Derek Ott, M.D., M.S.Assistant Clinical Professor

UCLA David Geffen School of MedicineDivision of Child & Adolescent Psychiatry

Director, Pediatric Neuropsychiatry Clinic

Neuropsychiatric issues in TSIndividuals can be affected by a wide array of

intellectual, academic, neuropsychological , psychosocial, behavioral, and psychiatric difficulties

Many individuals with TS will experience some of these difficulties in their lifetime

May be directly related to the dysregulation of the mTOR signalingmTOR inhibitors relevance for these symptoms as well?

outlineUCLA Pediatric neuropsychiatry clinicUCLA developmental center clinics-Westside + Lanterman

Discussion of neuropsychiatric issues in TSCAssessment of behavioral issuesAssessment of medical + medication issuesAssessment of psychiatric issuesTreatment options + issues

Neuropsychiatric issues in TSIn 2003 international consensus panel convened to develop

guidelines for the assessment of these issuesRecommendations published in 2005 include:

Regular assessment of cognitive development and behavior in all children and adolescents with TSC to establish baseline

Comprehensive assessment in response to sudden or unexpected changes in cognitive development or behavior to identify and treat the underlying cause of neurobehavioral change Literature A

Neuropsychiatric issues in TSIn the 2010 survey of members of the UK TS Association, only

18% of all families have ever received any of the evaluations or treatments

Prior research suggests that > 90% of individuals with TS are likely to have some of these neuropsychiatric issues

Literature B

Suggests that the “treatment gap” is > 70%Consistent with findings in other fields where individuals with

mental disorders do not receive treatment Literature C

Intellectual level in TSIntellectual disability

50% IQ <70 30%-IQ < 20 (Profound intellectual disability)Normal range-30%

Literature D & E

Those with ASD have greater cognitive impairment Literature F

Important to determine the overall level of function when examining supports, academic + residential placement, behaviors, possible psychiatric issues, etc.

Academic issues in TSEven those within normal range IQ(30%) have many academic

difficultiesReading, writing, mathematics, spelling

Literature G

Frequently not recognized or acknowledged by the school or othersViewed as “lazy” “stubborn”

May benefit from an individualized education plan (IEP) because of these learning issues Difficult especially with a normal range IQ and average range of

academic performanceEducational advocate/support

Neuropsychological issues in TSNeuropsychological evaluations are used to determine strengths

and weaknesses of the individual’s neurocognitive profileRelevant for learning, thinking, social interactions, behavior, overall

functioningInclude executive function skills (planning, working memory,

perspective taking), attention (selective, sustained, dual tasking), language skills (receptive + expressive, grammatical + pragmatic use of language), memory skills and visuospatial skills

Specific deficits in working memory, cognitive flexibility or dual tasking associatedImportant consideration for behavioral issues

Literature H, I, & J

Behavioral issues in TSBehavioral issues/concerns may not constitute psychiatric

disorders per se but could be the result of other issues/circumstances

Need to take into account developmental/intellectual issuesTemper tantrums in a 2-year-old versus 15-year-old with

intellectual disabilityHyperactivity in a 2-year-old versus a 10-year-old with intellectual

disabilityFears/phobias in a 2-year-old versus 15-year-old with intellectual

disability

“Diagnostic overshadowing”=tendency to assess comorbid psychopathology in persons

with intellectual disability less accurately than in persons without (Rice, Leviton + Szyszko (1982))

Assume that cognitive deficits negatively impact clinician judgments about psychopathology

May impact Severity-how severe the symptoms are?Category/diagnosis-what diagnosis the person hasTreatment-how the disorder should be treated

Literature K

Behavioral issues in TSTypically identified through self-report or reports from

parents, caregivers, teachers or other professionalsDirect report

Need to understand reporters role, experience and training

Rating scalesInherent limitations of rating scales given age, circumstances,

reporters

TAND Checklist

Sudden change in behavior/functioning in TSAs recommended in the 2005 guidelines a sudden change

in behavior/functioning and individuals with TSC should prompt medical or clinical evaluation to identified any treatable medical causes

Need to coordinate with other providers such as neurologist, nephrologist, internist, pediatrician, etc.

