Chapter 5 - Second-Line, Adjunct, and Investigational Medications for PTSD

Summary

In addition to the first-line selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), there are many second-line and adjunct pharmacologic options for PTSD. In this chapter, the mechanisms of action of such agents are explained and clinical characteristics are briefly reviewed. Several agents under investigation for their potential use in PTSD are reviewed as well.

Combination of MAOIs with agents that inhibit serotonin reuptake can also be dangerous, as combining two different methods of increasing serotonin may lead to a dramatic accumulation of serotonin. This can cause excessive stimulation of postsynaptic serotonin receptors and lead to hyperthermia, coma, seizures, cardiovascular problems, and death. This is known as the “serotonin syndrome” or serotonin toxicity and is why the combination of an MAOI with any drug that has SRI properties is strictly contraindicated (B).

• (A) One mechanism for preserving the effects in the brain while avoiding effects in the gut is reversible inhibition of MAO-A (RIMA). RIMAs can be removed from the enzyme by competitors (e.g., norepinephrine). Thus the accumulation of norepinephrine released by tyramine can displace the RIMA, allowing norepinephrine to be destroyed and reducing risk of a tyramine reaction.

• (B) A second way to combat this dilemma is with transdermal selegiline. The selective MAO-B inhibitor must be administered in high doses in order to inhibit MAO-A as well. Transdermal administration of selegiline delivers the drug directly into the systemic circulation, hitting the brain in high doses but avoiding a first pass through the liver and thus reducing risk of a tyramine reaction.

Alpha 2 delta ligands bind selectively to VSCCs and actually appear to bind with higher affinity to VSCCs in the open channel conformation. Thus they may exert greater effects in situations where neurons have excessive activity, as hypothesized for amygdala circuits in anxiety disorders, while not interfering with normal neurotransmission in neurons uninvolved in mediating the pathological anxiety state.

GABA-A receptors consist of five subunits with a central chloride channel and have binding sites not only for GABA but also for benzodiazepines. When a benzodiazepine binds to the GABA-A receptor in the absence of GABA it has no effect on the GABA channel—chloride conductance is the same as in the resting state (A).