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Lamotrigine for TreatmentLamotrigine for Treatment
Refractory Mood Disorders inRefractory Mood Disorders in
Adolescents: A Case SeriesAdolescents: A Case Series
Carlo G. Carandang, MD, ABPNCarlo G. Carandang, MD, ABPN
Assistant ProfessorAssistant Professor
Department of PsychiatryDepartment of Psychiatry
Dalhousie UniversityDalhousie University
IWK Health CentreIWK Health Centre
DisclosureDisclosure
 Grant/Research Support:Grant/Research Support:
 GlaxoSmithKlineGlaxoSmithKline
 Maine Medical Center Research InstituteMaine Medical Center Research Institute
ObjectivesObjectives
 Learn about prevalence and treatment interventions forLearn about prevalence and treatment interventions for
refractory depression in adolescentsrefractory depression in adolescents
 Summarize the intervention studies in refractory moodSummarize the intervention studies in refractory mood
disorders in adolescentsdisorders in adolescents
 Dissect the 9 cases of lamotrigine for treatmentDissect the 9 cases of lamotrigine for treatment
refractory mood disorders in adolescentsrefractory mood disorders in adolescents
 Learn pharmacokinetics and pharmacodynamics ofLearn pharmacokinetics and pharmacodynamics of
lamotriginelamotrigine
 Learn safe titration schedule to minimize rashLearn safe titration schedule to minimize rash
Treatment-Refractory Depression inTreatment-Refractory Depression in
AdolescentsAdolescents
 Serotonin Reuptake Inhibitors (SRI’s) have responseSerotonin Reuptake Inhibitors (SRI’s) have response
rate of 50-60% for depression in youth (Birmaher 2004)rate of 50-60% for depression in youth (Birmaher 2004)
 SRI’s have low effect size (about 0.26) in youth (JureidiSRI’s have low effect size (about 0.26) in youth (Jureidi
et al., 2004)et al., 2004)
 Almost half do not respond to SRI monotherapyAlmost half do not respond to SRI monotherapy
 30% do not respond to Fluoxetine with concurrent30% do not respond to Fluoxetine with concurrent
Cognitive-Behavioral Therapy (March et al., 2004)Cognitive-Behavioral Therapy (March et al., 2004)
 Treatment-refractory depression associated with poorTreatment-refractory depression associated with poor
prognosis and high suicide riskprognosis and high suicide risk
 What is the treatment for the adolescents withWhat is the treatment for the adolescents with
depression who are treatment-resistant?depression who are treatment-resistant?
Course of Youth DepressionCourse of Youth Depression
 Significant mortality by suicide (Rao, 1993)Significant mortality by suicide (Rao, 1993)
 MMean duration 32 weeks (SD=28weeks), withean duration 32 weeks (SD=28weeks), with
age of onset having an inverse relationship toage of onset having an inverse relationship to
time to recovery (Kovacs, 1984a)time to recovery (Kovacs, 1984a)
 In 10% of depressed adolescents, theIn 10% of depressed adolescents, the
depressive episode lasted more than 2 yearsdepressive episode lasted more than 2 years
(Strober, 1993)(Strober, 1993)
 Within 5 years of the initial diagnosis, 72% ofWithin 5 years of the initial diagnosis, 72% of
depressed youth develop recurrence (Kovacs,depressed youth develop recurrence (Kovacs,
1984b)1984b)
Youth Depression and BipolarityYouth Depression and Bipolarity
 In prepubertal depression, 32% developIn prepubertal depression, 32% develop
bipolar disorder within 5 years (Geller,bipolar disorder within 5 years (Geller,
1994)1994)
 In adolescent depression, 20% developIn adolescent depression, 20% develop
bipolar disorder within 4 years (Strober,bipolar disorder within 4 years (Strober,
1982)1982)
 28% of hospitalized adolescents with28% of hospitalized adolescents with
psychotic depression develop bipolarpsychotic depression develop bipolar
disorder within 2 years (Strober, 1993)disorder within 2 years (Strober, 1993)
Treatment-Refractory Depression inTreatment-Refractory Depression in
Youth: Lithium StudiesYouth: Lithium Studies
 Ryan et al. 1988Ryan et al. 1988
 Retrospective case series, Dx: MDD (TCA non-responders)Retrospective case series, Dx: MDD (TCA non-responders)
 Lithium augmentation to TCALithium augmentation to TCA
 N=14, age 14-19, lithium dosing 600-1200N=14, age 14-19, lithium dosing 600-1200
 6/14 (43%) responded6/14 (43%) responded
 Strober et al. 1992Strober et al. 1992
 Open label prospective, Dx: MDD (IMI non-responders)Open label prospective, Dx: MDD (IMI non-responders)
 Lithium augmentation to imipramineLithium augmentation to imipramine
 N=24, mean age 15.4, lithium dosing variableN=24, mean age 15.4, lithium dosing variable
 10/24 (42%) responded10/24 (42%) responded
 Walter et al. 1998Walter et al. 1998
 Retrospective case series, Dx: MDD (venlafaxine non-responders)Retrospective case series, Dx: MDD (venlafaxine non-responders)
 Lithium augmentation to venlafaxineLithium augmentation to venlafaxine
 N=2, age 16, lithium dosing 500-1250N=2, age 16, lithium dosing 500-1250
 Helpful in both casesHelpful in both cases
Treatment-Refractory Mood Disorders inTreatment-Refractory Mood Disorders in
Youth: Lamotrigine StudiesYouth: Lamotrigine Studies
 Mandoki 1997Mandoki 1997
 Retrospective case series, Dx: Bipolar D/O (VPA non-responders)Retrospective case series, Dx: Bipolar D/O (VPA non-responders)
 Lamotrigine augmentation to valproateLamotrigine augmentation to valproate
 N=10, age not reported, ‘children and adolescents,’ LTG dosing 50-200,N=10, age not reported, ‘children and adolescents,’ LTG dosing 50-200,
VPA dosing 500-1500VPA dosing 500-1500
 Outcome: ‘all responded,’ but no CGI-I reported, no rashOutcome: ‘all responded,’ but no CGI-I reported, no rash
 Carandang et al. 2003 (discussed later)Carandang et al. 2003 (discussed later)
 Saxena et al. 2004 (AACAP Meeting, Washington D.C.)Saxena et al. 2004 (AACAP Meeting, Washington D.C.)
 Prospective open label, Dx: BP I, II, NOS; depressed or mixed maniaProspective open label, Dx: BP I, II, NOS; depressed or mixed mania
 N=18, 12-17 yo (Mean 15.3), 8 weeks,N=18, 12-17 yo (Mean 15.3), 8 weeks, mean dose 132mean dose 132
 Open LTG monotherapy or add-on (to either Li, VPA, CBZ,Open LTG monotherapy or add-on (to either Li, VPA, CBZ,
antipsychotics)antipsychotics)
 Responders by CGI-C:Responders by CGI-C: 15/1715/17 (88%)(88%) (response 1 or 2)(response 1 or 2)
 Responders by CDRS-R:Responders by CDRS-R: 11/1711/17 (65%)(65%) (response 50% dec)(response 50% dec)
 No weight gain or rash during the studyNo weight gain or rash during the study
Treatment-Refractory Depression inTreatment-Refractory Depression in
Adolescents: InterventionsAdolescents: Interventions
 What to do after fluoxetine nonresponse?What to do after fluoxetine nonresponse?
 Switch to different antidepressant?Switch to different antidepressant?
