Validity of prototype diagnosis for mood and anxiety disorders.

CONTEXT With growing recognition that most forms of psychopathology are best represented as dimensions or spectra, a central question becomes how to implement dimensional diagnosis in a way that is empirically sound and clinically useful. Prototype matching, which involves comparing a patient's clinical presentation with a prototypical description of the disorder, is an approach to diagnosis that has gained increasing attention with forthcoming revisions to both the DSM and the International Classification of Diseases. OBJECTIVE To examine prototype diagnosis for mood and anxiety disorders. DESIGN, SETTING, AND PATIENTS In the first study, we examined clinicians' DSM-IV and prototype diagnoses with their ratings of the patients' adaptive functioning and patients' self-reported symptoms. In the second study, independent interviewers made prototype diagnoses following either a systematic clinical interview or a structured diagnostic interview. A third interviewer provided independent ratings of global adaptive functioning. Patients were recruited as outpatients (study 1; N = 84) and from primary care clinics (study 2; N = 143). MAIN OUTCOME MEASURES Patients' self-reported mood, anxiety, and externalizing symptoms along with independent clinical ratings of adaptive functioning. RESULTS Clinicians' prototype diagnoses showed small to moderate correlations with patient-reported psychopathology and performed as well as or better than DSM-IV diagnoses. Prototype diagnoses from independent interviewers correlated on average r = .50 and showed substantial incremental validity over DSM-IV diagnoses in predicting adaptive functioning. CONCLUSIONS Prototype matching is a viable alternative for psychiatric diagnosis. As in research on personality disorders, mood and anxiety disorder prototypes outperformed DSM-IV decision rules in predicting psychopathology and global functioning. Prototype matching has multiple advantages, including ease of use in clinical practice, reduced artifactual comorbidity, compatibility with naturally occurring cognitive processes in diagnosticians, and ready translation into both categorical and dimensional diagnosis.

Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report.

In April 2010 a workshop on the "Role of Pharmacokinetics in Establishing Bioequivalence for Orally Inhaled Drug Products" was sponsored by the Product Quality Research Institute (PQRI) in coordination with Respiratory Drug Delivery (RDD) 2010. The objective of the workshop was to evaluate the current state of knowledge and identify gaps in information relating to the potential use of pharmacokinetics (PK) as the key indicator of in vivo bioequivalence (BE) of locally acting orally inhaled products (OIPs). In addition, the strengths and limitations of the PK approach to detect differences in product performance compared with in vitro and pharmacodynamic (PD)/clinical/therapeutic equivalence (TE) studies were discussed. The workshop discussed the relationship between PK and lung deposition, in vitro assessment, and PD studies and examined potential PK study designs that could serve as pivotal BE studies. It has been recognized that the sensitivity to detect differences in product performance generally decreases as one moves from in vitro testing to PD measurements. The greatest challenge in the use of PD measurements with some OIPs (particularly inhaled corticosteroids) is the demonstration of a dose-response relationship (for local effects), without which the bioassay, and hence a PD study, may not have sufficient sensitivity to detect differences in product performance. European authorities allow demonstration of in vivo BE of OIPs based solely on pharmacokinetic studies. This workshop demonstrated broader interest among discipline experts and regulators to explore approaches for the use of PK data as the key determinant of in vivo equivalence of locally acting OIPs. If accepted, the suggested approach (PK alone or in conjunction with in vitro tests) could potentially be applied to demonstrate BE of certain orally inhaled drugs.

Calibration of the modified Electrical Low-Pressure Impactor (ELPI) for use with pressurized pharmaceutical aerosols.

