2022; 20(3): 536-547  
Blood Levels of Ammonia and Carnitine in Patients Treated with Valproic Acid: A Meta-analysis
Saaya Yokoyama1, Norio Sugawara1, Kazushi Maruo2, Norio Yasui-Furukori1, Kazutaka Shimoda1
1Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, 2Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
Correspondence to: Norio Sugawara
Department of Psychiatry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan
E-mail: nsuga3@dokkyomed.ac.jp
ORCID: https://orcid.org/0000-0001-7058-664X
Received: May 25, 2021; Accepted: July 28, 2021; Published online: August 31, 2022.
© The Korean College of Neuropsychopharmacology. All rights reserved.

Abstract
Objective: Long-term valproic acid (VPA) administration is associated with adverse metabolic effects, including hyperammonemia and hypocarnitinemia. However, the pathogeneses of these adverse events remain unclear, and not enough reviews have been performed. The aim of this study was to conduct a meta-analysis of studies examining blood levels of ammonia and carnitine in patients treated with VPA.
Methods: We conducted database searches (PubMed, Web of Science) to identify studies examining blood levels of ammonia and carnitine in patients treated with VPA. A meta-analysis was performed to conduct pre- and post-VPA treatment comparisons, cross-sectional comparisons between groups with and without VPA use, and estimations of the standardized correlations between blood levels of ammonia, carnitine, and VPA.
Results: According to the cross-sectional comparisons, the blood ammonia level in the VPA group was significantly higher than that in the non-VPA group. Compared to that in the non-VPA group, the blood carnitine level in the VPA group was significantly lower. In the meta-analysis of correlation coefficients, the blood VPA level was moderately correlated with blood ammonia and blood free carnitine levels in the random effects model. Furthermore, the blood ammonia level was moderately correlated with the blood free carnitine level.
Conclusion: Although the correlation between ammonia and free carnitine levels in blood was significant, the moderate strength of the correlation does not allow clinicians to infer free carnitine levels from the results of ammonia levels. Clinicians should measure both blood ammonia and free carnitine levels, especially in patients receiving high dosages of VPA.
Keywords: Bipolar disorder; Valproic acid; Free carnitine; Acylcarnitine; Ammonia
INTRODUCTION

Valproic acid (VPA) is commonly used for the treatment of psychiatric or neurological diseases. The mechanism of VPA is not fully understood, although the regulation of glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission has been postulated [1]. While VPA is usually tolerated, adverse metabolic effects, such as hypocarnitinemia as well as hyperammonemia, have been associated with long-term VPA administration [2].

Carnitine is essential for the transport of long-chain fatty acids into mitochondria for beta-oxidation. When carnitine is lacking, fatty acids accumulate and inhibit the urea cycle via multiple pathways, resulting in elevated ammonia [3,4]. A recent meta-analysis indicated that carnitine supplementation significantly reduces blood levels of ammonia [5]. Although the abovementioned mechanisms suggest that carnitine deficiency could promote VPA-induced hyperammonemia, previous studies conducted in participants receiving VPA reported inconsistent results regarding the relationship between ammonia and carnitine [2,3,6,7]. Clarifying the relationship between ammonia and carnitine could be important for clinicians to decide monitoring plans for patients taking VPA.

Therefore, we conducted a meta-analysis of studies evaluating blood levels of ammonia and carnitine in patients treated with VPA. We aimed to (1) clarify the mean differences in ammonia and carnitine levels between patients with and without VPA treatment (cross-sectional comparisons), (2) describe the mean differences in ammonia and carnitine levels after VPA treatment (pre- and post-VPA comparisons), and (3) estimate the standardized correlations between blood levels of ammonia, carnitine, and VPA (meta-correlational analyses).

METHODS

Study Selection

The systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards (a protocol used to evaluate systematic reviews) [8]. Electronic databases, including PubMed and Web of Science, were initially searched using six terms. The search phrases for PubMed were “(valproic acid [ALL] OR valproate [ALL] OR divalproex [ALL]) AND carnitine [ALL])” OR “(valproic acid [ALL] OR valproate [ALL] OR divalproex [ALL]) AND (ammonia [ALL] OR hyperammonemia [ALL])”. We used comparable search terms for Web of Science.

