Panic disorder mechanisms

Inositol, the building block of the phosphoinositide intracellular signaling pathway, has been examined as a potential anxiolytic. In clinical trials, inositol has reported to be effective in both panic disorder [114, 115] and depression [116], and animal data are also favorable. Because of inositol s status as a dietary supplement, there is little financial backing for studies of its efficacy and safety. The mechanism of action of inositol is not entirely clear, but it is believed to facilitate phosphoinositide-signaling-coupled neurotransmission. 

Clonidine (Catapres). Like the beta blockers, clonidine acts by reducing norepinephrine activity, though by a different mechanism. Studies show that clonidine can provide early relief from the symptoms of a panic attack, but patients unfortunately relapse with continued treatment. Therefore, clonidine is not used in the treatment of panic disorder. 

Isoproterenol, a synthetic sympathomimetic amine acting selectively at both Pi - and P2-adrenoceptors, is also able to induce panic attacks in a subset of patients suffering from panic disorder. There is, however, a discrepancy in the findings, and the rehability and mechanisms of isoproterenol-induced panic remain to be clarified. It should also be emphasized that isoproterenol is not able to cross the blood-brain barrier. 

Gabapentin acts by increasing GABA activity, although its exact mechanism of action is unclear. It causes dose-related sedation and dizziness. It has been shown in randomised controlled trials to be effective in social anxiety disorder (Pande et al. 1999) and to benefit some patients with panic disorder (Pande et al. 2000). Pregabalin is a related compovmd that has recently demonstrated efficacy in GAD in a phase III study (Pande et al. 2003). 

Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J (1995) A placebo-controlled trial of L-365,260, a CCK antagonist, in panic disorder. Biol Psychiatry 37 462-466 Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek IJ, Reines SA, Snavely D, Wyatt-Knowles E, Hayle EJ (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281 1640-1645 Kriegsfeld LJ, Dawson TM, Dawson VL, Nelson RJ, Snyder SH (1997) Aggressive behavior in male mice lacking the gene for neuronal nitric oxide synthase requires testosterone. Brain Res 769 66-70... 

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. 

Klein PS, Melton DA A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A 93 8455-8459, 1996 Klein RG Is panic disorder associated with childhood separation anxiety disorder ... 

Weiss SRB, Post RM, Sohn E, et al Cross tolerance between carbamazepine and valproate on amygdala-kindled seizures. Epilepsy Res 16 37-44, 1993 Weiss SRB, Clark M, Rosen JB, et al Contingent tolerance to the anticonvulsant effects of carbamazepine relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 20 305-325, 1995 Weissman MM Panic disorder impact on the quality of life. J Clin Psychiatry 52 [suppl) 6-8, 1991... 

In addition to its efficacy as a first-line antidepressant, mirtazapine may have enhanced efficacy due to its dual mechanism of action (Fig. 7—3), especially in combination with other antidepressants that block serotonin and/or norepinephrine reuptake. This will be discussed below in the section on antidepressant combinations. Mirtazapine may also have utility in panic disorder, generalized anxiety disorder, and other anxiety disorders, but has not been intensively studied for these indications. 

Cholecystokinin (CCK) The tetrapeptide CCK causes more panic attacks when infused into patients with panic disorder than it does in normal volunteers, which suggests increased sensitivity of the brain type of CCK receptor, known as CCK-B. Unfortunately, in early investigations CCK-B antagonists did not appear to be effective for panic disorder. Nevertheless, agents with novel pharmacological mechanisms of action are sometimes evaluated for their potential antipanic actions by testing whether they can block CCK-induced panic attacks. 

High-potency benzodiazepines (alprazolam, clonazepam) generally are more effective in panic disorder than low-potency benzodiazepines (diazepam, lorazepam, etc.). Although less research has been done on the low-potency benzodiazepines, it is generally accepted that they frequently result in sedation prior to adequately relieving panic attacks. The reader is referred to the discussion of benzodiazepines in Chapter 8 for a detailed overview of mechanism of action. A critique of the issues of benzodiazepine dependence and appropriate use is given in Chapter 13-... 

Alprazolam (Xanax /Pharmacia), a benzodiazepine derivative is used for the treatment of both anxiety and panic disorder and buspirone (Buspar /Bristol-Myers Squibb) is indicated for the treatment of anxiety disorders. The mechanism of action of buspirone is distinct from that of the benzodiazepines and is believed to be mediated mainly through modulation of serotonergic neurotransmission via its interaction with the 5-HT1A serotonin receptor subtype. 

---