Advanced Search

The American Journal of Psychiatry, VOL. 155, No. 1

Special Articles | January 01, 1998

Mood Stabilizer Combinations: A Review of Safety and Efficacy

Marlene P. Freeman, M.D.; Andrew L. Stoll, M.D.

Am J Psychiatry 1998;155:12-21.

Article

Tables

References

text A A A

Abstract

OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar disorder. The purpose of this article is to review the safety and efficacy of mood stabilizers in combinations. METHOD: A manual and computer (MEDLINE) search was performed for combinations of the most commonly used mood-stabilizing agents. RESULTS: The authors review safety and efficacy data on the more frequently encountered combinations of established and putative mood stabilizers. CONCLUSIONS: There have been few controlled studies of the use of combinations of mood stabilizers. The interactions of such combinations are sometimes complex, often very useful, and potentially dangerous. One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. The safest and most efficacious mood stabilizer combinations appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action. (Am J Psychiatry 1998; 155:12–21)

Figures in this Article

The treatment of bipolar disorder remains an ongoing challenge to psychiatrists. The illness includes a diversity of clinical manifestations. In the course of the illness, the range of symptoms for an individual can fluctuate greatly, as cycling from one mood episode to another is characteristic. Recurrences of manias and depressions are common. Complicating matters further, subtypes of bipolar disorder have been differentiated, and clinicians must take into account whether a patient has classic, euphoric manias (bipolar I), hypomanias with episodes of depression (bipolar II), mixed episodes, or rapid cycling.

Over the past 50 years, we have experienced revolutionary changes in the pharmacologic treatment of mental illness, including bipolar disorder. Lithium was recognized as an antimanic agent by John Cade in 1949 and gained favor in Europe in the 1950s–1960s. In the United States, chlorpromazine, which was introduced in the 1950s, was the treatment of choice for bipolar illness until lithium gained popularity in this country in the 1960s. Haloperidol became widely used for the treatment of mania after its introduction in the late 1960s. Anticonvulsants, initially carbamazepine, were first used for bipolar disorder in the 1970s. Subsequently, valproate has become widely used and has recently been the only medication other than lithium approved by the U.S. Food and Drug Administration for treating bipolar disorder. Also, calcium channel blockers came under study in the 1980s. As atypical antipsychotics have been introduced, the use of clozapine and risperidone for bipolar disorder has increased substantially. To our knowledge there are not yet any published data specific to bipolar disorder for olanzapine, the most recently approved antipsychotic in the United States. Two new anticonvulsants, lamotrigine and gabapentin, have been used increasingly for bipolar disorder in the past several years. Despite this array of options, bipolar disorder remains a difficult disorder to treat. Some subtypes, such as those characterized by rapid cycling or mixed episodes, have been especially resistant to lithium treatment. Also, many patients cannot tolerate the side effects associated with available medications. Hence, monotherapy is often inadequate and polypharmacy has become common (1).

Combination mood stabilizer therapy, the concomitant use of more than one agent, has become commonplace in the treatment of refractory bipolar disorder. This article is a review of the available data for combinations of mood stabilizers. When appropriate, "Treatment of Bipolar Disorder" (2), from the Expert Consensus Guideline Series, is cited. This guideline is a systematic survey of responses to treatment decisions given by 61 national experts in the treatment of bipolar disorder. We have incorporated these data to indicate the current state of the art for the treatment of bipolar disorder.

As lithium and valproate are the most commonly used mood-stabilizing agents, the results of our review are divided into the following sections: 1) Combinations With Lithium, 2) Combinations With Valproate, and 3) Other Combinations.

METHOD

Abstract | METHOD | RESULTS | DISCUSSION | References

A manual and computerized (MEDLINE) search was performed to examine the English-language literature on mood stabilizer combinations. The following key words were used in the computer search: bipolar disorder, refractory, lithium, valproate, carbamazepine, verapamil, nimodipine, amlodipine, lamotrigine, gabapentin, neuroleptics, clonazepam, benzodiazepines, clozapine, olanzapine, and risperidone.

RESULTS

Abstract | METHOD | RESULTS | DISCUSSION | References

Combinations With Lithium (table 1)

Lithium and valproate. The use of the combination of lithium and valproate is gaining favor, and it appears to be a safe and effective regimen. Use of valproate, both as monotherapy and in combinations, has increased substantially over the past 5 years (3). As reported in the consensus guideline for bipolar disorder (2), the addition of valproate to lithium has been recognized as a first-line treatment for mania that is refractory to lithium monotherapy, and conversely, the treatment of choice for acute mania with partial but inadequate response to valproate is the addition of lithium. Generally, the addition of valproate is most effective for patients with rapid cycling or mixed episodes. In one recent placebo-controlled double-blind study (4), patients receiving a combination of lithium and valproate were significantly less likely to suffer a relapse than were patients receiving lithium and placebo. The study involved 12 patients followed for a minimum of 14 weeks, and most patients were followed for 1 year. In open-label (5) and retrospective (6) studies, this combination was effective in both the manic and depressive phases of the illness. Single case reports (7, 8) also support the efficacy of lithium and valproate together, especially for rapid cycling.

Lenox et al. (9) suggested that the combination of lithium and valproate may be synergistic. They found that the combination produced additive suppression of the protein myristoylated alanine-rich C kinase substrate.

Safety was examined in a controlled crossover trial (10) in which lithium was administered to 16 patients receiving either divalproex sodium or placebo. Lithium's pharmacokinetics were found to be unchanged by valproate, and there was no significant difference in adverse events reported by the valproate and placebo groups.

Potential drawbacks to concurrent treatment with lithium and valproate include additive adverse reactions, such as weight gain, sedation, gastrointestinal complaints, and tremor. Overall, on the basis of the available data, the combination of lithium and valproate appears to be well tolerated and effective in treating bipolar illness.

Lithium and carbamazepine. The use of carbamazepine for bipolar disorder is declining because of the difficulties generated by carbamazepine's pharmacokinetic interactions with other medications, its side effects, and the rising popularity of valproate (3). However, the concurrent use of lithium and carbamazepine is still common. As reported in the consensus guideline for bipolar disorder (2), almost one-half of the recognized experts consider the addition of carbamazepine to lithium a first-line treatment for mania refractory to lithium monotherapy.