We included studies that had ≥ 10 participants with VPA use, regardless of clinical setting (inpatient, outpatient); (1) observational studies (cross-sectional, longitudinal studies), (2) randomized controlled trials, and (3) case reports. We excluded the following: (1) comments, editorials, letters; (2) studies not performed in human participants; (3) non-English publications; (4) studies including conditions likely to significantly affect the distribution of ammonia or carnitine levels (e.g., participants with valproate-induced hyperammonemic encephalopathy, carnitine palmitoyltransferase deficiency, hepatitis, or liver failure); and (6) studies including participants who used VPA for less than 1 month. Two researchers (SY and NS) independently searched the literature. After all papers had been assessed, any discrepancies in the responses were identified and discussed until consensus was reached.

Data Extraction

The following data were extracted: first author’s name, publication year, sample size, means and standard deviation (SD) values of blood ammonia and free carnitine levels in each group, and correlation coefficients between blood levels of ammonia, carnitine, and VPA among participants taking VPA (Tables 14) [9-54]. Subjects whose mean levels of ammonia or carnitine were more than twice as high as the upper limit of the normal range were excluded from the final analysis.

Statistical Analysis

We calculated the mean (SD) as a one group, when there were two or more groups taking VPA in one article. Additionally, all non-VPA groups in one article were considered a single group for data synthesis purposes.

For the cross-sectional comparison, we calculated the standardized mean differences (SMDs) between the groups using the metacont function in the meta package with the option for SMD (sm = “SMD”).

Regarding the pre- and post-VPA comparison, most studies included only the mean and SD of each pre- and postvisit, not the mean and SD of the difference from baseline. Therefore, we calculated the mean and SD of the differences from baseline for such studies under the assumption that the correlations between pre- and postvariables were equivalent to 0.5. We calculated the mean differences from baseline visit data using the metamean function in the meta package of R software with the default settings [55].

For the meta-correlational analysis, we transformed Spearman’s correlation coefficients to Pearson’s coeffi-cients using transformation functions on the assumption that the variables followed a normal distribution after applying an adequate statistical transformation (e.g., Box-Cox transformation) [56]. We synthesized the correlations between the variables using the metacor function in the meta package with the default settings.

All meta-analyses were conducted using random effect models, and the heterogeneity for each analysis result was evaluated with I-square statistic.

RESULTS

After excluding duplicates and nonrelevant studies, our search yielded 50 publications that fulfilled the inclusion criteria (Fig. 1). In the cross-sectional comparison, the blood ammonia level in the VPA group was significantly higher than that in the non-VPA group (n = 16, n = 4,821, SMD = 0.7, confidence interval [CI]: 0.5, 1.0, p < 0.01; I2 = 88%) (Fig. 2). Compared to that in the non-VPA group, the blood carnitine level in the VPA group was significantly lower (n = 26, n = 3,505, SMD = −1.1, CI: −1.4, −0.8, p < 0.01; I2 = 90%) (Fig. 3).

According to the pre- and post-VPA comparison, VPA treatment significantly increased the blood ammonia level (n = 3, n = 274, MRAW = 14.3 micromol/L, CI: 8.3, 20.4, p < 0.01; I2 = 96%) (Fig. 4) and significantly decreased the blood carnitine level (n = 7, n = 180, MRAW = −8.7 micromol/L, CI: −11.4, −5.9, p < 0.01; I2 = 79%) (Fig. 5).

The correlation coefficient between VPA and blood ammonia level was 0.36 (CI: 0.20, 0.50) (n = 16, n = 1,098, p < 0.01; I2 = 86%) in the random effects model (Fig. 6). Under the same analytical conditions, the correlation coefficient between VPA and free carnitine in blood was −0.24 (CI: −0.43, −0.03) (n = 7, n = 367, p < 0.01; I2 = 67%) (Fig. 7), and the correlation coefficient between ammonia and free carnitine in blood was −0.44 (CI: −0.73, −0.02) (n = 7, n = 460, p < 0.01; I2 = 95%) (Fig. 8).

