International Journal of Psychiatry in Clinical Practice
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania R. Gregory Lande To cite this article: R. Gregory Lande (2004) Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania, International Journal of Psychiatry in Clinical Practice, 8:1, 37-40 To link to this article: http://dx.doi.org/10.1080/13651500310003336
Published online: 13 Sep 2010.
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Date: 13 October 2015, At: 07:05
# 2004 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2004
Volume 8
Pages 37 /40
37
Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania
Downloaded By: [informa internal users] At: 15:12 7 September 2010 Downloaded by [Universite Laval] at 07:05 13 October 2015
R. GREGORY LANDE
Correspondence Address R. Gregory Lande, D.O., 13826 Bison Court, Silver Spring, MD 20906, USA Tel: /(1) 803 7831015 E-mail: [email protected]
Received 1 April 2003; accepted for publication 3 September 2003
A twelve-week study examined the efficacy, safety, and tolerability of oxcarbazepine in the treatment of mania. Twenty male subjects, all of whom were stable on valproic acid, qualified for the study. The conversion from valproic acid to oxcarbazepine was completed over a three-week period. Scores from the BPRS, CGI and SATEE-GI were collected and analyzed. The results of the study supported the efficacy, safety, and tolerability of oxcarbazepine for the treatment of mania. Another potential advantage of oxcarbazepine is a metabolic pathway that may reduce drug interactions. (Int J Psych Clin Pract 2004; 8: 37 40) /
Keywords treatment oxcarbazepine
INTRODUCTION
T
he first medication approved for the treatment of bipolar disorder was lithium carbonate.1 The FDA granted approval in 1970, following a rather lengthy delay based on lingering toxicity concerns. As with many medications, the promise of a safe, effective treatment waned as failure rates and side effects with lithium developed. Tolerability, safety, and efficacy directly influenced medication compliance. This is particularly important when longterm treatment is necessary, as with bipolar disorder. The search for an alternative to lithium continues, with interest centered on a small group of medications. The cycling nature of bipolar disorder suggests a seizurelike etiology. Initial recipients of this interest were antiseizure medications, principally carbemazepine (CBZ) and valproic acid. Both have proven effectiveness in the treatment of acute mania and in longer-term mood stabilization.1 The FDA approved the use of valproic acid for the treatment of acute mania in 1995.1 Reports of fatal hepatotoxicity in young children delayed the initial approval. Anti-manic properties of valproic acid result from a blend of dosing, blood level monitoring, clinical response, and limitations imposed by side effects. Most individuals respond to doses between 1000 and 2500 mg and blood levels in the range of 50 /125 mg/ml. Side effects are generally mild and dose related, although weight gain may pose a special problem. The pharmacokinetics of valproic acid produces certain drug interactions. Valproic acid is hepatically metabolized and inhibits the P450 enzymes. In addition, valproic acid has an aggressive affinity for plasma proteins and may displace weaker competitors. The combination of hepatic induction and aggressive plasma binding creates an environ-
mania
ment for important drug interactions. For example, combining valproic acid with benzodiazepines, CBZ, or lamotrigine produces clinically significant drug interactions.1 Like valproic acid, the antimanic properties of CBZ result from a blend of dosing, blood level monitoring, clinical response, and limitations imposed by side effects. Side effects are dose related and include sedation, leucopenia, elevated liver function tests, rash, and rare instances of agranulocytosis.2 Carbemazepine is almost entirely metabolized by the liver. Regular dosing results in hepatic P450 enzyme induction. In addition, CBZ is rather weakly bound to plasma proteins and displaced by more aggressive compounds. The pharmacokinetics of CBZ can alter the metabolism of other drugs. Clinically significant alterations can result from combinations of CBZ with most tricyclic antidepressants, selective serotonin reuptake inhibitors, many antipsychotic medications, and birth control pills.2 Lithium, valproic acid, and CBZ lead a growing list of medications targeting bipolar disorder. Investigators are studying newer anti-seizure medications, such as lamotrigine and topiramate.3 All medications are eventually judged in terms of efficacy, safety, and reliability. The best balance produces maximum medication compliance. Oxcarbazepine (OXC) is an anti-seizure medication that may offer certain advantages in the long-term management of bipolar disorder. The interesting pharmacokinetics of OXC may suggest its use as an alternative to lithium, CBZ, or valproic acid in the long-term treatment of bipolar disorder.4 OXC is the keto-analogue of CBZ. The active metabolite of OXC is 10-monohydroxy derivative (MHD). A rapid conversion of OXC to MHD leaves little detectable OXC in the blood. Following oral ingestion, the active metabolite DOI: 10.1080/13651500310003336
