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Carbamazepine to Treat Bipolar Disorder: Comparison
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Please note this is a comparison between Version 2 by Nora Tang and Version 1 by Benedikt Amann.

Carbamazepine and its derivatives all appear to have stronger efficacy in treating acute mania than depression, which also translates to better protection against manic than depressive relapses for carbamazepine. Still, there is a paucity of controlled acute studies on bipolar depression for all and, with the exception of carbamazepine, a lack of long-term monotherapy maintenance data. For eslicarbazepine, the efficacy in bipolar disorder remains largely unknown. Especially with carbamazepine, tolerability issues and drug–drug interactions need to be kept in mind.

  • bipolar disorder
  • carbamazepine
  • depression
  • eslicarbazepine
  • maintenance
  • mania
  • oxcarbazepine
  • predominant polarity

1. Introduction

The definition and use of the term mood stabilizers in the treatment of bipolar disorder (BD) remains a matter of discussion and disagreement. The classification suggested by Ketter and Calabrese [1] defines Class A mood stabilizers as stabilizing mood from 

above

 baseline and Class B mood stabilizers as stabilizing mood from 

below

 baseline, in which baseline means euthymia. It should be emphasized that the authors of this classification mainly focus on stabilizing mood, which includes the components of acute efficacy and maintaining this effect, but not primarily on prophylaxis, i.e., protection against recurrence of episodes in remitted patients.

Lithium (LI) might be a candidate for a mood stabilizer that comes close to fulfilling the criteria for both Classes A and B, although its relative strength in treating acute bipolar depression is not well evaluated [2,3] and results of double-blind, placebo (PLC)-controlled maintenance trials are inconsistent [4,5].

Lithium (LI) might be a candidate for a mood stabilizer that comes close to fulfilling the criteria for both Classes A and B, although its relative strength in treating acute bipolar depression is not well evaluated [2][3] and results of double-blind, placebo (PLC)-controlled maintenance trials are inconsistent [4][5].

With the emergence of atypical antipsychotics as evidence-based treatment in BD, the role of anticonvulsants, with the exception of lamotrigine, has diminished, although in some countries, they are still popular and constitute at least a second line treatment for BD. Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine (ESL, available as eslicarbazepine acetate) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel and, to some degree, calcium channel blockers [6,7]. While CBZ blocks L-type calcium channels, OXC blocks N- and (or) P- and (or) R-type calcium channels. CBZ traditionally claims to be a mood stabilizer, at least in the sense of relapse prevention, despite the fact that it is not approved for this indication in most countries. Its neurochemical mechanisms of action support this assumption [8]. Theories on kindling mechanisms and behavioral sensitization have played a major role in translating antiepileptic efficacy into potential mood-stabilizing and prophylactic properties in bipolar patients [9,10,11]. Basic research also points toward some degree of similarities between LI and CBZ in the mechanisms of neuronal protection [12].

With the emergence of atypical antipsychotics as evidence-based treatment in BD, the role of anticonvulsants, with the exception of lamotrigine, has diminished, although in some countries, they are still popular and constitute at least a second line treatment for BD. Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine (ESL, available as eslicarbazepine acetate) belong to the dibenzazepine family of antiepileptic drugs and are all thought to primarily act as sodium channel and, to some degree, calcium channel blockers [6][7]. While CBZ blocks L-type calcium channels, OXC blocks N- and (or) P- and (or) R-type calcium channels. CBZ traditionally claims to be a mood stabilizer, at least in the sense of relapse prevention, despite the fact that it is not approved for this indication in most countries. Its neurochemical mechanisms of action support this assumption [8]. Theories on kindling mechanisms and behavioral sensitization have played a major role in translating antiepileptic efficacy into potential mood-stabilizing and prophylactic properties in bipolar patients [9][10][11]. Basic research also points toward some degree of similarities between LI and CBZ in the mechanisms of neuronal protection [12].

This narrative review now examines differential strengths and weaknesses of the three dibenzazepines CBZ, OXC, and ESL for treating and preventing the poles of BD, and whether these medications should be considered mood stabilizers according to the definition by Ketter and Calabrese [1].

2. Development and Findings

Especially for long-term treatment, tolerability and safety become almost as important as efficacy. Whereas some adverse drug reaction, e.g., allergic rash, manifest quite early in treatment, others, e.g., hyponatremia, osteoporosis, or hepatotoxicity, may develop over time. Thus, it is important to monitor bipolar patients taking CBZ with a similar rigor as patients on other antiepileptic mood stabilizers or second-generation antipsychotics. The German S3 guideline for bipolar disorder recommends to have a thorough physical examination at treatment initiation and every year and to monitor at the beginning and every six months the patient’s weight and the following lab parameters: hepatic and renal function, full blood count, and CBZ serum level [113]. Similar recommendations have been made by the International Society for Bipolar Disorder (ISBD) [114]. Clearly, in the first weeks after start of treatment, more frequent lab controls are indicated. Although not part of official bipolar guidelines, a similar monitoring scheme should apply to OXC and ESL.

