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Psychopharmacology, Neurophysiology & PTSD/Trauma Presented by Craig Strickland, Ph.D. https://sites.google.com/site/bioedcon [email protected] Learning Objectives • List the 3 general categories of symptoms associated with PTSD • Describe the role of structures in the central nervous system (CNS) associated with these symptoms • Summarize the advantages and disadvantages of the various psychotropic medication classes used to treat PTSD Overview of the Symptoms of Post-Traumatic Stress Disorder Major Symptom categories of PTSD 1. The event is persistently re-experienced 2. Persistent avoidance of stimuli and numbing of general responsiveness 3. Negative alterations in cognitions associated with the trauma 4. Persistent symptoms of increased arousal Differential Diagnosis • • • • • • • Adjustment Disorder Acute Distress Disorder Personality Disorders Mood Disorders Other Anxiety Disorders Psychotic Disorders Substance Induced Disorders • Other (e.g. medical?) Differential diagnosis is based not just on the mere presence or absence of certain symptoms Trauma as seen on a continuum Acute Stress Disorder PTSD Chronic PTSD Complex Trauma Symptom Duration & Severity Overview of the Human Nervous System Hierarchy of CNS Structures Inferior Parietal (Logical Processing) Prefrontal Cortex (motivation) Cingulate Cortex (attention & affect) Entorhinal Cortex Amygdala (fear/anxiety) Hippocampus Septal Nuclei Reticular Formation Peripheral Autonomics Lateral Hypothalamus The Hippocampus and PTSD The Hippocampus Hippocampus Normal Functions of the Hippocampus • • • • The hippocampus is a very complex structure Is part of the Limbic System Considered “transitional” tissue Normal functions include (but may not be limited to) – Memory consolidation: works together with newer cortical brain areas • Integration of “emotional tone” with “higher” cognitive functions • Cortex provides semantic influence to the more episodic (factual) “hippocampal” memories – Behavioral inhibition – Inhibitory influence on brainstem activity The Hippocampus & Trauma • Decrease volume (size) of the hippocampus – This is a robust finding • Vietnam vets: 8 to 26% reduction depending on the study • 7% reduction in women with history of childhood sexual abuse • 16% reduction in hippocampal volume in women with BPD (often associated with a history of abuse) – Seen in other psychiatric disorders such as schizophrenia – Has been shown to occur in animal models involving experimental stressors Chicken or the Egg? The Chicken or the Egg? (Gilbertson, et.al. 2002) Gilbertson, et.al. 2002 Chicken or Egg? (cont.) • Apfel, et. al. (2011) – Gilbertson study did not contain true longitudinal data – This of course would be nearly impossible to do in this type research – Apfel study looked at hippocampal volume in 244 male Gulf War Veterans • Study included those with current PTSD and those where the symptoms of PTSD were remitted Chicken or Egg? (cont.) • In addition to measuring symptoms of PTSD (using the Clinician Administered PTSD Scale (CAPS) assessment tool: – Measured presence or absence of depression – Measured lifetime drinking history – History of other (non-combat related) stressors • Used structural MRI techniques to measure hippocampal volume Chicken or Egg? (cont.) • Ended up with four groups of subjects – Subjects with no traumatic exposure – Subjects with exposure but no PTSD – Subjects with a previous diagnosis of PTSD but have recovered – Subjects with chronic PTSD (lifetime and current) • The first two groups had identical hippocampal volume and were combined into one group for the further analysis Chicken or Egg? (cont.) • Results – Subjects with current/lifetime PTSD • 6.5% smaller hippocampi than those who had recovered from PTSD – Subjects with current/lifetime PTSD: smaller hippocampi by 5.1% than those who had never developed PTSD – Note: there was no difference in hippocampal size between those who never had PTSD and those who had recovered from PTSD • Interpretations? Chicken or Egg? (cont.) • The results raise the possibility that hippocampal volume is state-dependent and might vary over time e.g. the hippocampus may itself recover from the effects of PTSD; support for this interpretation? – Duration & severity of PTSD symptoms are negatively correlated with hippocampal volume – Hippocampal volume can increase as a result of long-term Paxil treatment – Hippocampal volume might change as a result of exercise, other medications and abstinence from alcohol • E.G. Neurogenesis Symptoms Associated with Hippocampal Damage? (Re-experiencing) • Dissociation and/or intrusive thoughts • Illusions and/or hallucinations • Behavioral disinhibition: causes the definition of incoming stimuli towards fight/flight responses • Along