Crisis: Opportunity for Secondary Prevention

1
Crisis Opportunity for Secondary Prevention

• Is Pharmacological Prophylaxis Effective in
  Preventing Posttraumatic Stress Disorder?

2

• Dont know
• but in the light of initial evidence
• . Possibly

3
Prophylactic Treatment

• Based on the premise that the likelihood of
  developing a long-term psychiatric disorder, in
  this instance posttraumatic stress disorder, may
  be reduced if effective treatments can be
  implemented before the disorder becomes entrenched

4
Posttraumatic Stress Disorder

• 26 years since PTSD was defined and formally
  included in the DSM
• Clinically distinct entity that can be reliably
  described, measured, tracked back to a triggering
  event assigned to the brains memory alarm
  systems
• Remains one of the most challenging anxiety
  disorders for researchers clinicians alike

5
Gaps in Knowledge

• Gaps in our knowledge are myriad
• Include a limited understanding of
• The natural longitudinal course of psychological
  consequences from the immediate post-impact phase
  to months years after
• The psychobiological mechanisms underlying both
  acute (in 1st month) and long-term stress
  reactions

6
Who gets PTSD who doesnt?

• Little doubt that PTSD is a serious health
  problem
• Incidence rates of PTSD after MVA range between
  19 and 47
• Although coming to medical attention less
  frequently than MVAs, interpersonal traumas
  (rape, assault) often result in even higher rates
  of PTSD

7
Who gets PTSD who doesnt?

• As many as 95 of individuals who are exposed to
  these events will experience some degree of
  posttraumatic distress
• But despite the prevalence of acute stress
  reactions, there is also considerable evidence
  that the typical course of adaptation is to
  recover in the following weeks or months after
  exposure
• However, 30 will develop a persistent,
  incapacitating disorder that conforms to criteria
  for PTSD, major depression or another psychiatric
  disorder

8
Vulnerable or Resilient?

• Whether one develops a high-risk immediate
  reaction or PTSD itself - seems to be product of
  both nature nurture
• Development and maintenance of PTSD may be
  predicted by different pre-traumatic, traumatic
  and posttraumatic factors

9
Meta-Analysis Of Risk Factors
for PTSD
Pre-Trauma Characteristics
Post-Trauma Characteristics
Gender
Psych History
Child Abuse
Prior Adversity

Stress
Severity
Social Support
Brewin et al., J
Consult Clin Psychiatry, 2000
10
Gene-Environment Interactions

• A good predictor of who will develop PTSD after a
  catastrophic event is the way a person
  immediately reacts to the event
• Another strong predictor is prior trauma since
  repeated stress appears to the sensitize the
  bodys stress systems to subsequent traumatic
  events
• Recent reports demonstrating gene environment
  interactions between a polymorphism of the
  serotonin transporter gene, early life adversity,
  and the incidence of MDD suggest that genetic
  factors may also predict PTSD
• Other genes that may be prime candidates for
  influencing stress-reactions include CRF and BDNF
  

Caspi et al., Science, 2003
11
Physiological Markers

• Growing evidence that certain physiologic markers
  are also useful in predicting risk for PTSD
• For example, decreased cortisol increased heart
  rate in the aftermath of trauma have been shown
  in several prospective studies to predict the
  likelihood of subsequent disorder

12
Identifying those at risk

• If we are able to identify those at risk
• Can early interventions prevent development of
  acute stress symptoms as well as later-onset of
  PTSD?
• Questions of vulnerability and resilience have
  taken on a new urgency in attempting to
  determine when to respect natural recovery
  processes and when to provide formal intervention

13
Secondary Prevention

• Formal intervention would be at level of
  secondary prevention - intervening in the
  aftermath of a traumatic event to forestall the
  development of PTSD
• Until recently, the most popular early
  intervention for PTSD was psychological
  debriefing
• Recent reviews of controlled studies have failed
  to confirm efficacy and there has been at least 1
  study that has reported long-term adverse effects

Mayou et al., Br J Psychiatry, 2000
14
Secondary Prevention

• Treating acute stress disorder with CBT has been
  shown to have preventive value for subsequent
  PTSD
• Secondary pharmacological prevention of PTSD has
  received far less attention
• In the last few years there has been an
  intensification of effort to develop and test a
  variety of novel pharmacological interventions
  that may be suitable for adults and children
  during the acute trauma period