The available data suggest that the combination of lithium and carbamazepine is safe and effective, especially for rapid-cycling patients. Di Costanzo and Schifano (11) reported a retrospective examination of 16 rapid-cycling patients given lithium either alone or in combination with carbamazepine. Improvement was noted earlier in the group receiving both lithium and carbamazepine than in the patients receiving lithium monotherapy. Lithium and carbamazepine may work synergistically. Kramlinger and Post (12) observed improvement in seven manic patients receiving carbamazepine (who previously had not responded to lithium monotherapy) with the double-blind addition of lithium. Small et al. (13) reported giving neuroleptic or carbamazepine under blind conditions to 33 patients taking lithium; after 8 weeks both groups improved clinically, but the carbamazepine-lithium combination was tolerated better.

Furthermore, in a retrospective study of 18 patients conducted in 1992 (14), those receiving both lithium and carbamazepine experienced better prophylaxis against bipolar episodes than patients treated with either medication alone, and the addition of carbamazepine allowed patients to function better while maintaining lower lithium levels. Also, in a prospective study (15) of 14 patients with lithium-resistant bipolar disorder, treatment with the combination of lithium and carbamazepine for 1 year was superior to treatment with lithium and neuroleptics in the nine patients completing the study. Several other anecdotal reports (16–19) suggest that the combination of lithium and carbamazepine is effective and perhaps synergistic. Besides efficacy, another advantage noted in the literature is that lithium may counteract carbamazepine-induced leukopenia, although the clinical significance of this phenomenon is unclear (19–21).

Cases of neurotoxicity and asterixis have been reported with the concomitant use of lithium and carbamazepine (22, 23). Patients with preexisting CNS disease may be especially vulnerable to negative outcomes with this combination (24). Generally, most of the available data suggest that the combination of lithium and carbamazepine is safe and effective, but use of this combination for patients with comorbid CNS disease should be avoided.

Lithium and calcium channel blockers. It is advisable to use caution when combining lithium and calcium channel blockers. Multiple cases of toxicity, particularly neurotoxicity, have been reported (25–27). Also, Dubovsky et al. (28) reported two cases of severe bradycardia in elderly manic patients taking lithium and verapamil concomitantly.

Verapamil administration may decrease the serum lithium level by increasing excretion, potentially increasing the risk of relapse (29). The risk of neurotoxicity may be greater with verapamil and diltiazem and less with nifedipine, possibly owing to differences in interactions with calcium channels, metabolism, and/or ability to cross the blood-brain barrier (26, 27). Although possibly effective (30), lithium and calcium channel blockers in combination may be hazardous.

Lithium and traditional neuroleptics. Lithium is frequently used with neuroleptics. For patients with classic, euphoric acute mania with psychotic features, most experts consider the combination of a high- or medium-potency neuroleptic with lithium to be a first-line treatment (2). Substantial controversy exists in the literature regarding the safety of such combinations.

There have been only two controlled studies of the use of lithium with neuroleptics. Small et al. (13) reported giving neuroleptic or carbamazepine under blind conditions to 33 patients taking lithium; after 8 weeks both groups improved clinically, but poorer tolerance of the neuroleptic-lithium combination was noted. In another study, Esparon et al. (31) reported a double-blind comparison of depot flupenthixol and placebo for 11 bipolar patients taking lithium. Over the course of 2 years, it was concluded that the neuroleptic provided no prophylactic effect.

A number of prospective and retrospective studies (32–40) support the safety of lithium in conjunction with traditional neuroleptics. There are also case reports suggesting the clinical benefits of combining a neuroleptic and lithium, and synergism between lithium and neuroleptics has been suggested anecdotally (41, 42).

In contrast, there is also substantial evidence of adverse reactions to such combinations. These mainly consist of neurotoxicity. In one study (43), delirium, extrapyramidal signs, and cerebellar dysfunction were reported in three of five elderly bipolar patients receiving lithium and neuroleptics. In another study (35), two of 30 patients receiving lithium and a neuroleptic developed severe tremor. Cases in which use of lithium combined with a neuroleptic resulted in severe neurotoxicity, such as delirium, seizures, tardive dyskinesia, encephalopathy, or EEG abnormalities, have been reported, as have hypotension and cardiac arrhythmias (44–52). However, Krishna et al. (34) reported that neurologic symptoms are usually mild and resolve with discontinuation of medication. Given the possibility of long-term treatment, use of lithium in combination with neuroleptics may increase the risk of tardive dyskinesia (53, 54).

Goodwin and Jamison (55) emphasized that 1) the risk of neurotoxicity appears to be higher in patients with preexisting encephalopathy, 2) neuroleptics should be used in lower doses when combined with lithium, and 3) lithium levels should be maintained below 1.0 meq/liter when lithium is used with neuroleptics. Thus, as concomitant lithium and neuroleptic administration is widespread and generally effective, care should be used to minimize the risk of neurotoxicity.

Lithium and clozapine. Clozapine has been gaining acceptance as a highly effective mood stabilizer for refractory illness, both as monotherapy (56–61) and with other medication. Clozapine and lithium in combination have been reported anecdotally to be effective for refractory bipolar disorder (62–64).

However, the combination of lithium and clozapine has been reported to cause neurologic symptoms (65–67). Also, one case each of diabetic ketoacidosis (68) and neuroleptic malignant syndrome (69) associated with this combination has been reported. Although lithium may be helpful in counteracting clozapine-induced leukopenia (70), it will not prevent agranulocytosis (71).

The few available data include reports of both clinical improvement and adverse events. More study of this combination is needed before assertions of safety or efficacy can be made.

Lithium and risperidone. Tohen et al. (72) studied risperidone in combination with mood stabilizers in the treatment of mania. They found that for eight of 12 patients the combination of risperidone and lithium was well tolerated and efficacious. Also, safety and efficacy were noted in a retrospective study (73), in which nine patients were treated with this combination. The authors of this study did not differentiate between adverse reactions occurring with risperidone monotherapy and those associated with polypharmacy, and so the drawbacks of these specific treatments cannot be inferred.