with amygdaloid activation, hippocampal damage may prevent proper evaluation & categorization of experiences/stimuli – May lead to reacting to new or neutral stimuli as threatening – This would lead to either aggressive behavior or possibly to withdrawal The Limbic System and PTSD: The Amygdala Limbic System: The Amygdala Connections Revisited Inferior Parietal (Logical Processing) Prefrontal Cortex (motivation) Cingulate Cortex (attention & affect) Entorhinal Cortex Amygdala (fear/anxiety) Hippocampus Septal Nuclei Reticular Formation Peripheral Autonomics Lateral Hypothalamus Normal Functions of the Amygdala • Normal amygdala functioning – Evaluates the emotional significance of incoming stimuli (emotional meaning) – Amygdala activated by feared stimuli (conversely, destroying the amygdala through surgery eliminates fear responses) – Amygdala mediates fear related behaviors • Does so through the hippocampus, hypothalamus and certain cortical areas (prefrontal cortex) • E.g. has an “upstream” and “downstream” effect Symptoms associated with Amygdaloid hyperactivity (hyperarousal) • Neutral stimuli are seen as fearful – Through connections with other limbic structures, enhanced autonomic and neurohormonal responses • Increased sympathetic nervous system activity • Hypervigilance • Exaggerated startle response • Irritability or outbursts of anger – Increased Hypothalamic/Pituitary Adrenal axis activity (known as HPA) The HPA • Affected by amygdala activation or lack of hippocampal influence • Increased activity in persons with anxiety as well as persons with depression…hmmm… Cortical Areas and PTSD Frontal Cortex Dysfunction Inferior Parietal (Logical Processing) Prefrontal Cortex (motivation) Cingulate Cortex (attention & affect) Entorhinal Cortex Amygdala (fear/anxiety) Hippocampus Septal Nuclei Reticular Formation Peripheral Autonomics Lateral Hypothalamus Prefrontal Cortex: Activity Decrease Persistent Avoidance/Numbing • Symptoms include (but not limited to): – Cannot recall important trauma details (memory) – Markedly diminished interest/participation in significant activities – Felling of detachment/estrangement from others – Restricted range of affect (unable to express love, etc.) – Sense of foreshortened future WHAT OTHER DISORDER DO THESE SYMPTOMS REMIND YOU OF? (Are you ready for some “Craigism”?) MRI of Depression Dissociative Phenomena (cont.) • “Physiologically, they may respond as if they are being traumatized again, but this may be dissociated from semantic knowledge” (van der Kolk, 1997) Dissociative Phenomena (van der Kolk) • Failure of left-hemisphere functioning at the time of the trauma (i.e. during extreme arousal) – Decreased activation of Broca’s area (Broca’s area is involved in labeling emotions) • Cannot communicate what is going on, cannot label the internal state • Thus, during extreme arousal/intense emotions, the individual cannot “understand” what is going on – Left-hemisphere: also involved in sequencing events and categorizing experiences. Dysfunction leads to: • Trauma being seen as timeless • Trauma being seen as “ego-alien” Psychopharmacology and PTSD Psychopharmacology and PTSD • Issues regarding the use of medications with this disorder – There are no “anti-PTSD” medications (although there are two FDA approved medications for PTSD) – Co-occurring substance abuse disorders – Other co-occurring psychiatric disorders (both Axis I and Axis II diagnoses) – Co-occurring medical disorders – Lack of medication development compared with other disorders What are the Neurotransmitters? • Monoamines – Dopamine (DA) – Norepinephrine/epinephrine (NE/E) – Serotonin (5-HT) • Gamma amino butyric acid (GABA) and other amino acids (Glutamate, glycine, etc.) • Acetylcholine (ACh) • Hormones • Neuromodulators Variety of Medications Used • Anti-depressants – Monoamine Oxidase Inhibitors (MAOIs) – Selective Serotonergic Re-Uptake Inhibitors (SSRI)s: Prozac, Paxil, Zoloft, Celexa, Luvox and Lexapro) – Novel Anti-depressants: Desyrel, Serzone – Tricyclic anti-depressants: Elavil, Norpramin • Benzodiazepines • Anti-convulsant mood stabilizers • Anti-adrenergic: Inderal, Clonidine & Guanfacine • Opioid antagonists: Revex, Naltrexone • Anti-psychotic medications SSRIs: Increase Serotonin Activity • Advantages of the SSRIs (Zoloft, Paxil, etc.) – Can help treat both anxiety and depression – Can reduce impulsivity/enhance sobriety associated with substance abuse – Can be effective in all three symptom clusters associated with PTSD • Behaviors associated with serotonin in the brain include impulsivity, rage, suicidal behavior, depression, panic, obsessional thinking and behaviors associated with substance abuse • Difficult to OD on SSRIs – Disadvantages: do not (nor do any other medications) seem to affect dissociation Novel