 Columbia pooled analysis of 24 clinical trials involving 4,400 youth:Columbia pooled analysis of 24 clinical trials involving 4,400 youth:
4% suicidal events on medication versus 2% on placebo (p<0.05)4% suicidal events on medication versus 2% on placebo (p<0.05)
 Paroxetine (risk ratio 2.65) and venlafaxine (risk ratio 4.97) associatedParoxetine (risk ratio 2.65) and venlafaxine (risk ratio 4.97) associated
with significant suicide-related events compared to placebowith significant suicide-related events compared to placebo
 Fluoxetine is the only SSRI with an acceptable benefit/risk ratio forFluoxetine is the only SSRI with an acceptable benefit/risk ratio for
youth depression (AACAP position)youth depression (AACAP position)
 Need to treat 3 patients to see significant response to fluoxetine, versusNeed to treat 3 patients to see significant response to fluoxetine, versus
need to treat 50 patients to see SRI-induced suicidalityneed to treat 50 patients to see SRI-induced suicidality
 Combine antidepressants (youth studies?)Combine antidepressants (youth studies?)
 Augment (lithium CO3, stimulants, thyroxine)Augment (lithium CO3, stimulants, thyroxine)
 Lithium augmentation: 3 studies for refractory depression in youthLithium augmentation: 3 studies for refractory depression in youth
Risk Ratio of Serious Suicide-RelatedRisk Ratio of Serious Suicide-Related
Event on SSRI’sEvent on SSRI’s
N (drug)N (drug) N (PBO)N (PBO) Risk RatioRisk Ratio
FluoxetineFluoxetine 249249 209209 0.920.92
ParoxetineParoxetine 642642 549549 2.652.65
SertralineSertraline 281281 279279 1.481.48
CitalopramCitalopram 210210 197197 1.371.37
VenlafaxineVenlafaxine 339339 342342 4.974.97
MirtazapineMirtazapine 170170 8888 1.581.58
NefazodoneNefazodone 279279 189189 No eventsNo events
Total all trialsTotal all trials 1.781.78
Treatment-Refractory Depression inTreatment-Refractory Depression in
Adolescents: InterventionsAdolescents: Interventions
 Last resort treatmentsLast resort treatments
 MAOI’s (Frommer 1967, Ryan 1988, Strober 1998)MAOI’s (Frommer 1967, Ryan 1988, Strober 1998)
 Dietary restrictions (tyramine-associated hypertensiveDietary restrictions (tyramine-associated hypertensive
crisis) limits usecrisis) limits use
 ECT (Walter & Rey 1997)ECT (Walter & Rey 1997)
 Meta analysis of close to 400 youthMeta analysis of close to 400 youth
Lamotrigine for Treatment Refractory MoodLamotrigine for Treatment Refractory Mood
Disorders in Adolescents, a Case SeriesDisorders in Adolescents, a Case Series
 Carandang C, Maxwell D, Robbins D,Carandang C, Maxwell D, Robbins D,
Oesterheld J (2003), Lamotrigine in adolescentOesterheld J (2003), Lamotrigine in adolescent
mood disorders (letter).mood disorders (letter). J Am Acad Child AdolescJ Am Acad Child Adolesc
PsychiatryPsychiatry 42(7):750-75142(7):750-751
 Pilot data for $362,511.00 investigator-initiatedPilot data for $362,511.00 investigator-initiated
grant from GlaxoSmithKlinegrant from GlaxoSmithKline
LTG Case Series: AbstractLTG Case Series: Abstract
 Objective:Objective:
 Determine the safety and efficacy of lamotrigine forDetermine the safety and efficacy of lamotrigine for
treatment-refractory mood disorders in adolescents.treatment-refractory mood disorders in adolescents.
 Method:Method:
 A retrospective chart review was performed on allA retrospective chart review was performed on all
adolescents with mood disorders who were treatedadolescents with mood disorders who were treated
with lamotrigine (Lamictalwith lamotrigine (Lamictal®) within Maine Medical®) within Maine Medical
Center Department of Psychiatry from 1999 to 2003.Center Department of Psychiatry from 1999 to 2003.
 9 adolescents were assessed9 adolescents were assessed
LTG Case Series: DiagnosisLTG Case Series: Diagnosis
0
1
2
3
4
5
6
Number of patients
Bipolar Depression Unipolar Depression
Mood Disorder NOS
LTG Case Series: ConcurrentLTG Case Series: Concurrent
Medications with LamotrigineMedications with Lamotrigine
0
1
2
3
Number of patients
Lamotrigine Monotherapy Antidepressants
Antipsychotics Mood Stabilizer
Anxiolytics Hypnotics
LTG Case Series: Age at Initiation ofLTG Case Series: Age at Initiation of
Lamotrigine TreatmentLamotrigine Treatment
0
5
10
15
20
Age
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9
Mean age 16.4; range 14-18
LTG Case Series: LamotrigineLTG Case Series: Lamotrigine
DosingDosing
0
50
100
150
200
250
Daily dose
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9
Mean daily LTG dose was 141.7mg, ranging from 25 to 250mg/day
LTG Case Series: Clinical OutcomeLTG Case Series: Clinical Outcome
0
1
2
3
4
CGI-BP
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
Patient 7 Patient 8 Patient 9
CGI-BP (Clinical Global Impression-Bipolar Version); 1: very much improved;
2: much improved; 3: minimally improved; 4: no change
LTG Case Series: SummaryLTG Case Series: Summary
 Improvement was seen in 8 out of 9 subjects, asImprovement was seen in 8 out of 9 subjects, as
measured by the CGI-BP overall illness rating (Clinicalmeasured by the CGI-BP overall illness rating (Clinical
Global Impressions-Bipolar Version). AmongGlobal Impressions-Bipolar Version). Among
responders, 7 were rated as ‘much improved’ and 1 wasresponders, 7 were rated as ‘much improved’ and 1 was
rated as ‘very much improved.’ One subject developedrated as ‘very much improved.’ One subject developed
an erythematous rash, which remitted a few days afteran erythematous rash, which remitted a few days after
discontinuation of therapy.discontinuation of therapy.
 This case series provides preliminary data regarding theThis case series provides preliminary data regarding the
safety and effectiveness of LTG for treatment-safety and effectiveness of LTG for treatment-
refractory mood disorders in adolescents. Prospective,refractory mood disorders in adolescents. Prospective,
controlled studies are warranted.controlled studies are warranted.
Case DiscussionCase Discussion
 18 yo female, graduated from H.S., lives with father,18 yo female, graduated from H.S., lives with father,
part-time employment with father’s businesspart-time employment with father’s business
 Hospitalized at SHH at age 16 after O/D on Tylenol inHospitalized at SHH at age 16 after O/D on Tylenol in
suicide attemptsuicide attempt
 Multiple depressive sxs with acute onset: low moods,Multiple depressive sxs with acute onset: low moods,
EMA’s, hopelessness, fatigue, psychomotor retardation,EMA’s, hopelessness, fatigue, psychomotor retardation,
SI, declining school performanceSI, declining school performance
 Low moods started at age 13, after separation ofLow moods started at age 13, after separation of
parentsparents
 Possible history of exposure to domestic violence inPossible history of exposure to domestic violence in
childhoodchildhood
Case Discussion: cont.Case Discussion: cont.
 Stressors preceding hospitalization:Stressors preceding hospitalization:
 Mother moved to Houston, TX, Father startedMother moved to Houston, TX, Father started
dating, conflictual parental divorce, school pressures,dating, conflictual parental divorce, school pressures,
aunt and mat. GM diedaunt and mat. GM died
 One prior attempt: cut arms with razor age 15,One prior attempt: cut arms with razor age 15,
not medically seriousnot medically serious
 Past psych hx: age 13, short-term, weekly ind.Past psych hx: age 13, short-term, weekly ind.
therapy. Citalopram titrated to 40mg qd withtherapy. Citalopram titrated to 40mg qd with
only partial response after several monthsonly partial response after several months
Case Discussion: cont.Case Discussion: cont.
