Robert J. Pary, M.D. NADD November 2, 2016 Weaving Today’s Psychopharmacologic Solutions: - PowerPoint Presentation

Robert J. Pary, M.D.NADDNovember 2, 2016 Weaving Today’s Psychopharmacologic Solutions: Tomorrow’s Promises (?) - refractory aggression

Goal #1The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge Stephen Hawking in Duke et al., 2013

disclosuresJanssen Pharmaceuticals

aggressionPhysical behavior towards others that either injures others or significantly interferes with a person’s functioning

Aggression and ID Willner 2015 “Aggression is one of the main reasons that people with ID are referred for specialist services.”

There is not one cause or even one neurophysiologic mechanism Physical Aggression

What is refractory aggression?Multiple attempts to change the treatment plan fail to significantly reduce the severity and frequency of aggression

Types of Aggression Willner 2015 Proactive (aka Instrumental) Aggression to achieve some goal Decreases as IQ falls Reactive Part of “fight or flight” response to a perceived threat Not purely reflexive – shaped by learning

Proactive Aggression Willner 2015 May often be planned Persons at top of social hierarchy act to keep dominance OR get higher status Persons with severe ID are more often victims Bullying: example of proactive aggression

Reactive aggression causes willner 2015  Tendency to behave aggressively  Ability to inhibit aggressive behavior

Potential brain areas involved in aggression Comai et al. 2012 Orbito -prefrontal cortex Anterior (cingulate) cortex Amygdala Hippocampus Peri-aqueductal gray Septal nuclei

Tendency to behave aggressively willner 2015 Appraisal of aggression-provocation Emotional recognition of voices/faces in superior temporal gyrus & sulcus. Sent to amygdala & prefrontal cortex Organization of aggressive acts Amygdala analyzes the threat and sends message to other brain regions

 Ability to inhibit aggressive behavior willner 2015 Ventromedial prefrontal cortex appraises social information and primarily exerts control over the amygdala Reciprocal activity Reactive aggression  ventromedial prefrontal cortex & disinhibited amygdala

Anterior cingulate cortexConnected to amygdala, hypothalamus, and nucleus accumbens to assess emotional meaning and motivational information

Orbito-prefrontal cortex Marquez et al. 2013 A mygdala hyperactivity and orbitofrontal cortex dysfunction to increased emotionality, impulsivity and aggression

Amygdala Marquez et al. 2013Impulsive aggression in humans Amygdala hyper -functioning M edial-orbital cortex hypo -functioning

Hippocampus“Critical for effectively combining the ‘ what’, ‘when,’ and ‘where’ qualities of each experience to compose the retrieved memory.” wikipedia 10/10/16

Periaqueductal gray Willner 2015 R ole in generation of species-specific aggressive behavior

Septal nuclei Along with nucleus accumbens have role in reward and reinforcement Connected with amygdala, hippocampus, cingulate gyrus

Potential Neurotransmitters involved in aggression Comai et al. 2012 Dopamine Serotonin Glutamate GABA Norepinephrine

Dopamine wellner 2015 Dopamine release is increased in frontal cortex and nucleus accumbens D opamine has permissive effect during aggression and behavioral programming Unclear if dopamine antagonists have specific anti-aggressive effects

Serotonin chilmonczyk et al 2015 Relatively small number of serotonin neurons in the brain 250,000 out of an estimated 100 billion (10 11 neurons) Yet innervates entire neuraxis – 4106 axonal nerve terminals/mm 3 Modulator: slow and regular discharge – strong homeostatic effects

SerotoninSerotonin does not cross blood-brain barrier Synthesized in raphe nuclei of pons, medulla and midbrain nuclei Tryptophan is precursor

three methods to assess brain Serotonin and aggression Duke et al. 2013 CSF 5-hydroxyindoleacetic acid (5-HIAA) Acute typtophan depletion Pharmacologic/ Endocrine challenges

CSF 5-hydroxyindoleacetic acid (5-HIAA) and aggression Duke et al, 2013 Principle Serotonin metabolite Serotonin deficiency main cause for male aggressive behavior Brown et al 1979 Subsequent studies equivocal CSF 5-HIAA affected by age, stress, etc.

