Dr. Togay is a Visiting Researcher, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky. Dr. El-Mallakh is Professor and Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky.
Disclosures Dr. Togay is a speaker for Lundbeck, Janssen, Otsuka, Indivior, Sage, Teva, and Takeda. Dr. El-Mallakh is a speaker for Lundbeck, Janssen, Otsuka, Indivior, Sage, Teva, and Takeda.
Perhaps the greatest advance in the understanding of the pathophysiology of PTSD relates to changes in brain NE. The HPA axis is responsible for coordinating the hormonal response to stress. Dysregulation of this axis and increased activity of the central and peripheral noradrenergic systems are usually observed in patients with PTSD.53 Several monoamine neurotransmitters are important in the regulation and function of the HPA axis. Norepinephrine plays a major role in stress.
The clinical PTSD-specific criteria are all descriptions of excessive noradrenergic tone.54 For example, hypervigilance and hyperstartle are clearly anticipated as evidence of NE stimulation. Flashbacks, particularly those that might be precipitated by environmental cues, also can be a manifestation of the vigilance induced by NE. Sleep disturbances (insomnia and nightmares) are present; insomnia is reported more often than nightmares.55 Increased catecholamine levels, particularly NE, are a feature of sleep disturbances associated with middle insomnia. Dreams can be remembered only if you wake up during dreaming. Catecholamines do not change the content of dreams, just recall.56
In a study of central noradrenergic tone in patients with PTSD, 6 hourly CSF samples were collected from 11 male combat veterans with PTSD and 8 healthy controls.57 Participants with PTSD had significantly higher CSF NE concentrations (0.55 ± 0.17 pmol/ml vs 0.39 ± 0.16 pmol/mL in the PTSD and control groups, respectively; F = 4.49, P < .05).57 Overall PTSD symptoms correlated significantly with CSF NE levels (r = 0.82, P <.005), and PTSD-specific symptoms such as avoidance (r = 0.79, P = .004). Intrusive thoughts (r = 0.57, P = .07) and hyperarousal (r = 0.54, P = .09) were also related.57 This relationship is unique; patients with PTSD with predominant depressive symptoms do not have elevated plasma NE levels.58
In the human brain, there are 3 main groups of NE receptors: alpha-1 receptors, alpha-2 receptors, and beta receptors.59 Alpha-1 receptors (alpha-1A, alpha-1B, and alpha-1D) are postsynaptic and mediate increase in inositol trisphosphate (IP3) and intracellular calcium (Ca2+). Alpha-2 receptors (alpha-2A, alpha-2B, alpha-2C) in the CNS are presynaptic autoreceptors and serve to reduce NE release. Beta receptors (beta-1, beta-2, beta-3) inhibit cyclic adenosine monophosphate (cAMP) production.59 The effects of inhibition of alpha or beta receptors are different. Inhibition of beta receptors is associated with depressive symptoms and depressive syndrome, inhibition of peripheral beta receptors is associated with reductions in anxiety (generally reduction of pulse, sweating, tremor),60 and inhibition of central alpha-1 receptors is associated with reduced PTSD symptoms.61
Choice of agents for PTSD-specific symptoms
As outlined in the Table,8 PTSD is characterized by 3 types of symptoms that are specific for PTSD. Trauma-focused psychotherapy62,63 and selective serotonin reuptake inhibitors (SSRIs)64 are considered first-line therapy for PTSD. Only sertraline and paroxetine are FDA-approved for treating PTSD. However, the effect size for SSRIs is quite small; improvement is only 23% to 30% greater than placebo.64,65 Furthermore, studies have shown that these medications have little effect on insomnia, hyperarousal, or other PTSD-specific symptoms.66,67 Studies examining military veterans with PTSD have found that these patients tend to have little or no response to antidepressants.68,69