 PMH: No acute medical problems; regular mentrualPMH: No acute medical problems; regular mentrual
cyclecycle
 FH: Mat uncle bipolar D/O, mat GF and GMFH: Mat uncle bipolar D/O, mat GF and GM
depression, mat aunt: EtOH abuse, pat GF EtOHdepression, mat aunt: EtOH abuse, pat GF EtOH
abuse, pat GM anxiety D/Oabuse, pat GM anxiety D/O
 Dev./Social Hx: Normal pregnancy. No dev. delays.Dev./Social Hx: Normal pregnancy. No dev. delays.
Father and mother with conflictual divorce; now hardlyFather and mother with conflictual divorce; now hardly
communicate. Father owns construction business incommunicate. Father owns construction business in
Maine. Father dating again, mother moved to Houston.Maine. Father dating again, mother moved to Houston.
Older brother in college. No substance abuse.Older brother in college. No substance abuse.
Case Discussion: cont.Case Discussion: cont.
 MSE significant for marked psychomotor retardation,MSE significant for marked psychomotor retardation,
whispering voice, nonspontaneous speech, low moodwhispering voice, nonspontaneous speech, low mood
 Hospital course: Patient continued to exhibit severeHospital course: Patient continued to exhibit severe
depressive symptoms and SI. Lithium was added,depressive symptoms and SI. Lithium was added,
titrated to 675mg qd to augment Citalopram 40mg qd.titrated to 675mg qd to augment Citalopram 40mg qd.
Some improvement of mood, less SI.Some improvement of mood, less SI.
 Discharged to MCG for outpatient treatment withDischarged to MCG for outpatient treatment with
therapist and psychiatristtherapist and psychiatrist
Case Discussion: cont.Case Discussion: cont.
 On follow-up 2 months post-D/C, pt. self-D/C’s medsOn follow-up 2 months post-D/C, pt. self-D/C’s meds
secondary to psychic numbingsecondary to psychic numbing
 Meds took away “creativity” and happy moods, but did helpMeds took away “creativity” and happy moods, but did help
with low moods.with low moods.
 Now with relapse: multiple dep sxs and SI, as well asNow with relapse: multiple dep sxs and SI, as well as
mood reactivity to stressorsmood reactivity to stressors
 Lamotrigine started for severe depressive sxs (titratedLamotrigine started for severe depressive sxs (titrated
to 200mg qd), and frequency of ind tx increased toto 200mg qd), and frequency of ind tx increased to
twice weeklytwice weekly
 Significant response, does well for several months untilSignificant response, does well for several months until
winter, when pt. experiences another relapsewinter, when pt. experiences another relapse
Case Discussion: cont.Case Discussion: cont.
 Admitted to Adolescent Partial ProgramAdmitted to Adolescent Partial Program
 Pt. now with new development of AH: tiresPt. now with new development of AH: tires
squealing, glass breaking, door slammingsquealing, glass breaking, door slamming
 No voices, no frank delusions, reality testing intactNo voices, no frank delusions, reality testing intact
 Responds to addition of Risperidone 0.5mg qhsResponds to addition of Risperidone 0.5mg qhs
 Develops galactorrhea, decreased libido, anorgasmiaDevelops galactorrhea, decreased libido, anorgasmia
 Risperidone D/C’ed, Aripiprazole (Abilify®) started,Risperidone D/C’ed, Aripiprazole (Abilify®) started,
responds to 10mg qhs without SE’sresponds to 10mg qhs without SE’s
Case Discussion: cont.Case Discussion: cont.
 On D/C from Partial, pt. continues to have lowOn D/C from Partial, pt. continues to have low
moods, mood lability and EMA’smoods, mood lability and EMA’s
 Mirtazapine started, titrated to 30mg qhs, respondsMirtazapine started, titrated to 30mg qhs, responds
 During final quarter of Senior year, pt. developsDuring final quarter of Senior year, pt. develops
hypersensitivity to noises and has disorganizedhypersensitivity to noises and has disorganized
thoughts; AH of phone ringingthoughts; AH of phone ringing
 Stressors: graduation and collegeStressors: graduation and college
 Aripiprazole increased to 30mg qhs and psychoedAripiprazole increased to 30mg qhs and psychoed
instituted: respondsinstituted: responds
Case Discussion: cont.Case Discussion: cont.
 Stabilized on Lamotrigine 200mg qhs, MirtazapineStabilized on Lamotrigine 200mg qhs, Mirtazapine
30mg qhs, Aripiprazole 30mg qhs, and weekly30mg qhs, Aripiprazole 30mg qhs, and weekly
individual therapyindividual therapy
 Therapist leaves practice, pt. decompensates,Therapist leaves practice, pt. decompensates,
discontinues her meds, dep sxs with SIdiscontinues her meds, dep sxs with SI
 Depression somehow remits; uses coping skills andDepression somehow remits; uses coping skills and
social supports: withdraws college plans, works part-social supports: withdraws college plans, works part-
time with father, lives with father, father supervisestime with father, lives with father, father supervises
closelyclosely
 Now stabilized on just bimonthly supportive medicalNow stabilized on just bimonthly supportive medical
psychotherapy, close supervision by father, no schoolpsychotherapy, close supervision by father, no school
stressstress
Case Discussion: Differential DxCase Discussion: Differential Dx
 Major Depressive Disorder with comorbidMajor Depressive Disorder with comorbid
PTSDPTSD
 Affective psychosisAffective psychosis
 SchizophreniaSchizophrenia
LTG PharmacodynamicsLTG Pharmacodynamics
 LTG blocks voltage-dependent sodium and calciumLTG blocks voltage-dependent sodium and calcium
channels in presynaptic neurons with subsequentchannels in presynaptic neurons with subsequent
inhibition of glutamate (excitatory neurotransmitter)inhibition of glutamate (excitatory neurotransmitter)
release, leading to stabilization of the neuronalrelease, leading to stabilization of the neuronal
membrane.membrane.
 LTG weakly inhibits serotonin reuptake.LTG weakly inhibits serotonin reuptake.
 LTG inhibits completed amygdala and cortical-kindledLTG inhibits completed amygdala and cortical-kindled
seizures in rats.seizures in rats.
 LTG is associated with neuroprotective effects, asLTG is associated with neuroprotective effects, as
demonstrated in animal models of ischemia anddemonstrated in animal models of ischemia and
neuronal damage (possibly mediated via its effects onneuronal damage (possibly mediated via its effects on
the release of neuronal glutamate).the release of neuronal glutamate).
LTG Pharmacodynamics: continuedLTG Pharmacodynamics: continued
 Anticonvulsant effects of LTG mediated mainly fromAnticonvulsant effects of LTG mediated mainly from
ion channel effects (especially sodium channelion channel effects (especially sodium channel
blockade).blockade).
 Psychotropic effects of LTG postulated to be mediatedPsychotropic effects of LTG postulated to be mediated
from antiglutamatergic and neuroprotective actions.from antiglutamatergic and neuroprotective actions.
 Kindling theory has provided insight into the etiology,Kindling theory has provided insight into the etiology,
longitudinal course, progression, and treatment of bothlongitudinal course, progression, and treatment of both
epilepsy and recurrent mood disorders.epilepsy and recurrent mood disorders.
Kindling TheoryKindling TheorySeverityofSymptoms
Tim
e
Full Disorder Threshold
LTG PharmacokineticsLTG Pharmacokinetics
 Linear absorption kinetics.Linear absorption kinetics.
 Bioavailability approaches 100%; absorption notBioavailability approaches 100%; absorption not
affected by food.affected by food.
 Peak plasma concentration are reached 1-3Peak plasma concentration are reached 1-3
hours after a single LTG dose.hours after a single LTG dose.
 Metabolized in liver via N-glucoronidation, andMetabolized in liver via N-glucoronidation, and
conjugate is excreted in the urine.conjugate is excreted in the urine.
