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CME

Stabilizing Depression in Bipolar Disorder

  • Authors: Faculty: Robert M.A. Hirschfeld, MD; Guy Goodwin, MD; Erik Herman, MD; Martin Alda, MD; Joseph R. Calabrese, MD
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Target Audience and Goal Statement

This activity has been designed to meet the educational needs of physicians (psychiatry, psychology, and mental health professionals) involved in the care of patients with bipolar disorder.

Upon completion of this activity, participants will be able to:

  1. Discuss the psychosocial impact of bipolar depression, compared with that of mania and of unipolar depression.
  2. Describe the difficulty of diagnosing bipolar disorder and the role of screening tests in improving its recognition.
  3. Summarize the efficacy of mood stabilizers (including lithium, anticonvulsants, and atypical antipsychotics) for the management of bipolar depression vs mania.
  4. Discuss the role of antidepressants in the treatment of bipolar depression.
  5. Review the phenotypic spectrum of bipolar disorder and its proposed division into three main subtypes.
  6. Outline the evidence that clinical subtype may predict responsiveness to specific pharmacologic agents.
  7. Compare the various mood stabilizers in terms of tolerability, including the impact of tolerability on treatment outcomes.


Disclosures

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by FDA. The Postgraduate Institute for Medicine (PIM), WebMD Medscape, and GlaxoSmithKline do not recommend the use of any agent outside of the labeled indications.

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Author(s)

  • Guy M. Goodwin, MD

    W. A. Handley Professor of Psychiatry, University Department of Psychiatry, Warneford Hospital, Oxford, England

    Disclosures

    Disclosure: Grants/Research Support: Sanofi-Synthelabo; Consultant: Bristol-Myers Squibb Company, Lundbeck Pharmaceuticals, Pfizer Inc., GlaxoSmithKline, AstraZeneca Pharmaceuticals, LP.

  • Robert M.A. Hirschfeld, MD

    Titus Harris Chair; Professor and Chair, Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch

    Disclosures


    Disclosure: Grants/Research Support: Abbot Laboratories, Bristol-Myers Squibb Company, GlaxoSmithKline, Organon Inc., Wyeth-Ayerst; Consultant and/or on the Advisory Board: Abbot Laboratories, AstraZeneca, Bristol-Myers Squibb Company, GlaxoSmithKline, Forest Laboratories, Eli Lilly & Company, Pfizer, Inc., Organon Inc., Janssen Pharmaceutical Products, L.P., Wyeth-Ayerst Pharmaceuticals, Novartis Pharmaceutical Corporation, UCB Pharma, Inc., Shire US, Inc; Speaker's Bureau: Abbott Laboratories, Forest Laboratories.

  • Erik Herman, MD

    Psychiatric Office, Na Markvartce 8,160,00 Praha 6, Czech Republic

    Disclosures

    Disclosure: Dr. Herman has no financial interest/relationship or affiliation to disclose.

  • Martin Alda, MD

    Professor, Department of Psychiatry, Dalhousie University, Halifax, Canada

    Disclosures

    Disclosure: Professor Alda has no financial interest/relationship or affiliation to disclose.

  • Joseph R. Calabrese, MD

    Professor of Psychiatry, Case Western Reserve University, Cleveland, OH

    Disclosures

    Disclosure: Sources of Funding: National Institutes of Mental Health, Abbott Laboratories, Ciba-Geigy, Merck, Glaxo Smith Kline, Janssen Pharmaceutica, Lilly Research Laboratories, MacArthur Foundation, National Alliance for Research in Schizophrenia and Affective Disorders, Parke-Davis Pharmaceuticals, Robert Wood Johnson Pharmaceutical Research Institute, Sandoz Pharmaceuticals Corporation, SmithKline Beecham Pharmaceuticals, Stanley Foundation, TAP Holdings, Inc., UCB Pharma, Wyeth Ayerst Pharmaceuticals; Consulting Agreements/Advisory Boards: Abbott Pharmaceuticals, AstraZeneca, Bristol Myers Squibb/Otsuka, Eli Lilly, Glaxo Smith Kline, Janssen Cilag, Novartis, Parke-Davis/Warner Lambert, Robert Wood Johnson Pharmaceutical Research Institute, Shire Labs, Smith Kline, TAP Holdings, Teva Pharmaceuticals, UCB Pharma; Financial Interest/Stock Ownership: none.


