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Pharmacological Treatment of Acute Stress Reactions: A Neurobiological Systems Approach



This section is for Researchers, Providers, & Helpers

This section is for Researchers, Providers, and Helpers

Pharmacological Treatment of Acute Stress Reactions: A Neurobiological Systems Approach

The goal of early interventions with medication after exposure to a trauma is to ameliorate posttraumatic reactions and to prevent the later development of PTSD. Consideration of the neurocircuitry underlying the human stress response may help prescribers identify medications most likely to be effective.

The presumed circuitry involves excessive activation of the amygdala by stimuli perceived by the patient as threatening. Such activation produces outputs to various brain areas that mediate a number of functions: memory consolidation of emotional events and spatial learning (hippocampus), memory of emotional events and choice behaviors (orbital frontal cortex), autonomic and fear reactions (locus coeruleus, thalamus, and hypothalamus), and instrumental approach or avoidance behavior (dorsal and ventral striatum) (1).

In PTSD, the normal checks and balances on amygdala activation have been impaired, so that the restraining influence on the amygdala of the medial prefrontal cortex (PFC, especially the anterior cingulate gyrus and orbitofrontal cortex) is severely disrupted (2, 3). Disinhibition of the amygdala produces a vicious spiral of recurrent fear conditioning, in which ambiguous stimuli are more likely to be appraised as threatening; mechanisms for extinguishing such responses are nullified; and key limbic nuclei are sensitized, thereby lowering the threshold for fearful reactivity (2, 4-6).

The pharmacological challenge, therefore, is to identify where and how to intervene in order to rein in the amygdala and the cortical and subcortical effects it has set in motion. Clinicians should consider the following systems when formulating a pharmacological intervention for acute posttraumatic reactions:

Adrenergic mechanisms

The therapeutic goal of targeting the adrenergic system is to inhibit excessive alpha-1 and beta receptor activation and to augment the inhibitory influence of alpha-2 adrenergic receptors. The result of such treatment would be expected to reduce amygdala activation, enhance PFC function and inhibit stimulation of the locus coeruleus and its secondary activation of other cortical and subcortical structures.


An important reason for considering acute interventions to reduce excessive stress-induced HPA activation is the possibility that abnormal HPA activity may have neurotoxic effects. Prevention of neurotoxicity might be achieved by rectifying HPA abnormalities with CRF antagonists or glucocorticoids. It might also be achieved with glutamate antagonists, such as certain anticonvulsants, which through blockade of excitatory amino acid actions, protect neurons by preventing toxic calcium influx. Finally, reversal of neurotoxicity might be achieved with treatments that promote neurogenesis. For example the SSRI, paroxetine, has been shown to increase hippocampal volume in PTSD patients (7).


Glutamate is the major excitatory neurotransmitter in the brain. It plays a crucial role in the human stress response and probably in the pathophysiogy of PTSD. Anticonvulsant agents, also known as mood stabilizers, exert their primary actions on glutamate and/or gamma-amino-butyric acid (GABA) activity (see below). Such actions also have potential importance in ameliorating PTSD symptoms. The centrality of glutametergic actions in amygdala activation has strong empirical support from laboratory research. It suggests that anticonvulsants/mood stabilizers that antagonize glutamate activity might be useful for acute posttraumatic pharmacotherapy.


GABA is the brain's major inhibitory neurotransmitter. It suppresses stress-induced actions of the amygdala. GABA receptors within the basolateral amygdala inhibit glutamatergic excitation. This suggests that benzodiazepines or anticonvulsants/mood stabilizers that potentiate GABAergic mechanisms might be useful agents for acute posttraumatic pharmacotherapy.

The Serotonin System

The serotonergic system has important interactions with the adrenergic, HPA, glutamate, GABA and dopamine systems. There also appear to be synergistic interactions between 5-HT-1-A and GABA receptors with regard to acute stress and PTSD. Given the many different types of serotonin receptors, a review of the basic science literature suggests that effective early pharmacotherapeutic intervention might be achieved with agents that activate 5-HT-1-A receptors such as SSRIs, venlafaxine, tricyclic antidepressants or monoamine oxidase inhibitors. In addition, it suggests that medications that also block 5-HT-2 receptors, such as nefazadone or trazadone might also be useful.

