Download Valproic Acid to Treat Agitation in Dementia

Valproic Acid
to Treat
Agitation in
Dementia
By: Samia B
Original Question
Valproic acid is sometimes prescribed to help
manage agitated behavior in older
patients with dementia…

What is the evidence to support its use in
this area?

When prescribing valproic acid for this
reason, how is the drug dosed?

What is the relationship between treatment
of agitated behavior symptoms and the
valproic acid serum concentration?
Dementia

The loss of mental functions, such as
thinking, memory and reasoning

Can be caused by many factors—most
commonly Alzheimer’s, especially in elderly.

Manifests as forgetfulness at first then
culminates to eventual anxiety and
aggression.
 Termed Behavioral and psychological
symptoms of dementia (BPSD)

Agitation is especially a concern because it
makes it increasingly had for the patient to
be treated.
•"Dementia: MedlinePlus." U.S National Library of Medicine. U.S. National Library of Medicine. Web. <http://www.nlm.nih.gov/medlineplus/dementia.html>.
•Yi-Chun Yeh, Wen-Chen Ouyang, Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: An update review, The Kaohsiung Journal of
Medical Sciences, Volume 28, Issue 4, April 2012, Pages 185-193, ISSN 1607-551X, 10.1016/j.kjms.2011.10.025.
BPSD

The non-cognitive symptoms of dementia.

>50% of patients with dementia.

Behavioral symptoms: physical aggression,
agitation, wandering, culturally
inappropriate behaviors, etc.

Psychological symptoms; anxiety,
hallucinations, delusions and psychosis.

Biological, social, environmental causes.
•"Behavioural and Psychological Symptoms of Dementia." Department of Health and Aging. Web. <http://www.health.gov.au>.
•Yi-Chun Yeh, Wen-Chen Ouyang, Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: An update review, The Kaohsiung
Journal of Medical Sciences, Volume 28, Issue 4, April 2012, Pages 185-193, ISSN 1607-551X, 10.1016/j.kjms.2011.10.025.
Valproic Acid

Suggested to increase GABA.

Some animal studies show decrease in
aggression.

First because carbemazapine and few
antipsychotics were used.

Evidence

Uncontrolled trials, case studies and
case reports*

5 RCT trials, only 2 showed efficacy.
•Mellow AM, Solano-Lopez C, Davis S. Sodium valproatein the treatment ofbehavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6: 205-209.
•Yi-Chun Yeh, Wen-Chen Ouyang, Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: An update review, The Kaohsiung
Journal of Medical Sciences, Volume 28, Issue 4, April 2012, Pages 185-193, ISSN 1607-551X, 10.1016/j.kjms.2011.10.025.
Sodium Valproate in the
Treatment of Behavioral
Disturbance in Dementia

First study using valproic acid for agitation in
dementia.

Case series of four patients.

Case 1
 Patient verbally abusive, irritable
 500 mg t.i.d./8 days
 Serum level= 93 mcg/mL
 Stopped resisting care, became much less
irritable.

Case 2
 Patient abusive
 500 mg bid (over the course of a month)
 51 mcg/mL up to 72 mcg/mL
 Transient
Mellow AM, Solano-Lopez C, Davis S. Sodium valproatein the treatment ofbehavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6: 205-209.
Sodium Valproate in the
Treatment of Behavioral
Disturbance in Dementia

Case 3
 Patient agitated, physically aggressive
 250 mg tid then 500 tid for about a month
 Serum concentration: 71 mcg/mL
 Unchanged
 *Cerebrovascular Disease

Case 4
 Patient displayed verbal outbursts
 500 mg bid/ 1 week
 Serum concentration: 72 mcg/mL
 Verbal outbursts reduced

Conclusion: Worked in patients 1 and 4, who were
not severely compromised. Suggested valproic
acid may have activity and better clinical trials may
be favorable.
Mellow AM, Solano-Lopez C, Davis S. Sodium valproatein the treatment ofbehavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6: 205-209.
Safety and Tolerability of Divalproex
Sodium in the Treatment of Signs and
Symptoms of Mania in Elderly Patients with
Dementia.

