Transcript Slide Deck

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
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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
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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
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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
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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!