Int J Psychiatry Clin Pract 2014; 18: 288–292. © 2014 Informa Healthcare ISSN 1365-1501 print/ISSN 1471-1788 online. DOI: 10.3109/13651501.2014.941879
ORIGINAL ARTICLE
Effect of valproate on the plasma concentrations of aripiprazole in bipolar patients
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Gul Eryilmaz1, Gökben Hizli Sayar1, Eylem Özten1, Işil Göğcegöz Gül1, Oğuz Karamustafalioğlu1 & Özgür Yorbik2 1
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2
Department of Psychiatry, Neuropsychiatry Istanbul Hospital, Uskudar University, Istanbul, Turkey and Department of Psychiatry, Maltepe University, Istanbul, Turkey
Abstract Objective. There is very limited documentation available on the effects of valproate co-medication on the pharmacokinetics of aripiprazole in a naturalistic setting. The aim of the present study was to investigate the effect of co-medication with valproate on serum concentrations of aripiprazole in bipolar disorder patients in a clinical setting. Method. Plasma samples of bipolar disorder patients (n ⫽ 69) on a stable dose of aripiprazole 20 mg/day were analyzed by a liquid chromatography-mass spectrometry method in a routine therapeutic drug monitoring setting. Therapeutic drug monitoring was done for the entire study group before and after valproate co-administration. Results. We observed a statistically significant difference between the aripiprazole monotherapy and aripiprazole-valproate combination with respect to total aripiprazole plasma levels (p ⬍ 0.01). However, no statistically significant differences were noted in aripiprazole levels between the first week and the second week of valproate co-administration. Conclusion. In conclusion, concurrent treatment with valproate resulted in changes in the total aripiprazole plasma levels by 23%. But a lower total aripiprazole concentration during co-medication with valproate, caused by protein binding displacement, is reported being clinically insignificant in previous studies. The results from these studies are important in order to clarify clinical safety and efficacy. Key words: Aripiprazole, drug interaction, valproate (Received 17 February 2014; accepted 2 July 2014)
Objectives Bipolar disorder is a chronic disease that is characterized by recurrent episodes of mania, depression, or mixed symptoms. Bipolar disorder has a prevalence of approximately 2–4% in the general population and is associated with a substantial burden in terms of morbidity and mortality. Mania is one of the most difficult to treat manifestations of bipolar disorder and antipsychotic drugs play a significant therapeutic role in this respect (De Fazio et al. 2010). Evidence-based guidelines for the treatment of bipolar disorder provided by the British Association for Psychopharmacology recommend that for severe manic or mixed episodes, an oral antipsychotic or valproate should be initiated because of its rapid antimanic effect. The guideline also suggests that, the atypical antipsychotics should be considered because of “their generally more favorable short term adverse effect profile, especially in relation to motor side effects and the evidence of their efficacy as anti-manic agents.”(Goodwin and Consensus Group of the British Association for Psychopharmacology 2009). Aripiprazole, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines (Vacheron-Trystram et al. 2004). Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and Correspondence: Gül Eryılmaz, Department of Psychiatry, Neuropsychiatry Istanbul Hospital, Uskudar University, Alemdag Cad. Siteyolu sk No: 27 Umraniye, Istanbul 34768, Turkey. Tel: ⫹ 902166330633. Fax: ⫹ 902166341250. E-mail: [email protected]
unipolar depression (Tadori et al. 2008). It has a half-life of 72 hours and reaches a stable plasma level in 14 days (Hiemke et al. 2011). Aripiprazole is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems (DeLeon et al. 2004). Adjustment of the aripiprazole dose does not appear to be required according to age, gender, race, and smoking or in populations with hepatic or renal impairment (Mallikaarjun et al. 2008). The novel mechanism of action of aripiprazole that combines D2- and 5-HT1A-receptor partial agonist activity with 5-HT2A-receptor antagonist actions provide broad therapeutic use beyond schizophrenia for the treatment of affective disorders, such as acute bipolar mania (Stark et al. 2006; McKeage 2014). Recent research on aripiprazole in bipolar disorder, concluded that aripiprazole is clinically effective in managing acute mania (Tang et al. 2010), bipolar disorder depressive episode (Thase et al. 2012) and in preventing relapse (Fountoulakis and Vieta 2009). Valproate has been in clinical use for almost 40 years for the treatment of a variety of neuropsychiatric illnesses, including bipolar disorder. Valproate is about 90% bound to plasma proteins, and the level of binding decreases with increasing drug concentration. Valproate is metabolized mainly by glucuronidation and oxidation in the liver and at a rate of 10% by CYP2C9 and CYP2A6 enzyme systems (Ghodke-Puranik et al. 2013). The elimination half-life is 9–18 h. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase the plasma concentrations of certain coadministered drugs by this mechanism, including phenobarbital and lamotrigine (Perucca 2002). Survival analysis
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DOI: 10.3109/13651501.2014.941879
