1 Behavioral Pharmacological: UpdateUniversity of North Carolina School of Medicine

2 History: Psychiatry, Neuropharmacologist or AlchemistWe are but Dwarfs on the backs of giants Galileo, Bacon/Descartes/William James Instrumentality – what we know is useful because it predict what will happen. Reason is bane of science; experiment is the key; Cogito ergo est Pragmatist Anthropomorphizing/just the behavior, Ma’am

3 “Modern” Science Evidenced based medicine- the shoulders;Bacon is alive and well; Descartes is rolling over Empiricism, categorical diagnosis, description psychiatry; leave etiology to the Shamans Inductive-deductive reasoning: do the most recent findings explain the phenomenon Pharmacogenomics; molecular genetics and neurobiology- newer is better, or is it?

4 This presentation is not for sissiesBehavioral models- can be autopsied and teach us new things We are a generation of reductionists- Programming- the concept of timing, critical periods and interactive specialization Shiva and brain development- neurogenesis- apoptosis; LTP/LTD- synaptic pruning; Glymphatics, inflammatory autophhagy

5 Challenging BehaviorsDisruptive social , aggressive, self-injurious, and repetitive behaviors, fear-related behaviors Functional behavioral analysis- ABCs, operationalized, quantitative and qualitative data Boundary between behavioral excesses and deficiency states Biopsychosocial, ethological factors There are problems inherent in rigidly categorizing complex human behaviors into dichotomous categories. For example trying to distinguish observations as behaviors versus psychiatric symptoms, psychiatric or neurological, or as environmentally or genetically influenced is in the long run not helpful. Ultimately behavior is determined by brain activity and so these distinction are both artificial and reductionistic. All to often these dichotomies reflect the belief systems of the observer more than reality. For example, aggression can be both a symptom and a behavior as well as triggered by environmental cues or events that affected by genetic factors, or brain disorders. It may be more helpful to categorize in broad terms, beginning with the a specific behavior and then proceeding to include other factors that may be risk, vulnerability or protective factors. A functional behavioral analysis is a good starting point but we should proceed from not stop there.

6 Challenging Behavior- Treatment IssuesLimited success finding drugs for specific behaviors Most challenging behaviors are extremely heterogeneous conditions Functional Behavioral Analysis is a critical step but more information is needed Relationship between brain function, neurochemistry, and target behavior Because of the considerably heterogeneity of most challenging behaviors it is not surprising that there is no specific anti-SIB, aggressive. Another factor to consider is that psycho-active drugs work at a basic level of brain function influencing the basic substrates of a given behavior by altering neurophysiological processes. In short psychotropic meds work in the basement and indirectly effect the hierarchical organization of complex experiences and cognition..

7 Analysis of Functional Behavioral AnalysisFunction: approach-avoidance, intensity of drive, valence of reinforcement, arousal, positive negative affective state Antecedents: assessment of stimulus/setting, pos/neg affective valence Behaviors: careful subtyping Consequences: ease of reinforcement; resistance to extinction Antecedents- apparent triggers for behavior. These can include both specific cues, social relationships affective states or context related conditioned experiences. Sexual abuse in the bathroom may change the individual’s various modes of escape behaviors from specific contexts or increased agitation in the presence of the perpetrator (cue specific). For psychopharmacologists it is helpful to investigate difference in temperament, presence of brain disorders, medication side effects and co-occurring psychiatric disorders since each can affect the intensity of response or valence of the trigger stimulus (positive or negative reaction to it) Behaviors- intensity and frequency can both be affected and need to be considered with medication assessment. Consider baseline exaggeration, pain and other dysphoric states in many appetitive, self-soothing, impulsive-compulsive and escape behaviors Consequences- usually involve either positive, negative, punishment, social contact, or sensory intrinsic subsets. The importance (valence of reinforcers) can change from positive to negative in depression or anxiety disorders. A past history of abuse might change all three components

8 Analysis of Function Function of behavior- arousal, reactivity, motivational state, approach-avoidance, autonomic regulation Drive or craving, reward potential, hedonic drive Neuroticism- negative, emotional reactivity Behavioral inhibition, conflict Escape behaviors-sensitivity, threshold, anxiety tolerance, perception Rather than focus on specific topographies or typologies many clinicians address the function of a behavior (escape demands or obtain preferred reinforcers) Tracking the frequency and severity/intensity of challenging behaviors is quite helpful in monitoring response. Adding such things as serum drug level or free drug fractions, side effete profiles, and rating scales for specific psychiatric disorders can be helpful.