Evaluation of behaviorMedical issuesMedication issues/side effects (new, chronic)Behavioral issues

Acute vs chronicChronic SIB vs new onsetChronic outbursts/trantrums vs new onset

Changes/transitionsAdaptive dysfunctionAdjustment Disorder?

Psychiatric condition

• Often multiple causes/triggers

Medical issuesSeizure issues

Change of anticonvulsantsBrand to generic or vice versaIntroduction of new anticonvulsant

Confusion/delirium related to frequent seizures, polypharmacy with anticonvulsants, etc

Other medical issuesHydrocephalus from obstructionMalignant transformation of tumorsRenal disease, pulmonary issues, etc.Medical issue unrelated to TS

Medication Side EffectsMultiple medicationsDrug interactionsConfounded by

Multiple providersCurrent and historical information often

limited especially in adultsMedication noncompliance

Medication –Drug interactionsAnticonvulsants

Some can induce metabolism via impact on liver enzymesCarbamazepine/Tegretol, valproic acid/Depakote, phenobarbitalAs a consequence, the effective dose of other drug can be loweredThus may require higher doses in the presence of these

anticonvulsantsAntidepressants

Inhibit metabolism via impact on liver enzymesFluoxetine/Prozac, paroxetine/PaxilAs a consequence the effective dose of another drug can be

increasedRisperidone in the presence of one of these drugs could be

effectively increased by twofold?

Medication Side Effects-anticonvulsantsPhenobarbital

Attention, other aspects of cognition,hyperactivity,depression

Topiramate/TopomaxMemory issues,word finding difficulties

Gabapentin/NeurontinPsychosis

Leviteracetam/KeppraMood symptoms including irritability, agitation, aggression and depression

May benefit from treatment with vitamin B12 (50-100 mg)

Medication Side Effects-benzodiazepinesLong acting/half-life

Clonazepam (Klonopin)Accumulate>drowsiness & mental clouding+ confusion

Short-actingLorazepam(Ativan),alprazolam(Xanax)

Interdose rebound symptoms (marked worsening of anxiety prior to scheduled doses)

Disinhibition?Tolerability generally fairly good in those with seizures

Medication Side EffectsAntipsychotic drugsRisperidone/Risperdal, aripiprazole/Abilify

Parkinsonism/akathisia (restlessness)Confused with worsening agitationLead to a counterproductive increase in dose

Alertness/mental performance Some have more negative cognitive impact

Precipitous reduction in dosage>agitation, behavioral deterioration> worsening abnormal involuntary

movements(transient withdrawal dyskinesias)

Changes as behavioral triggerPlacement in an environment where they are not well-suited

SchoolResidence-group home, supported living, etc.Family home-remarriage, adoption, etc.

School/day program/work changesTeacher, staff, care providersOther students/workers with different needs/behavior

Residential changesChange/rotation of staff-turnover high, illness, pregnancyOther residents

Change in daily life schedulestart of school/work, change in work activities,

inappropriate expectations to complete tasks or travel independently

Adaptive dysfunctionMismatch between needs, abilities, goals

of individual within his/her environmentExpectations of parents, clinicians, other

providers, teachers, aides, other staff, care providers, etc.

Schedule changeResidenceWork, school, day programIndependence ability

Emotional UpsetsSeasonal pattern

Related to return to school or similar transitionSeasonal affective disorder?

Anniversary reactionGrief reactions-often delayedAnxiety disorderTrauma/PTSD

Trauma OR abuse OR triggers related to past abuse

Psychiatric issues in TSSubjective assessment of the level of behavioral issues in the context of

the overall biological, psychological, developmental and social profile.If these behaviors are of significant intensity and duration and associated

with distress/impairment, the diagnosis of a psychiatric disorder may be warranted.Based upon the diagnostic and statistical manual for mental disorders, 5th

edition (DSM-5)Difficulties extrapolating to those with intellectual disability/neurologic

issues2007 Diagnostic Manual-Intellectual Disability (DM-ID)

