible.

Maternal expressed emotion and parental affective disorder: risk for childhood depressive disorder, substance abuse, or conduct disorder.

Expressed emotion (EE) refers to a set of emotional aspects of speech for which ratings have been derived. Seven independent studies have established that higher EE ratings in the relatives of patients with schizophrenia predict higher rates of relapse in these patients and two studies have established an association of higher EE in spouses with relapse of depression in their mate. There are no previous studies of parental EE as a predictor of childhood affective disorder or other disorders not in the schizophrenia spectrum. In this study we investigated the relationship between the level of maternal EE and the incidence of DSM-III affective disorder (major depression or mania or dysthymia), substance abuse, or conduct disorder in 273 children. We found that a higher degree of maternal expressed emotion was associated with a three-fold increase in a child's risk (odds multiplier) for having at least one of the following diagnoses: depressive disorder (major depression or dysthymia), substance abuse, or conduct disorder. This increased risk acts in addition to the increased risk of child diagnosis associated with parental affective illness. Research and clinical implications are discussed.

Affective disorder in childhood: separating the familial component of risk from individual characteristics of children.

In studying the risk of affective disorder in children, the investigator must deal with the problem that there are two possible units of analysis: the child and the family. An analysis based on children must take account of the intercorrelation within a sibship to produce correct results, while a family-based analysis makes it difficult to investigate individual characteristics of children that help determine the net risk. A two-stage iterative approach to this problem is proposed, yielding estimates of the effect of family-based factors (parental illness, family social class, marital status of parents) and individual factors (age and sex of child, previous non-affective illness). This technique is applied to a sample of 275 children from 143 families representing a wide range of familial risk for affective disorder. The final family-based model (predicting at least one child with affective disorder in the sibship) indicates a six-fold increase in risk to the child associated with maternal affective disorder (P less than 0.001), a three-fold increase in risk associated with paternal affective disorder (P less than 0.05) and divorce or separation of the biological parents, and a suggestion of increased risk in the highest social class (P = 0.06). The excess sibship risk, due to child factors age, prior anxiety disorder, and prior childhood diagnosis, contributed significantly to the family prediction (P less than 0.001).

Psychiatric disorder in adolescent offspring of parents with affective disorder in a non-referred sample.

The relationship between parental psychopathology and psychiatric disturbance in 153 offspring aged 6-19 was assessed in 81 families randomly selected from a prepaid health plan. Offspring of parents with a history of affective disorders and of parents with non-affective psychiatric disorders had higher rates of psychiatric diagnoses and poorer adaptive functioning than children of parents who had never experienced a psychiatric illness. Offspring whose parents had affective disorder had a rate of affective disorder of 30% compared to a rate of 2% in the rest of the sample. This relationship between parental affective disorder and poor child outcome was observed when the separated and divorced families were removed from the analyses.

Impact of severity and chronicity of parental affective illness on adaptive functioning and psychopathology in children.

We report on the impact of specific indexes of the severity and chronicity of parental depression, measures of familial discord, and demographic variables as predictors of impaired adaptive functioning and psychopathology in children. Seventy-two children and their mothers from 37 families were interviewed in person. At least one biological parent in each family had a depressive disorder but neither parent had a history of mania, schizophrenia, or schizoaffective disorder. Almost every measure of severity and chronicity of depression in the biological parents has a statistically significant association with currently impaired adaptation and the presence of a DSM-III-diagnosed disorder in the children, as do the measures of increased discord among married or separated parents. Depression in the mother is more strongly associated with increased psychopathology in the children than is depression in the father.