 Mean elimination half-life in adults 25-35 hours.Mean elimination half-life in adults 25-35 hours.
Hypothesis: LTG in refractoryHypothesis: LTG in refractory
depression in adolescentsdepression in adolescents
 Underlying BipolarityUnderlying Bipolarity
 Antiglutamatergic effectAntiglutamatergic effect
 Neuroprotective actionsNeuroprotective actions
 Prevention of kindling?Prevention of kindling?
Treatment Resistant Depression:Treatment Resistant Depression:
Clinical ConsiderationsClinical Considerations
 Is diagnosis correct?Is diagnosis correct?
 Consider utilizing KSADS, psychological/neuropsych testingConsider utilizing KSADS, psychological/neuropsych testing
 Treatment noncompliance?Treatment noncompliance?
 Simply dosing schedule, supervision from parents and schoolSimply dosing schedule, supervision from parents and school
nurse, consider referral to community-based outreachnurse, consider referral to community-based outreach
programprogram
 Quality of treatment?Quality of treatment?
 Consider referral to tertiary pediatric mood disorders clinicConsider referral to tertiary pediatric mood disorders clinic
that utilizes evidence-based therapies (CBT, IPT, multi-familythat utilizes evidence-based therapies (CBT, IPT, multi-family
psychoeducational groups)psychoeducational groups)
 Comorbid psychiatric and medical conditions?Comorbid psychiatric and medical conditions?
 Ongoing exposure to negative life events?Ongoing exposure to negative life events?
Ongoing Adolescent DepressionOngoing Adolescent Depression
Studies at Maine Medical CenterStudies at Maine Medical Center
 Lamotrigine for Treatment Refractory Depression inLamotrigine for Treatment Refractory Depression in
Adolescents: a Placebo-Controlled, Crossover StudyAdolescents: a Placebo-Controlled, Crossover Study
 Principal Investigator: Douglas Robbins, MDPrincipal Investigator: Douglas Robbins, MD
 Source: GlaxoSmithKlineSource: GlaxoSmithKline
 Treatment-Resistant Mood Disorders in Adolescents:Treatment-Resistant Mood Disorders in Adolescents:
Clinical Characteristics and Implications for TreatmentClinical Characteristics and Implications for Treatment
 Principal Investigator: Douglas Robbins, MDPrincipal Investigator: Douglas Robbins, MD
 Source: MMCRISource: MMCRI
Inclusion Criteria: MMC-Inclusion Criteria: MMC-
Portland LTG StudyPortland LTG Study
 Adolescents (13-17) diagnosed with a MajorAdolescents (13-17) diagnosed with a Major
Depressive Episode via KSADSDepressive Episode via KSADS
 Can be unipolar or bipolar depressionCan be unipolar or bipolar depression
 Moderate to severe depressionModerate to severe depression
 CDRS > 40 (Children’s Depression RatingCDRS > 40 (Children’s Depression Rating
Scale)Scale)
 CGAS < 60 (Children’s Global AssessmentCGAS < 60 (Children’s Global Assessment
Scale)Scale)
Treatment Algorithm: MMC-Treatment Algorithm: MMC-
Portland LTG StudyPortland LTG Study
 Open-label, run-inOpen-label, run-in
 Fluoxetine (Prozac®) with concurrent Group CBT for 8Fluoxetine (Prozac®) with concurrent Group CBT for 8
weeksweeks
 Randomized, double-blinded, placebo-controlledRandomized, double-blinded, placebo-controlled
crossovercrossover
 Fluoxetine + LTG, or Fluoxetine + placebo for 8 weeksFluoxetine + LTG, or Fluoxetine + placebo for 8 weeks
 Washout either LTG or placebo for 3 weeksWashout either LTG or placebo for 3 weeks
 Crossover to alternative treatment for 8 weeksCrossover to alternative treatment for 8 weeks
 Open-label, maintenanceOpen-label, maintenance
 Follow responders to Fluoxetine + LTG for 6 monthsFollow responders to Fluoxetine + LTG for 6 months
Safety and Tolerability of LTG inSafety and Tolerability of LTG in
Adolescent Mood DisordersAdolescent Mood Disorders
 Carandang, Mullany, Yazbek, Minot, Robbins,Carandang, Mullany, Yazbek, Minot, Robbins, rejectedrejected,,
AACAP/CACAP 2005 MeetingAACAP/CACAP 2005 Meeting
 Retrospective case series, multi-siteRetrospective case series, multi-site
 N=42, mean age 15.6 (SD 1.3)N=42, mean age 15.6 (SD 1.3)
 28 from MMC, 7 from the PIER program, and 7 from IWK28 from MMC, 7 from the PIER program, and 7 from IWK
 Diagnoses included 21 (50%) with Bipolar, 12 (29%) withDiagnoses included 21 (50%) with Bipolar, 12 (29%) with
Unipolar, and 9 (21%) with Mood NOSUnipolar, and 9 (21%) with Mood NOS
 The mean comorbid diagnoses: 0.8±0.7; 29% maleThe mean comorbid diagnoses: 0.8±0.7; 29% male
 38 (90%) had failed prior medication trials with mood stabilizers38 (90%) had failed prior medication trials with mood stabilizers
and/or antidepressantsand/or antidepressants
 The average number of concurrent medications with LTG wasThe average number of concurrent medications with LTG was
1.5±1.01.5±1.0
Safety and Tolerability of LTG inSafety and Tolerability of LTG in
Adolescent Mood DisordersAdolescent Mood Disorders
 Mean daily LTG dose 115.0mg (SD 76.0), range 10 toMean daily LTG dose 115.0mg (SD 76.0), range 10 to
300300
 The average duration of LTG treatment 29.1±31.8The average duration of LTG treatment 29.1±31.8
weeks.weeks.
 The mean CGI-S score decreased from 4.9±1.0The mean CGI-S score decreased from 4.9±1.0
(markedly ill range) at baseline to 3.5±1.4 (mildly ill(markedly ill range) at baseline to 3.5±1.4 (mildly ill
range) at endpoint (Wilcoxon signed ranks z-range) at endpoint (Wilcoxon signed ranks z-
score=3.204, p<0.002).score=3.204, p<0.002).
 Robust improvement in 22 subjects (52%) (CGI-I of 1Robust improvement in 22 subjects (52%) (CGI-I of 1
or 2)or 2)
Safety and Tolerability of LTG inSafety and Tolerability of LTG in
Adolescent Mood Disorders: AE’sAdolescent Mood Disorders: AE’s
 4 (10%) developed benign rash, which remitted after4 (10%) developed benign rash, which remitted after
discontinuation of LTG.discontinuation of LTG.
 1 additional subject developed severe generalized1 additional subject developed severe generalized
pruritis when she abruptly discontinued her oralpruritis when she abruptly discontinued her oral
conceptive (OC), which resolved when restarting theconceptive (OC), which resolved when restarting the
OCOC
 3 subjects (7%) developed excessive sedation, which led3 subjects (7%) developed excessive sedation, which led
to two discontinuations of LTG, and 1 subject wasto two discontinuations of LTG, and 1 subject was
stable with no adverse effects at a lower LTG dose.stable with no adverse effects at a lower LTG dose.