Downloaded By: [informa internal users] At: 15:12 7 September 2010 Downloaded by [Universite Laval] at 07:05 13 October 2015
38
R Gregory Lande
MHD reaches peak levels in 4 /6 h and a half-life of 8 /10 h. A steady state occurs in 2 or 3 days. The absorption of OXC is not influenced by food.5 OXC produces minimal hepatic inhibition of the P450 enzymes. The one exception is the CP2C19 enzyme which can produce clinically relevant changes in phenobarbital, valproic acid, phentoin, and CBZ.6 Mild to moderate hepatic dysfunction does not require an OXC dose adjustment. Individuals with impaired renal clearance (creatinine clearance B/30 ml/min) do require OXC dose adjustments. An asymptomatic hyponatremia (B/125 mmol/l) may occur in 2.5% of cases, mostly in the first 3 months of treatment. The most common (/50%) adverse reactions associated with discontinuance included dizziness, diplopia, ataxia, vomiting, and nausea.2,7 Animal studies suggest that deaths from extremely high doses or interdrug reactions are rare. OXC may favorably impact lipid levels, particularly in comparison to P450 enzyme inhibitors like CBZ. Substitution of CBZ with OXC normalized RBC counts and g-glutamyl elevations.2 Medications that impact oxidative metabolism, such as erythromycin and verapamil, produce toxicity when combined with CBZ but not OXC.8 OXC does not interact with either warfarin or cimetidine.2,9 OXC does reduce the effectiveness of birth control pills.2 OXC may offer an attractive alternative for the treatment of bipolar disorder, particularly given a pharmacokinetic profile that apparently reduces drug interactions.10,11 In addition, a number of clinical studies have demonstrated the effectiveness of OXC in the treatment of acute mania.12 15 Clinical investigators in Germany reported some of the earliest positive results using OXC for the treatment of mania.13 Another possible advantage of OXC is the ability to make dose adjustments without concomitant blood level monitoring.16 Based on these collective reports, this clinical study was undertaken to explore the tolerability, safety, and efficacy of OXC in the maintenance treatment of bipolar disorder.
MATERIALS AND METHODS This study sought the participation of 20 male volunteers. General inclusion criteria included a clinical diagnosis of bipolar disorder and a minimum of 6 months treatment with valproic acid. Exclusion criteria included known hypersensitivity to OXC, CBZ, or hyponatremia. Women were excluded from the study following a risk /benefit analysis that considered the possibility of an unprotected sexual encounter and the potential teratogenetic effects of OXC. In addition, OXC reduces the effectiveness of any preexisting hormonal contraception. All participating volunteers provided written consent after receiving a verbal and written description of the study. This clinical investigation was approved by the South Carolina Department of Mental Health’s Institutional Review
Board and funded with an unrestricted educational grant from Novartis Pharmaceuticals. Subjects were successively recruited from a long-term impatient forensic unit. The conversion from valproic acid to OXC was completed over a 3-week period. OXC was initiated at 300 mg along with a corresponding reduction in valproic acid. Dose adjustments were completed once a week. Tolerability, safety, and efficacy of OXC was monitored using three instruments, the Clinical Global Impression Scale (CGI), the Systematic Assessment for Treatment Emergent Events /General Inquiry (SATEE-GI), and the Brief Psychiatric Rating Scale (BPRS).17 20 The CGI has three scales which measure seventy of illness, global improvement, and an efficacy index. The efficacy index attempts to relate therapeutic effects and side effects by creating a composite score. The SATEE-GI uses a general open-ended inquiry method to detect adverse incidents. BPRS scores asses changes in psychopathology. All three instruments were administered before OXC conversion and then the BPRS and SATEE-GI were completed weekly for 3 months. At week 12, the CGI was repeated. Each volunteer provided a sodium blood level at week 6.