9 Another Look at Antecedents and BehaviorAntecedents or trigger events, positive/negative experience, setting, memory, conditioning experiences, social factors Classical conditioning (initiating)- CS/CR impact motivation (escape); intensity of reward potential (approach); Temperamental and presence of psychiatric disorders Fear conditioning- LTP (panic disorder)

10 Other Factors Affecting ConsequencesEase of conditioning, extinction, reversal learning Operant learning- valence of re-inforcer Extinction- LTD (long term depression) Extinction spurt or increased appetitive behaviors Multiple layers of conditioning- panic disorder with agoraphobia

11 Behavioral PsychopharmacologyMerges behavioral and pharmacological models Neurobiology and neurochemistry of behavior and learning Look at the plasticity and changes in gene expression due to “environmental” factors Molecular genetics of some behavioral phenotypes It is important that any drug not interfere with new learning and memory. In recent years the neurobiology of extinction and novel learning is changing how we understand both behavioral and psychopharmacological interventions.

12 SIB: A Diverse Collection of BehaviorsTopography, typology, intensity, frequency, setting and trigger events Functional Behavioral Analysis is a critical tool but has limits Relationship to genetic disorders- specific topographies Developmental models- do not always address special vulnerabilities

13 SIB: Behavioral Pharmacological DissectionWhy do some people develop progressive SIB when others in the same environment don’t? Why does it persist in spite of pain, tissue destruction? What initiates and maintains this particular typography? What gets in the way of extinction- self-restraint?

14 Behavioral Pharmacology of Self-Injurious BehaviorsComplex relationship between SIB, behavioral phenotypes, and environment Gene expression is continually influenced by environmental events and learning Temperamental style influences helps shape life experiences and learning environment Think in terms of an ecosystem

15 Summary Behavioral pharmacology- neurobiological mechanisms associated with behavioral models- motivation, reinforcement, extinction etc Adds another layer of analysis to functional behavioral analytic data; makes things more complicated D-cycloserine, fenobam, NAC, anti-inflammatory drugs - new age of ideas Conditioning in its many forms depends on learning new associations, efficacy of reinforcers, extinction when reinforcers or unconditioned stimuli are no longer paired, and working memory of the extinction process that result in the inhibition of the target behaviors. Extinction like learning involves alteration at several levels. Synapses on neurons change but for complex organisms the changes must be integrated with wider networks of - neuronal level Both motivation or drive to act- reward pathways and initiation of action contingent on anticipated reward valence. Anhedonia may reduce initiation, PFC motivation and adaptation to ongoing environmental factors

16 How to Approach Treatment Nonresponders

17 Ideas on Drug ClassificationChallenging behavior- anti-aggressive drug Syndrome specific- antidepressant or antipsychotic Mechanism specific- serotonin re-uptake inh. or dopamine antagonist Behavioral pharmacology- drug effects on learning and types of conditioning Aggression is a heterogeneous group of behaviors that differ in terms of typology, neuropshysiology, neuro-endocrinology, and etiology: Ethologcal models- distinctions between territorial/defensive, maternal, and predatory aggression are difficult to classify in humans. Predatory of instrumental aggression is premeditated, goal directed, and maximizes chances for success. Affective aggression is usually poorly planned, associated with intense affective reactivity and intense. Temperamental models- difficult temperament, role of frustration tolerances, intensity of affective response. Distinctions from psychopathy (Hare et al), or subcortical hypoarousal/hypocortisolemic responses, and relatively intact prefrontal functions. Instrumental aggression without violence and relationship to dominance hierarchy. Reason without conscience.

