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1.  The Effect of Mineralocorticoid and Glucocorticoid Receptor Antagonism on Autobiographical Memory Recall and Amygdala Response to Implicit Emotional Stimuli 
Acutely elevated cortisol levels in healthy humans impair autobiographical memory recall and alter hemodynamic responses of the amygdala to emotionally valenced stimuli. It is hypothesized that the effects of the cortisol on cognition are influenced by the ratio of mineralocorticoid receptor to glucocorticoid receptor occupation. The current study examined the effects of acutely blocking mineralocorticoid receptors and glucocorticoid receptors separately on 2 processes known to be affected by altering levels of cortisol: the specificity of autobiographical memory recall, and the amygdala hemodynamic response to sad and happy faces.
We employed a within-subjects design in which 10 healthy male participants received placebo, the mineralocorticoid receptor antagonist spironolactone (600mg) alone, and the glucocorticoid receptor antagonist mifepristone (600mg) alone in a randomized, counter-balanced order separated by 1-week drug-free periods.
On autobiographical memory testing, mineralocorticoid receptor antagonism impaired, while glucocorticoid receptor antagonism improved, recall relative to placebo, as evinced by changes in the percent of specific memories recalled. During fMRI, the amygdala hemodynamic response to masked sad faces was greater under both mineralocorticoid receptor and glucocorticoid receptor antagonism relative to placebo, while the response to masked happy faces was attenuated only during mineralocorticoid receptor antagonism relative to placebo.
These data suggest both mineralocorticoid receptor and glucocorticoid receptor antagonism (and potentially any deviation from the normal physiological mineralocorticoid receptor/glucocorticoid receptor ratio achieved under the circadian pattern) enhances amygdala-based processing of sad stimuli and may shift the emotional processing bias away from the normative processing bias and towards the negative valence. In contrast, autobiographical memory was enhanced by conditions of reduced glucocorticoid receptor occupancy.
PMCID: PMC5043643  PMID: 27207909
cortisol; mineralocorticoid; glucocorticoid; autobiographical memory; amygdala
2.  Prediction of individual response to antidepressants and antipsychotics: an integrated concept 
In both clinical trials and daily practice, there can be substantial inter- and even intraindividual variability in response—whether beneficial or adverse—to antidepressants and antipsychotic medications. So far, no tools have become available to predict the outcome of these treatments in specific patients. This is because the causes of such variability are often not known, and when they are, there is no way of predicting the effects of their various potential combinations in an individual. Given this background, this paper presents a conceptual framework for understanding known factors and their combinations so that eventually clinicians can better predict what medication(s) to select and at what dose they can optimize the outcome for a given individual. This framework is flexible enough to be readily adaptable as new information becomes available. The causes of variation in patient response are grouped into four categories: (i) genetics; (ii) age; (iii) disease; and (iv) environment (internal). Four cases of increasing complexity are used to illustrate the applicability of this framework in a clinically relevant way In addition, this paper reviews tools that the clinician can use to assess for and quantify such inter- and intraindividual variability. With the information gained, treatment can be adjusted to compensate for such variability, in order to optimize outcome. Finally, the limitations of existing antidepressant and antipsychotic therapy and the way they reduce current ability to predict response is discussed.
PMCID: PMC4336923  PMID: 25733958
antidepressant; antipsychotic; genetics; age; disease; drug-drug interaction; multiple medication use; polypharmacy; regulatory protein
3.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
4.  Concurrent administration of donepezil HCl and risperidone in patients with schizophrenia: assessment of pharmacokinetic changes and safety following multiple oral doses 
This open-label, multiple-dose trial investigated the effect of concurrent administration of donepezil HCl with risperidone on the pharmacokinetics (PK) and safety profiles of both drugs.
Sixteen male patients with schizophrenia, who were receiving stable, physician-optimized risperidone (1–4 mg twice daily), and 15 healthy age- and weight-matched male controls, received donepezil HCl 5 mg daily for 7 days. Patients with schizophrenia remained on their physician-optimized dose of risperidone throughout the study. Pharmacokinetic parameters (Cmax, tmax and AUC) were assessed from plasma drug concentrations measured in blood collected before, during and after administration (for 12 h after risperidone on days 0 and 7, and for 24 h after donepezil HCl on day 7).
The mean age of all the subjects was 38.5 years. Donepezil PK parameters were similar between patients taking donepezil HCl + risperidone (AUC0–24 h = 329.0 ± 17.2 ng·h ml−1) and controls taking donepezil HCl alone (AUC0–24 h = 354.7 ± 28.2 ng·h ml−1). Pharmacokinetic parameters for risperidone and 9-OH risperidone were not altered in patients with schizophrenia after 7 days of donepezil HCl administration (AUC0–12 h standardized by dose: risperidone = 59.6 ± 16.3 ng·h ml−1 at day 0, 56.0 ± 15.8 ng·h ml−1 at day 7; 9-OH risperidone = 162.1 ± 19.2 ng·h ml−1 at day 0, 163.3 ± 15.0 ng·h ml−1 at day 7). The most common adverse event in both treatment groups was diarrhoea (6/16 risperidone + donepezil HCl patients and 9/16 donepezil HCl only subjects). There were no significant changes in physical examination, ECG, vital signs or treatment-emergent abnormal laboratory values associated with either of the treatment regimens. No subject developed extrapyramidal side-effects following donepezil administration.
These results suggest that once-daily dosing of 5 mg donepezil HCl does not alter the PK of risperidone in patients with schizophrenia. The combination of risperidone and donepezil HCl was well tolerated.
PMCID: PMC1884550  PMID: 15496223
acetylcholinesterase inhibitor; donepezil hydrochloride; PK interaction; risperidone; schizophrenia

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