results suggest a possible serum concentration target range of clinicians in providing optimal treatment response (Keck et al. 2005). Since its approval, aripiprazole has become a popular choice among clinicians in the maintenance treatment of bipolar disorder as monotherapy or in combination with mood stabilizers (McIntyre et al. 2011). When used in combination with valproate, aripiprazole was reported to be effective in the treatment of, especially, patients with bipolar disorder; it became an option in treatment-resistant cases (Vieta et al. 2008, 2010). As it is commonly used with mood stabilizers in the combination therapies, studies investigating drug interaction have been increasing in recent years. In their placebocontrolled study, Vieta et al. reported that when aripiprazole was added to valproate or lithium treatment, patients with bipolar disorder showed clinical improvement (Vieta et al. 2008). As reported by the manufacturer, drug interactions with aripiprazole have been observed with the co-administration of carbamazepine, ketoconazole, or quinidine but no drug interactions requiring dose adjustments were reported with valproate (Monkul and Akdede 2005). However, in a study it was reported that co-administration with valproate decreased the AUC (area under the curve) and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite (Citrome et al. 2005). The aim of this open study is to investigate the effect of valproate on aripiprazole plasma levels in patients receiving aripiprazole and valproate treatment simultaneously. Methods Medical files of 148 patients who were diagnosed with bipolar disorder in Uskudar University Health Practice and Research Centers between December 2010 and February 2013 and who received aripiprazole and valproate treatment simultaneously were examined in details retrospectively. In the research center hospital, drug plasma level monitoring on a weekly basis for the drug dose adjustment of all inpatients is a routine of clinical practice. Patients with hepatic or renal failure, whose treatment protocol was changed during treatment, receiving other medications such as carbamazepine, which may affect the plasma levels of aripiprazole, and patients on a treatment regimen of aripiprazole other than 20 mg/day doses were excluded. The study was performed with 69 patients presented with a manic episode based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria by a psychiatrist, and received 20 mg/day aripiprazole during the first 3 weeks of treatment, and 750–1500 mg/day valproate was added at the end of 3rd week of treatment. Reason for the treatment regimen of aripiprazole monotherapy only for the first three weeks and then co-administration of valproate is the electroconvulsive treatment (ECT) administration during the first 3 weeks. American Psychiatric Association Committee on Electroconvulsive Therapy recommends in its guidelines discontinuing administration of anticonvulsants during ECT (Jaffe 2002). During the aripiprazole 20 mg/day oral drug treatment, plasma levels of aripiprazole on the 7th and 14th days were measured. On the 21st day of the treatment, 750–1500 mg/day
Effect of valproate on aripiprazole concentrations 289 valproate was co-administered as an add-on treatment, and patients’ aripiprazole and valproate plasma levels were reassessed on the 28th and 35th day. Aripiprazole plasma levels of patients, before and after the addition of valproate, were compared statistically. In therapeutic drug monitoring (TDM), the sum of the parent drug and active metabolite is monitored. Dehydroaripiprazole, the active metabolite of aripiprazole, has similar D2 receptor activity as the parent drug and represents approximately 40% of the plasma aripiprazole concentration at steady state (Waade et al. 2009). Blood sampling With the object to measure plasma levels of aripiprazole and valproate, 5cc venous blood samples were taken into EDTA Vacutainer tubes 12 h after the last dose. The blood samples were processed immediately by centrifugation. Patient’s samples were stored at –70°C immediately after centrifuging. Plasma samples were withdrawn from freezer maintained at ⫺ 70°C and allowed to thaw at room temperature for 30–45 min. High Performance Liquid chromatography with Tandem Mass Spectrometry (HPLC/MS) analysis was administered. Statistical analysis In comparison of aripiprazole plasma levels before and after addition of valproate, Paired Samples Test was used. In the evaluation of all data, the statistical significance was designed as p ⬍ 0.05 confidence interval. Results The study sample consisted of 69 patients, of which 24 are (34. 8%) male and 45 are (65.2%) female patients. The mean age of the group was 32.08 ⫹/⫺ 11.4. The mean age at onset of illness was 22.3 (SD ⫽ 12.7, range ⫽ 14–52), the mean duration of illness was 10.6 years (SD ⫽ 7.2) and the mean number of mood episodes was 8.7. According to DSM-IV diagnostic criteria, 8 of 69 patients (5.5%) suffered from rapid cycling bipolar disorder. Six of the patients also had a secondary diagnosis of panic disorder, 7 had obsessive compulsive disorder, 2 had mental retardation, and 11 of 69 patients (7.6%) had a diagnosis of substance abuse or substance addiction as a comorbid condition. On the 21st day of treatment, with the end of ECT sessions, valproate was added to treatment of patients as a mood stabilizer for bipolar disorder maintenance treatment. Daily valproate dose was ranged from 750 mg/day to 1500 mg/day for all patients. Valproate plasma levels on the 28th day and 35th day of treatment (at the end of 1st week and 2nd week of valproate treatment) were 37.8 μg/ml and 56.7 μg/ml, respectively. There was no correlation between plasma concentration of valproic acid and percent change in plasma aripiprazole levels (the Spearman rank correlation coefficient (rs) ⫽ 0.68, not significant). The results of aripiprazole plasma level monitoring according to weeks of treatment are shown in Figure 1. There was a statistically significant difference between aripiprazole plasma levels measured on the 7th and 14th days of aripiprazole (195.97 ⫾ 83.44 ng/ml and
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Figure 1. The effect of co-administration of valproate on total aripiprazole plasma levels.