18 Basics of psychopharmacologyDrug mechanisms- more complex than originally described Pharmacokinetics- how do the drugs get there; genetic differences in rates Pharmacodynamics- what the drugs do when they get there; genetics of receptor variability Pharmaco-genomics Free drug fraction- amount of drug actually available to the brain- affected by other drugs and protein binding. Most commonly used for Valproic acid Metabolite related side effects- carbamazepine metabolite epoxide produces many of the side effects associated with t- more likely to be elevated in combination with valproic acid (epoxidase inh) Cytochromes P 450 activity- enzymes that break down drugs. For example fluoxetine is metabolized by 2D6, its first metabolite; norfluoxetine is broken down by 3A4 and others. Fluoxetine can inhibit both enzymes and affect the drug levels of many anticonvulsants and anti-psychotics. Tegretol has the opposite effect on 3A4 and increases the metabolism of many drugs, including birth control pills. Many people inherit low activity (slow metabolizers) and get toxic side effects at very low doses of drugs metabolized by that pathway Serum drug levels can help with metabolism and free drug fraction can help with situations in which side effects emerge at “normal” serum levels. Genetic studies (cyt p activity), transporter protein variations, structural receptor proteins, and second third messengers, neuromodulatory peptide activity, and gene activation are in the future

19 Pharmacology of LearningMotivational states- reward potential (BFS), inhibition (BIS) Linkage to VTA-n accumbens: reward pathways Septo-hippocampal system, memory circuitry, LTP/LTD MPF/orbital cortex- top down regulation Attachment/social pathways

20 What exactly is a nonresponder?Wrong person, wrong diagnosis or learning model, wrong drug or intervention Incomplete functional behavioral analysis Incomplete understanding of the bio-behavioral issues Drug issues- wrong dose; theory of drug effect and connection between it and behaviors is incomplete Problems where both are normal may reflect unusual sensitivities (autism), impaired transport into the brain (Glycoprotein A activity), problems where the drugs actually bind (receptor site issues), or problems up stream from the receptor (biochemical mechanisms within the nerve cell). In research setting radioactively labeled drugs that show binding characteristics or Magnetic resonance imaging can show problems within the cell. This sort of technology is not available for most clinical settings

21 Theories Intrinsic reinforcement- shift from positive to negative maintenance strategies; what happens to endorphins Factors that trigger SIB- stress, urge to act, balance between aggression and SIB when restricted; craving and HPA axis Problem with extinction- requires learning at a molecular biological level, LTD; Glutamate/NMDA activity; ACTH/AVP

22 Pharmacology of LearningMotivational states- reward potential (BFS), inhibition (BIS) Reward pathways Memory circuitry, LTP/LTD Top down regulation- extinction Attachment/social pathways

23 What Does All This Mean? We need to think beyond medications as syndrome or target behavior specific We need to expand our concept of functional behavioral analysis to include neurobiological and molecular genetic input We need to rethink our gene-environment; behavioral-psychiatric shibboleths

24 Summary and ConclusionsDon’t abandon any models, combine them where you can, apply new syntheses to problem cases first. Research Domain Criteria Functional Behavioral Analysis- there is no black box, no black slate Genetic disorders- genes are blueprints not the final product, think in transactional terms

25 Summary and Conclusions- cont’dMost psychopharmacological agents are not really syndrome specific- the brain is too complex Theories of action change and are often either wrong or incomplete Drugs can affect gene function, some are being applied to specific behavioral phenotypes

26 Summary and Conclusions- cont’dTarget symptoms, challenging behaviors and psychiatric disorders are final common pathways We aren’t very good at treating core features, yet Drugs effects on gene expression is a step beyond simple neurotransmitter models

27 How Do We Do This? Look at our existing tools of analysis- how can we adapt what we have Keep up as best you can with the neurosciences of developmental and genetic disorders Take a careful look at programs that don’t work, scatter plots, ethograms, and consider the neurobiology of function