of Inflammatory Psychiatric Disease with Particular Attention to PANS Margo Thienemann MD Immune Behavioral Health Clinic Stanford Childrens Health Stanford University School of Medicine ID: 935992
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Slide1
Psychiatric Medication Management
of
Inflammatory Psychiatric Disease
with
Particular Attention to PANS
Margo Thienemann MD
Immune Behavioral Health Clinic
Stanford Children’s Health
Stanford University School of Medicine
Slide2Case:
10-year-old boyChief Complaint:Parents : “He is unrecognizable.” Patient : “I am happy to be suicidal.” Compulsions: touching, drinking from only certain glassesHit his own larynx Scratched his face Repeatedly ran away, including barefoot, causing injury
Slide3HPI
November: Ear infection, mycoplasma pneumoniaJanuary: Head injury skiing: Post-concussive symptomsFebruary: “Sudden state change … manifesting as suicidal intent” Ran away from home at night, hid from parents and police. “Poker face” and “blank stare” Mood swingsOppositional behaviorOCDHandwriting terrible No illness: Group A Strep not assessedHospitalized psychiatrically X 4 d Dx’d depression, anxiety, PTSD, post-concussion syndrome. Rx’d quetiapine 6mg
150mg; no
improvement
Rx’d
sertraline 6.25
12.5mg, regression
Slide4HPI (cont.)
March: University Inpatient Unit hospitalization x 1 month
-
Sx
Severely obsessive
Ego-syntonic suicidal thoughts; “life is suffering”
Psychomotor restlessness
Frequent head banging
Catastrophic thinking
Resisted psychotherapy: “brainwashing”
-Dx:
MRI normal
Neuropsychiatric evaluation: no significant functional deficits
-Rx:
Beta-blocker
Escitalopram: 2.5 mg
20 mg
Started clawing himself, banging his head, was hyperactive
Slide5April: Initial Presentation PANS Clinic: ROS
OCD: Contamination, arranging, knitting, would only wear one outfit, 2-hour bedtime ritual.
RESTRICTED EATING: wanted to starve.
SEPARATION ANXIETY: Slept with parent. Refused school
OTHER ANXIETY: Phobias: spiders, water/swimming in murky water, heights, roller coasters
DEPRESSION: Anhedonia and SI
MANIA: Marked productivity, spending money, grandiose
RAGE ATTACKS: Running away required 24 h hired highly skilled aide
AGITATION: Since accident/concussion, threatened to kill people, self, excessive motor activity MOTOR: Handwriting changes, clumsiness
TICS: Verbal Tics
IMPULSIVITY: Worsened; cannot wait for anything
CONCENTRATION: Worsened
COGNITIVE: READING : Refused as was too difficult
MEMORY: Worsened
SENSORY: Light and sound sensitive. Vestibular issues
SLEEP: Initial insomnia, nightmares about falling
URINARY: New nocturia Enuresis x 1.
FATIGUE
INFECTION: Itchy rash on his thighs, buttocks. On Azithromycin
INFLAMMATION: On Azithromycin
Slide6Course of Illness/Treatment
Pediatric/Medical
Continue Azithromycin (helpful)
Rx Naproxen (NSAID)
Evaluate family members for strep
Per Psychiatry:
Decrease escitalopram to 17.25mg/day to address b
ehavioral activation, suicidality, agitation, nightmares Activation improved with decrease, but pace was limited by withdrawal symptoms. Underwent extremely slow taper 20 to 10 over 2 years!In-Home CBTParent therapy Behavior managementAddress family accommodation to OCD (felt hamstrung by patient’s report of SI)
Slide7What is the role of mental health treatment in PANS and other inflammatory brain disorders ?
