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, Maintenance treatment for rapid-cycling BP II (no antimanic properties) BP I recently manic or depressed

9. INDICATIONS Less effective for mixed episode, rapid cycling Borderline PD & schizoaffective disorder, also for migraine, impulsivity & compulsivity Bipolar II disorders, post traumatic stress disorder, Adjunctive therapy for "treatment-resistant" unipolar depression .

10. Indications The 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 Week 0 0.5 1 2 3 4 5 6 7 0 -2 *P < .05 vs placebo -4 -6 -8 MADRS Change From Baseline * -10 * -12 * * * -14 * * * Placebo -16 * Lamotrigine 50 mg/d -18 Lamotrigine 200 mg/d -20 Dose > 50 mg/d in lamotrigine 200 mg/d group only after week 3 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 WithBipolar Depression Is the patient already in treatment with amood 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 DepressionThen... 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

28. Skin Rash

29. Skin Rash

30. 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

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

33. Carbamazepine, phenytoin, Phenobarbital, and primidone decrease Lamotrigine concentrations by approximately 40%.

35. 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 ClinPsychiat 2002, 63, 1012-1019

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

39. Lamotrigine seems to be safe in Pregnancy?

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

42. 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

43. 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

44. Summary of DSM-IV-TR Classification of Bipolar Disorders Bipolar DisorderNot OtherwiseSpecified Cyclothymic Bipolar II Bipolar I One or more major depressive episodes accompanied by at least one hypomanic episode FEMALE>MALE 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 manic or mixed episodes, usually accompanied by major depressive episodes MALE=FEMALE * Symptoms do not meet criteria for manic and depressive episodes. First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

45. 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

46. 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

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

48. 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 Akiskal. J Clin Psychopharmacol. 1996;16(suppl 1):4S-14S.

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

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

51. Stage 1: Monotherapy* 1ALithium, valproate, atypicals excluding olanzapine and clozapine Nonresponse:Try alternate monotherapy Stage 2: Two-drug combination*Lithium, valproate, atypical antipsychoticChoose 2 (not 2 atypicals, not aripiprazole or clozapine) Partial response or nonresponse:Further medical consult or referralfor other treatment options Partial response TIMA Algorithm for Treatment of Acute Manic Episodes 1B: Olanzapine†or carbamazepine† Response:Continue with therapy Response:Continue with therapy *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.

52. TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 1–3) Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse Partial response or nonresponsive Taking no antimanic, with history of severe and/or recent mania Taking no antimanic, without history of severe and/or recent mania Taking otherantimanic Taking Li Increase to ≥ 0.8 mEq/L (continue) Stage 1 Antimanic + LTG LTG Stage 2 OFCaor QTPa Stage 3 Combination from Li, LTG, QTP, or OFC aNote 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.

53. Response: Continue with therapy Response: Continue with therapy Partial response or nonresponse Partial response or nonresponse TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 4–5) Stage 4 Li,LTGb, OFC, VPA, or CBZ + SSRIc, BUP, or VEN or ECT or QTP* Stage 5 MAOIs, tricyclics, pramipexole, other AAPsa, OXC, other combinations of drugs at stages, inositol, stimulants, thyroid aNote safety issue described in reference listed below (ie, olanzapine is associated with weight gain, quetiapine is associated with sedation and somnolence). bLamotrigine has limited antimanic efficacy and, in combination with an antidepressant, may require the addition of an antimanic. cSSRIs 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. Suppes T, et al. J Clin Psychiatry. 2005;66:870-886.

54. 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

56. Treatment with an antidepressant (e.g. selective serotoninreuptake 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

58. It is 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 .

59. If not already on an antipsychotic, consider adding an antipsychotic when patients have psychotic symptoms .

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

65. Choice of antidepressant 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

67. An ideal mood stabilizer would prevent relapse to either pole of the illness.

69. Aripiperzole prevents manic relapse .

71. Lamotrigine prevents depressive more than manic relapse.

72. Olanzapine prevents manic more than depressive relapse.

73. Quetiapine prevents both manic and depressive relapses.

75. When the burden is depressive, Lamitrogine or quetiapine may be more appropriate

77. 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 toplacebo 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

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

79. Background There is uncertainty about the efficacy of Lamotrigine in bipolardepressive episodes Aims To synthesize the evidence for the efficacy of Lamotrigine inbipolar depressive episodes Method Systematic review and meta-analysis of individual patient datafrom randomized controlled trials comparing Lamotrigine withplacebo.

80. Results Individual data from 1072 participants from five randomisedcontrolled trials were obtained. More individuals treated withlamotrigine than placebo responded to treatment on both theHamilton Rating Scale for Depression (HRSD) (relative risk(RR)=1.27, 95% CI 1.09–1.47, P=0.002) and Montgomery–ÅsbergDepression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41,P=0.005). There was an interaction (P=0.04) by baseline severityof depression: lamotrigine was superior to placebo in peoplewith 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 randomizedcontrolled trials were obtained. More individuals treated withLamotrigine than placebo responded to treatment on both theHamilton Rating Scale for Depression (HRSD) (relative risk(RR)=1.27, 95% CI 1.09–1.47, P=0.002) and Montgomery–ÅsbergDepression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06–1.41,P=0.005).

81. There was an interaction (P=0.04) by baseline severityof depression:lamotriginewas superior to placebo in peoplewith 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).

82. Conclusions There is consistent evidence that Lamitrogine has a beneficialeffect on depressive symptoms in the depressed phase of bipolardisorder. The overall pool effect was modest, although theadvantage over placebo was larger in more severely depressedparticipants

84. 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

85. 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

86. 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

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

88. 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

89. 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

90. 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.

92. Lamotrigine has demonstrated efficacy and safety in a multicenter double-blinded, placebo-controlled study of 195 outpatients with bipolar I disorder, depressed3 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.

93. 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.

94. 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.

95. Bipolar Disorder: Summary of Efficacy Evidence from RCTs Acute Mania MonoCombo AcuteDepression Maintenance Drug

96. 0 0 -5 -5 -10 -10 -15 -15 -20 -20 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Week Week Lamotrigine in Acute Treatment of Bipolar Depression LTG 50 mg/day (n = 64) LTG 200 mg/day (n = 63) Placebo (n = 65) LOCF Observed Change From Baseline of MADRS * † † † * † † † † † † † † † † * P<0.1; †P<0.05. LOCF = last-observation-carried-forward. Calabrese et al. J Clin Psychiatry. 1999;60:79-88.

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

98. Median = 13 weeks Lamotrigine vs Lithium vs Placebo: Relapse Prevention, Maintenance Therapy 1 Li vs PBO, P = 0.029 LTG vs PBO, P = 0.029 LTG vs Li, P = 0.915 0.9 0.8 0.7 Median = 24 weeks 0.6 Median = 29 weeks Survival Estimate 0.5 Li (n = 46) 0.4 LTG (n = 59) 0.3 PBO (n = 70) 0.2 0.1 0 60 70 0 10 20 30 40 50 LTG = lamotrigine 100 to 400 mg daily Li = lithium 0.8–1.1 mEq/L PBO = placebo Week Time to Intervention for a Mood Episode Bowden CL, et al. Arch Gen Psychiatry. 2003;60:392-400.

99. Summary 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.

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

101. THANK YOU www.walidsarhan.net