Case Reports in Psychiatry
Volume 2015 (2015), Article ID 542862, 12 pages
http://dx.doi.org/10.1155/2015/542862

Case Report

Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations

James Jackson,¹ Betsy McCollum,² Judy Ognibene,³ Francisco J. Diaz,⁴ and Jose de Leon1,5

¹Department of Psychiatry, College of Medicine, University of Kentucky, Lexington, KY 40509, USA
²Pharmacy, Eastern State Hospital, Lexington, KY 40511, USA
³Apalachee, Inc., Eastside Psychiatric Hospital, Tallahassee, FL 32308, USA
⁴Department of Biostatistics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
⁵University of Kentucky Mental Health Research Center, Eastern State Hospital, Lexington, KY 40511, USA

Received 28 February 2015; Accepted 8 April 2015

Academic Editor: Liliana Dell’Osso

Copyright © 2015 James Jackson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Valproic acid (VPA) can autoinduce its own metabolism. Cases requiring VPA doses >4000 mg/day to obtain therapeutic plasma concentrations, such as these 3 cases, have never been published. Case 1 received VPA for seizures and schizophrenia and had >50 VPA concentrations in 4 years. A high dose of 5,250 mg/day of VPA concentrate was prescribed for years but this dose led to an intoxication when switched to the enterocoated divalproex sodium formulation, requiring a normal dose of 2000 mg/day. VPA metabolic capacity was significantly higher (; df = 6.3, ) during the VPA concentrate therapy, possibly due to autoinduction in that formulation. Case 2 had VPA for schizoaffective psychosis with 10 VPA concentrations during an 8-week admission. To maintain a VPA level 50 μg/mL, VPA doses increased from 1500 to 4000 mg/day. Case 3 had tuberous sclerosis and epilepsy and was followed up for >4 years with 137 VPA concentrations. To maintain VPA concentrations 50 μg/mL, VPA doses increased from 3,375 to 10,500 mg/day. In Cases 2 and 3, the duration of admission and the VPA dose were strongly correlated (r around 0.90; ) with almost no change after controlling for VPA concentrations, indicating progressive autoinduction that increased with time.

1. Introduction

Valproic acid (VPA) is a classic antiepileptic drug (AED) and has been a major pharmaceutical tool in the management of a range of psychiatric and neurological diseases since the 1960s [1]. VPA is currently approved in the US for the treatment of several types of epilepsy, bipolar disorder, and migraine prophylaxis. The maximum recommended doses for epilepsy or bipolar disorder are 60 mg/kg/day [2]. It is rare to see patients taking >4000 mg/day. Moreover, therapeutic drug monitoring (TDM) is frequently used to establish and track VPA doses. Neurologists frequently use a therapeutic range of 50–100 μg/mL for epilepsy [3]. The therapeutic range in bipolar disorder is not very well established but some reviews recommend up to 125 μg/mL for mania [2].

In spite of decades of use, VPA metabolism is not completely understood [3–8]. VPA primarily undergoes hepatic metabolism, while <5% is eliminated and unchanged in the urine. The major mechanisms of hepatic metabolism are the uridine diphosphate glucuronosyltransferases (UGTs; 40%) and β-oxidation as a fatty acid (30%), with the cytochrome P450 (CYP; including CYP2C9, CYP2C19, and CYP2A6) as a minor component in the metabolic process. At low doses, β-oxidation may be the most important pathway, while at therapeutic doses glucuronidation may be more important [3–8]. Many UGTs appear to be involved in valproate glucuronidation including UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7, along with the primarily intestinal UGT1A8 and UGT1A10 [9].

Regarding the potential of causing drug-drug interactions (DDIs), VPA was traditionally considered to be a moderate inhibitor of several enzymes including CYP2C9, epoxide hydroxylase, several UGTs, and the N-glucosidation pathway of phenobarbital [4]. First, rat studies suggested that VPA may autoinduce its own glucuronidation [10]. The first clinical suggestions that VPA may autoinduce its own metabolism were from studies focused on felbamate [11] and lamotrigine [12]. More recent studies have been able to demonstrate that VPA induces (1) its own metabolism by inducing β-oxidation (prospective study) [13]; (2) CYP3A4 and P-gp gene expression (in vitro study) [14]; (3) possible UGT1A1 in a patient taking irinotecan (which has an active metabolite, SN-38, metabolized by UGT1A1) [15]; (4) aripiprazole metabolism to a mild degree (prospective study) [16]; (5) olanzapine metabolism (case series [17], TDM [18], a statistical model of TDM-DDI studies [19], and a prospective DDI study) [20]; (6) clozapine metabolism (case series [21, 22], a prospective case report [23], and statistical models of TDM-DDI studies [24, 25]); and (7) vitamin D metabolism in an in vitro study [26]. In summary, VPA may be like other AEDs, such as oxcarbazepine or topiramate, and act as a mild inducer for some metabolic enzymes and behave as a clinically relevant inhibitor of other metabolic enzymes.

The following 3 cases, accumulated by the senior author in the last 20 years of his clinical practice, describe 3 patients needing high doses of VPA to reach and maintain therapeutic concentrations ≥50 μg/mL. Recent advances in pharmacokinetic knowledge have allowed us to offer a hypothesis about these patients’ needs for such high VPA doses to reach therapeutic concentrations. On February 19, 2015, we conducted a PubMed search using the words “valproic acid and (high dose or high dosage)” limiting them to title or abstract, human participants, and case reports, which provided 33 articles. None of these 33 articles described the therapeutic use of VPA doses >4000 mg/day. We decided to publish these cases because it is very likely that other clinicians have seen similar patients but did not write about them.