RESULTS Twenty male subjects with an average age of 43 completed the 12-week study. All subjects had a primary Bipolar I Disorder diagnosis. Each subject also completed a minimum of 6 months therapy on valproic acid before switching to OXC. The average sodium level at week 6 was 138, with none of the subjects falling outside the normal range of 135 / 145 mEq/l. Twenty percent (four) of the study group participants met the clinical criteria for rapid cycling. As a group, the average number of prior episodes was four, ranging in length from 2 to 6 weeks. None of the subjects met the clinical criteria for a manic episode in the 6 months preceding the study. BPRS scores at weeks 1 and 12 were compared. The baseline or first week BPRS total score averaged 39.13 (s / 18.644). At 12 weeks, the BPRS total score decreased slightly to an average of 36.56 (s/20.677). A paired t -test was conducted and no significant difference in BPRS total scores was detected between the first week and the 12th week of treatment (t /1.12, P /0.2810). CGI data were collected at weeks 1 and 12, measuring severity of illness, global improvement, and therapeutic Table 1 Wilcoxon signed ranks test on CGI Z statistic Severity of illness Global improvement Therapeutic effect/side effect
/2.414 /2.565 /1.811
P value (two-tailed) 0.016 0.010 0.070
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Oxcarbazepine
effect/side effects (see Table 1). At the 12th week, seven patients reported that the severity of illness had decreased. The remaining 13 subjects reported no change in the severity of illness they experienced. A Wilcoxon signed ranks test indicates that this is a statistically significant change (z/ / 2.414, P /0.016). Analysis of CGI data indicated that 19 of the 20 subjects reported global improvement at the 12th week, while one subject reported no change. After the first week of the study, 11 patients reported they had minimally improved and remained minimally improved at the 12th week. Two patients reported that they had minimally improved after the first week of the study, but had much improved at the 12th week. Two patients reported that they had minimally improved after the first week of the study, but reported being very much improved after 12 weeks. One patient reported no change after the first week of the study and remained unchanged at the 12th week. Two patients reported no change after the first week of the study but were much improved at the 12th week. One patient was much improved after the first week of the study and at the 12th week was very much improved. One patient reported being minimally worse after the first week of the study and reported being very much improved at the 12th week. No patients reported feeling minimally worse or very much worse after 12 weeks in the study. A Wilcoxon signed ranks test indicates that this is a statistically significant improvement (z/ /2.565, P / 0.010). The CGI examined the therapeutic effect/side effect and the statistical analysis compared weeks 1 and 12. One patient reported a decrease in therapeutic effect/side effect. Six patients reported an increase in therapeutic effect/side effect, with the remaining 13 subjects reporting no change from the first week of the study. A Wilcoxon signed ranks test failed to detect a statistically significant change in therapeutic effect/ side effect (z / /1.811, P /0.070). The three open-ended questions of the SATEE-GI data collected at weeks 1 and 12 were compared (see Table 2). None of the 20 subjects reported any changes in their physical appearance between weeks 1 and 12. None of the
20 subjects reported that they had cut down on the things they usually do after the first week of the study. This held true throughout the study period. None of the patients reported any physical or emotional problems between weeks 1 and 12 of the study.
