Lamitrogine

the role of lamotrigine in the management of bipolar disorders

1. Lamotrigine : Update in psychiatric practice Walid Sarhan F.R.C.Psych . AMMAN-JORDAN

2. Newer Antiepileptic Drugs ( Second- Generation ) Vigabatrin 1989 Gabapentin 1993 Lamotrigine 1994 Topiramate 1996 Tiagabine 1997 levetiracetam 1999 Oxcarbazepine 2000 (safety profile similar to CBZ). Hyponatremia is also problem, however it is less likely to cause rash than CBZ. Zonisamide 2000

3. Description Lamotrigine an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)- as- triazine . Lamotrigine is a white to pale cream-colored powder . Lamotrigine is soluble in water .

4. Mechanism of action Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

5. Metabolism Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate . After oral administration , 94% was recovered in the urine and 2% was recovered in the feces .

6. INDICATIONS Epilepsy—adjunctive therapy in patients ≥2 years of age: partial seizures. primary generalized tonic-clonic seizures. generalized seizures of Lennox- Gastaut syndrome. Epilepsy—monotherapy in patients ≥16 years of age: conversion to monotherapy in patients with partial seizures who are receiving treatment with Carbamazepine, Phenobarbital, phenytoin, primidone, or Valproate as the single AED.

7. INDICATIONS Bipolar Disorder in patients ≥18 years of age: maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes .

8. INDICATIONS Acute treatment of bipolar depression I , M aintenance treatment for rapid-cycling BP II (no antimanic properties) BP I recently manic or depressed

9. INDICATIONS Less effective for mixed episode, rapid cycling B orderline PD & schizoaffective disorder, also for migraine, impulsivity & compulsivity B ipolar II disorders, post traumatic stress disorder, A djunctive therapy for "treatment-resistant" unipolar depression .

10. I ndications T he treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain.

11. NOTE Traditional anticonvulsant drugs are primarily antimanics, Lamitrogine is most effective in the treatment and prophylaxis of bipolar depression.

12. Bipolar I Depression: Lamotrigine Monotherapy Dose > 50 mg/d in lamotrigine 200 mg/d group only after week 3 Week -20 -18 -16 - 14 -12 -10 -8 -6 -4 -2 0.5 1 2 3 4 5 6 7 Placebo Lamotrigine 50 mg/d Lamotrigine 200 mg/d * P < .05 vs placebo * * * * * * * * * MADRS Change From Baseline Calabrese JR, et al. J Clin Psychiatry. 2002;63( suppl 3):5-9 .

13. The Evidence for Lamotrigine in Rapid-Cycling Bipolar Disorder Lamotrigine monotherapy is useful treatment for some patients with rapid-cycling bipolar disorder Among patients with rapid-cycling bipolar disorder, 41% of lamotrigine patients vs 26% of placebo patients were stable without relapse for 6 months of monotherapy Overall survival time in study favored lamotrigine (6 weeks longer than placebo) Calabrese JR, et al. J Clin Psychiatry . 2000;61:841-850 .

14. 2002 American Psychiatric Association guidelines Lamitrogine as a first-line treatment for acute depression in bipolar disorder as well as a maintenance therapy

15. Approach to the Patient With Bipolar Depression Is the patient already in treatment with a mood stabilizer? Yes Then optimize the dose of the mood stabilizer Then add antidepressant No Then … APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.

16. Approach to the Patient with Bipolar Depression Then... For less severely ill patients initiate lithium or lamotrigine For more severely ill patients initiate lithium and an antidepressant For those with psychosis or at high suicide risk add antipsychotic ECT APA Practice Guidelines Am J Psychiatry . 2002;159(4)supplement.

17. Adverse Reaction Most common adverse reactions (incidence ≥10%) in adult epilepsy clinical studies were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, and rash .

18. Adverse Reaction Additional adverse reactions (incidence ≥10%) reported in children in epilepsy clinical studies included vomiting, infection, fever, accidental injury, pharyngitis, abdominal pain, and tremor.

