Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are widespread and disabling. This has been known since Dr. Alois Alzheimer’s first case, Frau Auguste D., presented with emotional distress and delusions of infidelity/excessive jealousy, followed by cognitive symptoms. Being cognizant of this, in 2010 the Alzheimer’s Association convened a Research Roundtable on the topic of NPS in AD. A major outcome of the Roundtable was the founding of a Professional Interest Area (PIA) within the International Society to Advance Alzheimer’s Research and Treatment (ISTAART). The NPS-PIA has prepared a series of documents that are intended to summarize the literature and provide more detailed specific recommendations for NPS research. This overview paper is the first of these living documents that will be updated periodically as the science advances. The overview is followed by syndrome specific synthetic reviews and recommendations prepared by NPS-PIA Workgroups on depression, apathy, sleep, agitation, and psychosis.

The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.