A huge variety of medications have been used successfully for agitation is Alzheimer's and other dementia patients.  Anti-depressants, lithium, carbamazepine, valproate, anti-psychotics, beta-blockers, cholinesterase inhibitors, and some anti-anxiety agents have been used.  Studies have generally been short in duration with small numbers of patients.  Very low or low doses of anti-psychotics are the most popular in clinical practice.  There is only a very few comparative studies available.  I haven't had time to add very many of the numerous studies which have been done, but I hope to soon.

Allopurinol Used for Aggression in Dementia, Schizophrenia, and Neurologic Disorders: A Porto Alegre research group reports an open study of the xanthine oxidase inhibitor allopurinol in six demented patients with treatment-refractory verbal and physical aggression. Starting at 300 mg/d increased every other week up to 900 mg/d maximum over 6 weeks. Marked improvement was measured with the Modified Overt Aggression Scale as well as a significant improvement in the BPRS. Three had reports of mild cognitive improvement. Dizziness and confusion side-effects occurred in the one patient not improving at the top dose. Xanthine oxidase may increase adenosine and guanosine. Adenosine receptors have direct effects on aggression. Lara D, et al: Allopurinol for the treatment of aggressive behavior in patients with dementia. Internat Clin Psychopharm 2003;18:53-5. Also see: Lara D el at: Allopurinol augmentation for poorly responsive schizophrenia. Internat Clin Psychopharm 2001;16:235-7; Lara D et al: Allopurinol for refractory aggression and self-inflicted behavior. J Psychopharm 2000;14:81-3. (Ed: Remember, open studies aren't worth very much. Allopurinol is an interesting idea, but a real research study would be nice.)

Carbamazepine Helps Anti-Psychotic Failures in DB: NIMH. A 6-week, DB PC study of carbamazepine (400 mg/day) with 21 agitated subjects (16 completers) who had been treated unsuccessfully with antipsychotics. There was greater improvement for the carbamazepine group on the Clinical Global Impression of Change (P=0.055) and the Brief Psychiatric Rating Scale (BPRS) Hostility item (P=0.009), with a trend toward worsening on the BPRS Hallucination item (P=0.067). A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Olin JT, Fox LS, Pawluczyk S, Taggart NA, Schneider LS. Am J Geriatr Psychiatry 2001 Fall;9(4):400-5

Carbamazepine Helps Agitation in DB: 51 patients >60yo with Alzheimer's, vascular or mixed dementia were in a DB PC 6 weeks study of carbamazepine to 5-8 microg/mL, averaging 300mg/d. There was an eight point decrease in the BPRS vs. 1 point placebo. Agitation and hostility decreased. At least minimal improvement occurred in 77% on carbamazepine vs. 22%. One with tics on carbamazepine requiring discontinuation. 5 others had dosage reductions. Tariot P, et al: Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 98;155:54-61, U Rochester & Ciba Geigy

Dronabinol (Marijuana) Used in Poor Quality Study: Dronabinol (Marinol), the active ingredient in marijuana, was used in a Phase II, open label, 8-week randomized, parallel-group study involved 54 community-dwelling patients, all who demonstrated behavioral agitation (mean age = 81). Patients were randomized to dronabinol 2.5 mg bid or dronabinol 5 mg bid. The Cohen-Mansfield Agitation Inventory (CMAI), the Caregiver's Burden Inventory (CBI), CGI Severity of Alzheimer's disease (CGI-S AD), Instrumental Activities of Daily Living Scale (IADL) and MMSE were done serially. At eight weeks significant reductions of CMAI scores in both groups were reported. There also was a trend toward a decrease in CBI scores and increase in IADL scores in both groups, without a statistical difference between the two doses. The 5 mg bid group experienced a trend toward a decrease in CGI-S AD scores. American Society of Consultant Pharmacists' 34th annual meeting 11/18/03. Joel S. Ross, Monmouth Medical Center. (Ed: Marinol is extremely expensive and numerous less expensive and safer alternatives are available. This open trial report proves nothing other than the depths to which the FDA has deteriorated under President Bush.)

