What Can the Brain Teach Us About Treating PTSD? Thomas C. Neylan, MD Norbert Schuff, PhD Charles R. Marmar, MD Michael W.

Transcription

1 What Can the Brain Teach Us About Treating PTSD? Thomas C. Neylan, MD Norbert Schuff, PhD Charles R. Marmar, MD Michael W. Weiner, MD

2 Stress and Biological Sciences Abram Kardiner ( ) Described a syndrome of autonomic hyperarousal in traumatized war veterans Physioneurosis (1941) DSM-IV physiological reactivity on exposure to internal or external cue..

3 Psychophysiologic Observations in Chronic PTSD Significantly greater response to meaningful traumatic stimuli as measured by: heart rate systolic blood pressure galvanic skin response forehead electromyogram Exaggerated startle to acoustic stimuli

4 PTSD Associated With Increased 24 Hour Urinary Norepinephrine Plasma Norepinephrine pg/ml Normal (n=18) PTSD (n=23) Time of Day Yehuda R, et al. Biological Psychiatry. 1998;44:

5 Biology of PTSD: A Failure of Containment Neuroimaging: Amygdala is overactivation, but anterior cingulate and frontal lobes are underactivated Startle: Increased reactivity and reduced habituation Arousal Neurochemistry: Increased norepinephrine, CRF, glutamate, but decreased GABA

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7 Psychobiology of PTSD: A Disorder of Unmanageable Anxious Arousal Genetic factors, epigenetic events, and learned factors influence peritraumatic terror responses Prolonged peritraumatic panic and terror associated with increased risk for PTSD Prolonged elevations in brain arousal pathways increase fear conditioning, memory consolidation, and sustain some symptoms (e.g. insomnia, startle)

8 Medications Studied for PTSD Antidepressants SSRIs (Sertraline and Paroxetine FDA approved) SNRIs (Venlafaxine, Duloxetine) SARIs (Nefazodone and Trazodone) NaSSA (Mirtazapine) TCAs & MAOIs Adrenergic inhibiting agents Anxiolytics Anticonvulsants Atypical antipsychotics

9 Adrenergic Inhibiting Agents α-1 adrenergic blockers Prazosin α-2 agonists Guanfacine Clonidine β-blockers Propranolol (proximal to trauma)

10 α-1 Antagonists Agent Prazosin Molecular Target α-1 post-synaptic adrenergic receptor (antagonist) Clinical Significance α-1 receptors widely distributed in brain, including amygdala and hippocampus α-1 receptors modulate sleep and startle responses Adverse reactions: syncope, dizziness, drowsiness, decreased energy, headache

11 Dosing 7 to 15 mg QHS Data on Prazosin Gradual titration, limited by lightheadedness Double blind RCT 1 40 veterans, /- 3 mg/day Robust improvement in sleep quality and distressing dreams Medium to large effect size in each PTSD symptom cluster Raskind et al: Biol Psychiatry 2007; 61:

12 Agents α-2 Agonists Guanfacine ( mg at bedtime), Clonidine Molecular Target α-2 pre-synaptic adrenergic receptor (agonist) Clinical Significance Acts at autoreceptor slowing locus coeruleus firing Decreases central catecholamine release Adverse reactions: sedation, hypotension (clonidine > guanfacine), dry mouth

13 Guanfacine vs. Placebo (n=63) Neylan et al. Am J Psychiatry 2006

14 PTSD involves Fear Conditioning Pairing of neutral stimuli (contextual cues) and traumatic stimulus leads to fear responses to neutral cues After trauma, neutral cues leads to fear response PTSD maintained by avoidance behavior

15 Exposure Therapy and Extinction of Fear Conditioning Animal model: Repeated exposure to neutral cue (light) without shock decreases fear conditioning Involves active learning and is mediated by the neurotransmitter glutamate Extinction is the basis for exposure therapy in PTSD Patients learn to confront their feared memories and situations under safe circumstances with the goal of extinguishing fear

16 Exposure Based Cognitive Behavior Therapy for Acute Stress Disorder Impact of Event Scale Prolonged Exposure (PE) Prolonged Exposure/Stress Inoculation Training (PE/SIT) Supportive Counseling (SC) Pre-Tx Post-Tx 6 Mo. Follow Up Bryant RA, et al. Am J Psychiatry. 1999;156:

17 Treatment of PTSD by Exposure and/or Cognitive Restructuring IES Scores r c ec e r = relaxation c = cognitive restructuring e = prolonged exposure ec = e + c 0 Treatment Follow Up 1 month 3 months 6 months Marks I, et al. Arch Gen Psychiatry ;55:

18 D-Cycloserine and Exposure therapy Recent research suggests that D-Cycloserine (DCS), an NMDA partial agonist, may facilitate fear extinction DCS: FDA-approved medication for tuberculosis for over 20 years Partial agonist at NMDA receptor Has been studied as a cognitive enhancer in Alzheimer s disease and schizophrenia

19 D-Cycloserine (DCS) facilitates extinction learning in rats Startle reactivity after extinction training is lower in rats injected with DCS vs. saline Walker, D.L., et al., J Neurosci, (6): p

20 RCT of Exposure Therapy and DCS DCS reduced subjective fear ratings in patients with acrophobia Reduction in fear ratings after two therapy sessions Ressler, K.J., et al., Arch Gen Psychiatry, (11): p Reduction in fear ratings at three months follow-up

21 D-Cycloserine and Exposure Therapy in PTSD

22 Extinction in PTSD: Concerns A single training trial can restore conditioned fear long after apparent extinction In humans, dormant traumatic memories may be unexpectedly recalled Hippocampal damage may impair normal extinction

23 Effect Size Estimates for Hippocampal Volume in Adults With Chronic PTSD vs Healthy Subjects Pooled Meta-Analysis Demonstrates Smaller Hippocampal Volume in PTSD Overall Bremner 95 Bremner 97 Bremner 03 Gurvits 96 Stein 97 Notestine 02 Villareal 02 Schuff 01 Gilbertson 02 Overall Effect Size Bremner, 1995 Bremner, 1997 Bremner, 2003 Gurvits, 1996 Stein, 1997 Notestine, 2002 Villareal, 2002 Schuff, 2001 Gilbertson, p<.05 Left Hippocampus Right Hippocampus -4-5 p<.05 Effect size (black square) and 95% confidence interval (red line) measured with Hedges GU. Effect Size

24 PTSD and Neuronal Injury: Evidence for an Association Severe stress associated with neuronal damage in animals Attention and memory deficits in humans with PTSD Most MRI studies show volume loss of hippocampus Several mechanisms for neuronal injury have been proposed Increased excitatory amino acid toxicity: glutamate Decreased growth of new neurons (neurogenesis)

25 Stress Results in Decreased Hippocampal Neurogenesis Number of BrdU-Labeled Cells Dominant * Subordinate Gould et al, 2002.

26 Antidepressant Treatments Promote Hippocampal Neurogenesis BrdU Labeled Cells/DG * * * * 0 Control ECS TCP FLU REB Duman et al, 2002.

27 Increased Hippocampal Volume With Paxil in PTSD Hippocampal Volume (mm-3) Baseline Post-treatment *p<.05 * * 1180 Left Hippocampus Right Hippocampus Effects of 9-12 months of treatment with mg paroxetine. Vermetten et al. Biol Psychiatry

28 Effects of Paroxetine on Hippocampal-Based Verbal Declarative Memory in PTSD Wechsler Memory Scale-Delayed Paragraph Recall Baseline P<.05 Post-treatment Effects of 9-12 months of treatment with mg paroxetine. Vermetten et al. Biol Psychiatry Mean 35% improvement

29 Brain Chemistry in PTSD Magnetic Resonance Spectroscopy Brain MRI Healthy control Cr PTSD Cho Cr NAA NAA PTSD associated with reduced NAA, a marker of viable neurons

30 1H MR Spectroscopic Imaging in NAA/Cr Hippocampus PTSD NAA Right Anterior Cingulate 2.4 Right Left NAA [a.u.] P+A+ P+A- P-A+ P-A- P+A+ P+A- P-A+ P-A- Schuff et al, Psychiatry Research Neuroimaging, In Press

31 Hippocampal Subfields CA1 CA2 CA3,4 Subiculum Dentate Gyrus

32 Higher Resolution and Sensitivity of Brain Chemistry using a more Powerful 1.5 Tesla NAA Magnet Cho Cr 4 Tesla

33 Visualization of Brain Connectivity via Imaging of Neuronal Fiber Bundles Diffusion Tensor Imaging at 4 Tesla 3D View

34 Cerebral Blood Flow with MRI Perfusion-weighted MRI Maps of cerebral blood flow CBF CBF t ex Max Exchange Time Min

35 Summary Clinical Neuroscience has great promise in PTSD to: Identify areas of the brain affected by PTSD Test if treatment can reverse brain abnormalities Long term goal is to inform treatment development