DISCUSSION

To our knowledge, this is the first meta-analysis to assess the relationships between ammonia, free carnitine, and VPA. According to the pre- and post-VPA comparison and the cross-sectional comparison, VPA treatment significantly increased the blood ammonia level and decreased the blood carnitine level. The meta-correlational analysis revealed that the blood ammonia level had moderate associations with both VPA and free carnitine levels in blood. Furthermore, VPA level showed a weak correlation with free carnitine level in blood.

Hyperammonemia and hypocarnitinemia are well known as adverse metabolic effects of VPA treatment [2]. Ammonia is produced by the catabolism of proteins and other nitrogenated compounds. Under physiological conditions, ammonia exists as a constituent in body fluids and is transferred to the liver for its ultimate removal as urea. It is then excreted via the kidneys. Normally, circulating ammonia levels in blood are low, at less than 50 μmol/L (85 μg/dl) [46]. VPA is mainly metabolized by uridine diphosphate glucuronosyltransferases (UGTs) in the cytosol and partially via mitochondrial beta-oxidation and cytosolic omega-oxidation. The metabolites of VPA, such as valproyl-CoA, 2-propyl-4-pentenoate (4-ene VPA), and propionate, inhibit enzymes in the urea cycle, leading to an elevated blood ammonia level [50,57,58].

VPA treatment is also known as a cause of carnitine deficiency [2]. Carnitine, which is a carrier-type molecule required for the transport and oxidation of fatty acids in mitochondria, plays an important role in energy production [59]. Free plasma carnitine levels were significantly lower in patients who took VPA than in those who did not take VPA [24,26,36]. Although the mechanism of carnitine deficiency with VPA use is controversial, inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate might be a potential cause [60].

Despite high heterogeneity, there are no studies in which the non-VPA group had a significantly higher ammonia level than the VPA group in a cross-sectional comparison, and all studies that included pre- and post-VPA comparisons showed a significantly elevated ammonia level after VPA treatment. Regarding free carnitine levels, there were no studies in which the non-VPA group had a significantly lower free carnitine level than the VPA group in a cross-sectional comparison, and most of the studies included in the pre- and post-VPA comparison showed a significant reduction in the free carnitine level after VPA treatment. Our results confirmed the abovementioned results in the meta-analysis of both the cross-sectional and pre-and post-VPA comparisons. Even though the mechanisms of hyperammonemia and hypocarnitinemia with VPA use are controversial, our pooled analysis robustly supports concern about these adverse metabolic effects in patients with long-term VPA use.

In the meta-correlational analysis, both ammonia and free carnitine levels in blood showed a significant association with blood VPA level. Although our results had significant heterogeneity, there were no studies showing a significantly negative correlation between VPA and ammonia and a significantly positive correlation between VPA and free carnitine. Blood level-dependent relationships might indicate dose-dependent relationships in clinical settings. Clinicians should be aware of hyperammonemia and hypocarnitinemia, especially in patients receiving high-dose VPA treatment.

Our results also demonstrated a significant correlation between ammonia and free carnitine levels in blood. Although carnitine deficiency can promote VPA-induced hyperammonemia via inhibition of the urea cycle [3,4], the clinical implications of our findings should be interpreted with caution due to the moderate effect size of the observed correlation. Patients with hyperammonemia do not necessarily have hypocarnitinemia. Carnitine is synthesized endogenously from two essential amino acids, lysine and methionine, and is also obtained primarily by the ingestion of meat and dairy products. Dietary intake of carnitine could affect blood levels, even after VPA treatment. Clinicians prescribing VPA should monitor both blood ammonia and free carnitine levels.