DISCUSSION The selection of a specific psychiatric medication follows a clinical judgment evaluating safety, tolerability, and efficacy. Among broad classes of medications, such as the mood stabilizers lithium or valproic acid, gains in terms of therapeutic efficacy between specific medications are generally minimal. As a result, clinicians often select a specific psychiatric medication based on safety and tolerability. Finding the best match between efficacy, safety, and tolerability should promote medication compliance. Lithium is an effective treatment for mania along with valproic acid and CBZ. All three however, have different pharmacokinetic properties that influence safety and tolerability. CBZ is a potent hepatic enzyme inducer, valproic acid has hematological and hepatic side effects, and lithium may produce hematological, neurological, and renal side effects. All three require routine blood level monitoring. The hallmark of bipolar disorder is variability. With the exception of rapid cyclers, the number of episodes, length, and symptom-free intervals varies widely among individuals. This study demonstrated the efficacy, safety, and tolerability, of OXC over a 12-week period. Of particular note, none of the study participants experienced any significant difficulty during the cross-over from valproic acid to OXC. In addition, none of the rapid cyclers in the study deteriorated. OXC has other potential advantages. Routine blood levels are not required, promoting compliance and reducing the cost of this particular treatment. The unique pharmacokinetic properties of OXC may minimize drug /drug interactions. This is particularly valuable given the long-term treatment of mania, an aging population, and the increasing use of multiple medications.
Table 2 SATEE /GI Week
Frequency
Percent
39
Valid percent
Have you had any physical or emotional problems this week? 1 Valid No 20 100.0 100.0 12 Valid Yes 1 5.0 5.0 No 19 95.0 95.0 Total 20 100.0 100.0 Have you noticed any changes in your physical appearance? 1 Valid No 20 100.0 100.0 12 Valid No 20 100.0 100.0 Have you cut down on the things you usually do because of not feeling well? 1 Valid No 20 100.0 100.0 12 Valid No 20 100.0 100.0
Cumulative percent
100.0 5.0 100.0
100.0 100.0 100.0 100.0
40
R Gregory Lande
As with any new therapeutic approach, further clinical study is warranted. Future investigations could examine subjects for a greater length of time, in different clinical environments, or with different drug combinations. This study is one-step along a path that may eventually demonstrate the utility of OXC in the routine treatment of mania.
ACKNOWLEDGEMENTS The author would like to acknowledge the contributions of Michele Nichols, USC Department of Statistics
REFERENCES
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1.
Dunn RT, Frye MS, Kimbrell TA et al (1998) The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol 21 (4): 215 /35. 2. Wang PW, Ketter TA (2002) Pharmacokinetics of mood stabilizers and new anticonvulsants. Psychopharmacol Bull 36 (1): 44 /66. 3. Strakowski SM, DelBello MP, Adler CM (2001) Comparative efficacy and tolerability of drug treatments for bipolar disorder. CNS Drugs 15 (9): 701 /18. 4. Tecoma ES (1999) Oxcarbazepine. Epilepsia 40 (Suppl. 5): S37 / 46. 5. Degen PH, Flesch G, Cardot JM et al (1994) The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers. Biopharm Drug Dispos 15: S19 / 26. 6. Lakehal F, Wurden CJ, Kalhorn TF et al (2002) Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy Res 52 (2): 79 /83. 7. Ambrosio AF, Soares-Da-Silva P, Carvalho CM et al (2002) Mechanisms of action of carbamazeine and its derivatives, oxcarbazepine, BIA-093, and BIA 2-024. Neurochem Res 27 (1/ 2): 121 /30. 8. Keranen T, Jolkkonen J, Jensen PK et al (1992) Absence of interaction between oxcarbazepine and erythromycin. Acta Neurol Scand 86 (2): 120 /3. 9. Keranen T, Jolkkonen J, Klosterskov-Jensen P et al (1992) Oxcarbazepine does not interact with cimetidine in healthy volunteers. Acta Neurol Scand 85 (4): 239 /42. 10. Schmutz M, Brugger F, Gentsch C et al (1994) Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia 35 (Suppl. 5): S47 /50. 11. Schachter SC (1999) Oxcarbazepine: current status and clinical applications. Exp Opin Invest Drugs 8 (7): 1103 /12. 12. Velikonja M, Heinrich K (1984) Effect of oxcarbazepine (CG 47.680) on affective and schizoaffective symptoms */a
13. 14.