Acute typtophan depletion Duke et al, 2013 L-tryptophan is 1° serotonin precursor All L-tryptophan in humans is dietary Tryptophan competes with 5 AAto cross BBB Findings contradictory Acute tryptophan depletion  aggression if predisposed to act aggressively, not in persons with low aggressive trait levels

Pharmacologic/Endocrine challengeDuke et al., 2013 All challenges try to rapidly increase serotonin concentrations Activates hypothalamus-pituitary adrenal pathways Bottom line – different serotonin receptors do not influence behavior in the same way

Serotonin in lesch-nyhan syndrome Schroeder et al., 1998 Lesch-Nyhan syndrome – Severe SIB Post-mortem of striatal neurons of 3 cases 60-90% depletion of dopamine Elevation of serotonin

Serotonin Duke et al. 2013, chilmonczyk et al, 2015 Several anatomically distinct pathways 7 families of receptors encompass and 14 different receptor types Serotonin 1A, 1B receptors  aggression Serotonin 2A, 2C receptors  aggression

Serotonin Takahashi et al., 2012 Serotonin 1A receptor activator – e.g. buspirone However, some 1A receptors are pre-synaptic; others postsynaptic opposing effects Serotonin 2A receptor blocker – e.g. risperidone

Serotonin and aggression Willner 2015 High levels of serotonin in amygdala increases aggression Summary of serotonin research and aggression “has obscured a picture that was once deceptively clear”

GABA wellner 2015 GABA concentrations in subcortical structures INVERSELY correlate with aggression Benzodiazepines (BZD) and anticonvulsants are GABA agonists and  aggression Yet alcohol, also GABA agonist can  aggression Plus BZD can disinhibit:  aggression

Comorbidity, aggression & id crocker et al. 2014 296 M/F mild or moderate ID living in community and receiving services > Physical aggression in persons with M oderate ID S peech problems

Comorbidity, aggression & id crocker et al. 2014

Neuroleptics Baumeister et al, 1998 Evidence for aggression is less compelling (than for stereotypy) Great variation in response Many show little improvement Occasionally problems worsen No way to predict who will respond

Trajectory of psychotropics in ID and aggression Deb et al. 2015 Study of 100 adults with IDD and aggression in ten psych clinics in West Midlands, UK # based on sample size calculation Consecutive pts and carers who consented

Trajectory of psychotropics in ID and aggression Deb et al. 2015 Used MOAS - 4 aggression subscales Verbal aggression Physical aggression towards Self Objects Others

Trajectory of psychotropics in ID and aggression Deb et al. 2015 Most UK psychiatrists consider non-medication management for aggression in adults with ID Authors expected L ower proportion on psychotropics Reduction in proportion at 6 months

Most Common psychotropics in ID and aggression among study sample Deb et al. 2015 Psychotropic # prescribed med Risperidone 39 Carbamazepine 21 Sodium valproate 17 Chlorpromazine 13 Citalopram 10 Haloperidol 9 Lamotrigine 8 Propranolol 8

# psychotropics for aggression at baseline n=88 deb et al 2015

# psychotropics for aggression at 6 months n=71 deb et al 2015

Trajectory of psychotropics in ID and aggression Deb et al. 2015 Median dose of risperidone at baseline 1.95 (0.25 – 7); 6 mo 2.14 (0.25 – 7 ) Higher antipsychotic doses NOT associated to psych diagnosis Antipsychotics MAY have been 1° for aggression in absence of psych disorder

Polypharmacy of psychotropics in ID and aggression Deb et al. 2015 Baseline 6 months Antipsychotic 10% 9% All psychotropics 45% 41%