2. Methods

2.1. Clinical Setting

The senior author collected these 3 cases during the last 20 years while working as a clinician and/or consultant in the public mental health system in Kentucky, USA. During 8 of those years, he managed a 30-bed treatment-refractory unit for psychotic patients in a state hospital with approximately 1600 admissions/year. He acquired Cases 1 and 3 in that setting. For 14 years he has also acted as a consultant for difficult cases, including those needing high doses of psychiatric medications in 4 state hospitals for severe mentally ill patients, 4 hospitals for adults with intellectual disabilities, and 2 nursing homes. Case 2 was collected as a consultant for another psychiatrist (third author). In the senior author’s experience, VPA is probably the most frequently prescribed psychotropic drug in the public mental health system facilities of Kentucky, with more than 1000 patients every year treated with VPA at state facilities. The 3 patients in this paper participated in pharmacogenetic studies after written informed consent forms were signed by them and/or their guardians.

2.2. TDM

These 3 cases contain TDM information that was collected for clinical purposes many years ago. The VPA TDM was done by immunoassay in the same psychiatric hospital using the same clinical laboratory at the hospital; levels were taken as trough concentrations (early AM before taking medications) and after reaching steady state. The VPA concentrations were measured in μg/mL, which is the same as mg/L.

In the last 10 years, the senior author has increasingly used the pharmacological concept of concentration-to-dose ratio (C/D ratio) to study TDM in order to personalize the prescription of psychiatric medications in psychopharmacology. The C/D ratio is a measure of the ability to eliminate the drug and is influenced by genetic, personal, and environmental factors. Inducers decrease the C/D ratio and inhibitors increase the C/D ratio. In comparing individuals taking the same drug, a very low C/D ratio indicates an individual with very fast metabolism, while a very high C/D ratio indicates one with very slow metabolism. Each drug is different and unique and has its own normal ranges for C/D ratios determined by its own bioavailability and elimination from the body.

The senior author has used the C/D ratio to interpret TDM of clobazam [27], clozapine, and risperidone [28]. These 3 drugs, like the majority of drugs used in neuropsychopharmacology, follow linear kinetics. A linear relationship exists between typical doses and plasma concentrations. This means that the relationship between concentration and dose is stable; it does not change with different doses and concentrations, and the drug C/D ratio is constant in the same patient as long as there are no changes in environmental or personal variables.

VPA TDM, unfortunately, is a little more complicated since it does not follow linear kinetics. The relationship between VPA dose and total concentration is nonlinear; the concentration does not increase proportionally with the dose but increases to a lesser extent due to saturable plasma-protein binding [29]. As the VPA C/D ratio is not constant and changes with different doses and concentrations, one needs to further interpret VPA C/D ratios in the context of a set of concentrations or set of doses.

The senior author has started using VPA C/D ratios in his teaching and clinical practice in the last 3 years and is not aware of any published article using them. Therefore, as the reader may not be familiar with the use of C/D ratios for valproate VPA, this section provides a short introduction. Based on experience as a lecturer, the senior author has figured out that VPA C/D ratios have values too low to be easily understood by physicians, who do not tend to be particularly strong in mathematics. To more easily understand the VPA C/D values, they are also presented with a value obtained by multiplying by 1000. To understand this, let us assume that a VPA dose of 2000 mg/day provides a total VPA concentration of 100 μg/mL. Therefore the C/D ratio in this patient is 100/2000 or 0.05. The C/D ratio multiplied by 1000 would be 50, an easier number to grasp.

Next, we can use a published case of VPA toxicity [29] to explain the interpretation of VPA C/D ratio for clinical use. To simplify, Table 1 presents only the VPA data including C/D ratios using total VPA concentrations. This patient has relatively narrow variations, with a C/D ratio multiplied by 1000 ranging between 112 and 132 (Table 1). These values are normal in the experience of the senior author. Moreover, these values follow the usual pattern of VPA C/D ratios. In low doses, in this case 500 mg/day, the C/D ratio multiplied by 1000 ranged from 128 to 132. In high doses, in this case 1000 mg/day, the C/D ratio multiplied by 1000 was 112, indicating a faster metabolism at 1000 mg/day than at the 500 mg/day dose. At higher VPA doses, plasma proteins such as albumin are saturated by VPA and the percentage of free (unbound) VPA concentration increases. Since free VPA is the entity that is metabolized, the higher the percentage of free concentration is, the faster the VPA is metabolized. In the experience of the senior author, approximately 90% of VPA on average is carried by plasmatic proteins and 10% is free at standard therapeutic concentrations. With higher concentrations, the relative concentrations of free VPA increase (e.g., 85% bound and 15% free), and with low concentrations it decreases (e.g., 95% bound and 5% free). These percentages of free VPA concentration are also influenced by (1) the plasma concentration of albumin and other plasmatic proteins, (2) plasma concentrations of some endogenous compounds that may bind to the proteins (e.g., bilirubin), and (3) the presence of other drugs (e.g., aspirin), which may also compete for plasmatic protein binding [29].

Table 1: Explaining VPA C/D ratio use with VPA concentrations from a published case [29].

Formulation
VPA dose (mg/day)
Concentration (g/mL)
C/D ratio
C/D ratio × 1000

ECDVNa
1000
112
0.112
112

ECDVNa
750
87
0.116
116

ECDVNa
500
66
0.132
132

ECDVNa
500
64
0.128
128

C/D: concentration-to-dose; ECDVNa: divalproex sodium enterocoated; VPA: valproic acid.

Other examples of VPA C/D ratio are calculated using published data [30, 31]. A case [30] of a possible VPA adverse drug reaction (ADR) occurred in a patient who had a VPA concentration 78 μg/mL at a dose of 1500 mg/day (C/D ratio = 0.520 calculated by 78/1500). The VPA C/D ratio multiplied by 1000 was 520. In a study of VPA TDM [31], 14 females had an average VPA concentration of 76 μg/mL with an average maintenance dose of 629 mg/day (C/D ratio = 0.121 calculated by 76/629) and a VPA C/D ratio multiplied by 1000 of 121. In the same study, 23 males had an average VPA concentration of 70 μg/mL with an average maintenance dose of 617 mg/day (C/D ratio = 0.113 calculated by 70/617) with a VPA C/D ratio multiplied by 1000 of 113.

These 3 cases needing VPA doses >4000 mg/day to obtain VPA therapeutic concentrations had very low mean C/D ratios multiplied by 1000: in the 20s or lower, possibly due to VPA autoinduction.