254.88 ⫾ 133.65 ng/ml, p ⬍ 0.05), but after the 2nd week, aripiprazole plasma level was stabilized and remained almost same on the 3rd week. After addition of valproate at the end of the third week, aripiprazole plasma level decreased significantly compared to the previous week. (254.88 ⫾ 133.65 ng/ ml and 204.66 ng/ml, p ⬍ 0.05). The significant difference of aripiprazole plasma levels before and after addition of valproate continued also on the 5th week of treatment (on the 2nd week of valproate treatment). Discussion Antipsychotics, including aripiprazole are often coadministered with valproate in patients with bipolar disorder (Sayyaparaju et al. 2014; Kanba et al. 2014; Frye et al. 2000). Woo et al. investigated the safety and efficacy of aripiprazole and divalproex combination in preventing relapse of a mood episode in manic or mixed episode patients (Woo et al. 2011). Their results suggest that relapse of a mood episode occurred fewer and later for aripiprazole with divalproex treatment than divalproex monotherapy, but the differences were not statistically significant. As valproate-aripiprazole co-administration is not so unusual in clinical practice, this study was carried out to assess the impact of valproate on the plasma concentrations of aripiprazole in patients with bipolar disorder. The results suggest that valproate co-administration with aripiprazole cause a significant reduction in total aripiprazole plasma levels. As far as we know, there are no other studies investigating the relation between aripiprazole and valproate on bipolar disorder patient group. These results are consistent with some previous studies performed in other psychiatric diseases. Citrome et al. reported co-administration with valproate decreased the AUC of aripiprazole by 24% with minimal effects on the active metabolite (Citrome et al. 2005). Castberg et al. compared the serum concentrations of aripiprazole during monotherapy with the concentrations found during concomitant therapy with other drugs. They reported that subjects co-medicated with valproate had lower aripiprazole concentrations, while subjects co-medicated with lamotrigine, citalopram/escitalopram and lithium had higher concentrations than the subjects in the monotherapy group (Castberg and Spigset 2007). However, their study does not include diagnosis and medication dosages and further, they reported that this decline was found by comparing with another control group receiving aripiprazole monotherapy. But in another study, Waade et al. reported
that there was no apparent effect on the pharmacokinetics of aripiprazole in patients receiving aripiprazole and valproate (Waade et al. 2009). This is in contrast to the previous studies (Citrome et al. 2005; Castberg and Spigset 2007), while our research result showed approximately 23% reduction of aripiprazole plasma level after addition of valproate. This discrepancy may be due to differences in the study design, such as measurement of single samples versus area under the concentration curve (AUC), differences in the number of subjects included (n ⫽ 15 in Waade et al., n ⫽ 6 in Citrome et al., n ⫽ 9 in Castberg et al. and n ⫽ 69 in our study). Contradictory findings between studies may also be due to differences of aripiprazole doses. Daily aripiprazole dosage in the study performed by Citrome et al. was 30 mg (Citrome et al. 2005), while it was 20 mg in our study, but it has a mean of 15 mg/day in Waade study (Waade et al. 2009). In previous studies investigating valproate’s effect on aripiprazole plasma levels, studies other than Citrome et al. did not report statistical analysis with repeated measurements in the same patients. They formed a control group consisting of other patients. However, differences in the distribution of CYP2D6 genotype among the subjects complicate the interpretation of study results. In this study, repeated measurements increase the reliability. We did not observe any differences between the body mass indexes of male and female patients. Also, there was not any significant difference between the aripiprazole plasma levels of male and female bipolar patients. Cmax and AUC of aripiprazole and its active metabolite, are reported to be 30–40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight. No dosage adjustment is recommended based on gender. The mechanism of valproate’s effect of reducing plasma levels of aripiprazole is not known precisely. There are no data that valproate affects the CYP2D6 or CYP3A4 enzyme activity which is essential in the metabolism of aripiprazole (Rado and Janicak 2010). When drugs with high affinity to plasma proteins are used in conjunction, drugs compete for binding to plasma proteins. The free part of the drug with lower affinity to plasma proteins increases. Since free drug can easily be removed by renal way, total plasma level of the low affinity protein bounder drug decreases (DeLeon et al. 2004; Marcus et al. 2011). As valproate and aripiprazole share the same plasma protein-binding site II, valproate co-administered with aripiprazole may displace bound aripiprazole. The increase in the free fraction of aripiprazole may lead to increased oral clearance and a decrease in plasma concentrations of total drug, with no change in unbound plasma drug concentrations. The decrease in the steady-state total aripiprazole values after co-administration of valproate, observed in this study, is consistent with this hypothesis. Citrome et al. reported that although total aripiprazole levels decrease with co-administration of valproate, relatively minor changes in the pharmacokinetics of aripiprazole and its active metabolite are observed. According to FDA guidelines pharmacogenetic interaction of valproate and aripiprazole is low and dose adjust-
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DOI: 10.3109/13651501.2014.941879