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    For Physicians

  • This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    The Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.0 category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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CME

Stabilizing Depression in Bipolar Disorder: Lamotrigine: A Depression Mood Stabilizer

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Lamotrigine: A Depression Mood Stabilizer , Presented by Erik Herman, MD

Mood Stabilizers: A Proposed Reclassification

  • Most mood stabilizers were initially investigated for use in mania, and have not been well studied in bipolar depression. Until recently, there was no systematic effort to develop mood stabilizers for the depressed phase of bipolar disorder (BPD). Thus, there has been a lack of well-evaluated treatment options for bipolar depression, which has been especially problematic for patients with rapid cycling.[1]

  • Lamotrigine: A Depression Mood Stabilizer

    Slide 1.

    Lamotrigine: A Depression Mood Stabilizer

    (Enlarge Slide)
  • To highlight this unmet need, a reconceptualization of BPD has been proposed, in which euthymia is defined as the baseline. Mania, hypomania, and mixed states are "above baseline," while depression and subsyndromal depression are "below baseline."[1]

  • Reconceptualizing Bipolar Disorder

    Slide 2.

    Reconceptualizing Bipolar Disorder

    (Enlarge Slide)
  • Based on this conceptualization, 2 classes of mood stabilizers can be defined. Class A consists of agents that stabilize mood from above baseline â€' in other words, agents that have antimanic properties without inducing or worsening depression.

  • 'Class A' Mood Stabilizers

    Slide 3.

    'Class A' Mood Stabilizers

    (Enlarge Slide)
  • Class B consists of agents that stabilize mood from below baseline â€' in other words, agents that have antidepressant properties without inducing mania or cycle acceleration.[1]

    Conventional mood stabilizers â€' lithium and the anticonvulsants, carbamazepine (off-label use) and valproate or divalproex â€' are primarily antimanic agents, but do appear to have some antidepressant activity.[2] Of these agents, lithium probably comes closest to meeting the definition of both a Class A and a Class B mood stabilizer.[1] However, in acute treatment of bipolar depression, response to lithium is often delayed or incomplete.[1,3] In lithium prophylaxis, depressive breakthrough is usually more of a problem than manic breakthrough,[4] and several placebo-controlled trials have failed to show significant efficacy in preventing depressive relapses.[5-8] Lithium appears to be most effective in classical BPD, and less effective in atypical variants, such as rapid cycling.[1]

    On the other hand, the anticonvulsant lamotrigine may be considered the prototype of a Class B mood stabilizer.[5] In clinical trials it has been shown to benefit acute bipolar depression without inducing mania or cycle acceleration; it also prevents depressive relapse. Lamotrigine was approved in 2003 by the US Food and Drug Administration (FDA) for long-term maintenance treatment of BPD. Key data from lamotrigine clinical trials will be presented in the next section of this program (Lamotrigine for Bipolar Depression).

    Other anticonvulsants, including gabapentin, topiramate, and levetiracetam, have been used off-label in BPD. Gabapentin has anxiolytic properties, and may be a useful adjunct, particularly in patients with comorbid anxiety;[9] however, controlled data do not support its use as monotherapy for either mania or depression.[10] Controlled data for topiramate are scarce. One randomized study failed to show an acute antimanic effect (as monotherapy); another randomized study suggested an acute antidepressant effect (as an adjunct to mood stabilizer therapy).[11] However, topiramate has also been observed to induce depression in some epilepsy patients.[7] Levetiracetam (added on to previous treatment) has shown promise in stabilizing both mania and depression in case reports of refractory rapid cycling,[12] but there have been no controlled trials with this agent.