In contrast to the relative safety observed by Tohen et al. (72), cases of fever, high creatine phosphokinase levels and WBC counts, and delirium have been reported by others (74, 75). Therefore, caution should be exercised when using lithium and risperidone in combination.

Lithium and olanzapine. To our knowledge there are no published data at this time regarding this combination. Side effects (e.g., weight gain, sedation) may be additive.

Lithium and benzodiazepines. Although probably not effective as monotherapy for the long-term treatment of bipolar disorder (76), benzodiazepines are frequently used in combination with lithium. Combinations of lithium and benzodiazepines are generally well tolerated and effective. This is especially important in the consideration of the potential dangers of combining lithium and neuroleptics, as discussed earlier. For example, Sachs et al. (77, 78) reported that for some patients previously receiving both lithium and a neuroleptic, clonazepam successfully replaced the neuroleptic. Also, Adler (79) reported successful use of lithium and clonazepam to treat mania in a patient with neuroleptic malignant syndrome, which resolved after clonazepam treatment was started in place of the neuroleptic. Lorazepam has also been studied in combination with lithium. In an open study (N=4), Modell et al. (80) found the combination of lithium and lorazepam to be rapidly effective and safe for acute mania.

In contrast, Koczerginski et al. (81) described five cases in which the combination appeared to cause neurotoxicity, specifically ataxia and dysarthria. Also, long-term benzodiazepine use may be problematic for some patients with comorbid substance abuse.

Overall, the concomitant use of lithium with benzodiazepines appears effective and safe, may decrease the need for neuroleptics, and may treat comorbid anxiety.

Lithium and gabapentin. Gabapentin is currently being studied as a treatment for bipolar disorder, and there have been favorable reports regarding its potential as a mood stabilizer (82, 83). The advantages of gabapentin include the lack of interactions with other drugs in the cytochrome P450 system and the lack of protein binding (84). Since there is little risk of drug interactions, use with lithium is likely to be safe. The combination of lithium and gabapentin seems to be a reasonable treatment for patients with refractory illness.

Lithium and lamotrigine. The combination of lithium and lamotrigine appears promising for the treatment of bipolar disorder. Anecdotal reports (85) suggest that it may be especially helpful in cases of bipolar depression. In an open trial conducted by Calabrese et al. (86), after 12 months lamotrigine appeared to be both well tolerated and effective as monotherapy (N=17) and in combination with other mood stabilizers (N=50). Hence, lithium and lamotrigine in combination may be a rational regimen, but more data are needed.

Combinations With Valproate (table 2)

Valproate and lithium. See the previous discussion of the combination of lithium and valproate in the Combinations With Lithium section.

Valproate and carbamazepine. While the combination of valproate and carbamazepine has been generally found to be effective, its safety has been questioned. When Schaff et al. (6) gave divalproex sodium to patients taking carbamazepine, improvement was observed in 69% of patients who had failed to respond to carbamazepine alone (N=29). Tohen et al. (87) studied pharmacy records of patients treated with both medications simultaneously and found that all 12 of the bipolar disorder patients studied had moderate to marked responses, while only two patients had minor side effects.

A synergistic effect was suggested by Ketter et al. (88), who described a case of rapid-cycling bipolar disorder that had been refractory to both valproate and carbamazepine monotherapy but under double-blind conditions responded dramatically to the combination.

However, blood levels of these anticonvulsants must be monitored closely. Carbamazepine induces metabolism of both itself and valproate via the cytochrome P450 3A3/4 system, which may decrease the serum concentrations of both drugs and increase the risk of relapse (89, 90). Therefore, large doses of valproate are often necessary when used with carbamazepine. In addition, valproate may moderately inhibit the metabolism of carbamazepine and displace protein-bound carbamazepine and in some cases increase levels of free carbamazepine. This drug-drug interaction may result in neurotoxicity, even when valproate levels are relatively low (91).

Therefore, hazards exist with concomitant valproate and carbamazepine use. This treatment may be highly efficacious, but diligent monitoring of blood levels is required to reduce risk.

Valproate and calcium channel blockers. We found no published data regarding valproate and calcium channel blockers in combination, although one of us (A.L.S.) has used this combination on several occasions with moderate success and without adverse effects.

Valproate and traditional neuroleptics. For patients with mixed or rapid-cycling episodes or dysphoric mania with psychotic features, most experts consider the combination of a high- or medium-potency neuroleptic and valproate a first-line treatment (2). Wassef et al. (92) reported efficacy in treating psychosis in two schizophrenic patients and one schizoaffective patient, who responded dramatically to the combination of valproate and neuroleptics. Van Sweden and Van Moffaert (93) reported four cases of encephalopathy resulting from the concurrent administration of valproate and neuroleptics. Although combined use of valproate and traditional neuroleptics is widespread and may be a sensible treatment approach, more definitive studies are needed.

Valproate and clozapine. Presently, the data concerning the combination of valproate and clozapine are variable. In one open-label study of 55 patients (94), this combination was effective for 87% of the patients. The most common adverse reactions were sedation, enuresis, nausea, excessive salivation, and benign increase in liver function tests. One patient developed subsequent hepatic dysfunction. Conflicting reports suggest that valproate may slightly increase the serum concentrations of clozapine metabolites (95) or decrease concentrations of clozapine and metabolites (96). Furthermore, a case of neurotoxicity after several months of treatment with this combination has been described (97). In an uncontrolled study, Wilson (98) retrospectively examined records of sequential patients who received clozapine for refractory psychosis and concluded that concomitant anticonvulsant administration may decrease the efficacy of clozapine. The 20 patients receiving concurrent anticonvulsant treatment were judged to have poorer clinical outcomes than the 68 patients who did not receive anticonvulsants.

At this time, the efficacy and safety of this combination are not established. Clozapine lowers the seizure threshold, so adding valproate can prevent associated seizures. Both drugs exhibit antikindling properties, raising intriguing questions about epileptogenesis and mood stabilization (99). Hence, more data regarding combination treatment with valproate and clozapine are needed.