Allows for the facilitated diagnosis of a full standard DSM psychopathology in individuals with ID

Psychiatric disorders in TSWell-established that individuals with intellectual disability have a 4-5

fold increase in the rate of psychiatric disorders across the lifespan and in TS 3111, 21

Neurodevelopmental disordersAutism spectrum disorders (25-50%)Attention deficit hyperactivity disorder (30-50%

Other psychiatric disordersDepressive + anxiety disorders (30-60%)11 12 20 25-28

Literature L, M, N, O, P

Attentional/learning issuesNeurotransmitters dopamine and norepinephrine modulate

information processing circuits in the brainThese circuits/cells could be impacted in TSC

Optimal levels enhance processing of relevant cognitive, emotional or behavioral information (signal) and inhibit processing the background information (noise).Improvements to signal noise ratio clinically manifested as

improvements is the and/or efficiency of cognitionU-shaped curve

Treatment for ADHD in TSCPsychostimulants

Amphetamine Amphetamine-Dexedrine tabs + Spansules, VyvanseMixed amphetamine salts-Adderall, Adderall XR

MethylphenidateRitalin, Metadate CD, Ritalin LA, Concerta, Daytrana

DexmethylphenidateFocalin, Focalin XR

Non-stimulantsStrattera

Treatment of ADHD-PsychostimulantsMethylphenidate and dextroamphetamine increase the

release of dopamine and norepinephrineAt higher doses block the reuptake of these neurotransmitters as

wellImpact on arousal, speed of processing and attentionExtensively studied and much research in children and

adolescents and adults In TSC, limited data

Once the proper dose is achieves effect is immediateCan have profound impact on attention, learning, impulse

control, emotional regulation, anxiety and mood

Stimulant side effects

Transient/dose increase VariableGI issuesHeadache

Weight loss InsomniaChange of “personality”Activation

Limit efficacy

Emergent

“Rebound”Return of prior

symptoms often to slightly higher level

Anxiety/nervousnessIrritabilityDysphoriaSuicidalityPsychosisTics

Psychostimulants and seizuresStimulants lower seizure threshold?

Commonly held belief and included on package insertLimited data in those with prior hx of seizures, those with EEG

abnormalities (no clear seizures), and very rarely in those with neither

Higher doses (i.e. 100-1000x usual dose in abuse) which can be associated with seizures

Stimulants can be USED an anticonvulsants in certain patientMethylphenidate-more data which demonstrates good

tolerability and efficacyAmphetamines-less data but still seems to be efficacious and

tolerated

Mood symptoms in TSCDepressionIrritability/poor frustration tolerance

More severe considered with impulse controlAnxietyBipolar disorder NOS/hypomania/mania

Treatment of mood symptoms in TS

Selective serotonin reuptake inhibitors (SSRIs)Other serotonergic drugsSelective noradrenergic reuptake inhibitors

(SNRIs)Tricyclic antidepressantsOther antidepressants

Serotonergic antidepressant drugsSelective Serotonin Reuptake Inhibitors (SSRI’s)

Inhibit serotonin (5-HT) reuptake Prozac (fluoxetine)Paxil (CR) (paroxetine)Zoloft (sertraline)Luvox (XR) (fluvoxamine)Celexa (citalopram)Lexapro (escitalopram)

Other serotonergic drugsDesyrel (trazodone)Serzone (nefazodone)Viibryd (vilazodone)Brintellex (vortioxetine)

SSRI’s indications Depression/Mood disordersAnxiety disorders (including panic)Social PhobiaObsessive-compulsive disorder (OCD)

(higher doses required)Post Traumatic Stress Disorder (PTSD)BulimiaPremenstrual Dysphoric Disorder (PMDD)

SSRI’s Uses Used also to treat symptoms

Aggression/irritabilityCompulsive, repetitive behaviorsRigid thinking/perseveration

similarity to OCDInsomnia/sleep problems

Trazodone/DesyrelSerzone/NefazodoneRemeron/Mirtazapine

SSRI’s Uses Because of the good tolerability often

first choiceEasier to use as compared to other

antidepressantsMany lack drug-drug interactions

Citalopram/Celexa, escitalopram/Lexapro-least

Sertraline/Zoloft-minimalFluvoxamine/Luvox-middleParoxetine/Paxil, fluoxetine/Prozac-most

SSRI-side effects-transientGI upset (mild nausea, loose stool)

Usually time limitedWorse with sertraline?