    Antidepressants, though widely used to treat bipolar depression, do not meet the criteria for Class B mood stabilizers because they can potentially induce switching into mania and cycle acceleration. Tricyclic antidepressants appear to carry the highest risk,[13] while newer agents, such as selective serotonin reuptake inhibitors (SSRIs) and bupropion, have been associated with low rates of switching in most (but not all) reports.[2,13,14] However, treatment-emergent mania has been reported with all major antidepressant classes.[13] An estimated 20% to 40% of bipolar patients may be at risk,[13] especially those with rapid cycling.[4,7,14] Naturalistic observations suggest that concurrent use of mood stabilizers may reduce the risk by as much as 50%.[15] Antidepressants are not recommended as monotherapy for bipolar depression.[16]

    Antipsychotic agents are also used in BPD â€' not only for their antipsychotic activity, but also for their mood-stabilizing effects. Conventional antipsychotics do not meet the criteria for Class A mood stabilizers, because they can induce or worsen depression.[1,7,9,17] However, atypical antipsychotics do not appear to have depressive effects.[1,14] Olanzapine and (more recently) risperidone[18] and quetiapine[19] have been FDA approved for acute mania.

    Olanzapine, both as monotherapy and in combination with fluoxetine, has also shown antidepressant efficacy in an 8-week placebo-controlled trial involving 833 patients with acute bipolar depression. The olanzapine-fluoxetine combination was significantly more effective than olanzapine alone,[20] and was FDA approved in 2003 for acute treatment of bipolar depression.[21] Further studies are needed to determine whether the combination has the potential to induce mania or rapid cycling with long-term use.[22]

    Olanzapine has now also been approved for maintenance therapy in BPD, based on the results of a double-blind, placebo-controlled trial in which 361 patients with manic or mixed episodes, who had responded to olanzapine during an initial open-label phase, were randomly assigned to continue on either olanzapine or placebo. The olanzapine group had a significantly longer time to either manic or depressive relapse than the placebo group.[23]

    Although olanzapine appears to meet the criteria for both a Class A and a Class B mood stabilizer, it should be noted that there have been anecdotal reports associating olanzapine and other atypical antipsychotics with induction of mania or hypomania (mostly in patients with psychotic disorders).[17,24] Whether or not there is a causal relationship is controversial.[17,24,25] In the 8-week trial comparing olanzapine, olanzapine-fluoxetine, and placebo, the incidence of treatment-emergent mania was similar in all 3 groups. However, the investigators note that the study population had not been specifically selected for high-risk characteristics, such as a recent manic episode.[20] There is also a single case report in which a major depressive episode (in a patient with a history of nonbipolar psychotic depression) was attributed to a pharmacokinetic interaction between olanzapine and fluoxetine.[26]

  • Slide

    Slide 4.

    'Class B' Mood Stabilizers

    (Enlarge Slide)

Lamotrigine for Bipolar Depression: Efficacy Data for Acute Treatment

  •  
  • Lamotrigine: Effective in Acute Bipolar I Depression

    Slide 5.

    Lamotrigine: Effective in Acute Bipolar I Depression

    (Enlarge Slide)

Acute Treatment

  • In a double-blind, parallel-group, multicenter bipolar I disorder (BP I) trial, 192 BP I outpatients with an acute episode of major depression were randomly assigned to receive lamotrigine (either 50 mg/day or 200 mg/day) or placebo for 7 weeks. The 17-item Hamilton Rating Scale for Depression (HAMD-17), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions Scale for Improvement (CGI-I) were completed at each weekly visit. A response was defined as a 50% reduction on either the HAMD-17 or MADRS, or as a rating of much or very much improved on the CGI-I.[27]

    By week 7, more than 50% of patients on the higher lamotrigine dose met all 3 response criteria. Compared with placebo, the percentage of responders was significantly higher with both lamotrigine doses -- by the MADRS criterion in the 50-mg/day group, and by both MADRS and CGI-I criteria in the 200-mg/day group.[27]

  •  
  • In a double-blind randomized refractory BPD crossover trial, lamotrigine was compared with gabapentin and placebo (6 weeks of each treatment) in 31 patients with refractory mood disorders â€' 11 with BP I, 14 with bipolar II disorder (BP II), and 6 with unipolar depression. Of the 25 bipolar patients, 23 had rapid cycling. Doses were titrated to clinical efficacy or maximum tolerable dose (500 mg/day lamotrigine, 4800 mg/day gabapentin). At 6 weeks, the mean doses were lamotrigine 274 mg/day and gabapentin 3987 mg/day. Response was defined as an overall Clinical Global Impressions Scale for Bipolar Illness (CGI-BP) rating of much improved or very much improved.[28]