Valproate and risperidone. Data regarding the combined use of valproate and risperidone are scarce. In two studies that examined this issue, the investigators did not differentiate efficacy and adverse reactions occurring with risperidone monotherapy from those associated with several different combinations of mood stabilizers and risperidone. Advantages and drawbacks of specific combinations are difficult to infer, but Ghaemi et al. (73) rated three of four patients treated with a combination of risperidone, lithium, and valproate as "much improved." Tohen et al. (72) reported that in their study two patients treated with a combination of risperidone, valproate, and lithium were able to complete the 6-week study, and they stated that no patients who completed the study worsened clinically. The data regarding the combination of valproate with traditional neuroleptics, described earlier, may also be applicable to the combination of risperidone and valproate.

Valproate and olanzapine. To our knowledge there are no published data at this time regarding this combination. Side effects (e.g., weight gain, sedation) may be additive.

Valproate and lamotrigine. Most of the known information about the combination of valproate and lamotrigine is based on use with seizure patients. Most important, concomitant valproate treatment substantially increases the blood level of lamotrigine (100, 101) because of the inhibition of glucuronidation. Adverse reactions, particularly skin rash, may occur with greater frequency or severity. Other side effects that may occur are ataxia, tremor, sedation, and fatigue (100–105). However, such symptoms should improve as the dose of lamotrigine is decreased (102, 103). Also important, when lamotrigine is added to valproate therapy, valproate concentrations may be possibly decreased (106).

Specifically concerning bipolar disorder, in the previously mentioned open study by Calabrese et al. (86), valproate plus lamotrigine was used (N=18), and preliminary results indicate efficacy. Six of the eight patients who dropped out because of adverse events experienced rash, a finding that emphasizes the need to monitor patients receiving this combination closely for dermatologic side effects.

In summary, the combination of valproate and lamotrigine may be highly effective, but extreme caution is warranted. The most troubling factor is the increased risk of serious dermatologic reactions. Hence, the combination of valproate and lamotrigine may be a rational treatment if patients are adequately informed about the risks of adverse reactions, low doses of lamotrigine are used, and lamotrigine is discontinued at the onset of severe rash or rash with systemic symptoms.

Valproate and gabapentin. Valproate and gabapentin in combination require further study, as few data are currently available. These agents appear to be safe together and to have no major interactions, and no adverse reactions have been reported (107). Hence, no dose adjustment or additional serum blood level monitoring is indicated. Efficacy for bipolar disorder patients is not yet established for gabapentin monotherapy, but the combination of valproate and gabapentin may be a reasonable treatment approach for patients with refractory illness.

Other Combinations (table 3)

Carbamazepine and clozapine. The combination of carbamazepine and clozapine is generally contraindicated. First, carbamazepine and clozapine each produce hematologic side effects at higher frequencies than do most other available drugs (108). Another consideration is that carbamazepine lowers the level of clozapine, possibly more than it lowers levels of traditional neuroleptics (109, 110).

Raising further questions regarding safety, Müller et al. (111) reported a case of neuroleptic malignant syndrome in a patient taking clozapine and carbamazepine. Asterixis has also been reported (23).

The combination of carbamazepine and clozapine should not be considered safe. Therefore, careful consideration of risks and benefits is mandatory before a regimen of this combination is begun. Should carbamazepine and clozapine be used together, vigilant monitoring of the WBC count and drug levels is crucial.

Carbamazepine and traditional neuroleptics. For patients with classic, euphoric acute mania with psychotic features, the combination of a high- or medium-potency neuroleptic and carbamazepine is considered by most experts to be a first-line treatment (2).

As stated earlier, carbamazepine increases the metabolism of most neuroleptics. The levels of traditional neuroleptics are decreased by the induction of their metabolism by carbamazepine. This can lead to a recurrence of psychiatric symptoms, as seen in case reports (112, 113).

Therefore, the simultaneous use of carbamazepine and traditional neuroleptics can be considered useful for bipolar disorder. Increasing the neuroleptic dose may be necessary to achieve therapeutic gains. More studies would be helpful in establishing safety and efficacy.

Carbamazepine and calcium channel blockers. Carbamazepine and calcium channel blockers should be used together with extreme caution. Both diltiazem and verapamil have been shown to increase levels of carbamazepine (114, 115). Toxicity has been reported, most often in the form of neurologic symptoms. In one study (116), six patients with epilepsy were given concurrent verapamil and carbamazepine, and within a few days all experienced neurotoxicity. In another study of seizure patients (117), toxicity was seen with carbamazepine in combination with diltiazem and verapamil, but not with nifedipine.

Hence, carbamazepine and calcium channel blockers should be used together with caution. Different calcium channel blockers may pose distinct risks of neurotoxicity with carbamazepine, but combined use of carbamazepine and any calcium channel blocker should be considered potentially hazardous.

Carbamazepine and lamotrigine. Carbamazepine likely speeds the metabolism of lamotrigine, but the clinical significance is unclear. In children with seizure disorders, adjustments of carbamazepine dose were not necessary when lamotrigine was added (101). Although one study of the pharmacokinetics (118) has shown that lamotrigine has no effect on the metabolism of carbamazepine, another study (119) showed that lamotrigine increased carbamazepine metabolite concentrations by 45% and resulted in neurotoxicity.

In a study of bipolar patients mentioned earlier (86), both lamotrigine monotherapy and combination therapy have appeared effective and well tolerated, and one group received concomitant lamotrigine and carbamazepine (N=6).

As the data are contradictory, more study is required to assess the safety and efficacy of concurrent treatment with lamotrigine and carbamazepine, but these two agents have less significant pharmacologic interactions than do lamotrigine and valproate.

Carbamazepine and gabapentin. As with valproate, the coadministration of carbamazepine with gabapentin appears safe, with no significant interactions (107). Hence, dose adjustments and additional blood level monitoring are not necessary. The combination of carbamazepine and gabapentin has not been established as efficacious in bipolar disorder, but to our knowledge no adverse reactions have been reported to date. At this time, concurrent carbamazepine and gabapentin treatment appears benign and may be reasonable in treating refractory bipolar disorder.