2.3. Scale

For this paper, we have completed the Drug Interaction Probability Scale (DIPS) [32] for each of the 3 cases.

2.4. Statistics

Available data for each of the 3 cases was dictated by clinical care; many years later we tried to use statistical techniques to accommodate the available data and the questions asked in each case. The Statistical Package for the Social Sciences (SPSS 22) was used to analyze the data. In Case 1 an independent sample -test compared mean VPA C/D ratios from the two VPA formulations, one probably accompanied with autoinduction and the other not. Pearson correlations between VPA dose and day of admission were used in Cases 2 and 3 to demonstrate that higher doses were needed to keep the VPA concentrations therapeutic over time, which is consistent with a pattern of autoinduction. Partial correlations were used to demonstrate that VPA concentrations did not explain the correlation between VPA dose and day of admission.

3. Case Presentations

3.1. Case 1

A Caucasian male was followed up for more than 4 years between the ages of 30 and 34 years. His initial weight was 85 Kg. He smoked 10 cigarettes per day. His psychosis started when he was 12 years old and had been refractory to treatment for many years at the time of admission. The patient had three seizures of unknown origin in the 3 months before coming under the care of the senior author. Academic neurologists had examined him at least twice. All tests, including a CT scan of the head, were negative. After a careful review of all records, it was the impression of the senior author that at least 1 or 2 of the 3 seizures might have been associated with rapid withdrawal of high doses of benzodiazepines, particularly temazepam, used as PRNs. He arrived at the unit with four antiepileptic medications in his regimen: carbamazepine, phenytoin, diazepam, and VPA. These medications had been progressively added by the neurology consultants. The blood levels of all four of these medications were subtherapeutic. After several months the senior author was able to change the regimen to VPA only, without the patient having any seizures during his long admission. The VPA treatment is described in detail in Table 2. To avoid too much irrelevant information, day 164 of admission was selected as day 1 to describe the time-course of VPA treatment. The senior author was surprised that this patient needed 5250 mg/day of VPA concentrate to get therapeutic VPA concentrations. After more than 3.5 years of admission, the patient was finally stabilized on clozapine at 700 mg/day, his psychotic symptoms had greatly improved, and he was getting ready to be discharged. However, he then began to complain about the taste of the VPA concentrate in his mouth. With the assumption of bioequivalent formulations and dosing, the patient was switched to divalproex sodium at a total daily dose of 5250 mg/day. This led to an unexpected VPA intoxication despite the absence of any other medication changes. This unexpected outcome left the senior author perplexed and led him to a brief preliminary publication on VPA concentrations during the last 3 months of admission [33], despite having no pharmacological explanation at that time. Table 2 presents a comprehensive list of the VPA concentrations during most of 4 years, as well as the corresponding VPA C/D ratios. While the patient was being maintained on 5250 mg/day of VPA concentrate for many years, the VPA C/D ratio multiplied by 1000 yielded values ranging from 10 to 21 with a mean of 15. Divalproex sodium treatment yielded VPA C/D values which, multiplied by 1000, ranged from 28 to 48, with a mean of 39. The means of 19 and 39 were found to be significantly different (Table 2, footnote 1), indicating that the patient’s ability to metabolize VPA was significantly higher on VPA concentrate than on divalproex sodium.

Table 2: VPA C/D ratio in Case 1.

Day
VPA dose (mg/day)
Concentration (g/mL)
C/D ratio
C/D ratio × 1000

Valproic acid concentrate (C/D ratio × 1000: mean ± SD = 15¹  ± 2.6, range = 10–21)

7³
5250
54
0.010
10

14⁴
5250
68
0.013
13

21⁵
5250
68
0.013
13

29⁵
5250
76
0.014
14

70⁵
5250
59
0.011
11

98⁶
5250
66
0.013
13

119⁶
5250
85
0.016
16

126⁶
5250
61
0.012
12

140⁶
5250
75
0.014
14

175⁶
5250
79
0.015
15

188⁶
5250
64
0.012
12

202⁷
5250
64
0.012
12

238⁸
5250
88
0.017
17

252⁸
5250
110
0.021
21

260⁹
5250
86
0.016
16

280⁹
5250
92
0.018
18

287⁹
5250
87
0.017
17

301¹⁰
5250
87
0.017
17

319¹⁰
5250
92
0.018
18

350¹⁰
5250
99
0.019
19

378¹¹
5250
85
0.016
16

420¹²
5250
91
0.017
17

427¹²
5250
97
0.018
18

434¹²
5250
87
0.017
17

470¹²
5250
87
0.017
17

498¹³
5250
90
0.017
17

552¹³
5250
95
0.018
18

582¹³
5250
81
0.015
15

609¹³
5250
88
0.017
17

637⁷
5250
80
0.015
15

928¹⁴
5250
111
0.021
21

945¹⁵
5250
93
0.018
18

978¹⁶
5250
78
0.015
15

998¹⁷
5250
67
0.013
13

1026¹⁸
5250
67
0.013
13

1054¹⁹
5250
66
0.013
13

1082¹⁹
5250
71
0.014
14

1110¹⁹
5250
63
0.012
12

1145²⁰
5250
69
0.013
13

1166²¹
5250
93
0.018
18

1202²²
5250
89
0.017
17

1208²³
5250
75
0.014
14

1236²⁴
5250
88
0.017
17

1251²⁵
5250
87
0.017
17

EC divalproex sodium (C/D ratio × 1000: mean ± SD = 39¹  ± 6.3, range = 28–48)

1306²⁵
5250
145²
0.028
28

1320²⁵
3750
135
0.036
36

1334²⁵
3000
127
0.042
42

1373²⁵
2500
120
0.048
48

1348²⁵
2000
73
0.037
37

1362²⁵
2000
82
0.041
41

1376²⁵
2000
78
0.039
39

C/D: concentration-to-dose; EC: enterocoated; VPA: valproic acid.

¹According to an independent -test calculated with equal variance not assumed, there was significant difference (; df = 6.3, ) between these two means, 15 in VPA concentrate and 39 in divalproex sodium.