    The percentage of responders was significantly higher with lamotrigine than with either gabapentin or placebo. Response rates for manic and depressive components were also higher with lamotrigine, but the differences did not reach statistical significance.[28]

    This study was later extended to include 45 patients with refractory mood disorders â€' 15 with BP I, 20 with BP II, and 10 with unipolar depression. Of the 35 bipolar patients, 26 had rapid cycling. Overall response rates were similar to those previously reported.[29]

  • Lamotrigine: Effective in Refractory Bipolar or Unipolar Mood Disorder

    Slide 6.

    Lamotrigine: Effective in Refractory Bipolar or Unipolar Mood Disorder

    (Enlarge Slide)

Efficacy Data for Rapid-Cycling Maintenance Therapy

  •  
  • Lamotrigine: Maintenance Efficacy in Rapid Cycling

    Slide 7.

    Lamotrigine: Maintenance Efficacy in Rapid Cycling

    (Enlarge Slide)

Maintenance Therapy

  • Lamotrigine maintenance therapy has been studied in a group of 324 BP I and BP II patients with rapid cycling. During an open-label treatment phase, lamotrigine was added to their current regimens. Stabilized patients were then tapered off their other medications and (if they remained stable) were randomly assigned in a double-blind manner to either lamotrigine or placebo for 6 months. The primary outcome was the time to emerging symptoms requiring additional pharmacotherapy. A secondary outcome was survival in the study (time to discontinuation for any reason).[30]

    One hundred eighty-two patients (56%) were randomized, of whom 177 were included in the efficacy analysis. The primary outcome measure did not differ significantly between the groups. However, survival in the study was significantly longer in the lamotrigine group, with a median survival time of 14 weeks, compared with 8 weeks in the placebo group. A statistically significant 41% of the lamotrigine group, compared with 26% of the placebo group, remained stable throughout the 6-month study period.[30]

  •  
  • In a post-hoc subgroup analysis, the survival benefit was statistically significant in patients with BP II (n = 52), but not BP I (n = 125).[30]

  • Survival in Rapid-Cycling Study

    Slide 8.

    Survival in Rapid-Cycling Study

    (Enlarge Slide)

Efficacy Data for Bipolar I Disorder Maintenance Therapy

  • Two large, randomized, double-blind trials compared lamotrigine, lithium, and placebo in maintenance therapy of BP I. One trial (GW605/2003) focused on patients with a recent depressive episode (n = 966);[8] the other (GW606/2006), on patients with a recent manic, hypomanic, or mixed episode (n = 349).[6] These pivotal studies were designed prospectively for pooled analysis.[5]

    Each trial had an initial 8- to 16-week open-label phase, during which lamotrigine was started and other medications withdrawn. Responders (n = 175 in the mania study, and n = 463 in the depression study) were then randomized to receive lamotrigine, lithium, or placebo for up to 18 months. The primary end point was time to intervention for any mood episode. Secondary end points included time to intervention for a depressive or for a manic/hypomanic/mixed episode.[5,6,8]

    In each study separately and in the pooled analysis, both lamotrigine and lithium significantly prolonged time to intervention for any mood episode, compared with placebo. There was no significant difference between the 2 active treatments.[5,6,8,31]

    In each study separately, lithium (but not lamotrigine) significantly prolonged the time to manic relapse, compared with placebo. Conversely, lamotrigine (but not lithium) significantly prolonged the time to depressive relapse. (Lamotrigine and lithium did not differ significantly from each other on either of these secondary outcomes).[5,6,8]

  • Median Time to Relapse: Any Mood Episode

    Slide 9.

    Median Time to Relapse: Any Mood Episode

    (Enlarge Slide)
  • In the pooled analysis, lithium was significantly superior to lamotrigine â€' and both agents were significantly superior to placebo â€' in prolonging the time to manic relapse. Lamotrigine, but not lithium, was significantly superior to placebo in prolonging the time to depressive relapse (lamotrigine and lithium were not statistically different).[5,31] Lamotrigine reduced the risk of depressive relapse by 36% compared with placebo (statistically significant), while lithium reduced the risk of depressive relapse by 24% compared with placebo (nonsignificant).[31] The authors concluded that lamotrigine was effective against both mania and depression (with more robust activity against depression), while lithium was effective only against mania.[31]

  • Reduced Risk of Intervention for Depression

    Slide 10.