Lamotrigine and gabapentin. Our search revealed no published data regarding the coadministration of lamotrigine and gabapentin in bipolar disorder. To our knowledge no adverse reactions have been reported with concurrent use for epilepsy patients. One of us (A.L.S.) has eight patients with refractory bipolar disorder who are taking the combination of lamotrigine and gabapentin with satisfactory results.

DISCUSSION

Abstract | METHOD | RESULTS | DISCUSSION | References

Several combinations of mood stabilizers appear to be safe and effective. Unfortunately, there is a conspicuous lack of controlled data regarding mood stabilizer combinations, despite their widespread use. Limited data from open-label studies are available for many such combinations. As there is a bias in the literature toward the reporting of adverse reactions, it is likely that many of these combinations are being used with good results more often than is reflected in the published data. As with any medication regimen, combination therapy requires that the prescribing clinician continually assess risks and benefits. Combination therapy introduces considerations such as drug interactions and additional side effects. The interactions of combinations of mood stabilizers are sometimes complex, often very useful, and potentially dangerous. Combination therapy may also decrease compliance (120). One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. This strategy of using low doses is particularly relevant for the elderly bipolar patient.

Currently, the most useful mood stabilizer combinations are the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Carbamazepine, lamotrigine, and gabapentin have also been added to lithium with apparent safety. Combinations of anticonvulsants have also been used with success, although pharmacokinetic interactions may complicate this strategy, particularly when valproate plus carbamazepine or valproate plus lamotrigine is used. Combinations of lithium or anticonvulsant mood stabilizers with standard or atypical antipsychotic agents and benzodiazepines have also been used with relatively good success.

As more potential mood stabilizers are identified, more permutations of combinations will come into use. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action (121).

TABLE 1

View Large | Download Slide(.ppt)
Add to My POL

TABLE 2

View Large | Download Slide(.ppt)
Add to My POL

TABLE 3

View Large | Download Slide(.ppt)
Add to My POL

Received March 31, 1997; revision received July 24, 1997; accepted Aug. 8, 1997. From the Psychopharmacology Unit, Division of Psychiatry, Brigham and Women's Hospital, and the Department of Psychiatry, Harvard Medical School, Boston. Address reprint requests to Dr. Freeman, Psychopharmacology Unit, Division of Psychiatry, Brigham and Women's Hospital, 221 Longwood Ave., Boston, MA 02115; mpfreeman@bics.bwh.harvard.edu (e-mail). Supported in part by a Young Investigator Award to Dr. Stoll from the National Alliance for Research on Schizophrenia and Depression.

References

Abstract | METHOD | RESULTS | DISCUSSION | References

Nichol MB, Stimmel GL, Lange SC: Factors predicting the use of multiple psychotropic medications. J Clin Psychiatry 1995; 56:60–66[PubMed]

Frances A, Docherty JP, Kahn DA: Treatment of bipolar disorder. J Clin Psychiatry 1996; 57(suppl 12A):5–58

Fenn HH, Robinson D, Luby V, Dangel C, Buxton E, Beattie M, Kraemer H, Yesavage JA: Trends in pharmacotherapy of schizoaffective and bipolar affective disorders: a 5-year naturalistic study. Am J Psychiatry 1996; 153:711–713[PubMed]

Solomon DA, Ryan CE, Keitner GI, Miller IW, Shea T, Kazim A, Keller MB: A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder. J Clin Psychiatry 1997; 58:95–99[PubMed][CrossRef]

Sharma V, Persad E, Mazmanian D, Karunaratne K: Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium. Can J Psychiatry 1993; 38:137–139[PubMed]

Schaff M, Fawcett J, Zajecka J: Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry 1993; 54:380–384[PubMed]

Sharma V, Persad E: Augmentation of valproate with lithium in a case of rapid cycling affective disorder. Can J Psychiatry 1992; 37:584–585[PubMed]

Mitchell P, Withers K, Jacobs G, Hickie I: Combining lithium and sodium valproate for bipolar disorder. Aust NZ J Psychiatry 1994; 28:141–143[CrossRef]

Lenox RH, McNamara RK, Watterson JM, Watson DG: Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain? J Clin Psychiatry 1996; 57(suppl 13):23–31

Granneman GR, Schneck DW, Cavanaugh JH, Witt GF: Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium. J Clin Psychiatry 1996; 57:204–206[PubMed]

Di Costanzo E, Schifano F: Lithium alone or in combination with carbamazepine for the treatment of rapid-cycling bipolar affective disorder. Acta Psychiatr Scand 1991; 83:456–459[PubMed][CrossRef]

Kramlinger K, Post R: Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania. Acta Psychiatr Scand 1989; 79:378–385[PubMed][CrossRef]

Small JG, Klapper MH, Marhenke JD, Milstein V, Woodham GC, Kellams JJ: Lithium combined with carbamazepine or haloperidol in the treatment of mania. Psychopharmacol Bull 1995; 31:265–272[PubMed]

Kishimoto A: The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16:483–493[PubMed][CrossRef]

Shukla S, Cook BL, Miller MG: Lithium-carbamazepine versus lithium-neuroleptic prophylaxis in bipolar illness. J Affect Disord 1985; 9:219–222[PubMed][CrossRef]

Inoue K, Arima S, Tanaka K, Fukui Y, Kato N: A lithium and carbamazepine combination in the treatment of bipolar disorder—a preliminary report. Folia Psychiatr Neurol Jpn 1981; 35:465–475[PubMed]

Stromgren LS: The combination of lithium and carbamazepine in treatment and prevention of manic-depressive disorder: a review and a case report. Compr Psychiatry 1990; 31:261–265[PubMed][CrossRef]

Lipinski JF, Pope HG Jr: Possible synergistic action between carbamazepine and lithium carbonate in the treatment of three acutely manic patients. Am J Psychiatry 1982; 139:948–949[PubMed]

Brewerton T: Lithium counteracts carbamazepine-induced leucopenia while increasing its therapeutic effect. Biol Psychiatry 1996; 21:677–685

Joffe R: Hematological effects of lithium potentiation of carbamazepine in patients with affective illness. Int Clin Psychopharmacol 1988; 3:53–57[PubMed][CrossRef]