²This VPA concentration was measured 4 weeks after switching from VPA concentrate to divalproex sodium. With a high VPA concentration at that time, the patient showed increased drowsiness.

³Other scheduled oral medications included benztropine 3 mg/day, gemfibrozil 1200 mg/day, propranolol 80 mg/day, and quetiapine 700 mg/day.

⁴Other scheduled oral medications included benztropine 3 mg/day, gemfibrozil 1200 mg/day, olanzapine 5 mg/day, propranolol 80 mg/day, and quetiapine 500 mg/day.

⁵Other scheduled oral medications included benztropine 3 mg/day, gemfibrozil 1200 mg/day, olanzapine 5 mg/day, and propranolol 80 mg/day.

⁶Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 5 mg/day, and propranolol 80 mg/day.

⁷Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 5 mg/day, and propranolol 60 mg/day.

⁸Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 30 mg/day.

⁹Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 40 mg/day.

¹⁰Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 60 mg/day.

¹¹Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 120 mg/day.

¹²Other scheduled oral medications included benztropine 4 mg/day, clonidine 0.1 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 60 mg/day.

¹³Other scheduled oral medications included benztropine 4 mg/day, gemfibrozil 1200 mg/day, olanzapine 2.5 mg/day, and propranolol 60 mg/day.

¹⁴Other scheduled oral medications included benztropine 4 mg/day, clozapine 25 mg/day, gemfibrozil 1200 mg/day, olanzapine 10 mg/day, and propranolol 80 mg/day.

¹⁵Other scheduled oral medications included benztropine 4 mg/day, clozapine 300 mg/day, gemfibrozil 1200 mg/day, olanzapine 10 mg/day, and propranolol 80 mg/day.

¹⁶Other scheduled oral medications included benztropine 4 mg/day, clozapine 600 mg/day, gemfibrozil 1200 mg/day, olanzapine 10 mg/day, and propranolol 80 mg/day.

¹⁷Other scheduled oral medications included benztropine 4 mg/day, clozapine 400 mg/day, gemfibrozil 1200 mg/day, olanzapine 10 mg/day, and propranolol 80 mg/day.

¹⁸Other scheduled oral medications included benztropine 4 mg/day, clozapine 700 mg/day, gemfibrozil 1200 mg/day, olanzapine 10 mg/day, and propranolol 80 mg/day.

¹⁹Other scheduled oral medications included benztropine 4 mg/day, clozapine 800 mg/day, gemfibrozil 1200 mg/day, and propranolol 80 mg/day.

²⁰Other scheduled oral medications included atorvastatin 10 mg/day, benztropine 4 mg/day, clozapine 800 mg/day, and propranolol 80 mg/day.

²¹Other scheduled oral medications included atorvastatin 20 mg/day, benztropine 4 mg/day, clozapine 800 mg/day, and propranolol 80 mg/day.

²²Other scheduled oral medications included atorvastatin 20 mg/day, clozapine 700 mg/day, docusate 250 mg/day, and propranolol 80 mg/day.

²³Other scheduled oral medications included atorvastatin 20 mg/day, benztropine 0.5 mg/day, clozapine 700 mg/day, docusate 250 mg/day, and propranolol 80 mg/day.

²⁴Other scheduled oral medications included atorvastatin 20 mg/day, benztropine 1 mg/day, clozapine 600 mg/day, docusate 250 mg/day, and propranolol 80 mg/day.

²⁵Other scheduled oral medications included atorvastatin 20 mg/day, benztropine 1 mg/day, clozapine 700 mg/day, docusate 250 mg/day, and propranolol 80 mg/day.

It is likely that this case presentation reflects the result of VPA autoinduction only present during VPA concentrate versus no autoinduction during divalproex sodium use. The DIPS score was 6, which corresponds to a probable drug interaction in this case (scored as 1 point each for questions 2, 3, 4, 7, 8, and 9).

3.2. Case 2

Patient 2 was a 66-year-old Caucasian male nonsmoker with a 26-year history of bipolar disorder and a history of polysubstance abuse (alcohol and cocaine). His initial weight was 90 Kg. He had 7 prior psychiatric admissions. On presentation the patient met the criteria for hypomanic episode with psychotic features. He had a positive viral panel for hepatitis C and his Hep C RNA PCR was positive, but his liver function profile and metabolic panel were unremarkable. Sublingual asenapine 20 mg/day, one of his outpatient medications, was restarted by the third author on hospital day 2 in addition to VPA 1000 mg/day, which the patient had not received as an outpatient. Other medications are described in Table 3. The patient did not experience any signs of VPA toxicity as the dose was increased during his admission. However, he remained hypomanic and continued to display rapid, pressured speech and flight of ideas in addition to increased levels of energy. His VPA concentrations were monitored closely with gradual increases in his enterocoated divalproex sodium. Despite increasing his daily dose and switching to concentrate and then back to enterocoated divalproex sodium, the dose had to be progressively increased to a total of 4000 mg/day to continue to have a therapeutic response and therapeutic levels. By the time of discharge, the patient’s mood had become more euthymic. He was discharged after 10 weeks of inpatient management in stable condition and with a medication regimen including VPA at 4000 mg/day. This patient was remarkable because, in order to maintain the therapeutic response and a VPA level around 70 μg/mL, progressively higher doses from 1500 to 4000 mg/day were needed to the point that the last VPA C/D ratio multiplied by 1000 had a value remarkably low (at 17) while being on a high dose of 4000 mg/day and with a VPA concentration of only 67 μg/mL. The mean C/D ratio multiplied by 1000 was 25 with a range from 17 to 33 (Table 3). As a matter of fact, in spite of the limited number of VPA concentrations, there was a very strong correlation (; ) between the number of days of admission and the dose, indicating that, with an increasing length of admission, the dose increased, and this high value remained after correcting for VPA concentrations using a partial correlation (; ) (Table 3, footnote 1). This is compatible with a progressive autoinduction; as the time after admission increased, it was necessary to increase the VPA dose. The patient was discharged on 4000 mg/day; we do not know what happened after discharge, except that the patient had no relapses for 2 years after this admission.

Table 3: VPA C/D ratio in Case 2.