HeadacheUsually transient

Sleep disturbanceIncreased awakenings > worsening insomniaAlso usually time-limited

SSRI side effectsSexual dysfunction

most studies demonstrate 20-25%Frequent reason for discontinuation

Sedation?Primarily with escitalopram/Lexapro + paroxetine/Paxil

Cognitive side effects?Not frequently seen but sometimes with some such as

escitalopram/Lexapro + paroxetine/PaxilFeeling of “blah” or apathy

Emerges with long-term treatment in someNeed to distinguish between relapse of depression or other

mood issuesoften requires change to different SSRI or other antidepressant

SSRI side effectsActivation/increased anxiety

May occur with some agents more than othersFluoxetine, sertraline

May be related to rate of titrationDisinhibition

Reduction of anxiety can contribute to increased impulsivity?More likely in younger individuals?Predisposition in those with neurologic issues?

SSRI side effectsRestlessness

Also may be related to rate of dose increaseAkathisia-office scene with antipsychotics

“Flip” into manic/hypomania?Concern probably greater than actual rate of occurrence even those

with strong family history of mood disordersMuch more likely with TCA’s vs SSRI’sMonitor for significant changes in mood + sleep

Treatment of impulsivity/agitation/aggression in TSCAlpha-2 agonists

Clonidine, guanfacineTraditional mood stabilizers

Lithium, valproic acid/Depakote, carbamazepine/Tegretol

Other mood stabilizersOxcarbazepine/Trileptal, lamotrigine/LamictalTopiramate/Topamax,

Atypical antipsychotics

Treatment of agitation/aggression/impulsivity-Atypical antipsychotics-usesNonpsychiatric

Preoperative anesthesiaMovement disorders

Tics/Tourette syndrome Huntington’s chorea

PsychiatricPsychotic disordersMood disorders including depression+ bipolarAnxiety disorders including PTSD + OCDDeliriumAutism

Atypical AntipsychoticsClozapine Clozaril 1989

Risperidone Risperdal 1993Olanzapine Zyprexa/Zydis 1996Quetiapine Seroquel 1997

Ziprasidone Geodon 2001Abilify (ODT) Arapiprazole 2003

Paliperidone Invega 2007Risperidone Consta (IM) 2007Quetiapine Seroquel XR 2008

Paliperidone Invega Sustena (IM) 2010Fanapt Iloperidone 2010Asenepine Saphris 2010Lurasidone Latuda 2010

Atypical AntipsychoticsCan be very effective for control of agitation,

aggression + impulsivityOften can work very rapidly

Relevant for a wide variety of conditions including mood, psychosis, anxiety, etc. which may be contributing to the current situation

Often lack the potential to worsen the situation especially in the short term as opposed to antidepressants, benzodiazepines, etc.

Atypical Antipsychotic -Side EffectsWeight gain

Can be substantial 20-40 poundsCreates new issues

Glucose levelsNew onset diabetes

Lipid levels Prolactin levels

Gynecomastia(breast growth)

Antipsychotic Medications:Side EffectsExtrapyramidal symptoms (EPS)

Acute dystonia, Parkinsonism, AkathisiaTardive dyskinesia (TD)

Develops after 3 mos.Choreoathetoid movements-oral, limbs, trunkLower incidence with new agents Risk- >40 yrs, higher dose, duration

Side Effects* With Atypical AgentsRelativelyCommon

RelativelyUncommon Rare

Sedation

Weight gain

Confusion

Impotence

Enuresis

Dizziness

EPS

Gynecomastia

Galactorrhea

Amenorrhea

Diabetes

TD

NMS

*Side effects depend on the particular agent.EPS = extrapyramidal symptoms; TD = tardive dyskinesiaNMS = neuroleptic malignant syndrome

Thank you

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