19. Adverse Reaction Most common adverse reactions (incidence >5%) in adult bipolar clinical studies were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia.

20. Black box: WARNING: SERIOUS SKIN RASHES Cases of life-threatening serious rashes, including Stevens-Johnson syndrome , toxic epidermal necrolysis , and/or rash-related death, have been caused by LAITROGINE. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include : - coadministration with Valproate -exceeding recommended initial dose . -exceeding recommended dose escalation . Benign rashes are also caused by LAMITROGINE; however, it is not possible to predict which rashes will prove to be serious or life threatening. LAMITROGINE should be discontinued at the first sign of rash, unless the rash is clearly not drug related.

21. Risk factors Existing medical conditions. Viral infections, , human immunodeficiency virus (HIV) and systemic lupus erythematosus . Genetics. Carrying a gene called HLA-B12 is more susceptible to Stevens-Johnson syndrome

22. Causes of Stevens-Johnson syndrome Medication causes Anti-gout medications, such as allopurinol Nonsteroidal anti-inflammatory drugs . Anticonvulsants.

23. Causes of Stevens-Johnson syndrome Infectious causes Herpes (herpes simplex or herpes zoster) Influenza HIV Diphtheria Typhoid Hepatitis Other causes physical stimuli, such as radiation therapy or ultraviolet light.

24. Signs and symptoms of Stevens-Johnson syndrome include Facial swelling Tongue swelling Skin pain A red or purple skin rash that spreads within hours to days over the skin and mucous membranes, mouth, nose and eyes

25. Stevens-Johnson syndrome

26. Skin Rash

27. Skin Rash

28. Concomitant use of Lamitrogine and aripiperzole increases risk of Stevens-Johnson syndrome? Shen , Yu- Chiha b c; Chen, Shaw- Jia b; Lin, Chaucer C.H.a b c; Chen, Chia-Hsianga b c International Clinical Psychopharmacology: July 2007 - Volume 22 - Issue 4 - pp 247-248 doi : 10.1097/01.yic.0000224789.21406.81

29. RECENT MAJOR CHANGES Warnings and Precautions, Aseptic Meningitis 35 cases in children October 2010

30. Drug interaction Valproate increases Lamotrigine concentrations more than 2-fold. Carbamazepine, phenytoin, Phenobarbital, and primidone decrease Lamotrigine concentrations by approximately 40%. Oral estrogen-containing contraceptives and rifampin also decrease Lamotrigine concentrations by approximately 50%.

31. Dose As mono or adjunctive therapy, dosage: 100-400mg/day (slow titration upwards); minimal side effects profile , thus better compliance

32. Dosing of Lamitrogine in adults & adolescents (once daily nocte) Week Daily dose (mg) 1 25 2 25 3 50 4 50 5 100 6 200 NB 50% dose with Valproate & 200% with Carbamazepine; caution if on birth control pills (increased during the active hormone days, but reduced during the off hormone days) Ref : Calabrese et al, J Clin Psychiat 2002, 63, 1012-1019

33. Frequency Linear pharmacokinetics and a half-life of 24 hours allows a once-daily dosing; rapid absorption.

34. Administration Initiation/titration : start with 25 mg daily X 2 weeks then increase to 50mg X 2 weeks then increase to 100mg- faster titration has a higher incidence of serious rash If the patient stops the medication for 5 days or more have to start at 25mg again .

35. USE IN SPECIFIC POPULATIONS Hepatic impairment: Dosage adjustments required. Lamotrigine seems to be safe in Pregnancy? . Reduced maintenance doses may be effective for patients with significant renal impairment

36. Hepatic failure No dosage adjustment is needed in patients with mild liver impairment. Initial , escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites. and 50% in patients with severe liver impairment with ascites.