Mental Health Providers’ Role
Psychoeducation
Coordination with other parts of the treatment team
Environmental interventions (safety, schools)
Behavioral strategies (behavior modification techniques, minimize accommodation)
Psychotherapies
Evidence-supported therapies for other symptoms (
eg CBT for OCD)PharmacotherapyScreen/treat for medical PTSD
Slide8Using Psychopharmacology in Inflammatory Brain Disorders/PANS
WhenAcutely, perhaps, to facilitate cooperation with evaluation and treatmentAcutely, perhaps, to decrease suffering and improve functionBefore, with, or after immunomodulation for - Delirium (antipsychotics) - Catatonia (lorazepam) - Steroid side-effects (antipsychotics) Later, for residual psychiatric symptomsHowOther interventions can also be essential at same timeTreating infectionTreating inflammationIllness’ natural, changing course is an additional variable
Try to change only one
treatment
variable at a time
Slide9PANS Patients Treated with Psychiatric Medications Can Do Very Poorly
A number of children were hospitalized for agitation, behavioral dyscontrol, suicidality, and mood lability when when their symptoms failed to respond to higher and higher doses of antidepressants and antipsychotics as used in conventional, evidence-based psychopharmacotherapy. We have seen children and adolescents who have been treated with the medications, sent to residential treatment because of lack of response and worsening due to escalating dosing of “standard” pharmacotherapies.
Slide10Psychiatric Medications for Psychiatric Symptoms
Alpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntihistaminesAntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockersMood stabilizers (lithium. etc)Other (amantadine)Other (melatonin, zolpidemAgitationAnxietyCatatonia
Cognitive disturbances
Delirium
Eating restriction
Mood disturbances
OCD
Psychotic symptoms
Sleep disturbanceSteroid side-effects Tics
Slide11Psychiatric Medications Psychiatric Symptoms
Alpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntihistaminesAntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockersMood stabilizers (lithium. etc)Other (amantadine)Other (melatonin, zolpidemAgitationAnxietyCatatonia
Cognitive disturbances
Delirium
Eating restriction
Mood disturbances
OCD
Psychotic symptoms
Sleep disturbanceSteroid side-effects Tics
Slide12We Reviewed 263 Consecutive PANS Cases
in the Stanford Immune Behavioral Health Clinic who had had Trials of Antipsychotics and/or Antidepressants Looking at Side Effects and Doses.2012-2017
Patients with abrupt early-onset OCD due to PANS tolerate lower doses of antidepressants and antipsychotics.
Thienemann M, Park M, Chan A,
Frankovich
J.
J Psychiatr Res. Mar 2021
263
188
Slide13Indications for Medication Trials
Slide14Most common
antidepressant side effects in our sample
Behavioral activation
anxiety (15%)
agitation (12%)
akathisia or restlessness (12%)
aggression (9%)
Suicidality (
7% ) lower than what has been seen in PANS patients in general (30-40 % in reported samples)we prescribe using low starting doses
Slide15Antidepressant Dose Tolerability: Fluoxetine Equivalents
6 mg
20 mg
12 mg
“Low starting dose” AACAP guidelines after Black Box warning inserted
Slide16Most common side effects in our sample
Antipsychotics
dystonia (16%)
weight gain (9%)
sedation (9%)
non-specific movement abnormalities (10%)
anxiety (9%)
Slide17Antipsychotic
Tolerability
Antipsychotic Tolerability: Risperidone equivalents. < half of target dose for other childhood indications
0.7 mg
1.3 mg
1.5 mg
Schizophrenia,
Bipolar Mood,
Tourette
Slide18Findings: Doses of Antidepressants and Antipsychotics
‘Tolerated doses’ and ‘doses at which side effects were noted’ were lower than or equal to the typical recommended starting doses and treatment doses for each medication used.For most patients (76%) who developed side effects, there existed an antidepressant or antipsychotic dose that could be tolerated without side effects or toxicity sometime during the course of treatment.The severity of brain inflammation may impact the likelihood of side effects. can have initial poor tolerability of antipsychotics but then benefit from them after receiving immunotherapy (Kuppuswamy et al., 2014). My opinion: Our review did not separate out flare/remission status at time of medication trial. Our analyses likely combined data from patients in flares and remissions (medications used to treat residual symptoms)If medications are better tolerated when patients are in remission, as clinical experience suggests, then the doses that were not tolerated
during flares
were likely even
lower
that our data indicates.