ment and monitoring not recommended (Product Information 2002). Many patients with bipolar disorder use multiple drugs. Besides the benefits of multiple drug usage, it increases the risk in terms of drug interactions and side effects. Arbeitsgemeinschaft fur europsychopharmakologie und Pharmakopsychiatrie (AGNP) 2011 suggested that TDM might be useful in multiple drug usage, dosage adjustment, and in reducing drug interactions. In the AGNP–TDM guide, assessment of aripiprazole and valproate plasma levels is recommended on the second level (Hiemke et al. 2011). This study showed a 23% reduction in total aripiprazole plasma levels at about 7 days after co-administration of valproate. No untoward effects were seen in aripiprazolevalproate combination group. The number of subjects of this study is higher than previous studies, the group is more homogeneous, and results have been achieved with repeated measures on the same subjects. However, this study’s results should be carefully evaluated. Aripiprazole is transformed in the liver through CYP 3A4 and 2D6 to its active metabolites aripiprazole and dehydroaripiprazole but in this study only the level of total aripiprazole measured. This is the main limitation of the study. TDM enables rational dose adjustments to manage side effects or therapeutic failure. When drug and metabolite display similar pharmacological activity, the reference interval is usually based on the concentration sum of both agents (Baumann et al. 2005). Molden et al. reported that a significant proportion of absolute concentrations versus dose was found both for aripiprazole and the sum of aripiprazole and dehydroaripiprazole with a similar median metabolic ratio of dehydroaripiprazole/aripiprazole across all doses (approximately 0.35–0.4) (Molden et al. 2006). Further, larger prospective studies are needed to establish the impact of aripiprazole and valproate combination on the active metabolite, dehydroaripiprazole. Conclusion Aripiprazole, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines. Our findings suggest that steady-state total aripiprazole plasma levels decrease by 23% after coadministration of valproate, but a lower total aripiprazole concentration during co-medication with valproate, caused by protein binding displacement, is reported being clinically insignificant in previous studies. The results from these studies are important in order to interpret clinical safety and efficacy. Key points • • •
Steady-state total aripiprazole plasma levels decreased by 23% after co-administration of valproate. There are no data available that valproate affects the CYP2D6 or CYP3A4 enzyme activity which is essential in the metabolism of aripiprazole. Protein binding displacement causes a decline of total aripiprazole concentration during communication with valproate.
Effect of valproate on aripiprazole concentrations 291 Acknowledgement The authors would like to thank Prof. (Dr.) Nevzat Tarhan for his support and Selma Özilhan for her assistance with this project. Statement of interest None of the authors reports conflicts of interest. References Baumann P, Ulrich S, Eckermann G, Gerlach M, Kuss HJ, Laux G, et al. 2005. The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants. Dialogues Clin Neurosci 7:231–247. Castberg I, Spigset O. 2007. Effects of comedication on the serum levels of aripiprazole: evidence from a routine therapeutic drug monitoring service. Pharmacopsychiatry 40:107–110. Citrome L, Josiassen R, Bark N, Salazar DE, Mallikaarjun S. 2005. Pharmacokinetics of aripiprazole and concomitant lithium and valproate. J Clin Pharmacol 45:89–93. De Fazio P, Girardi P, Maina G, Mauri MC, Mauri M, Monteleone P, et al. 2010. Aripiprazole in acute mania and long-term treatment of bipolar disorder: a critical review by an Italian working group. Clin Drug Investig 30:827–841. DeLeon A, Patel NC, Crismon ML. 2004. Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther 26:649–666. Fountoulakis KN, Vieta E. 2009. Efficacy and safety of aripiprazole in the treatment of bipolar disorder: a systematic review. Ann Gen Psychiatry 27:1–15. Frye MA, Ketter TA, Leverich GS, Huggins T, Lantz C, Denicoff KD, Post RM. 2000. The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry 61:9–15. Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. 2013. Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 23: 236–241. Goodwin GM, Consensus Group of the British Association for Psychopharmacology. 2009. Evidence-based guidelines for treating bipolar disorder: revised second edition–recommendations from the British Association for Psychopharmacology. J Psychopharmacol 23:346–388. Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, et al. 2011. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: Update 2011. Pharmacopsychiatry 44:195–235. Jaffe R. 2002. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association, 2nd ed. Am J Psychiatry 159:331. Kanba S, Kawasaki H, Ishigooka J, Sakamoto K, Kinoshita T, Kuroki T. 2014. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole for the treatment of acute manic or mixed episodes in Asian patients with bipolar I disorder (the AMAZE study). World J Biol Psychiatry 15:113–121. Keck PE, Bowden CL, Meinhold JM, Gyulai L, Prihoda TJ, Baker JD, et al. 2005. Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy. Int J Psychiatry in Clin Pract 9:271–277. Mallikaarjun S, Shoaf SE, Boulton DW, Bramer SL. 2008. Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole. Clin Pharmacokinet 47:533–542. McIntyre RS, Yoon J, Jerrell JM, Liauw SS. 2011. Aripiprazole for the maintenance treatment of bipolar disorder: a review of available evidence. Neuropsychiatr Dis Treat 7:319–323. McKeage K. 2014. Aripiprazole: a review of its use in the treatment of manic episodes in adolescents with bipolar I disorder. CNS Drugs 28:171–183.
