Objective: Indications for use of anti-noradrenergic medications remain to be established in Alzheimer’s diseases (AD). Loss of noradrenergic neurons in the locus ceruleus with compensatory changes have been variably demonstrated in Alzheimer’s disease (AD), increasing with disease severity. The hypothesis of this study was that central noradrenergic responsivity should be a predictor of decreased aggression subsequent to treatment with noradrenergic agents (e.g., pindolol).
Design: Following placebo washout of psychotropic medications, the growth hormone (GH) response to clonidine challenge (5µg/kg p.o.) was used as an index of central noradrenergic function. Patients were then treated with pindolol (20 mg b.i.d.) for 7 weeks (including tapering) and placebo (x7 weeks) in a randomly allocated order in a double-blind, cross-over design. Placebo washout between treatments was used to decrease carry-over.
Materials and Methods: 15 institutionalized elderly (11M/4F, mean age±SD: 81.5±5.5) with probable AD (NINCDS-ADRDA criteria), severe cognitive impairment (MMSE=3.3±4.6) and significant behavioral disturbance (Neuropsychiatric Inventory [NPI] score ³ 8) were studied. 14 of 15 patients were aggressive as demonstrated by scores ³1 on the retrospective Overt Aggression Scale (r-OAS)(mean r-OAS±SD: 28.4±22.4, range 0-83). Pindolol response was summarized as the end of drug treatment minus end of placebo treatment r-OAS difference.
Results: 5 of 11 (45%) completers (33% of enrolled) had decreased r-OAS aggression following pindolol compared to placebo due to a significant decrease in verbal aggression (paired t=-2.5, p=.03). Higher baseline aggression was associated with greater response to drug treatment (r=.72, p=.02). Lower GH response (as % of baseline) was also correlated with decreased r-OAS aggression (r=.61, p=.045). When baseline aggression, GH response, age, gender, and MMSE were entered into a regression analysis, r-OAS aggression and GH response predicted change in aggression, accounting for 68% of the variance (r=.83, F=8.5, p=.01). Comparing mean change on r-OAS by order showed no evidence of an order effect (t=-.07, p=.94).
Conclusion: These results suggest that blunted central noradrenergic responsiveness may predict decreased aggression following pindolol. Furthermore, modulation of the noradrenergic system with b-blockers may help decrease aggression in a subgroup of AD patients without compensatory increases in noradrenergic responsiveness.
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