Recommended LTG Titration inRecommended LTG Titration in
AdolescentsAdolescents
 Recommend halving the FDA recommendedRecommend halving the FDA recommended
titration for adult bipolar disordertitration for adult bipolar disorder
 12.5mg weeks 1 and 212.5mg weeks 1 and 2
 25mg weeks 2 and 425mg weeks 2 and 4
 50mg week 550mg week 5
 100mg week 6100mg week 6
 Watch drug-drug interactions with ValproateWatch drug-drug interactions with Valproate
(inc. LTG), Oral Contraceptives (dec. LTG), and(inc. LTG), Oral Contraceptives (dec. LTG), and
Sertraline (inc. LTG)Sertraline (inc. LTG)

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Lamotrigine for Treatment Refractory Mood Disorders in Adolescents: A Case Series

  • 1. Lamotrigine for TreatmentLamotrigine for Treatment Refractory Mood Disorders inRefractory Mood Disorders in Adolescents: A Case SeriesAdolescents: A Case Series Carlo G. Carandang, MD, ABPNCarlo G. Carandang, MD, ABPN Assistant ProfessorAssistant Professor Department of PsychiatryDepartment of Psychiatry Dalhousie UniversityDalhousie University IWK Health CentreIWK Health Centre
  • 2. DisclosureDisclosure  Grant/Research Support:Grant/Research Support:  GlaxoSmithKlineGlaxoSmithKline  Maine Medical Center Research InstituteMaine Medical Center Research Institute
  • 3. ObjectivesObjectives  Learn about prevalence and treatment interventions forLearn about prevalence and treatment interventions for refractory depression in adolescentsrefractory depression in adolescents  Summarize the intervention studies in refractory moodSummarize the intervention studies in refractory mood disorders in adolescentsdisorders in adolescents  Dissect the 9 cases of lamotrigine for treatmentDissect the 9 cases of lamotrigine for treatment refractory mood disorders in adolescentsrefractory mood disorders in adolescents  Learn pharmacokinetics and pharmacodynamics ofLearn pharmacokinetics and pharmacodynamics of lamotriginelamotrigine  Learn safe titration schedule to minimize rashLearn safe titration schedule to minimize rash
  • 4. Treatment-Refractory Depression inTreatment-Refractory Depression in AdolescentsAdolescents  Serotonin Reuptake Inhibitors (SRI’s) have responseSerotonin Reuptake Inhibitors (SRI’s) have response rate of 50-60% for depression in youth (Birmaher 2004)rate of 50-60% for depression in youth (Birmaher 2004)  SRI’s have low effect size (about 0.26) in youth (JureidiSRI’s have low effect size (about 0.26) in youth (Jureidi et al., 2004)et al., 2004)  Almost half do not respond to SRI monotherapyAlmost half do not respond to SRI monotherapy  30% do not respond to Fluoxetine with concurrent30% do not respond to Fluoxetine with concurrent Cognitive-Behavioral Therapy (March et al., 2004)Cognitive-Behavioral Therapy (March et al., 2004)  Treatment-refractory depression associated with poorTreatment-refractory depression associated with poor prognosis and high suicide riskprognosis and high suicide risk  What is the treatment for the adolescents withWhat is the treatment for the adolescents with depression who are treatment-resistant?depression who are treatment-resistant?
  • 5. Course of Youth DepressionCourse of Youth Depression  Significant mortality by suicide (Rao, 1993)Significant mortality by suicide (Rao, 1993)  MMean duration 32 weeks (SD=28weeks), withean duration 32 weeks (SD=28weeks), with age of onset having an inverse relationship toage of onset having an inverse relationship to time to recovery (Kovacs, 1984a)time to recovery (Kovacs, 1984a)  In 10% of depressed adolescents, theIn 10% of depressed adolescents, the depressive episode lasted more than 2 yearsdepressive episode lasted more than 2 years (Strober, 1993)(Strober, 1993)  Within 5 years of the initial diagnosis, 72% ofWithin 5 years of the initial diagnosis, 72% of depressed youth develop recurrence (Kovacs,depressed youth develop recurrence (Kovacs, 1984b)1984b)
  • 6. Youth Depression and BipolarityYouth Depression and Bipolarity  In prepubertal depression, 32% developIn prepubertal depression, 32% develop bipolar disorder within 5 years (Geller,bipolar disorder within 5 years (Geller, 1994)1994)  In adolescent depression, 20% developIn adolescent depression, 20% develop bipolar disorder within 4 years (Strober,bipolar disorder within 4 years (Strober, 1982)1982)  28% of hospitalized adolescents with28% of hospitalized adolescents with psychotic depression develop bipolarpsychotic depression develop bipolar disorder within 2 years (Strober, 1993)disorder within 2 years (Strober, 1993)
  • 7. Treatment-Refractory Depression inTreatment-Refractory Depression in Youth: Lithium StudiesYouth: Lithium Studies  Ryan et al. 1988Ryan et al. 1988  Retrospective case series, Dx: MDD (TCA non-responders)Retrospective case series, Dx: MDD (TCA non-responders)  Lithium augmentation to TCALithium augmentation to TCA  N=14, age 14-19, lithium dosing 600-1200N=14, age 14-19, lithium dosing 600-1200  6/14 (43%) responded6/14 (43%) responded  Strober et al. 1992Strober et al. 1992  Open label prospective, Dx: MDD (IMI non-responders)Open label prospective, Dx: MDD (IMI non-responders)  Lithium augmentation to imipramineLithium augmentation to imipramine  N=24, mean age 15.4, lithium dosing variableN=24, mean age 15.4, lithium dosing variable  10/24 (42%) responded10/24 (42%) responded  Walter et al. 1998Walter et al. 1998  Retrospective case series, Dx: MDD (venlafaxine non-responders)Retrospective case series, Dx: MDD (venlafaxine non-responders)  Lithium augmentation to venlafaxineLithium augmentation to venlafaxine  N=2, age 16, lithium dosing 500-1250N=2, age 16, lithium dosing 500-1250  Helpful in both casesHelpful in both cases
  • 8. Treatment-Refractory Mood Disorders inTreatment-Refractory Mood Disorders in Youth: Lamotrigine StudiesYouth: Lamotrigine Studies  Mandoki 1997Mandoki 1997  Retrospective case series, Dx: Bipolar D/O (VPA non-responders)Retrospective case series, Dx: Bipolar D/O (VPA non-responders)  Lamotrigine augmentation to valproateLamotrigine augmentation to valproate  N=10, age not reported, ‘children and adolescents,’ LTG dosing 50-200,N=10, age not reported, ‘children and adolescents,’ LTG dosing 50-200, VPA dosing 500-1500VPA dosing 500-1500  Outcome: ‘all responded,’ but no CGI-I reported, no rashOutcome: ‘all responded,’ but no CGI-I reported, no rash  Carandang et al. 2003 (discussed later)Carandang et al. 2003 (discussed later)  Saxena et al. 2004 (AACAP Meeting, Washington D.C.)Saxena et al. 2004 (AACAP Meeting, Washington D.C.)  Prospective open label, Dx: BP I, II, NOS; depressed or mixed maniaProspective open label, Dx: BP I, II, NOS; depressed or mixed mania  N=18, 12-17 yo (Mean 15.3), 8 weeks,N=18, 12-17 yo (Mean 15.3), 8 weeks, mean dose 132mean dose 132  Open LTG monotherapy or add-on (to either Li, VPA, CBZ,Open LTG monotherapy or add-on (to either Li, VPA, CBZ, antipsychotics)antipsychotics)  Responders by CGI-C:Responders by CGI-C: 15/1715/17 (88%)(88%) (response 1 or 2)(response 1 or 2)  Responders by CDRS-R:Responders by CDRS-R: 11/1711/17 (65%)(65%) (response 50% dec)(response 50% dec)  No weight gain or rash during the studyNo weight gain or rash during the study
  • 9. Treatment-Refractory Depression inTreatment-Refractory Depression in Adolescents: InterventionsAdolescents: Interventions  What to do after fluoxetine nonresponse?What to do after fluoxetine nonresponse?  Switch to different antidepressant?Switch to different antidepressant?  Columbia pooled analysis of 24 clinical trials involving 4,400 youth:Columbia pooled analysis of 24 clinical trials involving 4,400 youth: 4% suicidal events on medication versus 2% on placebo (p<0.05)4% suicidal events on medication versus 2% on placebo (p<0.05)  Paroxetine (risk ratio 2.65) and venlafaxine (risk ratio 4.97) associatedParoxetine (risk ratio 2.65) and venlafaxine (risk ratio 4.97) associated with significant suicide-related events compared to placebowith significant suicide-related events compared to placebo  Fluoxetine is the only SSRI with an acceptable benefit/risk ratio forFluoxetine is the only SSRI with an acceptable benefit/risk ratio for youth depression (AACAP position)youth depression (AACAP position)  Need to treat 3 patients to see significant response to fluoxetine, versusNeed to treat 3 patients to see significant response to fluoxetine, versus need to treat 50 patients to see SRI-induced suicidalityneed to treat 50 patients to see SRI-induced suicidality  Combine antidepressants (youth studies?)Combine antidepressants (youth studies?)  Augment (lithium CO3, stimulants, thyroxine)Augment (lithium CO3, stimulants, thyroxine)  Lithium augmentation: 3 studies for refractory depression in youthLithium augmentation: 3 studies for refractory depression in youth