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Tang Ching-Shu, Yeh Chin-Bin, Huang Yu-Shu, Wang Liang-Jen, Chou Wen-Jiun, Chou Miao-Chun, Chen Chih-Ken et al. 2010. Long-term effectiveness of aripiprazole in adolescents and young adults with bipolar disorder: A naturalistic study. Int J Psychiatry Clin Pract 14:252–256. Thase ME, Bowden CL, Nashat M, Eudicone JM, Marcus R, McQuade RD, et al. 2012. Aripiprazole in bipolar depression: a pooled, post-hoc analysis by severity of core depressive symptoms. Int J Psychiatry Clin Pract 16:121–131. Vacheron-Trystram MN, Braitman A, Cheref S, Auffray L. 2004. Antipsychotics in bipolar disorders. Encephale 30:417–424. Vieta E, T’joen C, McQuade RD, Carson WH, Marcus RN, Sanchez R, et al. 2008. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: A placebo-controlled study. Am J Psychiatry 165:1316–1325. Vieta E, Owen R, Baudelet C, McQuade R.D, Sanchez R, Marcus R.N. 2010. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study. Curr Med Res Opin 26:1485–1496. Waade RB, Christensen H, Rudberg I, Refsum H, Hermann M. 2009. Influence of comedication on serum concentrations of aripiprazole and dehydroaripiprazole. Ther Drug Monit 31: 233–238. Woo YS, Bahk WM, Chung MY, Kim DH, Yoon BH, Lee JH, et al. 2011. Aripiprazole plus divalproex for recently manic or mixed patients with bipolar I disorder: a 6-month, randomized, placebocontrolled, double-blind maintenance trial. Hum Psychopharmacol 26:543–553.
ORIGINAL ARTICLE
Effect of valproate on the plasma concentrations of aripiprazole in bipolar patients
informahealthcare.com/ijpcp
Gul Eryilmaz1, Gökben Hizli Sayar1, Eylem Özten1, Işil Göğcegöz Gül1, Oğuz Karamustafalioğlu1 & Özgür Yorbik2 1
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2
Department of Psychiatry, Neuropsychiatry Istanbul Hospital, Uskudar University, Istanbul, Turkey and Department of Psychiatry, Maltepe University, Istanbul, Turkey
Abstract Objective. There is very limited documentation available on the effects of valproate co-medication on the pharmacokinetics of aripiprazole in a naturalistic setting. The aim of the present study was to investigate the effect of co-medication with valproate on serum concentrations of aripiprazole in bipolar disorder patients in a clinical setting. Method. Plasma samples of bipolar disorder patients (n ⫽ 69) on a stable dose of aripiprazole 20 mg/day were analyzed by a liquid chromatography-mass spectrometry method in a routine therapeutic drug monitoring setting. Therapeutic drug monitoring was done for the entire study group before and after valproate co-administration. Results. We observed a statistically significant difference between the aripiprazole monotherapy and aripiprazole-valproate combination with respect to total aripiprazole plasma levels (p ⬍ 0.01). However, no statistically significant differences were noted in aripiprazole levels between the first week and the second week of valproate co-administration. Conclusion. In conclusion, concurrent treatment with valproate resulted in changes in the total aripiprazole plasma levels by 23%. But a lower total aripiprazole concentration during co-medication with valproate, caused by protein binding displacement, is reported being clinically insignificant in previous studies. The results from these studies are important in order to clarify clinical safety and efficacy. Key words: Aripiprazole, drug interaction, valproate (Received 17 February 2014; accepted 2 July 2014)
Objectives Bipolar disorder is a chronic disease that is characterized by recurrent episodes of mania, depression, or mixed symptoms. Bipolar disorder has a prevalence of approximately 2–4% in the general population and is associated with a substantial burden in terms of morbidity and mortality. Mania is one of the most difficult to treat manifestations of bipolar disorder and antipsychotic drugs play a significant therapeutic role in this respect (De Fazio et al. 2010). Evidence-based guidelines for the treatment of bipolar disorder provided by the British Association for Psychopharmacology recommend that for severe manic or mixed episodes, an oral antipsychotic or valproate should be initiated because of its rapid antimanic effect. The guideline also suggests that, the atypical antipsychotics should be considered because of “their generally more favorable short term adverse effect profile, especially in relation to motor side effects and the evidence of their efficacy as anti-manic agents.”(Goodwin and Consensus Group of the British Association for Psychopharmacology 2009). Aripiprazole, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines (Vacheron-Trystram et al. 2004). Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and Correspondence: Gül Eryılmaz, Department of Psychiatry, Neuropsychiatry Istanbul Hospital, Uskudar University, Alemdag Cad. Siteyolu sk No: 27 Umraniye, Istanbul 34768, Turkey. Tel: ⫹ 902166330633. Fax: ⫹ 902166341250. E-mail: [email protected]
