Derek Ott, M.D., M.S.
Assistant Clinical Professor
UCLA David Geffen School of Medicine
Division of Child & Adolescent Psychiatry
Director, Pediatric Neuropsychiatry Clinic
Neuropsychiatric issues in TS
 Individuals 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 signaling
 mTOR inhibitors relevance for these symptoms as well?
outline
 UCLA Pediatric neuropsychiatry clinic
 UCLA developmental center clinics-Westside + Lanterman
 Discussion of neuropsychiatric issues in TSC
 Assessment of behavioral issues
 Assessment of medical + medication issues
 Assessment of psychiatric issues
 Treatment options + issues
Neuropsychiatric issues in TS
 In 2003 international consensus panel convened to develop guidelines for
the assessment of these issues
 Recommendations 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 TS
 In 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 TS
 Intellectual 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 TS
 Even those within normal range IQ(30%) have many academic difficulties
 Reading, writing, mathematics, spelling

Literature G
 Frequently not recognized or acknowledged by the school or others
 Viewed 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
performance
 Educational advocate/support
Neuropsychological issues in TS
 Neuropsychological evaluations are used to determine strengths and
weaknesses of the individual’s neurocognitive profile
 Relevant for learning, thinking, social interactions, behavior, overall
functioning
 Include 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
associated
 Important consideration for behavioral issues

Literature H, I, & J
Behavioral issues in TS
 Behavioral 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 issues
 Temper tantrums in a 2-year-old versus 15-year-old with intellectual disability
 Hyperactivity in a 2-year-old versus a 10-year-old with intellectual disability
 Fears/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 has
 Treatment-how the disorder should be treated

Literature K
Behavioral issues in TS
 Typically identified through self-report or reports from parents,
caregivers, teachers or other professionals
 Direct report
 Need to understand reporters role, experience and training
 Rating scales
 Inherent limitations of rating scales given age, circumstances, reporters
 TAND Checklist
Sudden change in behavior/functioning in TS
 As 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 behavior
 Medical issues
 Medication issues/side effects (new, chronic)
 Behavioral issues
 Acute vs chronic
Chronic SIB vs new onset
 Chronic outbursts/trantrums vs new onset
 Changes/transitions
 Adaptive dysfunction
 Adjustment Disorder?
 Psychiatric condition
• Often multiple causes/triggers

Medical issues
 Seizure issues
 Change of anticonvulsants
 Brand to generic or vice versa
 Introduction of new anticonvulsant
 Confusion/delirium related to frequent seizures, polypharmacy
with anticonvulsants, etc
 Other medical issues
 Hydrocephalus from obstruction
 Malignant transformation of tumors
 Renal disease, pulmonary issues, etc.
 Medical issue unrelated to TS
Medication Side Effects
 Multiple medications
 Drug interactions
 Confounded by
 Multiple providers
 Current and historical information often limited
especially in adults
 Medication noncompliance
Medication –Drug interactions
 Anticonvulsants
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Some can induce metabolism via impact on liver enzymes
Carbamazepine/Tegretol, valproic acid/Depakote, phenobarbital
As a consequence, the effective dose of other drug can be lowered
Thus may require higher doses in the presence of these anticonvulsants
 Antidepressants
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Inhibit metabolism via impact on liver enzymes
Fluoxetine/Prozac, paroxetine/Paxil
As a consequence the effective dose of another drug can be increased
Risperidone in the presence of one of these drugs could be effectively
increased by twofold?
Medication Side Effects-anticonvulsants
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Phenobarbital
 Attention, other aspects of cognition,hyperactivity,depression
Topiramate/Topomax
 Memory issues,word finding difficulties
Gabapentin/Neurontin
 Psychosis
Leviteracetam/Keppra
 Mood symptoms including irritability, agitation, aggression
and depression
 May benefit from treatment with vitamin B12 (50-100 mg)
Medication Side Effects-benzodiazepines
 Long acting/half-life
 Clonazepam (Klonopin)
 Accumulate>drowsiness & mental clouding+
confusion
 Short-acting
 Lorazepam(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 Effects
 Antipsychotic drugs
 Risperidone/Risperdal, aripiprazole/Abilify
 Parkinsonism/akathisia (restlessness)
Confused with worsening agitation
 Lead to a counterproductive increase in dose
 Alertness/mental performance
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Some have more negative cognitive impact
 Precipitous reduction in dosage
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>agitation, behavioral deterioration
> worsening abnormal involuntary
movements(transient withdrawal dyskinesias)
Changes as behavioral trigger
 Placement in an environment where they are not well-suited
 School
 Residence-group home, supported living, etc.
 Family home-remarriage, adoption, etc.
 School/day program/work changes
 Teacher, staff, care providers
 Other students/workers with different needs/behavior
 Residential changes
 Change/rotation of staff-turnover high, illness, pregnancy
 Other residents
 Change in daily life schedule
 start of school/work, change in work activities, inappropriate
expectations to complete tasks or travel independently
Adaptive dysfunction
 Mismatch between needs, abilities, goals of
individual within his/her environment
 Expectations of parents, clinicians, other providers,
teachers, aides, other staff, care providers, etc.
 Schedule change
 Residence
 Work, school, day program
 Independence ability
Emotional Upsets
 Seasonal pattern
 Related to return to school or similar transition
 Seasonal affective disorder?
 Anniversary reaction
 Grief reactions-often delayed
 Anxiety disorder
 Trauma/PTSD
 Trauma OR abuse OR triggers related to past abuse
Psychiatric issues in TS
 Subjective 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 issues
 2007 Diagnostic Manual-Intellectual Disability (DM-ID)
 Allows for the facilitated diagnosis of a full standard DSM psychopathology in
individuals with ID
Psychiatric disorders in TS
 Well-established that individuals with intellectual disability have a 4-5 fold
increase in the rate of psychiatric disorders across the lifespan and in TS
 31
 11, 21
 Neurodevelopmental disorders
 Autism spectrum disorders (25-50%)
 Attention deficit hyperactivity disorder (30-50%
 Other psychiatric disorders
 Depressive + anxiety disorders (30-60%)
 11 12 20 25-28