Our findings should be interpreted with caution due to several limitations of this meta-analysis. First, considerable heterogeneity, indicating variations in relationships among studies, may have affected our results, although we employed random effects models throughout the analyses to conservatively estimate the relationships. The effect size of the observed relationships should be interpreted with caution. Second, the analyses were based on a limited number of studies and subjects due to stringent inclusion/exclusion criteria. Nonetheless, the comprehensive search of two electronic databases may have limited the risk of reporting bias. Third, several potential confounding factors, such as age, reason for VPA treatment, dietary intake of carnitine, and use of other antiepileptics, were not included in our analyses. Indeed, it is important to note that meat and dairy products are sources of carnitine. Future studies assessing the effects of potential confounders on blood levels of ammonia and carnitine in patients treated with VPA are needed.

This was the first meta-analysis to assess the relationships between ammonia and free carnitine and VPA. In line with previous findings, VPA treatment was associated with both hyperammonemia and hypocarnitinemia in a blood level-dependent manner. Although the correlation between ammonia and free carnitine levels in blood was significant, the moderate strength of the correlation does not allow clinicians to infer free carnitine levels from the results of ammonia levels. Clinicians should measure both blood ammonia and free carnitine levels, especially in patients receiving high dosages of VPA.

ACKNOWLEDGMENTS

We would like to thank Ms. Rui Ohashi and Ms. Naomi Natsume for their kind support.

Funding

None.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Saaya Yokoyama, Norio Yasui- Furukori. Methodology: Norio Sugawara. Data analysis; Kazushi Maruo. Overall study coordination; Norio Yasui- Furukori, Kazutaka Shimoda. Data interpretation: Saaya Yokoyama, Norio Sugawara, Kazushi Maruo, Norio Yasui- Furukori, Kazutaka Shimoda. Writing of the manuscript: Norio Sugawara, Kazushi Maruo, Saaya Yokoyama.

Figures
Fig. 1. A flow chart of the study selection process. VPA, valproic acid; CA, carnitine; NH3, ammonia.
Fig. 2. Mean difference of blood ammonia levels between with and without valproic acid (VPA) treatment. SD, standard deviation; CI, confidence interval; SMD, standardized mean difference.
Fig. 3. Mean difference of blood free carnitine levels between with and without valproic acid (VPA) treatment. SD, standard deviation; CI, confidence interval; SMD, standardized mean difference.
Fig. 4. Mean difference of blood ammonia levels after valproic acid treatment. MRAW, raw mean; CI, confidence inter-val.
Fig. 5. Mean difference of blood free carnitine levels after valproic acid treatment. MRAW, raw mean; CI, confidence interval.
Fig. 6. Forest plot of standardized correlation coefficient between blood valproic acid and ammonia levels. COR, correlation; CI, confidence interval.
Fig. 7. Forest plot of standardized correlation coefficient between blood valproic acid and free carnitine levels. COR, correlation; CI, confidence interval.
Fig. 8. Forest plot of standardized correlation coefficient between blood ammonia and free carnitine levels. COR, correlation; CI, confidence interval.
Tables