Day¹
Formulation
VPA dose¹ (mg/day)
Concentration (μg/mL)
C/D ratio
C/D ratio × 1000²

All 10 VPA concentrations (C/D ratio × 1000: mean ± SD = 25 ± 5.6, range = 17–33)

8 therapeutic² VPA concentrations (C/D ratio × 1000: mean ± SD = 24 ± 5.6, range = 17–33)

5³
ECDVNa
1500
39
0.026
26

8³
ECDVNa
1500
49
0.033
33

14⁴
ECDVNa
2500
61
0.024
24

20⁵
ECDVNa
2500
75
0.030
30

23⁶
ECDVNa
2500
82
0.033
33

29⁷
ECDVNa
3000
77
0.026
26

36⁷
Concentrate
3500
72
0.020
20

41⁷
Concentrate
3500
78
0.022
22

48⁸
Concentrate
4000
73
0.018
18

55⁹
ECDVNa
4000
67
0.017
17

C/D: concentration-to-dose; ECDVNa: enterocoated divalproex sodium; VPA: valproic acid.

¹The Pearson correlation between day of admission and VPA dose was (); VPA dose remained significant in a partial correlation while controlling for VPA concentration: (). This is compatible with a progressive autoinduction indicating, at least with dose range, that it was necessary to increase the dose as the duration lengthened.

²50–125 μg/mL concentrations are considered therapeutic concentrations. As this patient has 2 nontherapeutic concentrations, it would be better to compare a priori with other patients using only the VPA therapeutic concentrations. In reality, eliminating the first 2 VPA concentrations, which were subtherapeutic, made almost no difference.

³Other scheduled oral medications included asenapine 10 mg/day, naproxen 1000 mg/day, omeprazole 20 mg/day, trimethoprim/sulfamethoxazole 1600/320 mg/day (for skin breakdown over swollen lower extremities), and trazodone 100 mg/day.

⁴Other scheduled oral medications included asenapine 15 mg/day, gabapentin 900 mg/day, lisinopril 10 mg/day, meloxicam 15 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, trimethoprim/sulfamethoxazole 1600/320 mg/day (for skin breakdown over swollen lower extremities), tramadol 150 mg/day, and trazodone 150 mg/day.

⁵Other scheduled oral medications included asenapine 15 mg/day, gabapentin 900 mg/day, lisinopril 10 mg/day, meloxicam 15 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, tramadol 150 mg/day, and trazodone 150 mg/day.

⁶Other scheduled oral medications included asenapine 15 mg/day, furosemide 40 mg/day, gabapentin 900 mg/day, lisinopril 10 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, tramadol 150 mg/day, and trazodone 150 mg/day.

⁷Other scheduled oral medications included asenapine 15 mg/day, furosemide 20 mg/day, gabapentin 1200 mg/day, lisinopril 10 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, tramadol 200 mg/day, and trazodone 150 mg/day.

⁸Other scheduled oral medications included asenapine 15 mg/day, furosemide 20 mg/day, gabapentin 1200 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, tramadol 200 mg/day, and trazodone 150 mg/day.

⁹Other scheduled oral medications included asenapine 15 mg/day, furosemide 20 mg/day, gabapentin 1200 mg/day, metoprolol 50 mg/day, omeprazole 20 mg/day, polyethylene glycol 17 g/day, tramadol 200 mg/day, and trazodone 150 mg/day.

Considering the need for higher doses to maintain the same VPA concentration, the DIPS score was 5 (scoring 1 point each for questions 2, 3, 4, 7, and 8), indicating a “probable” relationship between VPA and autoinduction activity.

3.3. Case 3

Patient 3 was a Caucasian male nonsmoker with a history of tuberous sclerosis, which manifested as seizure disorder and mental retardation. His initial weight was 71 Kg. He had been an inpatient at a state psychiatric hospital for 22 years before the senior author started to manage his treatment (day 1) when the patient was 48 years old. Two years later he developed a right renal mass, which was highly suspicious for renal cell carcinoma on biopsy. It was followed by a right-sided nephrectomy and cholecystectomy (day 860). However, the final pathology suggested that the mass was actually angiomyolipoma, which is common if there is renal involvement in patients with tuberous sclerosis. Thorough investigation for left-sided pathology indicated that his left kidney was functioning well with stable masses present on CT. From day 1322, the patient progressively worsened with new-onset episodes of ataxia and confusion. High clinical suspicion for a brain mass led the senior author to investigate with MRI. The results indicated that the patient had a mass in the right lateral ventricle “suggestive of giant cell astrocytoma” and that “foci of enhancement at the gray-white junction and numerous signal abnormalities in the skull suggest the possibility of metastatic disease.” Giant cell astrocytomas occur in 6–14% of patients with tuberous sclerosis and should be suspected when there is a new focal deficit, signs of increased intracranial pressure, or unexplained behavioral changes. After day 1420, when the brain tumor was diagnosed, we started trying to reduce the VPA dose and manage it on the basis of the patient’s comfort rather than the VPA concentration level.

During the long follow-up of more than 4 years (almost 1500 days) described in Table 4, the patient had therapeutic levels of phenytoin initially with 500 mg/day and at the end with 400 mg/day. VPA showed a completely different pattern, requiring a progressive increase in the dose to keep VPA therapeutic concentrations >50 μg/mL. On day 1 the VPA dose was 3375 mg/day, on day 400 it was 5000 mg/day, on day 943 it was 9000 mg/day, and on day 1029 it was 10500 mg/day, which was maintained until it was clear that his physical deterioration was due to a brain tumor. At that time other medications were discontinued, only leaving phenytoin and a lower VPA dose (Table 4).

Table 4: VPA C/D ratio in Case 3.