Anti-Depressants • Trazodone (Desyrel) – Advantages: • Increases 5-HT similar to SSRIs • Can reverse insomnia caused by SSRI agents and may help reduce traumatic nightmares • Not addictive Anti-depressants and Lifestyle Anti-Adrenergic: Decrease NE levels • Inderal, Clonidine and Guanfacine all decrease norepinephrine levels – Advantages: • Reduces hyperarousal and perhaps symptoms of re-experiencing • May help reduce D/A dependence particularly opiate dependence • Side-effects are transient and mild (unless one has pre-existing cardiovascular issues) • Not addictive – Disadvantages: • Half-life is short (tolerance) • Can make co-occurring depression worse Recent data on NE antagonist • Prazosin: reduces NE activity – FDA approved to reduce BP and reduce enlarged prostate – Used to reduce traumatic nightmares – Not a sedating sleeping pill (does not induce sleep) – Blocking NE centrally may normalize and increase REM sleep – Does not induce tolerance although the beneficial effects wear off once & symptoms return once the drug is stopped Reducing NE at the time of the traumatic event • Reducing NE shortly after the traumatic event may have two neurological effects: – May have an anti-anxiety effect (established by reducing NE peripherally) – May help reduce memory consolidation by blocking NE centrally (NE activity is part of memories being consolidated ); this may lessen the more long-term reactions associated with stimuli resembling the traumatic event (article in Neuropsychiatry) Benzodiazepines (BZDs) • Includes meds. such as Valium, Librium, Halcion, Xanax, Ativan – Advantages: • Very effective at reducing anxiety, insomnia and irritability • Reduces these symptoms very quickly – Disadvantages • BZDs have addictive potential • Do not reduce core PTSD symptoms (e.g. reexperiencing, avoidant nor numbing symptoms) • Behavioral disinhibition (similar to alcohol) • Memory interference • Consumers may confuse the sedative properties with the anti-anxiety properties Anti-Convulsants (Mood Stabilizers) • Includes Tegretol, Depakote and Gabapentin – Advantages: • May reduce proposed “kindling” of limbic structures • Tegretol: may reduce re-experiencing and arousal symptoms • Depakote may reduce avoidant/numbing and arousal symptoms – Disadvantages: • Need to be careful of potential OD (toxicity) • Sedation – Neurontin, Lamictal and Topamax Opiate Antagonists (Naltrexone, Revex) • The brain: releases increased amounts of endogenous opiates (endorphins, etc.) in response to stimuli which resemble the original traumatic event – This may account for the symptoms of emotional numbing and stress-induced analgesia • Advantages: – May reduce numbing and stress-induced analgesia – May interfere with drug (alcohol/opiate) seeking behavior – Reduce self-mutilation behaviors (BPD) • Disadvantages: – May make hyperarousal/anxiety worse Eye Movement Desensitization & Reprocessing (EMDR) Normal Sleep Processes: REM Sleep • Re: memory formation, information flows from the hippocampus to cortical areas during non-REM sleep (basis for reinforcement of old memories) • During REM sleep the flow is reversed – Information flows from cortical areas to the hippocampus and – Hippocampal outflow is blocked • During REM sleep there is a preferential activation of limbic structures (including amygdala) • Thus, REM sleep provides a method of forming new associative links (provides/enhances semantic processes and integrates this with any appropriate emotional tone) REM Sleep and EMDR • PTSD interrupts the normal REM process: – Intrusive replay of hippocampal episodic memories of the traumatic events occurs – The associated primitive emotional reactions (via the amygdaloid) occur as well – However, the cortical input which provides meaning or sense to the events is missing • Eye Movement Desensitization & Reprocessing (EMDR): may be a treatment which allows for the proper integration of cortical input with episodic memory and emotional tone Sleep Disorders Classification of Sleep Disorders: Secondary to other conditions • • • • Psychiatric Disorders Drug or alcohol use Psychiatric medications Medical disorders (e.g. respiratory; cardiac) • Medications for medical disorders • Pain syndromes (taken from M. Gitlin, 1996: The Psychotherapist’s Guide to Psychopharmacology) Medications used to regulate sleep • • • • • Ambien/Ambien CR Chloral hydrate Lunesta Sonata Hydroxyzine (Vistaril; Atarax) • Rozerem • Benzodiazepines (BZDs) – Restoril – Ativan – Other BZDs • Sedating antidepressants • Anti-histamines • Sedating neuroleptics How do sleep aids work? BZDs BZD-like Antimeds. histamines Melatonin agonists Unknown Choral Hydrate Restoril Ambien Benadryl Rozerem Ativan Sonata Vistaril Melatonin supplements Other BZDs Lunesta Atarax Desyrel (trazodone) Thank you for Coming!!! WHEW!