unipolar depression (Tadori et al. 2008). It has a half-life of 72 hours and reaches a stable plasma level in 14 days (Hiemke et al. 2011). Aripiprazole is metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems (DeLeon et al. 2004). Adjustment of the aripiprazole dose does not appear to be required according to age, gender, race, and smoking or in populations with hepatic or renal impairment (Mallikaarjun et al. 2008). The novel mechanism of action of aripiprazole that combines D2- and 5-HT1A-receptor partial agonist activity with 5-HT2A-receptor antagonist actions provide broad therapeutic use beyond schizophrenia for the treatment of affective disorders, such as acute bipolar mania (Stark et al. 2006; McKeage 2014). Recent research on aripiprazole in bipolar disorder, concluded that aripiprazole is clinically effective in managing acute mania (Tang et al. 2010), bipolar disorder depressive episode (Thase et al. 2012) and in preventing relapse (Fountoulakis and Vieta 2009). Valproate has been in clinical use for almost 40 years for the treatment of a variety of neuropsychiatric illnesses, including bipolar disorder. Valproate is about 90% bound to plasma proteins, and the level of binding decreases with increasing drug concentration. Valproate is metabolized mainly by glucuronidation and oxidation in the liver and at a rate of 10% by CYP2C9 and CYP2A6 enzyme systems (Ghodke-Puranik et al. 2013). The elimination half-life is 9–18 h. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase the plasma concentrations of certain coadministered drugs by this mechanism, including phenobarbital and lamotrigine (Perucca 2002). Survival analysis
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results suggest a possible serum concentration target range of clinicians in providing optimal treatment response (Keck et al. 2005). Since its approval, aripiprazole has become a popular choice among clinicians in the maintenance treatment of bipolar disorder as monotherapy or in combination with mood stabilizers (McIntyre et al. 2011). When used in combination with valproate, aripiprazole was reported to be effective in the treatment of, especially, patients with bipolar disorder; it became an option in treatment-resistant cases (Vieta et al. 2008, 2010). As it is commonly used with mood stabilizers in the combination therapies, studies investigating drug interaction have been increasing in recent years. In their placebocontrolled study, Vieta et al. reported that when aripiprazole was added to valproate or lithium treatment, patients with bipolar disorder showed clinical improvement (Vieta et al. 2008). As reported by the manufacturer, drug interactions with aripiprazole have been observed with the co-administration of carbamazepine, ketoconazole, or quinidine but no drug interactions requiring dose adjustments were reported with valproate (Monkul and Akdede 2005). However, in a study it was reported that co-administration with valproate decreased the AUC (area under the curve) and Cmax of aripiprazole by 24% and 26%, respectively, with minimal effects on the active metabolite (Citrome et al. 2005). The aim of this open study is to investigate the effect of valproate on aripiprazole plasma levels in patients receiving aripiprazole and valproate treatment simultaneously. Methods Medical files of 148 patients who were diagnosed with bipolar disorder in Uskudar University Health Practice and Research Centers between December 2010 and February 2013 and who received aripiprazole and valproate treatment simultaneously were examined in details retrospectively. In the research center hospital, drug plasma level monitoring on a weekly basis for the drug dose adjustment of all inpatients is a routine of clinical practice. Patients with hepatic or renal failure, whose treatment protocol was changed during treatment, receiving other medications such as carbamazepine, which may affect the plasma levels of aripiprazole, and patients on a treatment regimen of aripiprazole other than 20 mg/day doses were excluded. The study was performed with 69 patients presented with a manic episode based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria by a psychiatrist, and received 20 mg/day aripiprazole during the first 3 weeks of treatment, and 750–1500 mg/day valproate was added at the end of 3rd week of treatment. Reason for the treatment regimen of aripiprazole monotherapy only for the first three weeks and then co-administration of valproate is the electroconvulsive treatment (ECT) administration during the first 3 weeks. American Psychiatric Association Committee on Electroconvulsive Therapy recommends in its guidelines discontinuing administration of anticonvulsants during ECT (Jaffe 2002). During the aripiprazole 20 mg/day oral drug treatment, plasma levels of aripiprazole on the 7th and 14th days were measured. On the 21st day of the treatment, 750–1500 mg/day
Effect of valproate on aripiprazole concentrations 289 valproate was co-administered as an add-on treatment, and patients’ aripiprazole and valproate plasma levels were reassessed on the 28th and 35th day. Aripiprazole plasma levels of patients, before and after the addition of valproate, were compared statistically. In therapeutic drug monitoring (TDM), the sum of the parent drug and active metabolite is monitored. Dehydroaripiprazole, the active metabolite of aripiprazole, has similar D2 receptor activity as the parent drug and represents approximately 40% of the plasma aripiprazole concentration at steady state (Waade et al. 2009). Blood sampling With the object to measure plasma levels of aripiprazole and valproate, 5cc venous blood samples were taken into EDTA Vacutainer tubes 12 h after the last dose. The blood samples were processed immediately by centrifugation. Patient’s samples were stored at –70°C immediately after centrifuging. Plasma samples were withdrawn from freezer maintained at ⫺ 70°C and allowed to thaw at room temperature for 30–45 min. High Performance Liquid chromatography with Tandem Mass Spectrometry (HPLC/MS) analysis was administered. Statistical analysis In comparison of aripiprazole plasma levels before and after addition of valproate, Paired Samples Test was used. In the evaluation of all data, the statistical significance was designed as p ⬍ 0.05 confidence interval. Results The study sample consisted of 69 patients, of which 24 are (34. 