37. Plasma Levels A therapeutic plasma concentration range has not been established for Lamotrigine. Dosing should be based on therapeutic response

38. Tips for Using Lamotrigine Very slow titration reduces risk of rash (25 mg/day as starting dose; can increase to 50 mg/day at week three, 100 mg/day at week five, and 200 mg/day at week six) Risk of serious rash with Lamotrigine is under 1% and is comparable to risk with carbamazepine, phenytoin, and phenobarbital

39. Tips for Using Lamotrigine To avoid unrelated rash Patients should not try new medications, bath products, or foods during the first three months of Lamotrigine treatment Patients should not start Lamotrigine within two weeks of viral infection, rash, or vaccination

40. Summary of DSM-IV-TR Classification of Bipolar Disorders * Symptoms do not meet criteria for manic and depressive episodes. Bipolar features that do not meet criteria for any specific bipolar disorders At least 2 years of numerous periods of hypomanic and depressive symptoms* One or more major depressive episodes accompanied by at least one hypomanic episode FEMALE>MALE One or more manic or mixed episodes, usually accompanied by major depressive episodes MALE=FEMALE Bipolar Disorder Not Otherwise Specified Cyclothymic Bipolar II Bipolar I First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

41. Bipolar Depression 50% of first bipolar episodes are depressive episodes Depressive episodes in bipolar disorder are associated with considerable morbidity and mortality Bipolar depressive episodes have a chronic course Goodwin FK and Jamison KR. Manic Depressive Illnessn

42. Bipolar Depression 80% of patients exhibit significant suicidality 60% of patients with dysphoric mania exhibit suicidality Depressive episodes dominate course of bipolar disorder (twice the amount of time as in mania) 25-30% of patients initially diagnosed with unipolar depression subsequently have a manic or hypomanic episode Goodwin FK and Jamison KR. Manic Depressive Illnessn

43. Bipolar Disorder > 50% alcohol and/or other substance abuse About 50% attempt suicide About 15% succeed 1 Cookson J. Br J Psychiatry . 2001;178(suppl. 41): s148 – s156. 2 Strakowski SM, et al. Expert Opin. Pharmacother . 2003;4:751-760.

44. Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S. Predictors of Suicide in Bipolar Disorder High Impulsivity Alcohol and Substance Abuse DEPRESSION and MIXED Episodes History of Abuse in Childhood Exacerbated by incorrect treatment

45. Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S. Treatment Challenges in Bipolar Disorder Often unrecognized Often untreated Often misdiagnosed Often inadequately treated Exacerbated by incorrect treatment

46. Texas Implementation of Medication Algorithms initiative that made specific recommendations for patients presenting with hypomanic, manic, mixed episodes, or depressive episodes . TIMA

47. Stage 1: Monotherapy * 1A Lithium, valproate , atypicals excluding olanzapine and clozapine Nonresponse : Try alternate monotherapy Partial response Response: Continue with therapy Stage 2: Two-drug combination * Lithium, valproate, atypical antipsychotic Choose 2 (not 2 atypicals, not aripiprazole or clozapine) Response: Continue with therapy 1B: Olanzapine † or carbamazepine † Partial response or nonresponse: Further medical consult or referral for other treatment options *Use targeted adjunctive treatment as necessary before moving to next stage. Agitation/Aggression─clonidine, sedatives; Insomnia─hypnotics; Anxiety─benzodiazepines, gabapentin. † All agents in Stage 1A and 1B are indicated for acute mania associated with bipolar I disorder. Safety and other concerns led to placement of olanzapine and carbamazepine as alternate first-stage choices. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. TIMA Algorithm for Treatment of Acute Manic Episodes

48. TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 1–3) Stage 1 Stage 2 Stage 3 Increase to ≥ 0.8 mEq/L (continue) a Note safety issue described in reference listed below ( ie , olanzapine is associated with weight gain, quetiapine is associated with sedation and somnolence). Li = lithium; LTG = lamotrigine ; OFC = olanzapine-fluoxetine combination; QTP = quetiapine. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886. Antimanic + LTG LTG Partial response or nonresponse OFC a or QTP a Combination from Li, LTG , QTP, or OFC Taking no antimanic, with history of severe and/or recent mania Taking no antimanic, without history of severe and/or recent mania Taking Li Taking other antimanic Response: Continue with therapy Response: Continue with therapy Partial response or nonresponsive

49. TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 4–5) Stage 4 Stage 5 Suppes T, et al. J Clin Psychiatry . 2005;66:870-886. Li, LTG b , OFC, VPA, or CBZ + SSRI c , BUP, or VEN or ECT or QTP * a Note safety issue described in reference listed below ( ie , olanzapine is associated with weight gain, quetiapine is associated with sedation and somnolence). b Lamotrigine has limited antimanic efficacy and, in combination with an antidepressant, may require the addition of an antimanic . c SSRIs include citalopram , escitalopram, fluoxetine , paroxetine , sertraline , and fluvoxamine . *Evidence supported by randomized controlled clinical trials with large effect sizes. AAP = atypical antipsychotic; BUP = bupropion ; CBZ = carbamazepine ; CONT = continuation; ECT = electroconvulsive therapy; Li = lithium; LTG = lamotrigine ; MAOI = monoamine oxidase inhibitor; OFC = olanzapine-fluoxetine combination; OXC = oxcarbazepine ; QTP = quetiapine; SSRI = selective serotonin reuptake inhibitor; VEN = venlafaxine ; VPA = valproate . MAOIs, tricyclics , pramipexole , other AAPs a , OXC, other combinations of drugs at stages, inositol , stimulants, thyroid Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse Partial response or nonresponse

50. Evidence-based guidelines for treating bipolar disorder: revised second edition recommendations from the British Association for Psychopharmacology J Psychopharmacology 2009 23: 346 originally published online 27 March 2009

51. Choice of an initial treatment For patients not already on long-term treatment for bipolar disorder Where an early treatment effect is desirable, consider quetiapine . Consider initial treatment with Lamotrigine, with the necessary dose titration . Treatment with an antidepressant (e.g. selective serotonin reuptake inhibitor (SSRI) and an anti-manic agent (e.g. lithium, Valproate or an antipsychotic) together may be considered for patients with a history of mania The patient on no treatment Acute depressive episode

52. It i s not recommended for such patients because of the increased risk of switch to mania , and should be used with caution in patients with a history of hypomania . If not already on an antipsychotic, consider adding an antipsychotic when patients have psychotic symptoms . Consider ECT for patients with high suicidal risk, psychosis, severe depression during pregnancy or life-threatening inanition Antidepressant Monotherapy

53. Simplifying pre-existing Polypharmacy which may change seizure thresholds. When depressive symptoms are less severe, lithium or possibly Valproate may be considered .

54. Clinicians and patients should be aware of the risk of hypomania or rapid cycling in patients with bipolar-II or bipolar spectrum disorder treated with antidepressants alone Antidepressants

55. Consider interpersonal therapy, cognitive behavior therapy or family-focused therapy (FFT) when available since these may shorten the acute episode Psychotherapy

56. treatment Ensure adequate doses of medicines and that serum levels of lithium are within the therapeutic range . Address current stressors, if any Depressive episode while on long-term

57. Ensure current choice of long-term treatments is likely to protect the patient from manic relapse (e.g. lithium, CBZ, Valproate, antipsychotic)

58. If t he patient fails to respond to optimization of long-term treatment, and especially if depressive symptoms are significant, initiate treatment as above or consider augmentation or change of treatment . see Next-step treatments following inadequate treatment response to an antidepressant below

59. The limited evidence supports the modest efficacy of antidepressants such as the SSRIs (specifically fluoxetine) in bipolar disorder . However, antidepressants should not be uncritically employed as first-line medicines given continuing doubts about relative efficacy and their potential to destabilize mood Choice of antidepressant

60. Consider long-term treatment following a single severe manic episode (i.e. diagnosis of bipolar-I disorder). the natural history of the illness implies that preventing early relapse may lead to a more benign illness course Prevention of new episodes

61. Options for Long-term agents are often called mood stabilizers. An ideal mood stabilizer would prevent relapse to either pole of the illness. The available medicines are probably more often effective against one pole than the other Long-term treatment

62. lithium specifically, is associated with a reduced risk of suicide in bipolar patients . Aripiperzole prevents manic relapse . CBZ is less effective than lithium , but may sometimes be employed as Monotherapy if lithium is ineffective and especially in patients who do not show the classical pattern of episodic euphoric mania Long-term treatment