Sheehan J, Shelley R: Leucopenia secondary to carbamazepine despite concurrent lithium treatment. Br J Psychiatry 1990; 157:911–912[PubMed][CrossRef]

Chaudhry RP, Waters BG: Lithium and carbamazepine interaction: possible neurotoxicity. J Clin Psychiatry 1983; 44:30–31

Rittmannsberger H, Leblhuber F: Asterixis induced by carbamazepine therapy. Biol Psychiatry 1992; 32:364–368[PubMed][CrossRef]

Shukla S, Godwin CD, Long LEB, Miller MG: Lithium-carbamazepine neurotoxicity and risk factors. Am J Psychiatry 1984; 141:1604–1606[PubMed]

Helmuth D, Ljaljevic Z, Ramirez L, Meltzer H: Choreoathetosis induced by verapamil and lithium treatment. J Clin Psychopharmacol 1989; 9:454–455[PubMed][CrossRef]

Finley P, Warner M, Peabody C: Clinical relevance of drug interactions with lithium. Clin Pharmacokinet 1995; 29:172–191[PubMed][CrossRef]

Wright B, Jarrett D: Lithium and calcium channel blockers: possible neurotoxicity. Biol Psychiatry 1991; 30:635–636[PubMed][CrossRef]

Dubovsky SL, Franks RD, Allen S: Verapamil: a new antimanic drug with potential interactions with lithium. J Clin Psychiatry 1987; 48:371–372[PubMed]

Weinrauch LA, Belok S, D'Elia J: Decreased serum lithium during verapamil therapy. Am Heart J 1984; 108:1378–1380[PubMed][CrossRef]

Valdiserri EV: A possible interaction between lithium and diltiazem: case report. J Clin Psychiatry 1985; 46:540–541[PubMed]

Esparon J, Kolloori J, Naylor GJ, McHarg AM, Smith AH, Hopwood SE: Comparison of the prophylactic action of flupenthixol with placebo in lithium treated manic-depressive patients. Br J Psychiatry 1986; 148:723–725[PubMed][CrossRef]

Juhl RP, Tsuang MT, Perry PJ: Concomitant administration of haloperidol and lithium carbonate in acute mania. Dis Nerv Syst 1977; 38:675–676[PubMed]

Goldney RD, Spence ND: Safety of the combination of lithium and neuroleptic drugs. Am J Psychiatry 1986; 143:882–884[PubMed]

Krishna NR, Taylor MA, Abrams R: Combined haloperidol and lithium carbonate in treating manic patients. Compr Psychiatry 1978; 19:119–120[PubMed][CrossRef]

Perenyi A, Rihmer Z, Banki C: Parkinsonian symptoms with lithium, lithium-neuroleptic, and lithium-antidepressant treatment. J Affect Disord 1983; 5:171–177[PubMed][CrossRef]

Miller F, Menninger J: Lithium-neuroleptic neurotoxicity is dose dependent. J Clin Psychopharmacol 1987; 7:89–91[PubMed]

Baastrup PC, Hollnagel P, Sorensen R, Schou M: Adverse reactions in treatment with lithium carbonate and haloperidol. JAMA 1976; 236:2645–2646[PubMed][CrossRef]

Garfinkel PE, Stancer HC, Persad E: A comparison of haloperidol, lithium carbonate, and their combination in the treatment of mania. J Affect Disord 1980; 2:279–288[PubMed][CrossRef]

Carman JS, Bigelow LB, Wyatt RJ: Lithium combined with neuroleptics in chronic schizophrenic and schizoaffective patients. J Clin Psychiatry 1981; 42:124–128[PubMed]

Ghadirian AM, Nair NP, Schwartz G: Effect of lithium and neuroleptic combination on lithium transport, blood pressure, and weight in bipolar patients. Biol Psychiatry 1989; 26:139–144[PubMed][CrossRef]

Loew MR: Rapid cycling disorders and the role of combined lithium and haloperidol decanoate. Can J Psychiatry 1986; 31:877–878[PubMed]

Bigelow LB, Weinberger DR, Wyatt RJ: Synergism of combined lithium-neuroleptic therapy: a double-blind, placebo-controlled case study. Am J Psychiatry 1981; 138:81–83[PubMed]

Miller F, Menninger J, Whitcup S: Lithium-neuroleptic neurotoxicity in the elderly bipolar patient. J Clin Psychopharmacol 1986; 6:176–178[PubMed]

Spring G: Neurotoxicity with combined use of lithium and thioridazine. J Clin Psychiatry 1979; 40:135–138[PubMed]

Mani J, Tandel S, Shah P, Karnad D: Prolonged neurological sequelae after combination treatment with lithium and antipsychotic drugs. J Neurosurg Psychiatry 1996; 60:350–351[CrossRef]

Byrne A, Zibin T, Chimich W, Hnatko G: Severe hypotension associated with combined lithium and chlorpromazine therapy: a case report and a review. Can J Psychiatry 1994; 39:294–296[PubMed]

Menes C, Burra P, Hoaken P: Untoward effects following combined neuroleptic-lithium therapy: cardiac arrhythmias and seizure. Can J Psychiatry 1980; 25:573–576[PubMed]

Cohen WJ, Cohen NH: Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 1974; 230:1283–1287[PubMed][CrossRef]

Marhold J, Zimanova J, Lachman M, Kral J, Vojtechovsky M: To the incompatibility of haloperidol with lithium salts. Act Nerv Super (Praha) 1974; 16:199–200[PubMed]

Loudon JB, Waring H: Toxic reactions to lithium and haloperidol (letter). Lancet 1976; 2:1088[PubMed]

Mann SC, Greenstein RA, Eilers R: Early onset of severe dyskinesia following lithium-haloperidol treatment (letter). Am J Psychiatry 1983; 140:1385–1386

Spring G, Frankel M: New data on lithium and haloperidol incompatibility. Am J Psychiatry 1981; 138:818–821[PubMed]

Dinan T, Kohen D: Tardive dyskinesia in bipolar affective disorder: relationship to lithium therapy. Br J Psychiatry 1989; 155:55–57[PubMed][CrossRef]