Estrogen Patches No Benefit: In an 8-week DB PC nursing home study of 27 men with established dementia and aggressive behavior not responding to treatment, those treated with estrogen patches up to 100 microg per day had no significant difference in aggressive behavior at 8 weeks, but had a "rebound" in aggressive behavior (change in scores between week 8 and week 10, p < 0.009) following removal of the patches. Transdermal estrogen patches for aggressive behavior in male patients with dementia: a randomized, controlled trial. Hall KA, et al. Monash University, Australia. . Int Psychogeriatr. 2005 Jun;17(2):165-78.

Estrogen Helps Aggressive Behavior in DB: In a DB PC study design to investigate the efficacy and safety of short-term estrogen therapy in decreasing aggressive behaviors in elderly patients with moderate-to-severe dementia, estrogen therapy was associated with lower total aggression scores (P<0.030) and with decreased frequency of physical aggression (P<0.019) over the 4-week trial. Verbally aggressive behaviors were decreased relative to control subjects, although this effect was not statistically significant. No drug-vs.-placebo differences were found for resistive, sexual, or self-directed aggressive behaviors. No adverse effects from the estrogen were observed during the course of the study. Estrogen therapy and aggressive behavior in elderly patients with moderate-to-severe dementia: results from a short-term, randomized, double-blind trial. Kyomen HH, Satlin A, Hennen J, Wei JY. Harvard Medical. Am J Geriatr Psychiatry. 1999 Fall;7(4):339-48

Estrogen: Two Cases Physical Aggression and Sexual Inappropriateness Helped: Case 1. A 78-year-old white man had probable Alzheimer dementia and aggression (verbal and physical) that was nonresponsive to antipsychotic, antidepressant, and mood stabilizer therapy. However, conjugated estrogens 1.875 mg/d reduced his physical aggression by a 75%. Case 2. A 78-year-old African-American man with vascular dementia, physical aggression, and sexual inappropriateness was unsuccessfully managed with several antipsychotic and benzodiazepine trials. Conjugated estrogen 0.625 mg/day was associated with a decline in physical and sexual aggression by 80%, as well as a 55% reduction in sexual comments. Estrogen was well tolerated by both patients. Database searches were performed to identify case reports, letters, or clinical trials discussing estrogen use in aggressive elderly patients. As with previous reports, these cases suggest that conjugated estrogens may be used to reduce physical and sexual aggression associated with dementia in elderly men. Estrogen for dementia-related aggression in elderly men. Shelton PS, Brooks VG. Campbell University. Ann Pharmacother. 1999 Jul-Aug;33(7-8):808-12

Gabapentin Used for Agitation: This is a very poor quality open trial report.  Regan, J Clin Psychopharm 2/97

Memantine Helped Agitation. In an analysis of data from two large DB PC studies one moderately to severe demented elderly, memantine's effect in the 252-patient monotherapy study was not significant although for the agitation/aggression subscale it was.  For a larger 404-patient study, where all patients were only on donepezil, the addition of memantine did make behavioral rating significantly better, especially the agitation/aggression. Int J Geriatr Psychiatry. 2005 Apr 25;20(5):459-464. Ed: With so many less expensive choices available, memantine would be far down on the list.

Olanzapine = Risperidone for Agitated Dementia: A DB randomized study of 39 elderly with agitation with delusions, hallucinations, or aggression given olanzapine up to 10 mg/d or risperidone up to 2 mg/d for 2 weeks. Neuropsychiatric Inventory (NPI) scores dropped 35% with no between group differences. 4 of 20 olanzapine discontinued and 3 of 20 reduced dosage. 8 of 19 risperidone patients had to reduce dosage. Univ Texas SW. Fontaine C, et al: A double-blind comparison of olanzapine vs. risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities. J Clin Psychiatry 2003;64:726-30. Eli Lilly.

