Dopamine Enhancement of Fear Extinction Learning in PTSD (1R21MH108753)
Condition: Stress Disorder, Post Traumatic
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to investigate a new use for a medication called levodopa
      (L-DOPA). L-DOPA has been approved for use in Parkinson 's disease, but not for Posttraumatic
      Stress Disorder (PTSD). L-DOPA is thought to enhance certain cognitive abilities that the
      investigators believe may be affected among women with PTSD. It is hypothesized that L-DOPA
      may enhance fear extinction learning to a conditioned fear stimulus. If this is true, L-DOPA
      may improve outcomes for those undergoing certain types of therapy for PTSD, though that aim
      is beyond the scope of this project. Additionally, the investigators are testing whether an
      individual's genetic profile affects how well L-DOPA works to enhance cognitive abilities.
    

Detailed description: 
      Current state-of-the art treatments for posttraumatic stress disorder (PTSD) are lacking in
      efficacy. There are two main evidence-based psychological treatments for PTSD. Prolonged
      Exposure (PE) is a largely-exposure based intervention that has been found efficacious for
      the reduction of PTSD symptoms; however, PE is associated with post-treatment remission rates
      of only ~53-60%. Cognitive Processing Therapy (CPT) is also a widely studied and efficacious
      psychological treatment for PTSD, which focuses both on exposure to the trauma memory as well
      as cognitive therapy techniques. As with PE, post-treatment remission rates for CPT are only
      ~53-60%, thus also indicating need for improvement in overall efficacy and consistency of
      response across individuals.

      There is emerging research demonstrating that dopamine is critical to the consolidation and
      subsequent recall of fear extinction learning. A recent study of healthy adult humans
      demonstrated that oral administration of 150 mg L-DOPA after fear extinction learning led to
      decreased fear responding, even when tested in a new context. Further, this study also found
      that resting-state functional connectivity, measured ~45 minutes after post-extinction
      learning L-DOPA administration, between the ventral tegmental area (VTA) and mPFC was
      correlated with magnitude of medial prefrontal cortex (mPFC) recruitment during recall of the
      fear extinction learning. This latter finding suggests that the mechanism by which L-DOPA
      boosts consolidation of fear extinction learning is through acutely reorganized dopaminergic
      resting-state networks. Indeed, other studies have demonstrated an acute effect of L-DOPA
      administration on resting-state functional connectivity within dopaminergic neural networks.
      Thus, agents that increase dopamine transmission acutely during the post-extinction learning
      consolidation window, and thereby acutely altering organization of dopaminergic neural
      networks, show promise for boosting the consolidation of fear extinction memories and
      decreasing fear responding.

      Genetic variation is a primary contributor to individual differences in baseline dopamine
      neurotransmission. Individuals with specific alleles in genes coding for high baseline
      dopamine demonstrate better performance on tasks probing working memory, cognitive control,
      and social cognition. Genetic variants in baseline dopamine neurotransmission would therefore
      be expected to modulate performance-enhancing effects of L-DOPA, such that individuals with
      low endogenous would be expected to have increased performance upon exogenously increasing
      dopamine neurotransmission; whereas individuals with high endogenous dopamine would be
      expected to have performance deteriorate from exogenously increasing dopamine
      neurotransmission. In support of this hypothesis, a recent study found an interaction between
      L-DOPA administration and endogenous dopamine neurotransmission (as indicated by a polygenic
      score pooled across catechol-O-methyltransferase (COMT), dopamine transporter protein (DAT),
      dopamine D1 receptor (DRD1-3)) on motor learning performance, such that individuals with a
      combination of alleles coding for higher baseline dopamine demonstrated a weaker learning
      benefit from L-DOPA, whereas individuals with a combination of alleles coding for lower
      baseline dopamine demonstrated a stronger learning benefit from L-DOPA. These data
      demonstrate the non-linear relationship between performance and dopamine levels, suggesting
      that any investigation of potential effects of boosting dopamine neurotransmission as a means
      of boosting learning needs to account for baseline dopamine neurotransmission.

      Overall, the proposed project seeks to demonstrate the engagement of post-extinction dopamine
      neurotransmission and downstream acute reorganization of dopaminergic resting-state neural
      networks as a means of increasing consolidation of generic fear extinction learning in adult
      women with PTSD.
    

Intervention name(s): Placebo; Levodopa
Intervention type(s): Drug; Drug
Intervention description(s): Sugar pill packaged to resemble levodopa; EIther 100mg or 200 mg, depending on arm assignment, administered once by mouth.
Other intervention name(s): L-DOPA; Larodopa
Intervention MeSH terms: Levodopa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Posttraumatic Stress Disorder; functional Magnetic Resonance Imaging; Levodopa (L-DOPA); Exposure Therapy; Fear Extinction