8%) male and 45 are (65.2%) female patients. The mean age of the group was 32.08 ⫹/⫺ 11.4. The mean age at onset of illness was 22.3 (SD ⫽ 12.7, range ⫽ 14–52), the mean duration of illness was 10.6 years (SD ⫽ 7.2) and the mean number of mood episodes was 8.7. According to DSM-IV diagnostic criteria, 8 of 69 patients (5.5%) suffered from rapid cycling bipolar disorder. Six of the patients also had a secondary diagnosis of panic disorder, 7 had obsessive compulsive disorder, 2 had mental retardation, and 11 of 69 patients (7.6%) had a diagnosis of substance abuse or substance addiction as a comorbid condition. On the 21st day of treatment, with the end of ECT sessions, valproate was added to treatment of patients as a mood stabilizer for bipolar disorder maintenance treatment. Daily valproate dose was ranged from 750 mg/day to 1500 mg/day for all patients. Valproate plasma levels on the 28th day and 35th day of treatment (at the end of 1st week and 2nd week of valproate treatment) were 37.8 μg/ml and 56.7 μg/ml, respectively. There was no correlation between plasma concentration of valproic acid and percent change in plasma aripiprazole levels (the Spearman rank correlation coefficient (rs) ⫽ 0.68, not significant). The results of aripiprazole plasma level monitoring according to weeks of treatment are shown in Figure 1. There was a statistically significant difference between aripiprazole plasma levels measured on the 7th and 14th days of aripiprazole (195.97 ⫾ 83.44 ng/ml and
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Figure 1. The effect of co-administration of valproate on total aripiprazole plasma levels.
254.88 ⫾ 133.65 ng/ml, p ⬍ 0.05), but after the 2nd week, aripiprazole plasma level was stabilized and remained almost same on the 3rd week. After addition of valproate at the end of the third week, aripiprazole plasma level decreased significantly compared to the previous week. (254.88 ⫾ 133.65 ng/ ml and 204.66 ng/ml, p ⬍ 0.05). The significant difference of aripiprazole plasma levels before and after addition of valproate continued also on the 5th week of treatment (on the 2nd week of valproate treatment). Discussion Antipsychotics, including aripiprazole are often coadministered with valproate in patients with bipolar disorder (Sayyaparaju et al. 2014; Kanba et al. 2014; Frye et al. 2000). Woo et al. investigated the safety and efficacy of aripiprazole and divalproex combination in preventing relapse of a mood episode in manic or mixed episode patients (Woo et al. 2011). Their results suggest that relapse of a mood episode occurred fewer and later for aripiprazole with divalproex treatment than divalproex monotherapy, but the differences were not statistically significant. As valproate-aripiprazole co-administration is not so unusual in clinical practice, this study was carried out to assess the impact of valproate on the plasma concentrations of aripiprazole in patients with bipolar disorder. The results suggest that valproate co-administration with aripiprazole cause a significant reduction in total aripiprazole plasma levels. As far as we know, there are no other studies investigating the relation between aripiprazole and valproate on bipolar disorder patient group. These results are consistent with some previous studies performed in other psychiatric diseases. Citrome et al. reported co-administration with valproate decreased the AUC of aripiprazole by 24% with minimal effects on the active metabolite (Citrome et al. 2005). Castberg et al. compared the serum concentrations of aripiprazole during monotherapy with the concentrations found during concomitant therapy with other drugs. They reported that subjects co-medicated with valproate had lower aripiprazole concentrations, while subjects co-medicated with lamotrigine, citalopram/escitalopram and lithium had higher concentrations than the subjects in the monotherapy group (Castberg and Spigset 2007). However, their study does not include diagnosis and medication dosages and further, they reported that this decline was found by comparing with another control group receiving aripiprazole monotherapy. But in another study, Waade et al. reported
that there was no apparent effect on the pharmacokinetics of aripiprazole in patients receiving aripiprazole and valproate (Waade et al. 2009). This is in contrast to the previous studies (Citrome et al. 2005; Castberg and Spigset 2007), while our research result showed approximately 23% reduction of aripiprazole plasma level after addition of valproate. This discrepancy may be due to differences in the study design, such as measurement of single samples versus area under the concentration curve (AUC), differences in the number of subjects included (n ⫽ 15 in Waade et al., n ⫽ 6 in Citrome et al., n ⫽ 9 in Castberg et al. and n ⫽ 69 in our study). Contradictory findings between studies may also be due to differences of aripiprazole doses. Daily aripiprazole dosage in the study performed by Citrome et al. was 30 mg (Citrome et al. 2005), while