  • 10. Risk Ratio of Serious Suicide-RelatedRisk Ratio of Serious Suicide-Related Event on SSRI’sEvent on SSRI’s N (drug)N (drug) N (PBO)N (PBO) Risk RatioRisk Ratio FluoxetineFluoxetine 249249 209209 0.920.92 ParoxetineParoxetine 642642 549549 2.652.65 SertralineSertraline 281281 279279 1.481.48 CitalopramCitalopram 210210 197197 1.371.37 VenlafaxineVenlafaxine 339339 342342 4.974.97 MirtazapineMirtazapine 170170 8888 1.581.58 NefazodoneNefazodone 279279 189189 No eventsNo events Total all trialsTotal all trials 1.781.78
  • 11. Treatment-Refractory Depression inTreatment-Refractory Depression in Adolescents: InterventionsAdolescents: Interventions  Last resort treatmentsLast resort treatments  MAOI’s (Frommer 1967, Ryan 1988, Strober 1998)MAOI’s (Frommer 1967, Ryan 1988, Strober 1998)  Dietary restrictions (tyramine-associated hypertensiveDietary restrictions (tyramine-associated hypertensive crisis) limits usecrisis) limits use  ECT (Walter & Rey 1997)ECT (Walter & Rey 1997)  Meta analysis of close to 400 youthMeta analysis of close to 400 youth
  • 12. Lamotrigine for Treatment Refractory MoodLamotrigine for Treatment Refractory Mood Disorders in Adolescents, a Case SeriesDisorders in Adolescents, a Case Series  Carandang C, Maxwell D, Robbins D,Carandang C, Maxwell D, Robbins D, Oesterheld J (2003), Lamotrigine in adolescentOesterheld J (2003), Lamotrigine in adolescent mood disorders (letter).mood disorders (letter). J Am Acad Child AdolescJ Am Acad Child Adolesc PsychiatryPsychiatry 42(7):750-75142(7):750-751  Pilot data for $362,511.00 investigator-initiatedPilot data for $362,511.00 investigator-initiated grant from GlaxoSmithKlinegrant from GlaxoSmithKline
  • 13. LTG Case Series: AbstractLTG Case Series: Abstract  Objective:Objective:  Determine the safety and efficacy of lamotrigine forDetermine the safety and efficacy of lamotrigine for treatment-refractory mood disorders in adolescents.treatment-refractory mood disorders in adolescents.  Method:Method:  A retrospective chart review was performed on allA retrospective chart review was performed on all adolescents with mood disorders who were treatedadolescents with mood disorders who were treated with lamotrigine (Lamictalwith lamotrigine (Lamictal®) within Maine Medical®) within Maine Medical Center Department of Psychiatry from 1999 to 2003.Center Department of Psychiatry from 1999 to 2003.  9 adolescents were assessed9 adolescents were assessed
  • 14. LTG Case Series: DiagnosisLTG Case Series: Diagnosis 0 1 2 3 4 5 6 Number of patients Bipolar Depression Unipolar Depression Mood Disorder NOS
  • 15. LTG Case Series: ConcurrentLTG Case Series: Concurrent Medications with LamotrigineMedications with Lamotrigine 0 1 2 3 Number of patients Lamotrigine Monotherapy Antidepressants Antipsychotics Mood Stabilizer Anxiolytics Hypnotics
  • 16. LTG Case Series: Age at Initiation ofLTG Case Series: Age at Initiation of Lamotrigine TreatmentLamotrigine Treatment 0 5 10 15 20 Age Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Mean age 16.4; range 14-18
  • 17. LTG Case Series: LamotrigineLTG Case Series: Lamotrigine DosingDosing 0 50 100 150 200 250 Daily dose Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Mean daily LTG dose was 141.7mg, ranging from 25 to 250mg/day
  • 18. LTG Case Series: Clinical OutcomeLTG Case Series: Clinical Outcome 0 1 2 3 4 CGI-BP Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 CGI-BP (Clinical Global Impression-Bipolar Version); 1: very much improved; 2: much improved; 3: minimally improved; 4: no change
  • 19. LTG Case Series: SummaryLTG Case Series: Summary  Improvement was seen in 8 out of 9 subjects, asImprovement was seen in 8 out of 9 subjects, as measured by the CGI-BP overall illness rating (Clinicalmeasured by the CGI-BP overall illness rating (Clinical Global Impressions-Bipolar Version). AmongGlobal Impressions-Bipolar Version). Among responders, 7 were rated as ‘much improved’ and 1 wasresponders, 7 were rated as ‘much improved’ and 1 was rated as ‘very much improved.’ One subject developedrated as ‘very much improved.’ One subject developed an erythematous rash, which remitted a few days afteran erythematous rash, which remitted a few days after discontinuation of therapy.discontinuation of therapy.  This case series provides preliminary data regarding theThis case series provides preliminary data regarding the safety and effectiveness of LTG for treatment-safety and effectiveness of LTG for treatment- refractory mood disorders in adolescents. Prospective,refractory mood disorders in adolescents. Prospective, controlled studies are warranted.controlled studies are warranted.
  • 20.
  • 21. Case DiscussionCase Discussion  18 yo female, graduated from H.S., lives with father,18 yo female, graduated from H.S., lives with father, part-time employment with father’s businesspart-time employment with father’s business  Hospitalized at SHH at age 16 after O/D on Tylenol inHospitalized at SHH at age 16 after O/D on Tylenol in suicide attemptsuicide attempt  Multiple depressive sxs with acute onset: low moods,Multiple depressive sxs with acute onset: low moods, EMA’s, hopelessness, fatigue, psychomotor retardation,EMA’s, hopelessness, fatigue, psychomotor retardation, SI, declining school performanceSI, declining school performance  Low moods started at age 13, after separation ofLow moods started at age 13, after separation of parentsparents  Possible history of exposure to domestic violence inPossible history of exposure to domestic violence in childhoodchildhood
  • 22. Case Discussion: cont.Case Discussion: cont.  Stressors preceding hospitalization:Stressors preceding hospitalization:  Mother moved to Houston, TX, Father startedMother moved to Houston, TX, Father started dating, conflictual parental divorce, school pressures,dating, conflictual parental divorce, school pressures, aunt and mat. GM diedaunt and mat. GM died  One prior attempt: cut arms with razor age 15,One prior attempt: cut arms with razor age 15, not medically seriousnot medically serious  Past psych hx: age 13, short-term, weekly ind.Past psych hx: age 13, short-term, weekly ind. therapy. Citalopram titrated to 40mg qd withtherapy. Citalopram titrated to 40mg qd with only partial response after several monthsonly partial response after several months
  • 23. Case Discussion: cont.Case Discussion: cont.  PMH: No acute medical problems; regular mentrualPMH: No acute medical problems; regular mentrual cyclecycle  FH: Mat uncle bipolar D/O, mat GF and GMFH: Mat uncle bipolar D/O, mat GF and GM depression, mat aunt: EtOH abuse, pat GF EtOHdepression, mat aunt: EtOH abuse, pat GF EtOH abuse, pat GM anxiety D/Oabuse, pat GM anxiety D/O  Dev./Social Hx: Normal pregnancy. No dev. delays.Dev./Social Hx: Normal pregnancy. No dev. delays. Father and mother with conflictual divorce; now hardlyFather and mother with conflictual divorce; now hardly communicate. Father owns construction business incommunicate. Father owns construction business in Maine. Father dating again, mother moved to Houston.Maine. Father dating again, mother moved to Houston. Older brother in college. No substance abuse.Older brother in college. No substance abuse.