15.
16.
17.
18.
19.
20.
preliminary report. In: Emrich HM et al (eds) Anticonvulsants in Affective Disorders, International Congress Series No. 626 . Amsterdam: Excerpta Medica: 208 /10. Emrich HM (1990) Studies with oxcarbazepine (Trileptal† ) in acute mania. Int Clin Psychopharmacol 5 (1): 83 /8. Greil W, Kru¨ger R, Roßnagl G, et al (1985) Prophylactic treatment of affective disorders with carbamzaepine and oxcarbazepine: an open clinical trial. In: Pichot P, et al (eds) Psychiatry. The State of the Art. Vol 3: Pharmacopsychiatry. Proc VII World Congr Psychiatry; 11 /16 July 1983; Vienna, Austria. New York: Plenum Press: 491 / 4. Mu¨ller AA, Stoll KD (1984) Carbamazepine and oxcarbazepine in the treatment of manic syndromes / studies in Germany. In: Emrich HM et al (eds) Anticonvulsants in Affective Disorders. International Congress Series No. 626 . Amsterdam: Excerpta Medica: 139 /47. Gonzalez-Esquivel DF, Ortega-Gavilan M, Alcantart-Lopez G et al (2000) Plasma level monitoring of oxcarbazepine in epileptic patients. Arch Med Res 31 (2): 202 /5. Guy, W (1976) ECDEU assessment manual for psychopharmacology. US Dept. of Health, Education 4 Welfare, Public Health Service, ADAMHA, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs: 218 /22. Overall JE, Gorham DR (1998) The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment 4 scaling. Psychopharmacol Bull 24: 97 /9. Lenine J, Schooler NR (1986) SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull 22: 343 /82. Rabkin JG, Markowitz JS, Ocepk-Weliksank, et al (1992) General versus systematic inquiry about emergent clinical events with SAFTEE: implications for clinical research. J Clin Psychopharmacol 12: 448.
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania R. Gregory Lande To cite this article: R. Gregory Lande (2004) Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania, International Journal of Psychiatry in Clinical Practice, 8:1, 37-40 To link to this article: http://dx.doi.org/10.1080/13651500310003336
Published online: 13 Sep 2010.
Submit your article to this journal
Article views: 6
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [Universite Laval]
Date: 13 October 2015, At: 07:05
# 2004 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2004
Volume 8
Pages 37 /40
37
Oxcarbazepine: Efficacy, safety, and tolerability in the treatment of mania
Downloaded By: [informa internal users] At: 15:12 7 September 2010 Downloaded by [Universite Laval] at 07:05 13 October 2015
R. GREGORY LANDE
Correspondence Address R. Gregory Lande, D.O., 13826 Bison Court, Silver Spring, MD 20906, USA Tel: /(1) 803 7831015 E-mail: [email protected]
Received 1 April 2003; accepted for publication 3 September 2003
A twelve-week study examined the efficacy, safety, and tolerability of oxcarbazepine in the treatment of mania. Twenty male subjects, all of whom were stable on valproic acid, qualified for the study. The conversion from valproic acid to oxcarbazepine was completed over a three-week period. Scores from the BPRS, CGI and SATEE-GI were collected and analyzed. The results of the study supported the efficacy, safety, and tolerability of oxcarbazepine for the treatment of mania. Another potential advantage of oxcarbazepine is a metabolic pathway that may reduce drug interactions. (Int J Psych Clin Pract 2004; 8: 37 40) /
Keywords treatment oxcarbazepine
INTRODUCTION
T
he first medication approved for the treatment of bipolar disorder was lithium carbonate.1 The FDA granted approval in 1970, following a rather lengthy delay based on lingering toxicity concerns. As with many medications, the promise of a safe, effective treatment waned as failure rates and side effects with lithium developed. Tolerability, safety, and efficacy directly influenced medication compliance. This is particularly important when longterm treatment is necessary, as with bipolar disorder. The search for an alternative to lithium continues, with interest centered on a small group of medications. The cycling nature of bipolar disorder suggests a seizurelike etiology. Initial recipients of this interest were antiseizure medications, principally carbemazepine (CBZ) and valproic acid. Both have proven effectiveness in the treatment of acute mania and in longer-term mood stabilization.1 The FDA approved the use of valproic acid for the treatment of acute mania in 1995.1 Reports of fatal hepatotoxicity in young children delayed the initial approval. Anti-manic properties of valproic acid result from a blend of dosing, blood level monitoring, clinical response, and limitations imposed by side effects. Most individuals respond to doses between 1000 and 2500 mg and blood levels in the range of 50 /125 mg/ml. Side effects are generally mild and dose related, although weight gain may pose a special problem. The pharmacokinetics of valproic acid produces certain drug interactions. Valproic acid is hepatically metabolized and inhibits the P450 enzymes. In addition, valproic acid has an aggressive affinity for plasma proteins and may displace weaker competitors. The combination of hepatic induction and aggressive plasma binding creates an environ-