    Reduced Risk of Intervention for Depression

    (Enlarge Slide)
  • Ratings of mood symptoms were also performed during the double-blind phases of the 2 trials, and were compared using multiple analytic techniques. In patients with recent depression, lamotrigine and lithium both prevented depressive symptoms as measured on the HAMD-17. Compared with baseline (time of randomization), the placebo group had a mean score increase of almost 5 points, while both active treatment groups had smaller score increases (statistically significant compared with placebo).

  • Lamotrigine: Prevents Depression Symptoms

    Slide 11.

    Lamotrigine: Prevents Depression Symptoms

    (Enlarge Slide)
  • Furthermore, in recently depressed patients, lamotrigine was significantly superior to placebo in reducing overall illness severity, as measured by the Clinical Global Impressions Scale for Severity (CGI-S). A statistically significant difference was observed as early as the second week.[32] Although the absolute values of the HAMD-17 and CGI-S differences are small, they are potentially clinically significant.

  • Lamotrigine: Reduces Illness Intensity

    Slide 12.

    Lamotrigine: Reduces Illness Intensity

    (Enlarge Slide)
  • There was no evidence that lamotrigine induced mania or cycle acceleration.[5,31] In recently depressed patients, the mean change in Mania Rating Scale (MRS-11) scores at 18 months did not differ significantly among the 3 groups.[32]

  • Lamotrigine: Does Not Destabilize Mood

    Slide 13.

    Lamotrigine: Does Not Destabilize Mood

    (Enlarge Slide)

Efficacy Data for Bipolar II Disorder Maintenance Therapy

  • Data on lamotrigine maintenance in BP II are available from an open-label, naturalistic study of patients with depressive index episodes.[33] Characteristics of the study population are shown here.

  • Lamotrigine in Bipolar II Disorder: Study Population

    Slide 14.

    Lamotrigine in Bipolar II Disorder: Study Population

    (Enlarge Slide)
  • Patients were initially treated with a combination of lamotrigine and SSRIs. Lamotrigine was titrated from an initial dose of 25 mg/day to a target dose of 100 mg/day, in weekly increments of 12.5 mg/day. After remission of the episode, SSRIs were tapered. Of the patients who reached the target lamotrigine dose, and whose antidepressants were discontinued, 22 were evaluated during 6 months of lamotrigine monotherapy. If breakthrough depressive or hypomanic episodes occurred, they were treated with short-term paroxetine or risperidone, respectively. The number and duration of mood episodes during lamotrigine therapy were compared with those during the 6 months prior to lamotrigine initiation. Psychosocial adaptation was evaluated on the Global Assessment of Function (GAF) scale.[33]

  • Lamotrigine Maintenance Therapy: Bipolar II Disorder

    Slide 15.

    Lamotrigine Maintenance Therapy: Bipolar II Disorder

    (Enlarge Slide)
  • Ten patients (45%) developed breakthrough depression, and were treated with paroxetine. Hypomania occurred in 8 patients (36%), who were then treated with risperidone.[33] Mean doses and durations of adjunctive treatment are shown here.

  • Lamotrigine in Bipolar II Disorder: Combination Therapy

    Slide 16.

    Lamotrigine in Bipolar II Disorder: Combination Therapy

    (Enlarge Slide)
  • During the 6 months of lamotrigine therapy, there was a significant reduction in the mean number of depressive and hypomanic episodes, compared with the 6 months before lamotrigine.

  • Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    Slide 17.

    Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    (Enlarge Slide)
  • The mean duration of depressive and hypomanic episodes was also significantly lower during than before lamotrigine therapy.

  • Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    Slide 18.

    Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    (Enlarge Slide)
  • Furthermore, after 6 months of lamotrigine, GAF scores were significantly better than they had been when lamotrigine was initiated &mash; not only in the study population as a whole, but also in both rapid-cycling and non-rapid-cycling subgroups.[33]

  • Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    Slide 19.