The Dopaminergic System

During uncontrollable stress, amygdala activation produces PFC dopamine release (2). This and other research findings suggest that administration of dopamine antagonists, such as atypical or conventional antipsychotic agents might ameliorate acute posttraumatic reactions and prevent the later development of PTSD.

Neuropeptide Y

Neuropeptide Y (NPY) is an amino acid neurotransmitter, co-localized in noradrenergic neurons, that inhibits the release of both norepinephrine and corticotropin releasing factor (CRF, see below). Research findings have suggested that medications that enhance NPY function might ameliorate acute stress reactions, PTSD, and other stress-induced problems (8). No pharmacological agents of this nature are currently available.

Corticotropin Releasing Factor (CRF)

Given its key role in mobilizing the human stress response as well as its increased expression among PTSD patients, there is good reason to predict that CRF antagonists might have beneficial clinical effects on PTSD-related symptoms. Although CRF antagonists are currently utilized in animal research and under development by pharmaceutical companies, none is available for clinical use.

Future pharmacological treatment for acutely traumatized individuals will seek to reduce the magnitude of the stress response and to promote rapid recovery of normal function. This might be accomplished in the following ways:

  • By reducing CRF activity with CRF antagonists or enhancing NPY activity
  • By reducing HPA activation with glucocorticoids (such as cortisol or hydrocortisone) with an adrenal steroid such as dehydroepiandosterone (DHEA)
  • By reducing adrenergic activation with NPY agonists and/or a variety of antiadrenergic agents (such as clonidine/guanfacine, propranolol, or prazosin)

As more psychobiological research is carried out with acutely traumatized individuals, other pharmacological strategies will undoubtedly become apparent. Among those of greatest theoretical interest are anticonvulsant/antikindling agents that exert their effects through inhibition of glutamatergic agents, potentiation of GABAergic agents, or both.

This page was based on: Friedman, M. J. (2008). The role of pharmacotherapy in early interventions. In M. Blumenfield & R. Ursano (Eds.), Intervention and resilience after mass trauma (pp. 107-125). Cambridge, UK; New York: Cambridge University Press.


  1. Davis, M., & Whalen, P.J. (2001). The amygdala: Vigilance and emotion. Mol Psychiatry, 1, 13-34.
  2. Charney, D.S. (2004). Psychobiological mechanisms of resilience and vulnerability: Implicationis for the successful adaptation to extreme stress. American Journal of Psychiatry, 161, 195-216.
  3. Vermetten, E., & Bremner, J.D. (2002). Circuits and systems in stress. II. Applications to neurobiology and treatment in posttraumatic stress disorder. Depression and Anxiety, 16, 14-38.
  4. Charney, D.S., Deutch, A.Y., Krystal, J.H., Southwick, S.M., & Davis, M. (1993) Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry, 50, 295-305.
  5. Friedman MJ. (1994). Neurobiological sensitization models of posttraumatic stress disorder: Their possible relevance to multiple chemical sensitivity syndrome. Toxicol Ind Health, 10, 449-462.
  6. Southwick, S.M., Davis, L.L., Aikins, D.E., Rasmusson, A.M., Barron, J., & Morgan, C.A. (2007). Neurobiological alterations associated with PTSD. In M.J. Friedman, T.M. Keane, & P.A. Resick (Eds.), Handbook of PTSD: Science and practice (pp. 166-189). New York, Guilford Publications.
  7. Vermetten, E., Vythilingam, M., Southwick, S.M., Charney, D.S., & Bremner, J.D. (2003). Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biological Psychiatry, 54, 693-702.
  8. Friedman MJ. (2002). Future pharmacotherapy for PTSD: Prevention and treatment. Psychiatr Clin North Am, 25, 1-15.
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