Day¹
VPA
Phenytoin

Formulation
Dose¹ (mg/day)
Concentration (μg/mL)
C/D ratio
C/D ratio × 1000
Dose (mg/day)
Concentration (μg/mL)

All 137 VPA concentrations (C/D ratio × 1000: mean ± SD = 8 ± 3.5, range = 3–20)

70 therapeutic² VPA concentrations (C/D ratio × 1000: mean ± SD = 9 ± 3.4, range = 5–18)

1³
ECDVNa
3375
46
0.014
14
500
15

33³
ECDVNa
3375
59
0.017
17
500
18

62³
ECDVNa
3375
43
0.013
13
500
16

86³
Concentrate
3350
22
0.007
7
500

117³
ECDVNa
3450
43
0.012
12
500
11

147³
ECDVNa
3375
38
0.011
11
500
10

162³
Concentrate
3450
9
0.003
3
500

174³
Concentrate
3450
28
0.008
8
500
18

177³
Concentrate
3450
31
0.009
9
500
18

189³
ECDVNa
3375
36
0.011
11
500

202³
ECDVNa
3750
40
0.011
11
500
10

208³
ECDVNa
4125
40
0.010
10
500
14

212³
ECDVNa
4500
68
0.015
15
500
15

244³
ECDVNa
4500
61
0.014
14
500
15

274³
ECDVNa
4500
67
0.015
15
500
15

307³
ECDVNa
4500
46
0.010
10
500
23

310³
ECDVNa
4500
50
0.011
11
0
23

313³
ECDVNa
4500
39
0.009
9
500
10

316³
ECDVNa
4500
81
0.018
18
500
11

320³
ECDVNa
4500
31
0.007
7
500
15

324³
ECDVNa
4500
46
0.010
10
500
16

335³
ECDVNa
5000
64
0.013
13
500
19

350³
ECDVNa
5000
75
0.015
15
500
24

398³
ECDVNa
5000
52
0.010
10
460
16

400³
ECDVNa
5000
85
0.017
17
460
11

430³
ECDVNa
5000
59
0.012
12
460
16

439³
ECDVNa
5000
65
0.013
13
460
18

470³
ECDVNa
5000
54
0.011
11
460
16

502³
ECDVNa
5000
53
0.011
11
460
20

530⁴
ECDVNa
5000
77
0.015
15
460
17

559⁴
ECDVNa
5000
50
0.010
10
460
13

590⁵
ECDVNa
5000
48
0.010
10
460
12

621⁶
ECDVNa
5000
37
0.007
7
460
10

635⁶
ECDVNa
5000
39
0.008
8
460
11

646⁶
ECDVNa
5250
35
0.007
7
460
13

681⁷
ECDVNa
5250
37
0.007
7
460
8

713⁷
ECDVNa
5250
46
0.009
9
460
7

734⁷
ECDVNa
5250
40
0.008
8
460
10

762⁷
ECDVNa
6000
53
0.009
9
460
9

770⁷
ECDVNa
6000
43
0.007
7
460
8

798⁷
ECDVNa
6000
23
0.004
4
460
9

806⁷
ECDVNa
6000
32
0.005
5
460
10

817⁷
ECDVNa
7500
36
0.005
5
200
9

831⁷
ECDVNa
7500
43
0.006
6
460
5

838⁷
ECDVNa
7500
47
0.006
6
460
15

846⁷
ECDVNa
7500
24
0.003
3
460
10

852⁷
ECDVNa
7500
35
0.005
5
460
8

860⁷
ECDVNa
7500
51
0.007
7
460

866⁷
ECDVNa
7500
42
0.006
6
460
3

888⁷
ECDVNa
7500
71
0.009
9
460
20

890⁷
ECDVNa
7500
81
0.011
11
460
20

916⁷
ECDVNa
7500
45
0.006
6
460
7

919⁷
ECDVNa
7500
46
0.006
6
460
7

929⁷
ECDVNa
8250
43
0.005
5
460

943⁷
ECDVNa
9000
43
0.005
5
460

950⁷
ECDVNa
9000
50
0.006
6
460

957⁷
ECDVNa
9000
75
0.008
8
460

964⁷
ECDVNa
9000
37
0.004
4
460

971⁷
ECDVNa
9000
28
0.003
3
460

972⁷
ECDVNa
9000
44
0.005
5
460
8

979⁷
ECDVNa
9000
64
0.007
7
460
6

985⁷
ECDVNa
9000
38
0.004
4
460
9

989⁷
ECDVNa
9000
50
0.006
6
460
8

992⁷
ECDVNa
9000
59
0.007
7
460
9

999⁷
ECDVNa
9000
54
0.006
6
460
6

1014⁷
ECDVNa
9000
35
0.004
4
460
6

1020⁷
ECDVNa
9000
42
0.005
5
460
5

1029⁷
ECDVNa
10500
43
0.004
4
460
7

1035⁷
ECDVNa
10500
102
0.010
10
460
6

1039⁷
ECDVNa
10500
54
0.005
5
460
1

1042⁷
ECDVNa
10500
77
0.007
7
460
6

1056⁷
ECDVNa
10500
120
0.011
11
460
6

1062⁷
ECDVNa
10500
39
0.004
4
460
8

1064⁷
ECDVNa
10500
47
0.004
4
460
7

1070⁷
ECDVNa
10500
56
0.005
5
460
6

1080⁷
ECDVNa
10500
51
0.005
5
460
10

1091⁷
ECDVNa
10500
54
0.005
5
460
11

1098⁷
ECDVNa
10500
63
0.006
6
460
12

1105⁷
ECDVNa
10500
49
0.005
5
460
12

1112⁷
ECDVNa
10500
47
0.004
4
460
8

1119⁷
ECDVNa
10500
51
0.005
5
460
6

1133⁷
ECDVNa
10500
91
0.009
9
460
7

1148⁷
ECDVNa
10500
50
0.005
5
460
13

1163⁷
ECDVNa
10500
40
0.004
4
460
9

1168⁷
ECDVNa
10500
62
0.006
6
460
10

1175⁷
ECDVNa
10500
63
0.006
6
460
13

1182⁷
ECDVNa
10500
110
0.010
10
460
11

1184⁷
ECDVNa
10500
61
0.006
6
460
10

1189⁷
ECDVNa
10500
56
0.005
5
460
10

1196⁷
ECDVNa
14000
133
0.010
10
460
9

1210⁷
ECDVNa
10500
67
0.006
6
460
13

1217⁷
ECDVNa
10500
65
0.006
6
460
14

1224⁷
ECDVNa
10500
87
0.008
8
460
11

1231⁷
ECDVNa
10500
70
0.007
7
460
13

1245⁷
ECDVNa
10500
65
0.006
6
460
15

1252⁷
ECDVNa
10500
97
0.009
9
460
9

1259⁷
ECDVNa
10500
77
0.007
7
460
13

1266⁷
ECDVNa
10500
56
0.005
5
460
12

1273⁷
ECDVNa
10500
97
0.009
9
460
14

1280⁷
ECDVNa
10500
60
0.006
6
460
16

1287⁸
ECDVNa
10500
39
0.004
4
460
19

1294⁸
ECDVNa
10500
103
0.010
10
460
15

1301⁸
ECDVNa
10500
48
0.005
5
460
19

1307⁸
ECDVNa
10500
72
0.007
7
460
13

1316⁸
ECDVNa
10500
54
0.005
5
460
13

1322⁸
ECDVNa
10500
71
0.007
7
460
13

1329⁸
ECDVNa
10500
75
0.007
7
460
13

1336⁸
ECDVNa
10500
98
0.009
9
460
12

1344⁸
ECDVNa
10500
93
0.009
9
460
11

1350⁸
ECDVNa
10500
65
0.006
6
460
15

1357⁸
ECDVNa
10500
58
0.006
6
460
23

1364⁸
ECDVNa
10500
73
0.007
7
460
18

1371⁸
ECDVNa
10500
106
0.010
10
460
24

1373⁸
ECDVNa