The modified Electrical Low Pressure Impactor (ELPI) is currently being used in several laboratories to determine inherent electrostatic charge of pharmaceutical aerosols as a function of their particle size. However, the ELPI appears to underestimate the aerodynamic particle size distributions (aPSDs) of pressurized metered dose inhalers (pMDIs), casting doubt upon the manufacturer's calibration. In the present study, four commercially available pMDIs with a range of aPSDs were used to recalibrate cutoff diameters (d50s) of the ELPI stages using a reference ACI. Particle size analyses were performed in a mensurated ACI and a calibrated modified ELPI (n = 5); stage coating was employed in both instruments. The ACI data were fitted to a lognormal cumulative distribution function by nonlinear regression analysis. Best estimates for mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) for each pMDI were obtained and used in combination with impaction results from the modified ELPI to determine new d50s for each of the ELPI stages by numerical methods. Ventolin HFA was employed to validate the new ELPI d50 values. The curve-fitting procedure produced excellent fits of the ACI data for all the calibration pMDIs, which were well modeled as mono-modal and lognormally distributed. The mean d50s obtained following recalibration of the modified ELPI were found to deviate increasingly from the manufacturer-supplied values as aerodynamic diameter decreased. Ventolin HFA's MMAD determined using the modified ELPI with the manufacturer-supplied d50s was 2.06 +/- 0.08 microm. The MMAD calculated using the recalibrated d50s was 2.63 +/- 0.09 microm, which was statistically indistinguishable (p = 0.0852) from that determined for Ventolin HFA using the ACI (2.73 +/- 0.09 microm). In the absence of a comprehensive recalibration of the ELPI using monodisperse aerosols, the mean d50s for stages 4-12 of ELPI reported offer a practical way of analyzing the aPSD of pharmaceutical aerosols based on the collection and chemical analysis of ELPI deposition data.

Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?

BACKGROUND: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. METHOD: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. RESULTS: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. CONCLUSIONS: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.

Physiochemical and pharmacological characterization of a Delta(9)-THC aerosol generated by a metered dose inhaler.

The goal of the present study was to formulate a Delta(9)-tetrahydrocannabinol (Delta(9)-THC) metered-dose inhaler (MDI) that can be used to provide a systemic dose of Delta(9)-THC via inhalation. Following physiochemical characterization and accelerated stability testing of the aerosol, mice were exposed to the aerosol and evaluated for pharmacological effects indicative of cannabinoid activity, including hypomotilìty, antinociception, catalepsy, and hypothermia. The fine particle dose of Delta(9)-THC was 0.22 +/- 0.03 mg (mean +/- S.D.) or 25% of the emitted dose and was not affected by accelerated stability testing. A 10-min exposure to aerosolized Delta(9)-THC elicited hypomotility, antinociception, catalepsy, and hypothermia. Additionally, Delta(9)-THC concentrations in blood and brain at the antinociceptive ED(50) dose were similar for both inhalation and intravenous routes of administration. Finally, pretreatment with the CB(1) receptor antagonist SR 141716A (10 mg/kg, i.p.) significantly antagonized all of the Delta(9)-THC-induced effects. These results indicate that an MDI is a viable method to deliver a systemic dose of Delta(9)-THC that elicits a full spectrum of cannabinoid pharmacological effects in mice that is mediated via a CB(1) receptor mechanism of action. Further development of a Delta(9)-THC MDI could provide an appropriate delivery device for the therapeutic use of cannabinoids, thereby reducing the need for medicinal marijuana.

Adhesion of powders for inhalation: an evaluation of drug detachment from surfaces following deposition from aerosol streams.

PURPOSE: To evaluate micronized powder retention and detachment from inhaler surfaces following reproducible deposition by impaction, coupled with centrifugal particle detachment (CPD). METHODS: Micronized albuterol sulfate (AS) and beclomethasone dipropionate (BDP) were aerosolized as dry powders and deposited by cascade impaction onto different contact surfaces. Drug detachment from the surfaces was characterized using CPD, coupled with HPLC assay and scanning electron microscopy. RESULTS: Drugs which accumulated as aggregates on model surfaces detached with distinctive profiles for % remaining vs. applied centrifugal force; each profile showed reproducible values for the minimum force required to initiate drug detachment, Fyield. While differences occurred in the observed detachment profiles for different drugs and contact surfaces (polyacetal vs. aluminum), the deposited drug particle size had the most significant effect on these profiles, e.g., Fyield for AS (2.1-3.3 microm) was 383 +/- 12.7 microN compared with 18 +/- 13.8 microN for AS (4.7-5.8 microm). CONCLUSIONS: A technique was developed which enabled the experimental review, and subsequent data analysis, of the adhesive properties between different DPI construction materials and drug substances deposited from aerosol clouds. The technique appears to be of greater relevance to inhaler design decisions than earlier studies in the literature claiming to show differences in the adhesion of single drug particles to surfaces.