    Lamotrigine Maintenance Therapy: Efficacy in Bipolar II Disorder

    (Enlarge Slide)

Lamotrigine for Bipolar Depression: Tolerability and Safety Data

  • In the open-label BP II study described above, 8 patients (36.4%) reported adverse events during lamotrigine monotherapy. The most frequent was dizziness, followed by ataxia, somnolence, headache, and insomnia. No cases of rash occurred. All adverse events were transient, and none required dose reduction or discontinuation of therapy.[33]

  • Lamotrigine Maintenance Therapy: Well-Tolerated in Bipolar II Disorder

    Slide 20.

    Lamotrigine Maintenance Therapy: Well-Tolerated in Bipolar II Disorder

    (Enlarge Slide)
  • Adverse events have been further evaluated using pooled data from 8 placebo-controlled, double-blind lamotrigine trials, involving a total of more than 1500 patients with BP I. Of the 8 studies, 4 evaluated acute therapy and 4 evaluated maintenance therapy. Lamotrigine (mean dose, 146 mg/day; range, 50-500 mg/day) was administered to 827 patients, while another 685 received placebo, for a mean duration of 124 days (range, less than 1 week to 100 weeks).[34]

    The percentages of patients who reported adverse events were broadly similar in the lamotrigine and placebo groups. (This is based on visual inspection of the data; individual adverse events were not specific end points, and were not analyzed statistically.) The most common adverse event in both groups was headache, with incidences of 25% and 21%, respectively. The incidence of any rash (including serious and nonserious rash) also did not differ significantly between the groups. Across all 8 studies, serious rash occurred in 3 patients, all of them on lamotrigine. In all 3 cases, the rash resolved after lamotrigine was discontinued.[34]

  • Lamotrigine: Side-Effect Profile Similar to Placebo

    Slide 21.

    Lamotrigine: Side-Effect Profile Similar to Placebo

    (Enlarge Slide)

Conclusions

  • Lamotrigine also was not associated with sexual side effects or weight gain, even after long-term treatment. Overall, the percentages of patients who withdrew from the trials due to an adverse event were comparable between lamotrigine and placebo (12% and 10%, respectively). These results demonstrate that lamotrigine is well tolerated, with an adverse event profile similar to that of placebo.[34]

    Lamotrigine also has a favorable adverse event profile when compared with lithium. In the combined analysis of the 2, 18-month maintenance trials (GW605/2003 and GW606/2006), the incidences of all adverse events were similar in the lamotrigine and placebo groups; however, the lithium group had significantly higher rates of nausea, diarrhea, tremor, and somnolence, compared with placebo. The lithium group also had significantly higher rates of diarrhea and tremor, compared with lamotrigine.[5]

    In the study comparing lamotrigine and gabapentin, the 2 agents differed significantly in their effect on body weight. Patients lost weight on lamotrigine, but gained weight on gabapentin.[28]

    Lamotrigine does not appear to cause mood destabilization. In the 7-week acute treatment study, switching to mania or hypomania occurred in 4.6% of the lamotrigine group, compared with 3% in the placebo group (a nonsignificant difference).[27] Similarly, in the randomized phase of 2, 18-month maintenance trials, mania occurred in 5% of patients receiving lamotrigine compared with 7% of those receiving placebo, and led to study discontinuation in 2% compared with 3%, respectively.[5] In the rapid-cycling maintenance study, the proportion of patients needing intervention for depressive vs manic symptoms did not differ between the lamotrigine and placebo groups, and the percentage of patients who remained stable for 6 months was significantly higher with lamotrigine.[30] Finally, in the pooled analysis of 8 placebo-controlled studies, the incidence of mania was similar between lamotrigine and placebo (5% and 4%, respectively).

  • Conclusions

    Slide 22.