Perenyi A, Szucs R, Frecska E: Tardive dyskinesia in patients receiving lithium maintenance therapy. Biol Psychiatry 1984; 19:1573–1578[PubMed]

Goodwin J, Jamison KR: Manic Depressive Illness. New York, Oxford University Press, 1990

Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA, Meltzer HY: Clozapine for treatment-refractory mania. Am J Psychiatry 1996; 153:759–764[PubMed]

McElroy SL, Dessain EC, Pope HG Jr, Cole JO, Keck PE Jr, Frankenberg FR, Aizley HG, O'Brien S: Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 1991; 52:411–414[PubMed]

Zarate CA Jr, Tohen M, Baldessarini RJ: Clozapine in severe mood disorders. J Clin Psychiatry 1995; 56:411–417[PubMed]

Zarate CA Jr, Tohen M, Banov MP, Weiss MK, Cole JO: Is clozapine a mood stabilizer? J Clin Psychiatry 1995; 56:108–112

Kimmel SE, Calabrese JR, Woyshville MJ, Meltzer HY: Clozapine in treatment-refractory mood disorders. J Clin Psychiatry 1994; 55(Sept suppl B):91–93

Banov MD, Zarate C Jr, Tohen M, Scialabba D, Wines JD Jr, Kolbrener M, Kim JW, Cole JO: Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. J Clin Psychiatry 1994; 55:295–300[PubMed]

Suppes T, Phillips KA, Judd CR: Clozapine treatment of nonpsychotic rapid cycling bipolar disorder: a report of three cases. Biol Psychiatry 1994; 136:338–340

Puri BK, Taylor DG, Alcock ME: Low-dose maintenance clozapine treatment in the prophylaxis of bipolar affective disorder. Br J Clin Pract 1995; 49:333–334[PubMed]

Fuchs DC: Clozapine treatment of bipolar disorder in a young adolescent. J Am Acad Child Adolesc Psychiatry 1994; 33:1299–1302[PubMed][CrossRef]

Blake LM, Marks RC, Luchins DJ: Reversible neurologic symptoms with clozapine and lithium. J Clin Psychopharmacol 1992; 12:297–299[PubMed]

Garcia G, Crismon M, Dorson P: Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol 1994; 14:426–428[PubMed]

Lemus C, Lieberman J, Johns C: Myoclonus during treatment with clozapine and lithium: the role of serotonin. Hillside J Clin Psychiatry 1989; 11:127–130[PubMed]

Peterson GA, Byrd SL: Diabetic ketoacidosis from clozapine and lithium cotreatment (letter). Am J Psychiatry 1996; 153:737–738

Pope HG Jr, Cole JO, Choras PT, Fulwiler CE: Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nerv Ment Dis 1986; 174:493–495[PubMed][CrossRef]

Adityanjee: Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate (letter). Am J Psychiatry 1995; 152:648–649[PubMed]

Valevski A, Modai I, Lahav M, Weizman A: Clozapine-lithium combined treatment and agranulocytosis. Int Clin Psychopharmacol 1993; 8:63–65

Tohen M, Zarate CA Jr, Centorrino F, Hegarty JI, Froeschl M, Zarate SB: Risperidone in the treatment of mania. J Clin Psychiatry 1996; 57:249–253[PubMed]

Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ: Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry 1997; 42:196–199[PubMed]

Swanson CL Jr, Price WA, McEvoy JP: Effects of concomitant risperidone and lithium treatment (letter). Am J Psychiatry 1995; 152:1096

Chen B, Cardasis W: Delirium induced by lithium and risperidone combination (letter). Am J Psychiatry 1996; 153:1233–1234[PubMed]

Aronson TA, Shukla S, Hirschowitz J: Clonazepam treatment of five lithium-refractory patients with bipolar disorder. Am J Psychiatry 1989; 146:77–80[PubMed]

Sachs GS, Rosenbaum JF, Jones L: Adjunctive clonazepam for maintenance treatment of bipolar affective disorder. J Clin Psychopharmacol 1990; 10:42–47[PubMed][CrossRef]

Sachs GS, Weilburg JB, Rosenbaum JF: Clonazepam vs neuroleptics as adjuncts to lithium maintenance. Psychopharmacol Bull 1990; 26:137–143[PubMed]

Adler LW: Mixed bipolar disorder responsive to lithium and clonazepam. J Clin Psychiatry 1986; 47:49–50

Modell JG, Lenox RH, Weiner S: Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol 1985; 5:109–113[PubMed][CrossRef]

Koczerginski D, Kennedy SH, Swinson RP: Clonazepam and lithium—a toxic combination in the treatment of mania? Int Clin Psychopharmacol 1989; 4:195–199

Schaffer CB, Schaffer LC: Gabapentin in the treatment of bipolar disorder (letter). Am J Psychiatry 1997; 154:291–292[PubMed]

Stanton SP, Keck PE Jr, McElroy SL: Treatment of acute mania with gabapentin (letter). Am J Psychiatry 1997; 154:287

Vollmer KO, Von Hodenberg A, Kolle EU: Pharmacokinetics and metabolism of gabapentin in rat, dog, and man. Arzneimittelforschung 1986; 36:830–839[PubMed]

Calabrese JR, Fatemi SH, Woyshville MJ: Antidepressant effects of lamotrigine in rapid cycling bipolar disorder (letter). Am J Psychiatry 1996; 153:1236

Calabrese J, Bowden C, McElroy S, Cookson J, Anderson J, Rhodes L, Woychville M, Keck P, Kundu F, Patterson G, Ascher J, Golden-Watson C: Efficacy of lamotrigine in bipolar disorder: preliminary data, in Mechanisms of Antibipolar Disorder Treatments. Edited by Manji H, Bowden C, Belmaker R. Washington, DC, American Psychiatric Press (in press)

Tohen M, Castillo J, Pope HG Jr, Herbstein J: Concomitant use of valproate and carbamazepine in bipolar and schizoaffective disorders. J Clin Psychopharmacol 1994; 14:67–70[PubMed]

Ketter TA, Pazzaglia PJ, Post RM: Synergy of carbamazepine and valproic acid in affective illness: case report and review of the literature. J Clin Psychopharmacol 1992; 12:276–281[PubMed]