Slide19Limitations
LimitationsDesign: retrospective chart reviewSome patients came to us already on medicationsDid not assess flare state/flare markers at time of medication trialDid not assess P450 metabolizer statusDid not have formal SE assessment measureDid not have blood levelsStrengthsFirst and largest venture into this inquiryWanted to get our clinical experience quantified and disseminated quickly as we saw so many difficulties in our patients and patients who had been treated before we met them
Slide20Antidepressants (and Antipsychotics) can cause behavioral activation.
Behavioral activation symptoms resemble target PANS symptoms!irritabilityagitationanxiety panic depression suicidalityrestlessness hostility aggression insomnia disinhibition emotional lability impulsivityhypomania/mania paranoia and other psychotic symptoms sleep disturbance (Murphy et al., 2008). (
Reid et al., 2015
).
Slide21Behavioral Activation
Most antidepressant side effects are related tobehavioral activation ( agitation, aggression, self-injury) mood disturbance (mania, anger)Typically starts early in treatment (within the first 3 months) with dosage increases abates with antidepressant discontinuation or dosage loweringHypothesized mechanisms increased mood instability sensitivity to increased serotonergic tone
Slide22Side Effect Monitoring: Using these medications in general, in inflammatory brain disorders
Assess baseline symptoms mimicking signs of activation from SSRIs before rximpulsivityrestlessnessagitation irritabilityInsomniadistractibility Watch forAcute and worsening anxiety
Induction of hypomania or mania
Suicidality: SSRIs carry a black box warning
Behavioral activation or
serotonin syndrome.
E
xplain to parents that higher and quicker doses challenges that children with inflammatory brain disorders tend to have more serious side effects.
Warn families to ask a pharmacist or their provider about potential risk of combining SSRIs with other medications or herbal supplements prior to taking them.
Slide23TEASAP
Treatment-Emergent Activation and Suicidality Assessment Profile 38 item questionnaire Queries:IrritabilityAkathisia, hyperkinesis and somatic anxietyManiaSelf-injury, suicidality and harm to othersPsychometric properties of the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP
) in youth with OCD.
Bussing R, Murphy TK, Storch EA, McNamara JP, Reid AM,
Garvan
, CW, Goodman WK Psychiatry Res. 2013 Feb 28;205(3):253-61
Slide24Why might antidepressants and antipsychotics tolerated at lower doses in our PANS population than might be expected?
Developmental factors/age Serotonin and dopamine receptors change with ageGenetically determined Cytochrome P450 enzyme metabolism differencesmetabolizer subtypes eliminate drug with different efficiencies inflammation may down-regulate P450 enzyme activity Inflammation affecting Blood Brain Barrier (BBB)keeps most drugs out of the central nervous systemreported to be dysfunctional in inflammatory brain diseasesBBB compromise may affect the amount of drug delivered to the brain in patients with PANS.
Slide25Why might children and adolescents with PANS tolerate only lower doses of medication?
Brain inflammation from other causes has been seen with poor antipsychotic tolerability, with resultant agitation and aggression. Acute infectious encephalitis: HIV or other viral NMDAR encephalitis 47% treated with neuroleptics experienced Neuroleptic Malignant Syndrome Bickerstaff (autoimmune) brainstem encephalitis Identified neuronal receptor antibodies target the same receptors as psychotropic drugsDopamine D1 and D2, and serotonin 5-HT2A and 5- HT2C antibodies found GAS-infected PANDAS-model rodents Dopamine levels/dopamine release affected by altered Ca2+/calmodulin-dependent protein kinase II enzyme (CaMK II) signaling that affectsfound in rodents exposed to GAS antigenand human PANDAS patients Anti-CNS striatal cholinergic antibodies found in sera of children with PANDAS
Slide26Antipsychotics in other Inflammatory Brain Disorders: similar to PANS
Despite the risk of side effects at higher doses, antipsychotics [at the right (low) doses] may still be helpful for treating agitation, aggression, psychotic symptoms, tics, and OCD in other brain inflammatory disorders including LupusNMDAR encephalitisHashimoto's encephalitis.