Major characteristics of studies included for cross-sectional comparison

Author Group Unit Mean ± SD Number Mean ± SD Number Mean ± SD Number
Maldonado et al. [9], 2016 With VPA mg/dl 105.2 ± 57.2 28
Without VPA 61.7 ± 27.3 31 82.1 ± 35.6 41
Yamamoto et al. [10], 2013 With VPA mg/dl 85.8 ± 42.7 1,826
Without VPA 36.0 ± 21.1 445 56.0 ± 28.5 673
Castro-Gago et al. [11], 2010 With VPA mmol/L 39.8 ± 14.1 57
Without VPA 29.5 ± 10.5 75 29.9 ± 8.1 17
Agarwal et al. [12], 2009 With VPA mg/dl 86.4 ± 39.9 100
Without VPA 68.7 ± 30.1 100
Hamed and Abdella [6], 2009 With VPA mg/dl 75.6 ± 18.0 60
Without VPA 36.4 ± 10.8 40
Verrotti et al. [13], 1999 With VPA mg/dl 36.7 ± 12.4 32 59.9 ± 16.3 28
Without VPA 31.1 ± 14.7 24 29.7 ± 12.1 40
Hirose et al. [14], 1998 With VPA mmol/L 26.0 ± 9.2 45
Without VPA 29.4 ± 11.8 45
Altunbaşak et al. [15], 1997 With VPA mg/dl 29.8 ± 14.6 44 32.0 ± 19.4 24
Without VPA 21.6 ± 20.4 16
Thom et al. [16], 1991 With VPA mmol/L 32.0 ± 24.3 37
Without VPA 21.0 ± 18.8 22
Beghi et al. [17], 1990 With VPA mg/dl 62.5 ± 40.9 55 56.1 ± 32.6 54
Without VPA 49.4 ± 31.3 51 36.5 ± 24.6 53
Komatsu et al. [18], 1987 With VPA mg/dl 39.9 ± 13.6 8 61.7 ± 24.1 25 121.9 ± 48.6 31
Without VPA 39.3 ± 12.5 12 48.6 ± 13.2 16 39.3 ± 9.9 13
48.1 ± 17.6 17 68.9 ± 20.0 15
Kugoh et al. [19], 1986 With VPA mg/dl 40.5 ± 23.3 53 56.6 ± 26.5 140
Without VPA 40.7 ± 15.2 63
Farrell et al. [20], 1986 With VPA mmol/L 30.2 ± 9.3 31 34.9 ± 9.0 19
Without VPA 29.8 ± 10.8 25
Ratnaike et al. [21], 1986 With VPA mmol/L 37.1 ± 31.8 23 37.6 ± 21.4 33
Without VPA 21.5 ± 7.8 25
Haidukewych et al. [22], 1985 With VPA mg/ml 0.8 ± 0.5 33 0.6 ± 0.3 27 0.6 ± 0.2 13
0.3 ± 0.2 14 0.3 ± 0.2 38
Without VPA 0.5 ± 0.1 32
Ohtani et al. [23], 1982 With VPA mg/dl 143.8 ± 42.4 14
Without VPA 55.1 ± 15.0 11 46.7 ± 72.2 27

Mean ± standard deviation (SD) of blood ammonia levels.

VPA, valproic acid.

