In PTSD patients

HT model. GAD symptoms may reflect excessive 5-HT transmission or overactivity of the stimulatory 5-HT pathways. Patients with SAD have greater prolactin response to buspirone challenge, indicating an enhanced central serotonergic response. The role of 5-HT in panic disorder is unclear, but it may have a role in development of anticipatory anxiety. Preliminary data suggest that the 5-HT and 5-HT2 antagonist meta-chlorophenylpiperazine causes increased anxiety in PTSD patients. 

Finally, a single open label trial of bupropion, a novel antidepressant with an obscure mechanism, found it helpful for depressive symptoms in PTSD patients but largely ineffective for the core symptoms of PTSD itself. 

Anticonvulsants. Several antiseizure medicines have been studied in the treatment of PTSD, and some results have been encouraging. Open label studies, first with carbamazepine (800-1200 mg/day) and later with valproate (500-2000 mg/ day), demonstrated overall improvement in PTSD patients, though not for intrusive recollections per se. Recent open label studies of gabapentin, lamotrigine, tiagabine, and topiramate have suggested these anticonvulsants might also be helpful for some PTSD symptoms. 

Interestingly, while peripheral neuroendocrine function appears normal in patients with panic disorder, decreased basal cortisol concentrations have been reported in most studies in PTSD patients. This relative hypocortisolism occurs in the context of increased feedback inhibition of the HPA axis (see Yehuda, 2000). However, a dissociation between central and adrenocortical (re)activity has been found in animal models of severe early-life stress as well as in abused children and women, suggesting that adrenal dysfunction may, at least in part, contribute to hypocortisolism in PTSD. In the face of hypocortisolism, it seems surprising that hippocampal atrophy is one of the most prominent findings in patients with PTSD, including adult survivors of childhood abuse with PTSD (see Newport and Nemeroff, 2000). While increased glucocorticoid sensitivity of hippocampal cells may play a role in the development of hippocampal atrophy, another potential mechanism may involve toxic effects of markedly increased cortisol responses to everyday stress in patients with PTSD. 

The Treatment Outcome PTSD Scale (TOP-8) is a clinician-rated instrument that measures the presence and severity of eight PTSD symptoms that occur frequently in PTSD patients and are sensitive to treatment. The scale was developed from the Structured Interview for PTSD (SI-PTSD Davidson et at., 1997), an alternative to the SCID. The TOP-8 questions are representative of the three major PTSD symptom dimensions (intrusive, avoidant and hyperarousal symptoms). Each symptom is rated on a defined step scale (0 4), with a high numeric rating indicating greater symptom severity (Davidson and Colket, 1997). The TOP-8 has proved sensitive to changes of PTSD symptoms in studies with antidepressants. 

On the other side, PTSD does not correlate with an increase in basal NE transmission. However, robust increase in plasma concentrations of NE and its metabolites in PTSD patients are observed after their re-exposure to the traumatic contents. The administration of an a2-adrenoceptor antagonist, yohimbine, resulted in a panic attack in PTSD patients. These observations suggest that an increased NE tone is involved in acute anxiety and panic attack, rather than in the cognitive aspect of PTSD. Further imaging studies are required to study the role of the hippocampal and/or cortical NE system in neuropathology of PTSD (Newport and Nemeroff 2000). 

Marshall, R., Printz, D., Cardenas, D., Liebowitz, M. (1995). Adverse events in PTSD patients taking fluoxetine. American Journal of Psychiatry, 152, 1238-1239. 

When animals are exposed to inescapable shock, they exhibit consistent behavioral reactions—initially hypervigilance or arousal and ultimately a profound state of withdrawal and "depression." In addition, such animals eventually show a significant depletion of norepinephrine, likely accompanied by changes in NE receptor sensitivity in parts of the brain. Alterations of receptor sensitivity may leave the animals in a state of chronic hyperarousal. In essence, their nervous systems may be permanently altered such that traumatized animals and people alike are relatively unable to dampen or inhibit excessive emotional arousal. Antidepressants that affect norepinephrine appear to alter receptor sensitivity, both in humans and animals. Serotonergic antidepressants may also indirectly inhibit hypersensitive NE cells (Nagy et al. 1993), and thus can play a role in treating hyperarousal in PTSD patients. 

However, recent evidence has suggested that volume loss in the PFC and ACC could also be a consequence of PTSD rather than a preexisting risk factor (Kasai et al., 2008). Functional imaging studies have demonstrated a reduced activity of the medial PFC in PTSD patients in response to stimuli, such as trauma scripts (Shin et al., 2004 Britton et al., 2005), combat pictures and sounds (Bremner et al., 1999), trauma-unrelated negative narratives (Lanius et al., 2003), fearful faces (Shin et al., 2005), and impaired performance on PFC-dependent tasks (Koenen et al., 2001). Finally, PTSD patients show impaired abilities to extinguish fear (Peri et al., 2000) and reduced activities of PFC regions during extinction trials (Bremner et al., 2005). 

---