Slide27Psychotropics may improve inflammation?!!
Fluoxetine, paroxetine, and sertraline reduced inflammation by affecting cytokines and BBB integrity in mouse models of Parkinson's, ischemic stroke, brain injury, and spinal cord injurySSRI treatment was found to be associated with decreased levels of pro-inflammatory markers in adults with major depression and in another study with generalized anxiety disorderOne immunocompromised child with chronic enterovirus encephalitis who failed immunotherapy improved only when treated with fluoxetine Fluoxetine inhibits microglial activation and decreases microglial cytokine productionOngoing trials of fluoxetine and fluvoxamine in COVID.The antipsychotic, risperidone has been found neuroprotective in rats, as have olanzapine and aripiprazole in cultured human immune cell lines
Slide28We have observed that in our clinical practice of starting out at low doses (roughly ¼ of suggested starting doses) and slowly titrating upward, mindful of other concomitant treatments and inflammatory state.
We rarely begin treatment with antipsychotics or antidepressants, other than for prn use, before addressing infection and inflammation.We use psychopharmacology in concert with other psychotherapies:PsychoeducationBehavioral modificationEvidence supported psychotherapies for individual symptom clusters, such as CBT, CBIT/HRT…Parent PTSD group treatmentThough we have focused here on intolerable side effects from these psychotropic medications, they may be helpful and tolerated.It is worth investigating how those medications, properly dosed, might positively affect inflammation.
Slide29Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesEating restrictionMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntihistaminesAntipsychoticsAnti-seizure medications (gabapentin, etc
)
Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Slide30Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxiety – AcuteAnxiety PersistentCatatoniaCognitive disturbancesMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’)AntihistaminesAntipsychoticsAnti-seizure medications (gabapentin, etc
)
Benzodiazepines
Beta-blockers
Mood stabilizers (lithium, anti-
sz
meds)
Other (amantadine)Dexmedetomidine (by Anesthesia Service)
Slide31Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxiety acuteAnxiety persistentCatatoniaCognitive disturbancesMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc
)
Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Slide32Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesEating restrictionMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockers
Mood stabilizers (Lithium)
Other (amantadine, zolpidem)
Slide33What are the psychiatric symptoms? What are the standard psychiatric treatments?
AgitationAnxietyCatatoniaCognitive disturbancesMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockersMood stabilizers (Lithium)
Other (amantadine)
Stimulant medication
Slide34Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesFood restrictionMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’)Antihistamines (hydroxyzine)AntipsychoticsAnti-seizure medications (gabapentin,
etc
)
Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Other (amantadine)
Stimulant medication
Slide35Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, lamotrigine, etc
)
Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Other (amantadine, zolpidem)
Slide36Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockers
Mood stabilizers (Lithium)
N-acetyl cysteine
Other (amantadine, zolpidem)
Slide37Psychiatric Symptoms Standard Psychiatric Treatments
AgitationAnxietyCatatoniaCognitive disturbancesEating restrictionMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc)BenzodiazepinesBeta-blockers
Mood stabilizers (Lithium)
Other (amantadine, zolpidem)
Slide38What are the psychiatric symptoms? What are the standard psychiatric treatments?
AgitationAnxietyCatatoniaCognitive disturbancesEating restrictionsMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntihistaminesAntipsychoticsAnti-seizure medications (gabapentin, etc)
Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Other (amantadine, zolpidem)
Other (melatonin)
Slide39What are the psychiatric symptoms? What are the standard psychiatric medication treatments?
AgitationAnxietyCatatoniaCognitive disturbancesEating restrictionMood disturbancesOCDPsychotic symptomsSleep disturbanceTicsAlpha adrenergic agents (clonidine, guanfacine)Antidepressants/Serotonin Reuptake Inhibitors (SSRI’s)AntipsychoticsAnti-seizure medications (gabapentin, etc)Benzodiazepines
Beta-blockers
Mood stabilizers (Lithium)
Other (amantadine, zolpidem)
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Slide44T.K. Murphy, E.A. Storch, M.S. Strawser
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