mania
ment for important drug interactions. For example, combining valproic acid with benzodiazepines, CBZ, or lamotrigine produces clinically significant drug interactions.1 Like valproic acid, the antimanic properties of CBZ result from a blend of dosing, blood level monitoring, clinical response, and limitations imposed by side effects. Side effects are dose related and include sedation, leucopenia, elevated liver function tests, rash, and rare instances of agranulocytosis.2 Carbemazepine is almost entirely metabolized by the liver. Regular dosing results in hepatic P450 enzyme induction. In addition, CBZ is rather weakly bound to plasma proteins and displaced by more aggressive compounds. The pharmacokinetics of CBZ can alter the metabolism of other drugs. Clinically significant alterations can result from combinations of CBZ with most tricyclic antidepressants, selective serotonin reuptake inhibitors, many antipsychotic medications, and birth control pills.2 Lithium, valproic acid, and CBZ lead a growing list of medications targeting bipolar disorder. Investigators are studying newer anti-seizure medications, such as lamotrigine and topiramate.3 All medications are eventually judged in terms of efficacy, safety, and reliability. The best balance produces maximum medication compliance. Oxcarbazepine (OXC) is an anti-seizure medication that may offer certain advantages in the long-term management of bipolar disorder. The interesting pharmacokinetics of OXC may suggest its use as an alternative to lithium, CBZ, or valproic acid in the long-term treatment of bipolar disorder.4 OXC is the keto-analogue of CBZ. The active metabolite of OXC is 10-monohydroxy derivative (MHD). A rapid conversion of OXC to MHD leaves little detectable OXC in the blood. Following oral ingestion, the active metabolite DOI: 10.1080/13651500310003336
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38
R Gregory Lande
MHD reaches peak levels in 4 /6 h and a half-life of 8 /10 h. A steady state occurs in 2 or 3 days. The absorption of OXC is not influenced by food.5 OXC produces minimal hepatic inhibition of the P450 enzymes. The one exception is the CP2C19 enzyme which can produce clinically relevant changes in phenobarbital, valproic acid, phentoin, and CBZ.6 Mild to moderate hepatic dysfunction does not require an OXC dose adjustment. Individuals with impaired renal clearance (creatinine clearance B/30 ml/min) do require OXC dose adjustments. An asymptomatic hyponatremia (B/125 mmol/l) may occur in 2.5% of cases, mostly in the first 3 months of treatment. The most common (/50%) adverse reactions associated with discontinuance included dizziness, diplopia, ataxia, vomiting, and nausea.2,7 Animal studies suggest that deaths from extremely high doses or interdrug reactions are rare. OXC may favorably impact lipid levels, particularly in comparison to P450 enzyme inhibitors like CBZ. Substitution of CBZ with OXC normalized RBC counts and g-glutamyl elevations.2 Medications that impact oxidative metabolism, such as erythromycin and verapamil, produce toxicity when combined with CBZ but not OXC.8 OXC does not interact with either warfarin or cimetidine.2,9 OXC does reduce the effectiveness of birth control pills.2 OXC may offer an attractive alternative for the treatment of bipolar disorder, particularly given a pharmacokinetic profile that apparently reduces drug interactions.10,11 In addition, a number of clinical studies have demonstrated the effectiveness of OXC in the treatment of acute mania.12 15 Clinical investigators in Germany reported some of the earliest positive results using OXC for the treatment of mania.13 Another possible advantage of OXC is the ability to make dose adjustments without concomitant blood level monitoring.16 Based on these collective reports, this clinical study was undertaken to explore the tolerability, safety, and efficacy of OXC in the maintenance treatment of bipolar disorder.