Major characteristics of studies included for cross-sectional comparison

Author Group Unit Mean ± SD Number Mean ± SD Number Mean ± SD Number
Qiliang et al. [24], 2018 With VPA mmol/L 23.9 ± 10.6 299
Without VPA 36.4 ± 9.4 299
Maldonado et al. [9], 2016 With VPA mmol/L 39.8 ± 13.0 28
Without VPA 37.8 ± 8.6 31 50.1 ± 18.9 41
Cansu et al. [25], 2011 With VPA mmol/L 29.6 ± 7.1 28
Without VPA 30.9 ± 10.1 28
Nakajima et al. [7], 2011 With VPA mmol/L 40.8 ± 11.0 28 32.1 ± 8.4 23
Without VPA 47.7 ± 9.1 23
Hamed and Abdella [6], 2009 With VPA mmol/L 25.3 ± 8.1 60
Without VPA 40.9 ± 4.8 40
Anil et al. [26], 2009 With VPA mmol/L 16.5 ± 10.2 50
Without VPA 44.6 ± 7.3 30
Zelnik et al. [27], 2008 With VPA mg/ml 26.9 ± 8.6 18
Without VPA 38.5 ± 7.8 24 37.2 ± 7.8 28 40.4 ± 8.7 21
Werner et al. [28], 2007 With VPA mmol/L 44.4 ± 10.8 16 41.1 ± 11.5 9
Without VPA 48.7 ± 22.1 15 47.9 ± 9.5 27
Verrotti et al. [13], 1999 With VPA mmol/L 28.9 ± 5.1 32 25.7 ± 4.3 28
Without VPA 40.9 ± 7.1 24 42.9 ± 8.0 40
Castro-Gago et al. [29], 1998 With VPA mmol/L 25.8 ± 6.1 17
Without VPA 34.3 ± 8.3 10 27.8 ± 4.4 5 49.0 ± 5.9 71
Hirose et al. [14], 1998 With VPA mmol/L 42.7 ± 9.9 45
Without VPA 44.4 ± 9.9 45
Hiraoka et al. [30], 1997 With VPA mmol/L 35.6 ± 13.5 9 24.6 ± 5.2 13
Without VPA 42.7 ± 9.3 12
Zelnik et al. [31], 1995 With VPA mmol/L 29.1 ± 6.2 15
Without VPA 38.9 ± 14.6 14 37.2 ± 7.9 8 40.3 ± 12.8 34
Riva et al. [32], 1993 With VPA mmol/L 35.0 ± 13.0 22
Without VPA 48.0 ± 20.0 16
Hug et al. [33], 1991 With VPA mmol/L 27.0 ± 10.0 53 23.2 ± 9.3 18
Without VPA 42.5 ± 14.1 32 24.6 ± 12.3 119 31.4 ± 10.4 92
33.0 ± 8.3 141 24.0 ± 10.7 19 30.9 ± 11.0 17
38.8 ± 10.7 12
Thom et al. [16], 1991 With VPA mmol/L 30.8 ± 10.9 37
Without VPA 39.3 ± 6.6 22
Opala et al. [34], 1991 With VPA mmol/L 29.9 ± 10.0 43 21.4 ± 12.0 91
Without VPA 36.7 ± 10.0 43 36.8 ± 7.0 89
Matsumoto et al. [35], 1990 With VPA mmol/L 44.7 ± 30.1 198
Without VPA 53.4 ± 20.6 50
Beghi et al. [17], 1990 With VPA mmol/L 33.0 ± 11.7 55 36.2 ± 10.4 54
Without VPA 37.0 ± 9.4 51 41.4 ± 8.9 53
Melegh et al. [36], 1990 With VPA mmol/L 26.1 ± 7.1 10
Without VPA 42.7 ± 6.8 10
Rodriguez-Segade et al. [37], 1989 With VPA mmol/L 26.4 ± 8.4 34
Without VPA 41.2 ± 11.7 149 42.1 ± 10.0 26 47.1 ± 7.7 49
Komatsu et al. [18], 1987 With VPA mmol/L 55.7 ± 8.6 11 42.5 ± 9.5 25 36.6 ± 11.5 25
Without VPA 57.3 ± 7.7 7 51.3 ± 13.5 7 48.5 ± 11.2 26
53.2 ± 7.9 12 52.8 ± 17.4 5
Melegh et al. [38], 1987 With VPA mmol/L 16.8 ± 5.9 11
Without VPA 26.5 ± 7.0 11
Morita et al. [39], 1986 With VPA mmol/L 21.5 ± 7.4 12
Without VPA 31.5 ± 7.7 13 51.7 ± 8.8 32
Laub et al. [40], 1986 With VPA mmol/L 33.5 ± 8.0 21
Without VPA 41.2 ± 12.0 21 39.9 ± 9.0 21
Ohtani et al. [23], 1982 With VPA mmol/L 28.6 ± 9.7 14
Without VPA 43.0 ± 8.6 11 44.2 ± 63.3 27

Mean ± standard deviation (SD) of blood free carnitine levels.

VPA, valproic acid.