  • 24. Case Discussion: cont.Case Discussion: cont.  MSE significant for marked psychomotor retardation,MSE significant for marked psychomotor retardation, whispering voice, nonspontaneous speech, low moodwhispering voice, nonspontaneous speech, low mood  Hospital course: Patient continued to exhibit severeHospital course: Patient continued to exhibit severe depressive symptoms and SI. Lithium was added,depressive symptoms and SI. Lithium was added, titrated to 675mg qd to augment Citalopram 40mg qd.titrated to 675mg qd to augment Citalopram 40mg qd. Some improvement of mood, less SI.Some improvement of mood, less SI.  Discharged to MCG for outpatient treatment withDischarged to MCG for outpatient treatment with therapist and psychiatristtherapist and psychiatrist
  • 25. Case Discussion: cont.Case Discussion: cont.  On follow-up 2 months post-D/C, pt. self-D/C’s medsOn follow-up 2 months post-D/C, pt. self-D/C’s meds secondary to psychic numbingsecondary to psychic numbing  Meds took away “creativity” and happy moods, but did helpMeds took away “creativity” and happy moods, but did help with low moods.with low moods.  Now with relapse: multiple dep sxs and SI, as well asNow with relapse: multiple dep sxs and SI, as well as mood reactivity to stressorsmood reactivity to stressors  Lamotrigine started for severe depressive sxs (titratedLamotrigine started for severe depressive sxs (titrated to 200mg qd), and frequency of ind tx increased toto 200mg qd), and frequency of ind tx increased to twice weeklytwice weekly  Significant response, does well for several months untilSignificant response, does well for several months until winter, when pt. experiences another relapsewinter, when pt. experiences another relapse
  • 26. Case Discussion: cont.Case Discussion: cont.  Admitted to Adolescent Partial ProgramAdmitted to Adolescent Partial Program  Pt. now with new development of AH: tiresPt. now with new development of AH: tires squealing, glass breaking, door slammingsquealing, glass breaking, door slamming  No voices, no frank delusions, reality testing intactNo voices, no frank delusions, reality testing intact  Responds to addition of Risperidone 0.5mg qhsResponds to addition of Risperidone 0.5mg qhs  Develops galactorrhea, decreased libido, anorgasmiaDevelops galactorrhea, decreased libido, anorgasmia  Risperidone D/C’ed, Aripiprazole (Abilify®) started,Risperidone D/C’ed, Aripiprazole (Abilify®) started, responds to 10mg qhs without SE’sresponds to 10mg qhs without SE’s
  • 27. Case Discussion: cont.Case Discussion: cont.  On D/C from Partial, pt. continues to have lowOn D/C from Partial, pt. continues to have low moods, mood lability and EMA’smoods, mood lability and EMA’s  Mirtazapine started, titrated to 30mg qhs, respondsMirtazapine started, titrated to 30mg qhs, responds  During final quarter of Senior year, pt. developsDuring final quarter of Senior year, pt. develops hypersensitivity to noises and has disorganizedhypersensitivity to noises and has disorganized thoughts; AH of phone ringingthoughts; AH of phone ringing  Stressors: graduation and collegeStressors: graduation and college  Aripiprazole increased to 30mg qhs and psychoedAripiprazole increased to 30mg qhs and psychoed instituted: respondsinstituted: responds
  • 28. Case Discussion: cont.Case Discussion: cont.  Stabilized on Lamotrigine 200mg qhs, MirtazapineStabilized on Lamotrigine 200mg qhs, Mirtazapine 30mg qhs, Aripiprazole 30mg qhs, and weekly30mg qhs, Aripiprazole 30mg qhs, and weekly individual therapyindividual therapy  Therapist leaves practice, pt. decompensates,Therapist leaves practice, pt. decompensates, discontinues her meds, dep sxs with SIdiscontinues her meds, dep sxs with SI  Depression somehow remits; uses coping skills andDepression somehow remits; uses coping skills and social supports: withdraws college plans, works part-social supports: withdraws college plans, works part- time with father, lives with father, father supervisestime with father, lives with father, father supervises closelyclosely  Now stabilized on just bimonthly supportive medicalNow stabilized on just bimonthly supportive medical psychotherapy, close supervision by father, no schoolpsychotherapy, close supervision by father, no school stressstress
  • 29. Case Discussion: Differential DxCase Discussion: Differential Dx  Major Depressive Disorder with comorbidMajor Depressive Disorder with comorbid PTSDPTSD  Affective psychosisAffective psychosis  SchizophreniaSchizophrenia
  • 30. LTG PharmacodynamicsLTG Pharmacodynamics  LTG blocks voltage-dependent sodium and calciumLTG blocks voltage-dependent sodium and calcium channels in presynaptic neurons with subsequentchannels in presynaptic neurons with subsequent inhibition of glutamate (excitatory neurotransmitter)inhibition of glutamate (excitatory neurotransmitter) release, leading to stabilization of the neuronalrelease, leading to stabilization of the neuronal membrane.membrane.  LTG weakly inhibits serotonin reuptake.LTG weakly inhibits serotonin reuptake.  LTG inhibits completed amygdala and cortical-kindledLTG inhibits completed amygdala and cortical-kindled seizures in rats.seizures in rats.  LTG is associated with neuroprotective effects, asLTG is associated with neuroprotective effects, as demonstrated in animal models of ischemia anddemonstrated in animal models of ischemia and neuronal damage (possibly mediated via its effects onneuronal damage (possibly mediated via its effects on the release of neuronal glutamate).the release of neuronal glutamate).
  • 31. LTG Pharmacodynamics: continuedLTG Pharmacodynamics: continued  Anticonvulsant effects of LTG mediated mainly fromAnticonvulsant effects of LTG mediated mainly from ion channel effects (especially sodium channelion channel effects (especially sodium channel blockade).blockade).  Psychotropic effects of LTG postulated to be mediatedPsychotropic effects of LTG postulated to be mediated from antiglutamatergic and neuroprotective actions.from antiglutamatergic and neuroprotective actions.  Kindling theory has provided insight into the etiology,Kindling theory has provided insight into the etiology, longitudinal course, progression, and treatment of bothlongitudinal course, progression, and treatment of both epilepsy and recurrent mood disorders.epilepsy and recurrent mood disorders.
  • 33. LTG PharmacokineticsLTG Pharmacokinetics  Linear absorption kinetics.Linear absorption kinetics.  Bioavailability approaches 100%; absorption notBioavailability approaches 100%; absorption not affected by food.affected by food.  Peak plasma concentration are reached 1-3Peak plasma concentration are reached 1-3 hours after a single LTG dose.hours after a single LTG dose.  Metabolized in liver via N-glucoronidation, andMetabolized in liver via N-glucoronidation, and conjugate is excreted in the urine.conjugate is excreted in the urine.  Mean elimination half-life in adults 25-35 hours.Mean elimination half-life in adults 25-35 hours.