it was 20 mg in our study, but it has a mean of 15 mg/day in Waade study (Waade et al. 2009). In previous studies investigating valproate’s effect on aripiprazole plasma levels, studies other than Citrome et al. did not report statistical analysis with repeated measurements in the same patients. They formed a control group consisting of other patients. However, differences in the distribution of CYP2D6 genotype among the subjects complicate the interpretation of study results. In this study, repeated measurements increase the reliability. We did not observe any differences between the body mass indexes of male and female patients. Also, there was not any significant difference between the aripiprazole plasma levels of male and female bipolar patients. Cmax and AUC of aripiprazole and its active metabolite, are reported to be 30–40% higher in women than in men, and correspondingly, the apparent oral clearance of aripiprazole is lower in women. These differences, however, are largely explained by differences in body weight. No dosage adjustment is recommended based on gender. The mechanism of valproate’s effect of reducing plasma levels of aripiprazole is not known precisely. There are no data that valproate affects the CYP2D6 or CYP3A4 enzyme activity which is essential in the metabolism of aripiprazole (Rado and Janicak 2010). When drugs with high affinity to plasma proteins are used in conjunction, drugs compete for binding to plasma proteins. The free part of the drug with lower affinity to plasma proteins increases. Since free drug can easily be removed by renal way, total plasma level of the low affinity protein bounder drug decreases (DeLeon et al. 2004; Marcus et al. 2011). As valproate and aripiprazole share the same plasma protein-binding site II, valproate co-administered with aripiprazole may displace bound aripiprazole. The increase in the free fraction of aripiprazole may lead to increased oral clearance and a decrease in plasma concentrations of total drug, with no change in unbound plasma drug concentrations. The decrease in the steady-state total aripiprazole values after co-administration of valproate, observed in this study, is consistent with this hypothesis. Citrome et al. reported that although total aripiprazole levels decrease with co-administration of valproate, relatively minor changes in the pharmacokinetics of aripiprazole and its active metabolite are observed. According to FDA guidelines pharmacogenetic interaction of valproate and aripiprazole is low and dose adjust-
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ment and monitoring not recommended (Product Information 2002). Many patients with bipolar disorder use multiple drugs. Besides the benefits of multiple drug usage, it increases the risk in terms of drug interactions and side effects. Arbeitsgemeinschaft fur europsychopharmakologie und Pharmakopsychiatrie (AGNP) 2011 suggested that TDM might be useful in multiple drug usage, dosage adjustment, and in reducing drug interactions. In the AGNP–TDM guide, assessment of aripiprazole and valproate plasma levels is recommended on the second level (Hiemke et al. 2011). This study showed a 23% reduction in total aripiprazole plasma levels at about 7 days after co-administration of valproate. No untoward effects were seen in aripiprazolevalproate combination group. The number of subjects of this study is higher than previous studies, the group is more homogeneous, and results have been achieved with repeated measures on the same subjects. However, this study’s results should be carefully evaluated. Aripiprazole is transformed in the liver through CYP 3A4 and 2D6 to its active metabolites aripiprazole and dehydroaripiprazole but in this study only the level of total aripiprazole measured. This is the main limitation of the study. TDM enables rational dose adjustments to manage side effects or therapeutic failure. When drug and metabolite display similar pharmacological activity, the reference interval is usually based on the concentration sum of both agents (Baumann et al. 2005). Molden et al. reported that a significant proportion of absolute concentrations versus dose was found both for aripiprazole and the sum of aripiprazole and dehydroaripiprazole with a similar median metabolic ratio of dehydroaripiprazole/aripiprazole across all doses (approximately 0.35–0.4) (Molden et al. 2006). Further, larger prospective studies are needed to establish the impact of aripiprazole and valproate combination on the active metabolite, dehydroaripiprazole. Conclusion Aripiprazole, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines. Our findings suggest that steady-state total aripiprazole plasma levels decrease by 23% after coadministration of valproate, but a lower total aripiprazole concentration during co-medication with valproate, caused by protein binding displacement, is reported being clinically insignificant in previous studies. The results from these studies are important in order to interpret clinical safety and efficacy. Key points • • •
Steady-state total aripiprazole plasma levels decreased by 23% after co-administration of valproate. There are no data available that valproate affects the CYP2D6 or CYP3A4 enzyme activity which is essential in the metabolism of aripiprazole. Protein binding displacement causes a decline of total aripiprazole concentration during communication with valproate.
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