15
Model of PTSD Pathogenesis
16
Disrupting neuronal mechanisms that mediate
fear conditioning reconsolidation after
exposure to an acute trauma could
sabotage the development of PTSD
17
Pharmacological Inoculation

• Based on animal research to date the most
  promising candidate for intervening early to
  block the potentiation of memory consolidation by
  stress hormones is propranolol
• Propranolol when administered pre- or
  post-training in rats blocks post-synaptic
  B-adrenergic receptors in the amygdala and
  peripherally? central action responsible for
  blocking memory enhancement

18
Propranolol in MVA victims
Pitman et al., Biol Psychiatry,
2002
19
Propranolol in MVA

• Based on these physiological responses during
  script-driven imagery
• 0 of 8 propranolol, but 8 of 14 placebo, patients
  were physiologically classified as PTSD at 3
  months
• Consistent with reduced conditioned fear
  responses in the propranolol group

20
Propranolol

• In a 2nd controlled, non-blind, non-randomized
  study in 19 patients with HR gt90 BPM
• 11 patients (MVA or physical assault) who
  received propranolol 30mg 3x/daily within 2-20
  hrs for 7 days, followed by 8-12 day taper, were
  compared with 8 patients who refused propranolol
• The 2 groups did not differ on demographics,
  exposure characteristics, physical injury
  severity, or peritraumatic emotional responses
• At 2 months, PTSD rates were higher in the
  control group vs. the group who received the
  medication
• 80 of the time a patient who took propranolol
  had a score below that of patient who did not

Vaiva et al., Biol
Psychiatry, 2003
21
Hydrocortisone PTSD

• More recently, Schelling colleagues (2004)
  examined efficacy of peri- post-operative
  exogenous hydrocortisone in preventing PTSD
  symptoms following cardiac surgery
• 26 patients received 4 days of HCT
• 22 comparison subjects received standard Rx
• Patients who received HCT had significantly
  fewer PTSD symptoms

22
Imipramine Burns

• Small pilot study 25 children adolescents
  randomized to 7-day course of double-blind
  imipramine (1mg/kg) or chloral hydrate
• Severity of ASD measured at baseline rate of
  PTSD measured at 6 months
• Rate of improvement in ASD symptoms was
  significantly higher with imipramine (83) than
  chloral hydrate (38)
• Suggests a possible role for TCAs and other
  antidepressants in the prophylaxis of PTSD in
  pediatric patients

23
Benzodiazepines ???

• 2 studies have not shown these agents to have
  value in PTSD prevention
• Clonazepam (mean daily dose 2.7mg) or
  alprazolam (mean daily dose 2.5mg) administered
  within 1-week of trauma exposure to 13 victims
• 13 matched but untreated victims control group
• At 6-months, 69 of patients in BDZ group vs. 15
  in control group fulfilled criteria for a
  diagnosis of PTSD
• NB 7 of 13 patients treated with BDZ none of
  the controls had MDE at 6 months

Gelpin et al., J Clin Psychiatry1996
Mellman et al., J Trauma Stress, 1998
24
Summary

• Little empirical data on effective pharmacologic
  interventions in the immediate aftermath of
  extreme psychological trauma
• Less than 10 prospective, controlled, preventive,
  pharmacotherapy trials published - best regarded
  as preliminary

25
Other Strategies

• Studies in hot pursuit of other molecular
  mechanisms
• Given the association of the serotonin
  transporter gene with stress vulnerability and
  amygdala activation, early use of SSRIs or SNRIs
  might also be useful
• Other ideas (i) block the action of CRF with
  antagonist of CRF1 receptor, (ii) block activated
  fear circuits with a2d ligand e.g. pregabalin
  (iii) GABAergic agents

26
Other Strategies

• Neurophysiological kindling model of PTSD - that
  anti-kindling agents (i.e. tiagabine), may have
  preventive value
• Cortisol-induced neurotoxicity model of PTSD -
  drugs that block hippocampal damage (e.g. SSRIs,
  tianeptine) and ?anti-cortisol agents (e.g.
  mifepristone) may also be useful

27
Summary

• Too early to tell which, if any, of these
  potential medication interventions will
  effectively inoculate against PTSD
• Unanswered questions of timing, dose, and
  developmental, cultural, and other differences
  need to be systematically assessed