Lamotrigine: Update in psychiatric practice

Walid Sarhan F.R.C.Psych.

AMMAN-JORDAN

Newer Antiepileptic Drugs( Second- Generation )

1. Vigabatrin 1989 2. Gabapentin 19933. Lamotrigine 19944. Topiramate 19965. Tiagabine 19976. levetiracetam 19997. Oxcarbazepine 2000 (safety profile similar to CBZ).

Hyponatremia is also problem, however it is less likely to cause rash than CBZ.

8. Zonisamide 2000

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 .

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).

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.

INDICATIONSEpilepsy—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.

INDICATIONS

Bipolar Disorder in patients ≥18 years of age:

maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes .

INDICATIONS• Acute treatment of bipolar

depression I,• Maintenance treatment for rapid-

cycling BP II (no antimanic properties)

• BP I recently manic or depressed

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 .

Indications The treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain.

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

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

00 0.5 1 2 3 4 5 6 7

PlaceboLamotrigine 50 mg/dLamotrigine 200 mg/d

*P < .05 vs placebo

***

*

*

**

**

MA

DR

S C

hang

e Fr

om B

asel

ine

Calabrese JR, et al. J Clin Psychiatry. 2002;63(suppl 3):5-9.

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.

2002 American Psychiatric Association guidelines

Lamitrogine as a first-line treatment for acute depression in bipolar disorder as well as a maintenance therapy

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.

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.

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.

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.

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.

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.

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

Causes of Stevens-Johnson syndrome

Medication causes• Anti-gout medications, such as

allopurinol• Nonsteroidal anti-inflammatory drugs .• Anticonvulsants.

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.

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

Stevens-Johnson syndrome

Skin Rash

Skin Rash

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 247-248doi: 10.1097/01.yic.0000224789.21406.81

RECENT MAJOR CHANGES

• Warnings and Precautions, Aseptic

Meningitis 35 cases in children

• October 2010

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%.

Dose

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

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

Frequency

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

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.

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

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.

Plasma Levels

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

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

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

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 DisorderNot OtherwiseSpecified

CyclothymicBipolar IIBipolar I

First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev. Washington, DC: American Psychiatric Association; 2000:345-428.

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

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

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.

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

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

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

TIMA

Stage 1: Monotherapy* 1ALithium, valproate, atypicals excluding olanzapine and clozapine

Nonresponse:Try alternate monotherapy

Partial responseResponse:

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

TIMA Bipolar: Treatment of Acute Depressive Episodes (Stages 1–3)

Stage 1

Stage 2

Stage 3

Increase to ≥ 0.8 mEq/L (continue)

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.

Antimanic + LTG LTG

Partial response or nonresponse

OFCa or QTPa

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 otherantimanic

Response: Continue with

therapy

Response: Continue with

therapy

Partial response or nonresponsive

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, LTGb, OFC, VPA, or CBZ + SSRIc, BUP, or VEN or ECT

or QTP*

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.

MAOIs, tricyclics, pramipexole, other AAPsa, 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

Evidence-based guidelines for treatingbipolar disorder: revised second edition recommendationsfrom the British Association for Psychopharmacology

J Psychopharmacology 2009 23: 346 originally published online 27 March 2009

Choice of an initial treatment

For patients not already on long-term treatment for bipolar disorder Where an early treatment effect is desirable, considerquetiapine .

Consider initial treatment with Lamotrigine, with the necessary dose titration .

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 consideredfor patients with a history of mania

The patient on no treatmentAcute depressive episode

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 .

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

Simplifying pre-existing Polypharmacy

which may change seizure thresholds.

When depressive symptoms are less severe, lithium or possibly Valproate may be considered .

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

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

Psychotherapy

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

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

If the 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

The limited evidence supports themodest 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

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

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

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

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

Combination treatmentWhen 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

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

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

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

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.

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).

• 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).

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

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

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

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

78

Switch to mania

True antidepressant-induced polarity switches persist even after the medication is discontinued

79

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.

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.

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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.

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 depression1

• 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 weeks2

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

Antidepressants for acute treatment of bipolar depression: A systematic review and meta-analysis

JOURNAL OFCLINICAL PSYCHIATRYM.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.

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.

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

Ch

ang

e F

rom

Ba

selin

e o

f MA

DR

SLamotrigine in Acute Treatment of Bipolar

DepressionLTG 50 mg/day (n = 64) LTG 200 mg/day (n = 63) Placebo (n = 65)

Week

0

-5

-10

-15

-20

0 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

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

LOCF Observed

*

*†

†††

†

†† †

†

†† †

†

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70Week

Su

rviv

al E

stim

ate

PBO (n=188)

LTG200/400 (n=223)

Li (n=164)

Time to Intervention for a Mood EpisodeLamotrigine vs Lithium vs Placebo

Goodwin et al., 2003 submitted

26%22%

44%

37%

12 Mon. 18 Mon.

Index Manic or Depressed

LTG v. PBO, p < 0.001Li v. PBO, p < 0.001LTG v. Li, p = 0.629

Week

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70

Sur

viva

l Est

imat

e

PBO (n = 70)

LTG (n = 59)

Li (n = 46)

Median = 13 weeks

Median = 24 weeks

Median = 29 weeks

Li vs PBO, P = 0.029LTG vs PBO, P = 0.029LTG 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 dailyLi = lithium 0.8–1.1 mEq/LPBO = placebo Time to Intervention for a Mood Episode

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.

Summary• Skin rash does not mean always Stevens-

Johnson syndrome .• Drug interaction is very important .

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