MATERIALS AND METHODS This study sought the participation of 20 male volunteers. General inclusion criteria included a clinical diagnosis of bipolar disorder and a minimum of 6 months treatment with valproic acid. Exclusion criteria included known hypersensitivity to OXC, CBZ, or hyponatremia. Women were excluded from the study following a risk /benefit analysis that considered the possibility of an unprotected sexual encounter and the potential teratogenetic effects of OXC. In addition, OXC reduces the effectiveness of any preexisting hormonal contraception. All participating volunteers provided written consent after receiving a verbal and written description of the study. This clinical investigation was approved by the South Carolina Department of Mental Health’s Institutional Review
Board and funded with an unrestricted educational grant from Novartis Pharmaceuticals. Subjects were successively recruited from a long-term impatient forensic unit. The conversion from valproic acid to OXC was completed over a 3-week period. OXC was initiated at 300 mg along with a corresponding reduction in valproic acid. Dose adjustments were completed once a week. Tolerability, safety, and efficacy of OXC was monitored using three instruments, the Clinical Global Impression Scale (CGI), the Systematic Assessment for Treatment Emergent Events /General Inquiry (SATEE-GI), and the Brief Psychiatric Rating Scale (BPRS).17 20 The CGI has three scales which measure seventy of illness, global improvement, and an efficacy index. The efficacy index attempts to relate therapeutic effects and side effects by creating a composite score. The SATEE-GI uses a general open-ended inquiry method to detect adverse incidents. BPRS scores asses changes in psychopathology. All three instruments were administered before OXC conversion and then the BPRS and SATEE-GI were completed weekly for 3 months. At week 12, the CGI was repeated. Each volunteer provided a sodium blood level at week 6.
RESULTS Twenty male subjects with an average age of 43 completed the 12-week study. All subjects had a primary Bipolar I Disorder diagnosis. Each subject also completed a minimum of 6 months therapy on valproic acid before switching to OXC. The average sodium level at week 6 was 138, with none of the subjects falling outside the normal range of 135 / 145 mEq/l. Twenty percent (four) of the study group participants met the clinical criteria for rapid cycling. As a group, the average number of prior episodes was four, ranging in length from 2 to 6 weeks. None of the subjects met the clinical criteria for a manic episode in the 6 months preceding the study. BPRS scores at weeks 1 and 12 were compared. The baseline or first week BPRS total score averaged 39.13 (s / 18.644). At 12 weeks, the BPRS total score decreased slightly to an average of 36.56 (s/20.677). A paired t -test was conducted and no significant difference in BPRS total scores was detected between the first week and the 12th week of treatment (t /1.12, P /0.2810). CGI data were collected at weeks 1 and 12, measuring severity of illness, global improvement, and therapeutic Table 1 Wilcoxon signed ranks test on CGI Z statistic Severity of illness Global improvement Therapeutic effect/side effect
/2.414 /2.565 /1.811
P value (two-tailed) 0.016 0.010 0.070
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Oxcarbazepine
effect/side effects (see Table 1). At the 12th week, seven patients reported that the severity of illness had decreased. The remaining 13 subjects reported no change in the severity of illness they experienced. A Wilcoxon signed ranks test indicates that this is a statistically significant change (z/ / 2.414, P /0.016). Analysis of CGI data indicated that 19 of the 20 subjects reported global improvement at the 12th week, while one subject reported no change. After the first week of the study, 11 patients reported they had minimally improved and remained minimally improved at the 12th week. Two patients reported that they had minimally improved after the first week of the study, but had much improved at the 12th week. Two patients reported that they had minimally improved after the first week of the study, but reported being very much improved after 12 weeks. One patient reported no change after the first week of the study and remained