Major characteristics of studies included for pre-post comparison

Author Variables Group Unit Mean ± SD Number Mean ± SD Number
Hamed and Abdella [6], 2009 Ammonia Before VPA mg/dl 40.7 ± 5.4 60
After VPA 75.6 ± 18.0
Redden et al. [41], 2009 Ammonia Before VPA mmol/L 39.2 193
Mean difference 11.7 ± 21.3
Paganini et al. [42], 1984 Ammonia Before VPA mg/dl 39.1 ± 16.0 21
After VPA 57.6 ± 16.0
Cansu et al. [25], 2011 Free carnitine Before VPA mmol/L 32.9 ± 10.9 28
After VPA 29.6 ± 7.1
Hamed and Abdella [6], 2009 Free carnitine Before VPA mmol/L 36.9 ± 4.0 60
After VPA 25.3 ± 8.1
Werner et al. [28], 2007 Free carnitine Before VPA mmol/L 46.5 ± 8.5 16 47.4 ± 11.7 9
After VPA 44.4 ± 11.2 41.1 ± 11.5
Castro-Gago et al. [29], 1998 Free carnitine Before VPA mmol/L 34.4 ± 8.5 17
After VPA 25.8 ± 6.1
Van Wouwe [43], 1995 Free carnitine Before VPA mmol/L 32.7 ± 7.3 13
After VPA 20.9 ± 5.2
Zelnik et al. [31], 1995 Free carnitine Before VPA mmol/L 37.6 ± 24.0 15
After VPA 29.1 ± 6.2
Riva et al. [32], 1993 Free carnitine Before VPA mmol/L 49.0 ± 17.0 22
After VPA 35.0 ± 13.0

Mean ± standard deviation (SD) of blood ammonia and free carnitine levels.

VPA, valproic acid.

Major characteristics of studies included for meta-correlational analysis

Author Variables Correlational coefficient Number
Yokoyama et al. [20], 2020 VPA, ammonia 0.149 Pearson 182
Duman et al. [44], 2019 VPA, ammonia 0.207 Pearson 94
Maldonado et al. [9], 2016 VPA, ammonia 0.683 Pearson 28
Günaydin et al. [45], 2014 VPA, ammonia 0.742 Spearman 26
Tseng et al. [46], 2014 VPA, ammonia 0.210 Pearson 158
Sharma et al. [47], 2011 VPA, ammonia 0.820 Spearman 63
Castro-Gago et al. [11], 2010 VPA, ammonia 0.449 Spearman 57
Moreno et al. [48], 2005 VPA, ammonia 0.272 Pearson 29
Verrotti et al. [13], 1999 VPA, ammonia 0.410 Pearson 60
Altunbaşak et al. [15], 1997 VPA, ammonia 0.458 Pearson 68
Patsalos et al. [49], 1993 VPA, ammonia 0.080 Pearson 82
Kondo et al. [50], 1992 VPA, ammonia −0.233 Spearman 53
Kugoh et al. [19], 1986 VPA, ammonia 0.570 Pearson 53
Laub [51], 1986 VPA, ammonia −0.362 Pearson 10
Haidukewych et al. [22], 1985 VPA, ammonia 0.249 Pearson 125
Williams et al. [52], 1984 VPA, ammonia 0.054 Pearson 10
Yokoyama et al. [20], 2020 VPA, free carnitine −0.194 Pearson 182
Maldonado et al. [9], 2016 VPA, free carnitine −0.616 Pearson 28
Anil et al. [26], 2009 VPA, free carnitine 0.180 Pearson 50
Moreno et al. [48], 2005 VPA, free carnitine −0.301 Pearson 29
Hirose et al. [14], 1998 VPA, free carnitine −0.410 Pearson 45
Morita et al. [39], 1986 VPA, free carnitine −0.421 Pearson 12
Laub [51], 1986 VPA, free carnitine 0.097 Pearson 21
Yokoyama et al. [20], 2020 Ammonia, free carnitine −0.097 Pearson 182
Okumura et al. [4], 2019 Ammonia, free carnitine −0.392 Pearson 49
Ando et al. [53], 2017 Ammonia, free carnitine 0.020 Pearson 37
Nakajima et al. [7], 2011 Ammonia, free carnitine −0.546 Spearman 51
Hamed and Abdella [6], 2009 Ammonia, free carnitine −0.935 Pearson 60
Goto et al. [54], 2008 Ammonia, free carnitine −0.420 Pearson 60
Laub [51], 1986 Ammonia, free carnitine 0.013 Pearson 21

VPA, valproic acid.

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