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.. 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 , ISSN X, /j.kjms

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.. 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 , ISSN X, /j.kjms

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: 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 , ISSN X, /j.kjms

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:

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:

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:

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:

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.