Psychotropics and aggression willner 2015 No controlled studies of anti-aggressive effects of antidepressants in persons with ID No controlled studies of anti-aggressive effects of anticonvulsants in persons with ID Lithium - either negative or poor design Review of neuroleptics more complicated

2004 Cochrane review of studies < 1999Tyrer et al study 2008 of risperidone and haloperidol, though there was 70% placebo response Mainly children and adolescents (+ 1 adult) placebo-controlled studies with r isperidone (company sponsored) Multiple case reports with atypical antipsychotics antipsychotics and aggression in ID willner 2015 S upportive N egative

Clinical trials of physical aggression and Intellectual Disability (As of 9/28/16) Topiramate & PWS (completed) CBT & Children with ASD Staff training in Positive Behavior Supports Functional Communication Training for one family carer of young children

Topiramate & PWS Enrollment 12 – 45 years inclusive Presence of at least one of: S elf -harm Impulsive and / or aggressive Trouble eating and / or obesity

Children between the ages of 5-17 years old who have or display symptoms of emotional dysregulation (explosiveness, mood swings, irritability, and/or violent behavior ) Exclusion < IQ 70 Open-Label Study of N- Acetylcysteine wozniak mgh

N-AcetylcysteineAcetylcysteine has also been hypothesized to exert beneficial effects through its modulation of glutamate and dopamine Wikipedia 10/12/16 Used commonly in acetominophen overdoses

N-Acetylcysteine (NAC) hardan et al. 2012 G lutamatergic modulator & antioxidant DBRPC 12 weeks 14 NAC & 15 PLCB autism ( 31M, 2F; aged 3.2–10.7 years)  Irritability

NAC + risperidone ghanizadeh et al. 2013 DBRPC 40 C/A with autism NAC + risperidone had greater  on irritability than risperidone + placebo Published in peer-reviewed journal Funding not stated

One approach to refractory aggressionUtilize Contextual Behavioral Analysis (popularized by William Gardner, Ph.D )

One approach to refractory aggressionPlanned aggression unlikely to respond to psychotropics Persons with communication problems may respond to non-medication plan BUT will the strategies address their communication challenges?

Tomorrow’s promise? Lit et al. 2012Pre-( risperidone ) drug gene (RNF40) expression correlated with ABC-Irritability scores in children with autism 2 prior studies of genetic associations with risperidone in schizophrenia and autism did NOT identify same genes

Tomorrow’s promise? The core SNARE complex is formed by four α-helices S ynaptobrevin Syntaxin SNAP - 25 (2 helices) wikipedia 10/24/16

Tomorrow’s promise? SNARE core complex is believed to generate the free energy required to initiate fusion between the vesicle membrane and plasma membrane Wikipedia 10/24/16

Tomorrow’s promise? Gene RNF40 codes protein that degrades Syntaxin M ay reflect convergent downstream biological mechanisms across multiple genetic backgrounds that are associated with behavioral response to risperidone in ASD Lit et al. 2012

Tomorrow’s promise? As audience member how do you interpret the lack of other peer-reviewed studies since 2012 in ASD and/or ID about RNF40 and neuroleptic response?

referencesBaumeister AA et al 1998 in Reiss & Aman Intern. Consensus Handbk Nisonger Col. OH Brown GL et al. 1979 Psych Res 1(2):131-9 Chilmonczyk et al. 2015 Int J Mol Sci 16(8): 18474–18506. Comai S et al. 2012 J. Clin Psychopharm 32:83-94 Crocker et al 2014 JIDR 58:1032-44 Deb S et al. 2015 JIDR 59:11-25 G hanizadeh et al. 2013 BMC 13:196 Hardan et al 2012 Biol Psych 71 :956 – 961 Lit L et al. 2012 Pharmacogenomics 12:368-371 Marquez et al., 2013 Transl Psychiat 3 (1), e216–. Schroeder SR et al. 1998 in Reiss & Aman Intern. Consensus Handbk Nisonger Col. OH Takahashi A 2012 Curr Top Behav Neuosci 12:73-138 Willner P 2015 JIDR 59:82-92