10500
106
0.010
10
460
20

1378⁸
ECDVNa
10500
89
0.008
8
460
15

1386⁸
ECDVNa
10500
97
0.009
9
460
17

1392⁸
ECDVNa
10500
72
0.007
7
460
21

1393⁸
ECDVNa
10500
87
0.008
8
460
23

1394⁸
ECDVNa
10500
122
0.012
12
230
22

1395⁸
ECDVNa
3500
37
0.011
11
0
20

1399⁸
ECDVNa
10500
130
0.012
12
400
8

1406⁸
ECDVNa
10500
94
0.009
9
400
10

1413⁸
ECDVNa
10500
126
0.012
12
400
12

1420⁸
ECDVNa
10500
108
0.010
10
400
12

1427⁸
ECDVNa
6000
59
0.010
10
400
21

1435⁸
ECDVNa
9000
110
0.012
12
400
5

1440⁸
ECDVNa
9000
86
0.010
10
400
8

1444⁸
ECDVNa
9000
82
0.009
9
400
10

1448⁸
ECDVNa
9000
147
0.016
16
400
10

1454⁷
ECDVNa
7000
93
0.013
13
400
14

1457⁹
ECDVNa
7000
138
0.020
20
400
11

1461¹⁰
ECDVNa
7000
72
0.010
10
400
13

1470¹¹
ECDVNa
7000
101
0.014
14
400
13

1478
ECDVNa
7000
113
0.016
16
400
7

1483
ECDVNa
7000
97
0.014
14
400
6

C/D: concentration-to-dose; ECDVNa: enterocoated divalproex sodium; VPA: valproic acid.

¹After day 1420, VPA dose was guided more by physical comfort than VPA concentrations; therefore, these latter days were eliminated to calculate the Pearson correlation between day of admission and VPA dose, which was (); VPA dose remained very high in a partial correlation while controlling for VPA concentration: (). This is compatible with a progressive autoinduction indicating, at least with dose range, that it was necessary to increase the dose as the duration lengthened. When all values (including those after day 1420) were used to calculate correlations, the values were, not surprisingly, slightly reduced both for the total correlation of () and the partial correlation of ().

²50–100 μg/mL concentrations are considered therapeutic concentrations. As this patient has too many nontherapeutic concentrations, it may be better to compare with other patients using only the VPA therapeutic concentrations.

³Other scheduled oral medications included benztropine 4 mg/day, mesoridazine 200 mg/day, lorazepam 6 mg/day, and risperidone 12 mg/day.

⁴Other scheduled oral medications included benztropine 4 mg/day, lorazepam 6 mg/day, and risperidone 12 mg/day.

⁵Other scheduled oral medications included benztropine 4 mg/day, lorazepam 6 mg/day, and risperidone 4 mg/day.

⁶Other scheduled oral medications included benztropine 4 mg/day and lorazepam 6 mg/day.

⁷Other scheduled oral medications included lorazepam 6 mg/day.

⁸Other scheduled oral medications included lorazepam 6 mg/day and trazodone 150 mg/day.

⁹Other scheduled oral medications included lorazepam 4 mg/day.

¹⁰Other scheduled oral medications included lorazepam 3 mg/day.

¹¹Other scheduled oral medications included lorazepam 1 mg/day.

Despite the necessity of increasing the VPA dose to this very high dosage, the phenytoin dose remained stable with normal blood levels in the therapeutic range. This suggests that the progressive increase in VPA metabolism was not associated with an increase in phenytoin metabolism. The VPA C/D ratios in this patient were extremely low, frequently lower than 10. The mean C/D ratio multiplied by 1000 for 70 therapeutic concentrations was 8 with a range from 5 to 18 (Table 3). As a matter of fact, there was a very strong correlation (; ) between the number of days past admission and the dose, indicating that with an increasing length of admission, the dose increased, and this significance remained after correcting for VPA concentrations using a partial correlation (; ) (Table 4, footnote 1). This is compatible with a progressive autoinduction.

Using the DIPS as in the previous cases, the total score was 5 (scoring 1 point each for questions 2, 3, 4, 7, and 8), indicating a “probable” relationship between VPA and the autoinduction of its metabolism.

4. Discussion

4.1. Limitations

These 3 cases reflect 3 extremely challenging patients who required very high doses of VPA >4000 mg/day to maintain VPA therapeutic levels. As usual in these challenging cases, the pharmacological data is somewhat limited since patients were treated with polypharmacy and went through complex changes in medications. In spite of the data limitations, we think that these cases need to be published to acknowledge that while these patients are very rare, they exist. In support of the above findings, however, the senior author was closely involved in the treatment of the 3 patients and all VPA concentrations were measured in the same lab. It is rare to see publications describe so many large measures of VPA concentrations.