unchanged at the 12th week. Two patients reported no change after the first week of the study but were much improved at the 12th week. One patient was much improved after the first week of the study and at the 12th week was very much improved. One patient reported being minimally worse after the first week of the study and reported being very much improved at the 12th week. No patients reported feeling minimally worse or very much worse after 12 weeks in the study. A Wilcoxon signed ranks test indicates that this is a statistically significant improvement (z/ /2.565, P / 0.010). The CGI examined the therapeutic effect/side effect and the statistical analysis compared weeks 1 and 12. One patient reported a decrease in therapeutic effect/side effect. Six patients reported an increase in therapeutic effect/side effect, with the remaining 13 subjects reporting no change from the first week of the study. A Wilcoxon signed ranks test failed to detect a statistically significant change in therapeutic effect/ side effect (z / /1.811, P /0.070). The three open-ended questions of the SATEE-GI data collected at weeks 1 and 12 were compared (see Table 2). None of the 20 subjects reported any changes in their physical appearance between weeks 1 and 12. None of the
20 subjects reported that they had cut down on the things they usually do after the first week of the study. This held true throughout the study period. None of the patients reported any physical or emotional problems between weeks 1 and 12 of the study.
DISCUSSION The selection of a specific psychiatric medication follows a clinical judgment evaluating safety, tolerability, and efficacy. Among broad classes of medications, such as the mood stabilizers lithium or valproic acid, gains in terms of therapeutic efficacy between specific medications are generally minimal. As a result, clinicians often select a specific psychiatric medication based on safety and tolerability. Finding the best match between efficacy, safety, and tolerability should promote medication compliance. Lithium is an effective treatment for mania along with valproic acid and CBZ. All three however, have different pharmacokinetic properties that influence safety and tolerability. CBZ is a potent hepatic enzyme inducer, valproic acid has hematological and hepatic side effects, and lithium may produce hematological, neurological, and renal side effects. All three require routine blood level monitoring. The hallmark of bipolar disorder is variability. With the exception of rapid cyclers, the number of episodes, length, and symptom-free intervals varies widely among individuals. This study demonstrated the efficacy, safety, and tolerability, of OXC over a 12-week period. Of particular note, none of the study participants experienced any significant difficulty during the cross-over from valproic acid to OXC. In addition, none of the rapid cyclers in the study deteriorated. OXC has other potential advantages. Routine blood levels are not required, promoting compliance and reducing the cost of this particular treatment. The unique pharmacokinetic properties of OXC may minimize drug /drug interactions. This is particularly valuable given the long-term treatment of mania, an aging population, and the increasing use of multiple medications.
Table 2 SATEE /GI Week
Frequency
Percent
39
Valid percent
Have you had any physical or emotional problems this week? 1 Valid No 20 100.0 100.0 12 Valid Yes 1 5.0 5.0 No 19 95.0 95.0 Total 20 100.0 100.0 Have you noticed any changes in your physical appearance? 1 Valid No 20 100.0 100.0 12 Valid No 20 100.0 100.0 Have you cut down on the things you usually do because of not feeling well? 1 Valid No 20 100.0 100.0 12 Valid No 20 100.0 100.0
Cumulative percent
100.0 5.0 100.0
100.0 100.0 100.0 100.0
40
R Gregory Lande
As with any new therapeutic approach, further clinical study is warranted. Future investigations could examine subjects for a greater length of time, in different clinical environments, or with different drug combinations. This study is one-step along a path that may eventually demonstrate the utility of OXC in the routine treatment of mania.
ACKNOWLEDGEMENTS The author would like to acknowledge the contributions of Michele Nichols, USC Department of Statistics
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