Quetiapine Case for Dementia Hypersexuality: Cyproheptidine failed and paroxetine caused diarrhea. Quetiapine 25 HS stopped several hours of masturbation daily. MacKnight, J Amer Geriatric Society 2000;48:707

Quetiapine (Seroquel) Increased Dementia Impairment; Neither It Not Rivastigmine Helped Agitation: In a 26-week DB PC study of 93 agitated Alzheimer's patients comparing the atypical antipsychotic (quetiapine), cholinesterase inhibitor (rivastigmine) and placebo, neither medication group showed significant improvement on agitation either at six weeks or 26 weeks. For quetiapine, the worsening in severe impairment battery score from baseline was 14.6 points worse than in the placebo group at six weeks (P=0.009) and 15.4 points (-27.0 to -3.8) worse at 26 weeks (P=0.01). Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. Ballard C, Margallo-Lana M, et al. King's College, London SE5 8AF. Ed: Since haloperidol increases hyperphosphorylation of tau protein, a critical deterioration in Alzheimer's, perhaps some or all atypical anti-psychotics do as well. 

Risperidone Doubles Stroke and Death: In 4 placebo-controlled trials lasting 1–3 months and involving more than 1200 patients with Alzheimer's disease or vascular dementia, cerebrovascular adverse events were twice as common in the risperidone-treated group (4%) as in the placebo group (2%). A further search of international databases of postmarketing adverse events revealed 37 cases (1 in Canada) of such events in elderly dementia patients taking risperidone, of which 16 (43%) were fatal. Risperdal (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials [Dear Healthcare Professional Letter]. Toronto: Janssen–Ortho Inc.; 2002 Oct 11. Available: www .hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english /advisory /industry/risperdal1_e.pdf (accessed 2002 Oct 25). Ed: The drug industry has now rebutted this claim.

Trazodone = Haldol = Behavior Therapy for Agitation in DB: 149 AD patients with agitation in a DB PC 12-week study found haldol (average 1.8mg/d) and trazodone (average 200mg/d) each better than placebo but only 34% responded. All treatments equal. There was no difference in types of symptoms helped. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF, Tractenberg RE, Foster NL, Schneider LS, Sano M, Whitehouse P, Tariot P, Mellow AM, Auchus AP, Grundman M, Thomas RG, Schafer K, Thal LJ; Alzheimer's Disease Cooperative Study.

Trazodone Helped Agitation as Much as Haldol: In a 9-week DB PC study of 28 elderly demented and agitated patients of trazodone (50-250 mg/day) or haloperidol (1-5 mg/day), there was no significant difference in improvement between the medication groups. Adverse effects were more common in the group treated with haloperidol. Repetitive, verbally aggressive, and oppositional behaviors responded preferentially to trazodone, whereas excessive motor activity and unwarranted accusations responded preferentially to haloperidol. A double-blind comparison of trazodone and haloperidol for treatment of agitation in patients with dementia. Sultzer DL, Gray KF, Gunay I, Berisford MA, Mahler ME. UCLA. Am J Geriatr Psychiatry. 1997 Winter;5(1):60-9

Valproate: Divalproex with or without Anti-psychotics: A very small study with 25 patients claims divalproex for behavior problems associated with dementia works just as well as anti-psychotics. Narayan, J Clin Psychiatry 8/97

Valproate No Benefit in Small DB: 42 patients in a DB PC study were given placebos or valproate 240 mg bid. Sodium valproate in the treatment of aggressive behavior in patients with dementia--a randomized placebo controlled clinical trial. The Hague: Sival RC, Haffmans PM, Jansen PA, Duursma SA, Eikelenboom P. Int J Geriatr Psychiatry 2002 Jun;17(6):579-85

Valproate Not Proven to be Useful: In attempting to gather all of the well done studies with valproic acid and divalproex, the authors conclude that there are none. Individual reports suggest that low dose sodium valproate is ineffective in treating agitation among demented patients, and that high dose divalproex sodium is associated with an unacceptable rate of adverse effects. More research on the use of valproate preparations for agitation of people with dementia is needed. On the basis of current evidence, valproate preparations cannot be recommended for the treatment of agitation in dementia. Valproic acid for agitation in dementia. Lonergan E, Cameron M, Luxenberg J. UCSF. Cochrane Database Syst Rev. 2004;2:CD003945

Thomas E. Radecki, M.D., J.D.

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