Literature L, M, N, O, P
Attentional/learning issues
 Neurotransmitters dopamine and norepinephrine modulate information
processing circuits in the brain
 These 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 cognition
 U-shaped curve
Treatment for ADHD in TSC
 Psychostimulants
 Amphetamine
Amphetamine-Dexedrine tabs + Spansules, Vyvanse
 Mixed amphetamine salts-Adderall, Adderall XR
 Methylphenidate
 Ritalin, Metadate CD, Ritalin LA, Concerta, Daytrana
 Dexmethylphenidate
 Focalin, Focalin XR
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 Non-stimulants
 Strattera
Treatment of ADHD-Psychostimulants
 Methylphenidate and dextroamphetamine increase the release of
dopamine and norepinephrine
 At higher doses block the reuptake of these neurotransmitters as well
 Impact on arousal, speed of processing and attention
 Extensively studied and much research in children and adolescents and
adults
 In TSC, limited data
 Once the proper dose is achieves effect is immediate
 Can have profound impact on attention, learning, impulse control,
emotional regulation, anxiety and mood
Stimulant side effects
Transient/dose increase
 GI issues
 Headache
Variable
 “Rebound”
 Return of prior symptoms
often to slightly higher level
Emergent
Limit efficacy
 Anxiety/nervousness
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 Irritability
Weight loss
Insomnia
Change of “personality”
Activation
 Dysphoria
 Suicidality
 Psychosis
 Tics
Psychostimulants and seizures
 Stimulants lower seizure threshold?
 Commonly held belief and included on package insert
 Limited data in those with prior hx of seizures, those with EEG abnormalities
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(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 patient
Methylphenidate-more data which demonstrates good tolerability and
efficacy
Amphetamines-less data but still seems to be efficacious and tolerated
Mood symptoms in TSC
 Depression
 Irritability/poor frustration tolerance
 More severe considered with impulse control
 Anxiety
 Bipolar disorder NOS/hypomania/mania
Treatment of mood symptoms in TS
 Selective serotonin reuptake inhibitors (SSRIs)
 Other serotonergic drugs
 Selective noradrenergic reuptake inhibitors (SNRIs)
 Tricyclic antidepressants
 Other antidepressants
Serotonergic antidepressant drugs
 Selective 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 drugs
 Desyrel (trazodone)
 Serzone (nefazodone)
 Viibryd (vilazodone)
 Brintellex (vortioxetine)
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SSRI’s indications
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Depression/Mood disorders
Anxiety disorders (including panic)
Social Phobia
Obsessive-compulsive disorder (OCD)
 (higher doses required)
 Post Traumatic Stress Disorder (PTSD)
 Bulimia
 Premenstrual Dysphoric Disorder (PMDD)
SSRI’s Uses
 Used also to treat symptoms
 Aggression/irritability
 Compulsive, repetitive behaviors
 Rigid thinking/perseveration