6-week, multicenter, randomized, double-blind,
placebo-controlled, parallel-group study

enrolled elderly nursing home residents with
dementia and secondary mania.

172 patients enrolled; 87 received divalproex
sodium and 85 received placebo.

125 mg BID, daily titration in increments of
125 mg/d up to a target dosage of 20 mg/kg/d
P.N. Tariot, L.S. Schneider, J.E. Mintzer, A.J. Cutler, M.R. Cunningham, J.W. Thomas et al. Safety and tolerability of divalproex sodium in the
treatment of signs and symptoms of mania in elderly patients with dementia: results of a double-blind, placebo-controlled trial Current
Therapeutic Research, 62 (2001), pp. 51–67
Safety and Tolerability of Divalproex
Sodium in the Treatment of Signs and
Symptoms of Mania in Elderly Patients with
Dementia.

Efficacy for agitation the Cohen-Mansfield
Agitation Inventory (CMAI)

(also used BRMS, BPRMS, CGI)

CMAI showed significant improvement
(P<.05)

Conclusion: Using valproic acid showed
significant improvement in the study.


limited power.
Study still acknowledged additional studies
need to be conducted to confirm efficacy.
P.N. Schneider, J.E. Mintzer, A.J. Cutler, M.R. Cunningham, J.W. Thomas et al. Safety and tolerability of divalproex sodium in the treatment of signs
and symptoms of mania in elderly Tariot, L.S. patients with dementia: results of a double-blind, placebo-controlled trial Current Therapeutic
Research, 62 (2001), pp. 51–67
Drug Dosing

basic rule-of-thumb
 start with one medication on a low dose,
titrated gradually until improvement is
observed, side-effects are intolerable or a
maximum-allowable dose is achieved.
 case studies
 starting: 250 mg bid-500mg bid
 titrating up to 500mg tid, until reaching
doses between 750mg-2500 mg/day
 RCT
 Starting: 125 mg bid
 titrating with increments at 125 mg/day
reaching a target dose of 20mg/kg/day to
a maximum of 30/mg/kg/day.
•Rayner AV, O'Brien JG, Shoenbachler B. Behavior disorders of dementia: recognition and treatment. Am Fam Physician. 2006;73:647–52
•P.N. Schneider, J.E. Mintzer, A.J. Cutler, M.R. Cunningham, J.W. Thomas et al. Safety and tolerability of divalproex sodium in the treatment of signs and symptoms of mania in elderly
Tariot, L.S. patients with dementia: results of a double-blind, placebo-controlled trial Current Therapeutic Research, 62 (2001), pp. 51–67
•Mellow AM, Solano-Lopez C, Davis S. Sodium valproatein the treatment ofbehavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6: 205-209.
Agitated behavior
symptoms and the valproic
acid serum concentration

First four case studies suggested a plasma
concentration of > 50 mcg/mL resulted in the
optimal response to alleviate symptoms of
agitation.
 Consistent with previously observed
anticonvulsant and antimanic threshold level

Various open-label studies indicate patients
with dementia tolerate a lower serum plasma
concentration subtherapeutic in other
conditions.
 Basis in Randomized Control Trial

While there is no conclusive answer, it can be
inferred that elderly patients better tolerate a
lower serum concentration to treat agitation.
•P.N. Schneider, J.E. Mintzer, A.J. Cutler, M.R. Cunningham, J.W. Thomas et al. Safety and tolerability of divalproex sodium in the treatment of signs and symptoms of mania in elderly Tariot, L.S.
patients with dementia: results of a double-blind, placebo-controlled trial Current Therapeutic Research, 62 (2001), pp. 51–67
•Mellow AM, Solano-Lopez C, Davis S. Sodium valproatein the treatment ofbehavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6: 205-209.
Conclusions

There is some discrepancy in several other
randomized controlled studies that ultimately
show valproic acid is not efficacious in
treating agitation in dementia.

Available studies that show some
effectiveness serve as a testament to how
highly individualized therapy is in treating
agitation related to dementia.

All factors should collectively be taken into
consideration before a clinician administers
treatment.