63. Oxcarbazepine for its low potential for drug interaction. Lamotrigine prevents depressive more than manic relapse. Olanzapine prevents manic more than depressive relapse. Quetiapine prevents both manic and depressive relapses. Valproate prevents manic more than depressive relapses

64. Combination treatment When the burden of disease is mania, it may be logical to combine predominantly anti-manic agents (e.g. lithium, valproate, an antipsychotic) When the burden is depressive, Lamitrogine or quetiapine may be more appropriate In bipolar-I disorder,lamotrigine may usually require combination with an anti-manic long-term agent

65. It is not established by controlled trials, but they appear to be used effectively in a small minority of patients in the long term The role of antidepressants in long-term treatment

66. Lamitrogine: Efficacy in Bipolar Disorder Placebo controlled 18-month trials of Lamotrigine and lithium – pooled analysis 8-16 week open label treatment with Lamotrigine or lithium before randomization: N = 191 for placebo N = 280 for Lamotrigine (100-400 mgs/d) N = 167 for lithium (0.8-1.1 mEq /L) 18-month maintenance treatment phase Both Lamotrigine and lithium superior to placebo in preventing any mood episode Goodwin GM, et al;J Clin Psych 2004 Mar;65(3):432-441 Bowden CL, et al;Arch Gen Psych 2003 Apr;60(4):392-400 Calabrese JR, et al;J Clin Psych 2003 Sep;64(9):1013-1024

67. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomized trials The British Journal of Psychiatry (2009) 194: 4-9. doi : 10.1192/bjp.bp.107.048504 © 2009 The Royal College of Psychiatrists John R. Geddes Joseph R. Calabrese Guy M. Goodwin

68. Background There is uncertainty about the efficacy of Lamotrigine in bipolar depressive episodes Aims To synthesize the evidence for the efficacy of Lamotrigine in bipolar depressive episodes Method Systematic review and meta-analysis of individual patient data from randomized controlled trials comparing Lamotrigine with placebo.

69. Results Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09–1.47, P =0.002) and Montgomery– Åsberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41, P =0.005). There was an interaction ( P =0.04) by baseline severity of depression: lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87, P =0.001) but not in people with HRSD score   24 (RR=1.07, 95% CI 0.90–1.27, P =0.445). Results Individual data from 1072 participants from five randomized controlled trials were obtained. More individuals treated with Lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09–1.47, P =0.002) and Montgomery– Åsberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41, P =0.005).

70. There was an interaction ( P =0.04) by baseline severity of depression: lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16–1.87, P =0.001) but not in people with HRSD score 24 (RR=1.07, 95% CI 0.90–1.27, P =0.445).

71. Conclusions There is consistent evidence that Lamitrogine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants

72. Switch to mania “ Definite” switch involves fulfilling DSM-IV syndromic criteria for a manic, hypomanic, or mixed episode for at least 2 days, within 8 weeks of antidepressant introduction. 75

73. Switch to mania Recent literature suggests that the emergence of mania or hypomania can be reasonably attributed to antidepressant use in no more than 10% to 25% of patients with bipolar disorder

74. Switch to mania “Likely” switches call for at least 2 DSM-IV mania or hypomania symptoms plus a Young Mania Rating Scale (YMRS) score >12, occurring for at least 2 days, within 12 weeks of antidepressant introduction. 77

75. Switch to mania True antidepressant-induced polarity switches persist even after the medication is discontinued 78

76. Switch to mania The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)— found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent. 79

77. Switch to mania The largest dataset on this topic—the randomized controlled data from Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)— found that the risk for treatment-emergent manic switch with paroxetine or bupropion was almost identical (about 10%) with or without an FDA-approved antimanic agent. 80

78. Schneck CD, Miklowitz DJ, Miyahara S, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165:370-377 The use of antidepressants may increase a patient’s risk of rapid-cycling bipolar disorder. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) included 1742 patients treated with a variety of approved medications for bipolar I and bipolar II disorder, and 32% reported having rapid-cycling at baseline. After 2 years of treatment, 5% still had rapid-cycling bipolar disorder. Those who were treated with an antidepressant were 3.8 times more likely to have rapid-cycling bipolar disorder .