Especially for long-term treatment, tolerability and safety become almost as important as efficacy. Whereas some adverse drug reaction, e.g., allergic rash, manifest quite early in treatment, others, e.g., hyponatremia, osteoporosis, or hepatotoxicity, may develop over time. Thus, it is important to monitor bipolar patients taking CBZ with a similar rigor as patients on other antiepileptic mood stabilizers or second-generation antipsychotics. The German S3 guideline for bipolar disorder recommends to have a thorough physical examination at treatment initiation and every year and to monitor at the beginning and every six months the patient’s weight and the following lab parameters: hepatic and renal function, full blood count, and CBZ serum level [13]. Similar recommendations have been made by the International Society for Bipolar Disorder (ISBD) [14]. Clearly, in the first weeks after start of treatment, more frequent lab controls are indicated. Although not part of official bipolar guidelines, a similar monitoring scheme should apply to OXC and ESL.

The choice of alternative acute treatment has widened considerably over the past decade, especially with the emergence of second-generation antipsychotics; however, for maintenance and prophylactic treatment, CBZ still constitutes an option worth to consider. Especially, patients with atypical features and forms of BD do not respond as well to lithium, long-term data for VPA are less convincing than for CBZ, lamotrigine might be insufficient to protect against new manic episodes, and the long-term use of several second-generation antipsychotics is associated with weight gain and metabolic issues. In addition, except olanzapine, no second-generation antipsychotic has, so far, proven efficacy in a prophylaxis study, but only in continuation/maintenance trials in samples enriched for acute response and mostly lasting no longer than six months [115,116,117]. Finally, some groups, e.g., the elderly, may have medical safety issues prohibiting lithium therapy (renal impairment) or use of antipsychotics (cerebrovascular disorder, emerging dementia). Thus, the authors feel that there is still a place for CBZ, and possibly also OXC, in the treatment of BD.

The choice of alternative acute treatment has widened considerably over the past decade, especially with the emergence of second-generation antipsychotics; however, for maintenance and prophylactic treatment, CBZ still constitutes an option worth to consider. Especially, patients with atypical features and forms of BD do not respond as well to lithium, long-term data for VPA are less convincing than for CBZ, lamotrigine might be insufficient to protect against new manic episodes, and the long-term use of several second-generation antipsychotics is associated with weight gain and metabolic issues. In addition, except olanzapine, no second-generation antipsychotic has, so far, proven efficacy in a prophylaxis study, but only in continuation/maintenance trials in samples enriched for acute response and mostly lasting no longer than six months [15][16][17]. Finally, some groups, e.g., the elderly, may have medical safety issues prohibiting lithium therapy (renal impairment) or use of antipsychotics (cerebrovascular disorder, emerging dementia). Thus, the authors feel that there is still a place for CBZ, and possibly also OXC, in the treatment of BD.

3. Conclusions

A categorization of mood stabilizers, as suggested by Ketter and Calabrese, may be superficial, considering the complexity of illness; however, it may be of clinical utility. Two medications discussed in this review, CBZ and OXC, match Class A criteria, meaning acute antimanic efficacy, prevention of manic relapses, and not causing or worsening depression. There is no convincing data for either CBZ or OXC in the acute treatment of depression or the prevention of depressive relapses, and the duration of most controlled studies is insufficient to allow any conclusions about prophylactic efficacy over years. Clearly, more long-term observational data, similar to those for LI, are needed for these medications. For ESL, evidence is too scarce to allow for any statement about its effectiveness in BD.

References

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  13. DGBS e.V. und DGPPN e.V. S3-Leitlinie zur Diagnostik und Therapie Bipolarer Störungen. Langversion 2.0. Available online: (accessed on 8 February 2020).
  14. Yatham, L.N.; Kennedy, S.H.; Parikh, S.V.; Schaffer, A.; Bond, D.J.; Frey, B.N.; Sharma, V.; Goldstein, B.I.; Rej, S.; Beaulieu, S.; et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018, 20, 97–170.
  15. Nolen, W.; Grunze, H. Long-term treatment of mood disorders: Follow-up of acute treatment phase studies versus continuation and maintenance phase studies, and enriched versus non-enriched designs. In Clinical Trial Design Challenges in Mood Disorders; Tohen, M., Bowden, C., Nierenberg, A., Geddes, J., Eds.; Elsevier Academic Press: Amsterdam, The Netherlands, 2015; pp. 29–48.
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