Levy RH: Cytochrome P450 isoenzymes and antiepileptic drug interactions. Epilepsia 1995; 36(5, suppl):S8–S13

Sovner R: A clinically significant interaction between carbamazepine and valproic acid. J Clin Psychopharmacol 1988; 8:448–449[PubMed][CrossRef]

Onady AA, Calabrese JR: Carbamazepine auto- and hetero-induction complicating clinical care. J Clin Psychopharmacol 1989; 9:387–388

Wassef A, Watson DJ, Morrison P, Bryant S, Flack J: Neuroleptic-valproic acid combination in treatment of psychotic symptoms: a three-case report. J Clin Psychopharmacol 1989; 9:45–48[PubMed]

Van Sweden B, Van Moffaert M: Valproate as psychotropic agent: interactions and adverse cerebral reactions. Acta Psychiatr Scand 1985; 72:315–317[PubMed][CrossRef]

Kando JC, Tohen M, Castillo J, Centorrino F: Concurrent use of clozapine and valproate in affective and psychotic disorders. J Clin Psychiatry 1994; 55:255–257[PubMed]

Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpicelli SA, Puopolo PR, Flood JG: Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. Am J Psychiatry 1994; 151:123–125[PubMed]

Longo LP, Salzman C: Valproic acid effects on serum concentrations of clozapine and norclozapine (letter). Am J Psychiatry 1995; 152:650

Costello L, Suppes T: A clinically significant interaction between clozapine and valproate. J Clin Psychopharmacol 1995; 15:139–140[PubMed][CrossRef]

Wilson W: Do anticonvulsants hinder clozapine treatment? Biol Psychiatry 1995; 37:132–133

Graham SR, Kokkinidis L: Clozapine inhibits limbic system kindling: implications for antipsychotic action. Brain Res Bull 1993; 30:597–605[PubMed][CrossRef]

100

Peck WA: Clinical pharmacology of lamotrigine. Epilepsia 1991; 32(suppl 2):S9–S12

101

Eriksson AS, Hoppu K, Nergardh A, Boreus L: Pharmacokinetic interactions between lamotrigine and other antiepileptic drugs in children with intractable epilepsy. Epilepsia 1996; 37:769–773[PubMed][CrossRef]

102

Pisani F, Di Perri R, Perucca E, Richens A: Interaction of lamotrigine with sodium valproate (letter). Lancet 1993; 341:1224

103

Panayiotopoulos CP, Ferrie CD, Knott C, Robinson RO: Interaction of lamotrigine with sodium valproate (letter). Lancet 1993; 341:445

104

Yeun A, Land G, Weatherley B, Peck A: Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33:511–513[PubMed]

105

Reutens DC, Duncan JC, Patsalos PN: Disabling tremor after lamotrigine with sodium valproate. Lancet 1993; 342:185–186

106

Anderson G, Yau M, Gidal B, Harris S, Levy R, Lai A, Wolf K, Wargin W, Dren A: Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996; 60:145–156[PubMed][CrossRef]

107

Radulovic LL, Wilder BJ, Leppik IE, Bockbrader HN, Chang T, Posvar EL, Sedman AJ, Uthman BM, Erdman GR: Lack of interaction of gabapentin with carbamazepine or valproate. Epilepsia 1994; 35:155–161[PubMed][CrossRef]

108

Junghan U, Albers M, Woggon B: Increased risk of hematological side-effects in psychiatric patients treated with clozapine and carbamazepine? (letter). Pharmacopsychiatry 1993; 26:262[PubMed][CrossRef]

109

Tiihonen J, Vartiainen H, Hakola P: Carbamazepine-induced changes in plasma levels of neuroleptics. Pharmacopsychiatry 1995; 28:26–28[PubMed][CrossRef]

110

Raitasuo V, Lehtovaara R, Huttunen MO: Carbamazepine and plasma levels of clozapine (letter). Am J Psychiatry 1993; 150:169

111

Müller T, Becker T, Fritze J: Neuroleptic malignant syndrome after clozapine plus carbamazepine (letter). Lancet 1988; 2:1500

112

Fast DK, Jones BD, Kusalic M, Erickson M: Effect of carbamazepine on neuroleptic plasma levels and efficacy (letter). Am J Psychiatry 1986; 143:117–118[PubMed]

113

Ereshefsky L, Davis CM, Harrington CA, Jann MW, Browning JL, Saklad SR, Burch NR: Haloperidol and reduced haloperidol levels in selected schizophrenic patients. J Clin Psychopharmacol 1984; 4:138–142[PubMed]

114

Gadde K, Calabrese JR: Diltiazem effect of carbamazepine levels in manic depression. J Clin Psychopharmacol 1990; 10:378–379[CrossRef]

115

Price WA, DiMarzio LR: Verapamil-carbamazepine neurotoxicity (letter). J Clin Psychiatry 1988; 49:80[PubMed]

116

MacPhee GJ, McInnes GT, Thompson GG, Brodie MJ: Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction. Lancet 1986; 29:700–703

117

Bahls FH, Ozuna J, Ritchie DE: Interactions between calcium channel blockers and the anticonvulsants carbamazepine and phenytoin. Neurology 1991; 41:740–742[PubMed]

118

Pisani F, Xiao B, Fazio A, Spina E, Perucca E, Tomson T: Single dose pharmacokinetics of carbamazepine-10,11-epoxide in patients on lamotrigine monotherapy. Epilepsy Res 1994; 19:245–248[PubMed][CrossRef]

119

Warner T, Patsalos PN, Prevett M, Elyas AA, Duncan JS: Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Res 1992; 11:147–150[PubMed][CrossRef]

120

Keck PE Jr, McElroy SL, Strakowski SM, Stanton SP, Kizer DL, Balistreri TM, Bennett JA, Tugrul KC, West SA: Factors associated with pharmacologic noncompliance in patients with mania. J Clin Psychiatry 1996; 57:292–297[PubMed]

121

Stoll AL, Severus E: Mood stabilizers: shared mechanisms of action at postsynaptic signal-transduction and kindling processes. Harvard Rev Psychiatry 1996; 4:77–89[CrossRef]