    Conclusions

    (Enlarge Slide)

References

  1. Ketter TA, Calabrese JR. Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature. J Clin Psychiatry. 2002;63:146-151.
  2. Thase ME, Sachs GS. Bipolar depression: pharmacotherapy and related therapeutic strategies. Biol Psychiatry. 2000;48:558-572.
  3. Shelton RC. Treating bipolar depression. J Fam Pract. 2003;(suppl):S14-S17.
  4. Post RM, Leverich GS, Denicoff KD, et al. Alternative approaches to refractory depression in bipolar illness. Depress Anxiety. 1997;5:175-189.
  5. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;13(suppl 2):S57-S66.
  6. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392-400.
  7. Ernst CL, Goldberg JF. Antidepressant properties of anticonvulsant drugs for bipolar disorder. J Clin Psychopharmacol. 2003;23:182-192.
  8. Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64:1013-1024.
  9. Gnanadesikan M, Freeman MP, Gelenberg AJ. Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder. Bipolar Disord. 2003;5:203-216.
  10. Evins AE. Efficacy of newer anticonvulsant medications in bipolar spectrum mood disorders. J Clin Psychiatry. 2003;64(suppl 8):9-14.
  11. Ketter TA, Wang PW. The emerging differential roles of GABAergic and antiglutamatergic agents in bipolar disorders. J Clin Psychiatry. 2003;64(suppl 3):15-20.
  12. Braunig P, Kruger S. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol. 2003;17:239-241.
  13. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407-420.
  14. Moller HJ, Nasrallah HA. Treatment of bipolar disorder. J Clin Psychiatry. 2003;64(suppl 6):9-17; discussion 28.
  15. Keck PE Jr, McElroy SL. New approaches in managing bipolar depression. J Clin Psychiatry. 2003;64(suppl 1):13-18.
  16. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
  17. Brambilla P, Barale F, Soares JC. Atypical antipsychotics and mood stabilization in bipolar disorder. Psychopharmacology (Berl). 2003;166:315-332.
  18. [No authors listed]. FDA approves Risperdal (risperidone) for treatment of bipolar mania (news article). Available at: http://www.psychiatrysource.com/psychsource/DesktopDefault.html?tabid=39&tabindex=1&contentid=8525697700573E1885256DF3004CE624. Accessed December 16, 2003.
  19. [No authors listed.] AstraZeneca receives FDA approval for Seroquel in bipolar mania (press release). AstraZeneca, January 13, 2004. Available at: http://www.astrazenecapressoffice.com/taNS/index.asp?did=172&aid=6835#. Accessed January 19, 2004.
  20. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.
  21. [No authors listed.] Lilly announces FDA approval of first medication for bipolar depression (news release). Eli Lilly and Co., December 29, 2003. Available at: http://newsroom.lilly.com/news/Product/2003-12-24_symbyax_usapproval.html. Accessed January 5, 2003.
  22. Shelton RC. The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother. 2003;4:1175-1183.
  23. Zyprexa ® (olanzapine) product information. Eli Lilly and Company, 2004. Available at: http://pi.lilly.com/us/zyprexa-pi.pdf. Accessed January 20, 2004.
  24. Aubry JM, Simon AE, Bertschy G. Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. J Clin Psychiatry. 2000;61:649-655.
  25. Strakowski SM, Del Bello MP, Adler CM, Keck PE Jr. Atypical antipsychotics in the treatment of bipolar disorder. Expert Opin Pharmacother. 2003;4:751-760.
  26. Nelson LA, Swartz CM. Melancholic symptoms during concurrent olanzapine and fluoxetine. Ann Clin Psychiatry. 2000;12:167-170.
  27. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88.
  28. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.
  29. Obrocea GV, Dunn RM, Frye MA, et al. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biol Psychiatry. 2002;51:253-260.
  30. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry. 2000;61:841-850.
  31. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of two placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. In press.
  32. Gyulai L, Zajecka JM, Forrester BR, et al. Symptomatic response to lamotrigine maintenance in bipolar I disorder. Poster presented at 156th meeting of the American Psychiatric Association; May 17-22, 2003; San Francisco, CA. Abstract NR403.
  33. Herman E, Hovorka J, Syrovatka J, et al. Relapse prevention with lamotrigine in bipolar II disorder. Poster presented at 12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.
  34. Asnis G, Bowden CL, Calabrese JR, et al. Safety and tolerability of lamotrigine in bipolar I disorder. Poster presented at the 43rd Annual Meeting of the New Clinical Drug Evaluation Unit; May 27, 2003; Boca Raton, Florida.