similarity to OCD
 Insomnia/sleep problems
 Trazodone/Desyrel
 Serzone/Nefazodone
 Remeron/Mirtazapine
SSRI’s Uses
 Because of the good tolerability often first
choice
 Easier to use as compared to other
antidepressants
 Many lack drug-drug interactions
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Citalopram/Celexa, escitalopram/Lexapro-least
Sertraline/Zoloft-minimal
Fluvoxamine/Luvox-middle
Paroxetine/Paxil, fluoxetine/Prozac-most
SSRI-side effects-transient
 GI upset (mild nausea, loose stool)
 Usually time limited
 Worse with sertraline?
 Headache
 Usually transient
 Sleep disturbance
 Increased awakenings > worsening insomnia
 Also usually time-limited
SSRI side effects
 Sexual 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/Paxil
 Feeling of “blah” or apathy
 Emerges with long-term treatment in some
 Need to distinguish between relapse of depression or other mood issues
 often requires change to different SSRI or other antidepressant
SSRI side effects
 Activation/increased anxiety
 May occur with some agents more than others
 Fluoxetine, sertraline
 May be related to rate of titration
 Disinhibition
 Reduction of anxiety can contribute to increased impulsivity?
 More likely in younger individuals?
 Predisposition in those with neurologic issues?
SSRI side effects
 Restlessness
 Also may be related to rate of dose increase
 Akathisia-office scene with antipsychotics
 “Flip” into manic/hypomania?
 Concern probably greater than actual rate of occurrence even those with strong
family history of mood disorders
 Much more likely with TCA’s vs SSRI’s
 Monitor for significant changes in mood + sleep
Treatment of impulsivity/agitation/aggression in TSC
 Alpha-2 agonists
 Clonidine, guanfacine
 Traditional mood stabilizers
 Lithium, valproic acid/Depakote,
carbamazepine/Tegretol
 Other mood stabilizers
 Oxcarbazepine/Trileptal, lamotrigine/Lamictal
 Topiramate/Topamax,
 Atypical antipsychotics
Treatment of agitation/aggression/impulsivityAtypical antipsychotics-uses
 Nonpsychiatric
 Preoperative anesthesia
 Movement disorders
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Tics/Tourette syndrome
Huntington’s chorea
 Psychiatric
 Psychotic disorders
 Mood disorders including depression+ bipolar
 Anxiety disorders including PTSD + OCD
 Delirium
 Autism
Atypical Antipsychotics
Clozapine
Risperidone
Olanzapine
Quetiapine
Clozaril
Risperdal
Zyprexa/Zydis
Seroquel
1989
1993
1996
1997
Ziprasidone
Abilify (ODT)
Geodon
Arapiprazole
2001
2003
Paliperidone
Risperidone
Quetiapine
Invega
Consta (IM)
Seroquel XR
2007
2007
2008
Paliperidone
Invega Sustena (IM)
2010
Fanapt
Asenepine
Lurasidone
Iloperidone
Saphris
Latuda
2010
2010
2010
Atypical Antipsychotics
 Can be very effective for control of agitation, aggression +
impulsivity
 Often 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 Effects
 Weight gain
 Can be substantial 20-40 pounds
 Creates new issues
  Glucose levels
 New onset diabetes
  Lipid levels
  Prolactin levels
 Gynecomastia(breast growth)
Antipsychotic Medications:
Side Effects
 Extrapyramidal symptoms (EPS)
 Acute dystonia, Parkinsonism, Akathisia
 Tardive dyskinesia (TD)
 Develops after 3 mos.
 Choreoathetoid movements-oral, limbs, trunk
 Lower incidence with new agents
 Risk- >40 yrs, higher dose, duration
Side Effects* With Atypical Agents
Relatively
Common
Relatively
Uncommon
Sedation
Weight gain
Confusion
Impotence
Enuresis
Dizziness
EPS
Rare
Gynecomastia
Galactorrhea
Amenorrhea
Diabetes
TD
NMS
*Side effects depend on the particular agent.
EPS = extrapyramidal symptoms; TD = tardive dyskinesia
NMS = neuroleptic malignant syndrome
Thank you
Literature
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