79. The Evidence for Lamitrogine in Bipolar Depression 1. Muzina DJ, et al. Acta Psychiatr Scand . 2005;111(suppl 426):21-28. 2. Kusumaker V, Yatham L. Psychiatry Res . 1997;72:145-148. 3. Calabrese JR, et al. J Clin Psychiatry . 1999;60:79-88. Among antiepileptic drugs, clinical data favor lamotrigine as first-line treatment for acute bipolar depression 1 The first open study in bipolar depressed patients reported symptomatic improvement in 72% of patients by end of 4 weeks, with 63% reported in remission by 6 weeks 2 Lamotrigine has demonstrated efficacy and safety in a multicenter double-blinded, placebo-controlled study of 195 outpatients with bipolar I disorder, depressed 3

80. Antidepressants for acute treatment of bipolar depression: A systematic review and meta-analysis JOURNAL OFCLINICAL PSYCHIATRY M.Sidor & G.MacQueen --October 2010 Conclusion : although antidepressants were found to be safe for the acute treatment of bipolar depression ,their lack of efficacy may limit their clinical utility. further high quality studies are required to address the existing limitations in the literature.

81. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003;160:1252-1262 Guidelines state that patients with bipolar depression who are treated with an antidepressant should discontinue therapy within 3 to 6 months after achieving remission. However, discontinuation of antidepressants has been shown to cause depressive relapse in these patients.

82. Lithium ++ ++ + ++ Divalproex ++ ++ + + Carbamazepine ++ ND ND + Lamotrigine - ND + ++ Olanzapine ++ + + ++ Risperidone ++ + +/- ND Quetiapine ++ ++ + ND Ziprasidone ++ ND +/- ND Aripiprazole ++ ND ND + Bipolar Disorder: Summary of Efficacy Evidence from RCTs Drug Acute Mania Mono Combo Acute Depression Maintenance

83. Change From Baseline of MADRS Lamotrigine in Acute Treatment of Bipolar Depression LTG 50 mg/day (n = 64) LTG 200 mg/day (n = 63) Placebo (n = 65) Week -5 -10 -15 -20 1 2 3 4 5 6 7 * P <0.1; † P <0.05. LOCF = last-observation-carried-forward. Calabrese et al. J Clin Psychiatry . 1999;60:79-88. Week -5 -10 -15 -20 1 2 3 4 5 6 7 LOCF Observed * * † † † † † † † † † † † † †

84. Time to Intervention for a Mood Episode Lamotrigine vs Lithium vs Placebo Goodwin et al., 2003 submitted 12 Mon. 18 Mon. Index Manic or Depressed LTG v. PBO, p < 0.001 Li v. PBO, p < 0.001 LTG v. Li, p = 0.629

85. Week 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 10 20 30 40 50 60 70 Survival Estimate PBO (n = 70 ) LTG (n = 59) Li (n = 46) Median = 13 weeks Median = 24 weeks Median = 29 weeks Li vs PBO, P = 0.029 LTG vs PBO, P = 0.029 LTG vs Li, P = 0.915 Bowden CL, et al. Arch Gen Psychiatry . 2003;60:392-400 . Lamotrigine vs Lithium vs Placebo: Relapse Prevention, Maintenance Therapy LTG = lamotrigine 100 to 400 mg daily Li = lithium 0.8 – 1.1 mEq /L PBO = placebo Time to Intervention for a Mood Episode

86. S ummary Lamotrigine is well established antiepileptic Lamotrigine is the second approved drug by FDA for the treatment of B.A.D Type 1. It is useful in the management of bipolar disorder specially the prevention of depressive episodes. It has the potential of helping unipolar depression.

87. Summary Skin rash does not mean always Stevens-Johnson syndrome . Drug interaction is very important .

88. THANK YOU www.walidsarhan.net