  • 34. Hypothesis: LTG in refractoryHypothesis: LTG in refractory depression in adolescentsdepression in adolescents  Underlying BipolarityUnderlying Bipolarity  Antiglutamatergic effectAntiglutamatergic effect  Neuroprotective actionsNeuroprotective actions  Prevention of kindling?Prevention of kindling?
  • 35. Treatment Resistant Depression:Treatment Resistant Depression: Clinical ConsiderationsClinical Considerations  Is diagnosis correct?Is diagnosis correct?  Consider utilizing KSADS, psychological/neuropsych testingConsider utilizing KSADS, psychological/neuropsych testing  Treatment noncompliance?Treatment noncompliance?  Simply dosing schedule, supervision from parents and schoolSimply dosing schedule, supervision from parents and school nurse, consider referral to community-based outreachnurse, consider referral to community-based outreach programprogram  Quality of treatment?Quality of treatment?  Consider referral to tertiary pediatric mood disorders clinicConsider referral to tertiary pediatric mood disorders clinic that utilizes evidence-based therapies (CBT, IPT, multi-familythat utilizes evidence-based therapies (CBT, IPT, multi-family psychoeducational groups)psychoeducational groups)  Comorbid psychiatric and medical conditions?Comorbid psychiatric and medical conditions?  Ongoing exposure to negative life events?Ongoing exposure to negative life events?
  • 36. Ongoing Adolescent DepressionOngoing Adolescent Depression Studies at Maine Medical CenterStudies at Maine Medical Center  Lamotrigine for Treatment Refractory Depression inLamotrigine for Treatment Refractory Depression in Adolescents: a Placebo-Controlled, Crossover StudyAdolescents: a Placebo-Controlled, Crossover Study  Principal Investigator: Douglas Robbins, MDPrincipal Investigator: Douglas Robbins, MD  Source: GlaxoSmithKlineSource: GlaxoSmithKline  Treatment-Resistant Mood Disorders in Adolescents:Treatment-Resistant Mood Disorders in Adolescents: Clinical Characteristics and Implications for TreatmentClinical Characteristics and Implications for Treatment  Principal Investigator: Douglas Robbins, MDPrincipal Investigator: Douglas Robbins, MD  Source: MMCRISource: MMCRI
  • 37. Inclusion Criteria: MMC-Inclusion Criteria: MMC- Portland LTG StudyPortland LTG Study  Adolescents (13-17) diagnosed with a MajorAdolescents (13-17) diagnosed with a Major Depressive Episode via KSADSDepressive Episode via KSADS  Can be unipolar or bipolar depressionCan be unipolar or bipolar depression  Moderate to severe depressionModerate to severe depression  CDRS > 40 (Children’s Depression RatingCDRS > 40 (Children’s Depression Rating Scale)Scale)  CGAS < 60 (Children’s Global AssessmentCGAS < 60 (Children’s Global Assessment Scale)Scale)
  • 38. Treatment Algorithm: MMC-Treatment Algorithm: MMC- Portland LTG StudyPortland LTG Study  Open-label, run-inOpen-label, run-in  Fluoxetine (Prozac®) with concurrent Group CBT for 8Fluoxetine (Prozac®) with concurrent Group CBT for 8 weeksweeks  Randomized, double-blinded, placebo-controlledRandomized, double-blinded, placebo-controlled crossovercrossover  Fluoxetine + LTG, or Fluoxetine + placebo for 8 weeksFluoxetine + LTG, or Fluoxetine + placebo for 8 weeks  Washout either LTG or placebo for 3 weeksWashout either LTG or placebo for 3 weeks  Crossover to alternative treatment for 8 weeksCrossover to alternative treatment for 8 weeks  Open-label, maintenanceOpen-label, maintenance  Follow responders to Fluoxetine + LTG for 6 monthsFollow responders to Fluoxetine + LTG for 6 months
  • 39. Safety and Tolerability of LTG inSafety and Tolerability of LTG in Adolescent Mood DisordersAdolescent Mood Disorders  Carandang, Mullany, Yazbek, Minot, Robbins,Carandang, Mullany, Yazbek, Minot, Robbins, rejectedrejected,, AACAP/CACAP 2005 MeetingAACAP/CACAP 2005 Meeting  Retrospective case series, multi-siteRetrospective case series, multi-site  N=42, mean age 15.6 (SD 1.3)N=42, mean age 15.6 (SD 1.3)  28 from MMC, 7 from the PIER program, and 7 from IWK28 from MMC, 7 from the PIER program, and 7 from IWK  Diagnoses included 21 (50%) with Bipolar, 12 (29%) withDiagnoses included 21 (50%) with Bipolar, 12 (29%) with Unipolar, and 9 (21%) with Mood NOSUnipolar, and 9 (21%) with Mood NOS  The mean comorbid diagnoses: 0.8±0.7; 29% maleThe mean comorbid diagnoses: 0.8±0.7; 29% male  38 (90%) had failed prior medication trials with mood stabilizers38 (90%) had failed prior medication trials with mood stabilizers and/or antidepressantsand/or antidepressants  The average number of concurrent medications with LTG wasThe average number of concurrent medications with LTG was 1.5±1.01.5±1.0
  • 40. Safety and Tolerability of LTG inSafety and Tolerability of LTG in Adolescent Mood DisordersAdolescent Mood Disorders  Mean daily LTG dose 115.0mg (SD 76.0), range 10 toMean daily LTG dose 115.0mg (SD 76.0), range 10 to 300300  The average duration of LTG treatment 29.1±31.8The average duration of LTG treatment 29.1±31.8 weeks.weeks.  The mean CGI-S score decreased from 4.9±1.0The mean CGI-S score decreased from 4.9±1.0 (markedly ill range) at baseline to 3.5±1.4 (mildly ill(markedly ill range) at baseline to 3.5±1.4 (mildly ill range) at endpoint (Wilcoxon signed ranks z-range) at endpoint (Wilcoxon signed ranks z- score=3.204, p<0.002).score=3.204, p<0.002).  Robust improvement in 22 subjects (52%) (CGI-I of 1Robust improvement in 22 subjects (52%) (CGI-I of 1 or 2)or 2)
  • 41. Safety and Tolerability of LTG inSafety and Tolerability of LTG in Adolescent Mood Disorders: AE’sAdolescent Mood Disorders: AE’s  4 (10%) developed benign rash, which remitted after4 (10%) developed benign rash, which remitted after discontinuation of LTG.discontinuation of LTG.  1 additional subject developed severe generalized1 additional subject developed severe generalized pruritis when she abruptly discontinued her oralpruritis when she abruptly discontinued her oral conceptive (OC), which resolved when restarting theconceptive (OC), which resolved when restarting the OCOC  3 subjects (7%) developed excessive sedation, which led3 subjects (7%) developed excessive sedation, which led to two discontinuations of LTG, and 1 subject wasto two discontinuations of LTG, and 1 subject was stable with no adverse effects at a lower LTG dose.stable with no adverse effects at a lower LTG dose.
  • 42. Recommended LTG Titration inRecommended LTG Titration in AdolescentsAdolescents  Recommend halving the FDA recommendedRecommend halving the FDA recommended titration for adult bipolar disordertitration for adult bipolar disorder  12.5mg weeks 1 and 212.5mg weeks 1 and 2  25mg weeks 2 and 425mg weeks 2 and 4  50mg week 550mg week 5  100mg week 6100mg week 6  Watch drug-drug interactions with ValproateWatch drug-drug interactions with Valproate (inc. LTG), Oral Contraceptives (dec. LTG), and(inc. LTG), Oral Contraceptives (dec. LTG), and Sertraline (inc. LTG)Sertraline (inc. LTG)