The data is limited but undeniable and should indicate to any clinician that these 3 patients needed daily doses of VPA to get therapeutic VPA concentrations. The second and greater limitation in analyzing these cases is our interpretation of the data many years after they were collected—in the third case, almost 20 years. It has required that much time to accumulate evidence in the literature to understand what happened and to realize that VPA may be an inducer; in fact, it can induce its own metabolism. Therefore, although these VPA concentrations were collected prospectively and used to modify VPA doses, they were reviewed retrospectively to provide the unified hypothesis that it is possible that these high VPA doses were required because these 3 patients were unusually sensitive to VPA autoinduction. In retrospect, after having a possible pharmacological explanation now after many years, it would have been better to collect more frequent TDM data, but what is described is what is available. Although we acknowledge that the data is limited and our interpretation is even more limited, we have tried to support our interpretation through the use of statistical tests and a validated scale.

4.2. High Doses of VPA May Be Explained by VPA Autoinduction

We think these cases contribute to the scarce literature by indicating that clinicians must be aware that VPA may behave as an inducer. In Cases 1 and 3, patients with likely VPA autoinduction presented significant clinical challenges to the senior author, who had no idea why the patients required much higher VPA dosages to obtain therapeutic VPA concentrations. Case 2 was identified only 4 years ago when the senior author realized that VPA autoinduction was clinically relevant for some peculiar patients. As a matter of fact, Case 2 was identified by the third author, who had rarely seen similar cases. The senior author suggested to her that these cases were probably explained by autoinduction and she was able to identify this patient as a candidate for VPA autoinduction shortly after admission.

The first patient was very challenging, probably the most challenging patient in the senior author’s career, even with his more than 25-year history of treating treatment-refractory patients. The patient metabolized the CYP1A2 drugs clozapine and olanzapine normally but got intoxicated on clozapine during an infection [34]. He appeared unusual because he needed 5250 mg/day of VPA concentrate for several years to get therapeutic VPA concentrations. The senior author had experience in switching many patients back and forth from VPA concentrate to divalproex sodium using the same doses and getting similar VPA concentrations. In fact, the US prescribing information from the drug manufacturer recommended and continues to recommend initiating the same total daily doses when converting a patient from VPA to divalproex sodium. A published study reported a statistically significant decrease of 14.4% () in VPA plasma concentrations upon switching dosage forms from divalproex sodium to VPA [35]. Therefore, the senior author expected a minor increase of around 14.4% in switching from 5250 mg/day of VPA concentrate but, instead, he intoxicated the patient. The VPA concentration went from the 80s μg/mL to 145 μg/mL and required halving the dose to 2000 mg/day of divalproex sodium to get VPA concentrations in the 80s μg/mL. In retrospect, during treatment with VPA concentrate, the VPA C/D ratio multiplied by 1000 was extremely low, at a mean of 15 and a range of 10–21, indicating an extraordinarily high capacity to metabolize VPA. This is compatible with VPA concentrate inducing its own metabolism. We propose that after 4 weeks on divalproex sodium the autoinduction was lost and the patient’s metabolism normalized, with a mean VPA C/D ratio multiplied by 1000 of 39 and a range of 28 to 48. We cannot explain why this patient’s VPA concentrate appeared to induce its own metabolism while divalproex sodium did not; we assume this patient had some rare genetic variation that explains his peculiar response.

The second patient had a relatively short admission (<60 days) but demonstrated a very high and significant correlation between length of admission and VPA dose. The final C/D ratio was 17, extremely low. This type of patient is probably more common than Case 1; his treating psychiatrist, the third author, has seen several similar cases in her 25-year practice in patients with severe mental illness including 20 years at this psychiatric hospital.

The third patient probably deserved a Guinness record since he was treated with 10500 mg/day for 400 days and had a VPA C/D ratio multiplied by 1000 which yielded a value less than 10 most of the time. We have the impression that progressive VPA autoinduction explained the need to go from 3450 to 10500 mg/day to achieve and maintain VPA concentrations >50 μg/mL. It is possible that phenytoin treatment contributed in some way to the facilitation of VPA autoinduction, since phenytoin is a major inducer and can displace VPA from plasmatic proteins. It is remarkable that although increases in VPA dosage were needed to get therapeutic VPA concentrations, the phenytoin dosage needed to obtain therapeutic phenytoin concentrations was relatively stable throughout this time period. Phenytoin doses ranged from 500 mg/day at the beginning to 400 mg/day at the end. This minor reduction in dosage may be explained by the greater VPA concentrations at the end. VPA is an inhibitor of phenytoin metabolism. Unfortunately, 20 years ago, free VPA and phenytoin concentrations were not available at this psychiatric hospital. It would have been important to measure them [29].

4.3. The Pharmacological Mechanism behind VPA Induction

The induction of metabolic enzymes such as UGTs implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing protein synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors, and pregnane X receptors) or other transcription factors such as aryl hydrocarbon receptors. The potent AED inducers (carbamazepine, phenytoin, and phenobarbital) bind to the pregnane X receptors. Phenytoin and phenobarbital appear to also bind to the constitutive androstane receptors. VPA is a less potent inducer but probably works in a similar way. An in vitro study suggested that VPA might also activate constitutive androstane receptor and pregnane X receptor pathways [14].

We think it is possible that these unusual patients needing very high VPA dosages have unusual genetic variants at the nuclear receptors, which made them very sensitive to VPA autoinduction.

Disclaimer

No commercial organizations had any role in the writing of this paper for publication.

Conflict of Interests

In the last 3 years, the authors had no conflict of interests.

Acknowledgments

The authors acknowledge Lorraine Maw, M. A., who helped in editing this paper, and Kay Marshall, who was at that time Lab Director at the Psychiatric Hospital, and her staff were very helpful with the collection and analyses of the blood samples during all of these years.

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