|In This Special Report:|
Anxiety disorders are chronic conditions that follow a relapsing/remitting course.1 The evidence to support this view comes primarily from cross-sectional and retrospective assessments of duration of illness and, in part, from prospective studies. The waxing and waning nature of panic disorder and generalized anxiety disorder (GAD), for example, has been clearly demonstrated. Much less information is available about the course of illness of social phobia. However, both community studies and patient samples suggest an age of onset of social phobia in mid to late teens with a chronicity that is equal to or greater than that of panic disorder.2 Nevertheless, this recognition has not reshaped our basic treatment approach, which focuses almost entirely on the acute control of symptoms and only secondarily acknowledges relapse prevention.
In addition, the natural history of anxiety disorders is frequently complicated by Axis I and Axis II comorbidity that seems to be significantly higher among patients who seek treatment than in persons in the community who are not in treatment.1 In fact, it has been estimated that 73% of patients with panic disorder had other comorbid conditions that ranged from major depression to substance abuse until the onset of the Axis II disorders, mostly cluster C type 1 to 2. It is, therefore, evident that any long-term anxiolytic treatment strategy must take account of these high rates of comorbidity that appear to develop during the longitudinal phase of the anxiety disorder.
A variety of drug classes have been shown to be effective in treating anxiety disorders. SSRIs are the current gold standard for anxiety disorders. Effective in about 50% to 60% of patients, serotonin noradrenalin reuptake inhibitors are now considered the gold standard specifically for panic disorder and GAD. Benzodiazepines have a rapid onset of action, but their long-term use may lead to complications, such as abuse liability, dependence, and withdrawal risk if the dosage is not tapered properly. Moreover, in some patients, benzodiazepines may cause sedative effects and cognitive deficits that significantly affect quality of life and social functioning.
The basis for the use of anticonvulsant drugs in treating anxiety disorders can be found in the main cerebral structures involved in fear circuits. Although numerous brain regions are likely to be involved, the amygdala and the hippocampus play a key role.3 The amygdala is important in experiencing fear and its autonomic and endocrine response through the output to the hypothalamus, while the output to periaqueductal gray matter is mainly implicated in avoidance behavior, which is also typical of fear response.4 In addition, the hippocampus is important in the re-experiencing of fear and the cognitive aspects of fear and anxiety.
The reduction of an excessive output from these neurons may theoretically diminish anxiety symptoms. In fact, anticonvulsant drugs exert their antiseizure activity by decreasing the excessive outbursts from epileptic neurons. Therefore, these drugs could reduce symptoms of anxiety by decreasing neuronal activation within fear circuits. Unlike other drug classes, anticonvulsants are not usually categorized according to their mechanisms of action or chemical structure. This is because their actions are not completely understood at the molecular level, and current knowledge indicates that almost all antiepileptic drugs have more than one mechanism of action (Table 1). Among all known mechanisms, the potentiation of g-aminobutyric acid (GABA)-ergic inhibition and the modulation of voltage-activated calcium channels may be most responsible for the pathophysiology of anxiety.4
GABA is the principal inhibitory neurotransmitter and, along with serotonin and noradrenalin, is one of several neurotransmitters that appear to be involved in the pathogenesis of anxiety.3 Drugs that stimulate GABAA receptors, such as benzodiazepines, have both anxiolytic and antiseizure effects via GABAA mediated reduction of neuronal excitability. The GABAA receptor subtype regulates excitability and rapid changes in fear arousal, such as anxiety, panic, and acute stress response.
However, the sedative hypnotic effect of benzodiazepines is the result of an allosteric-positive modulation of GABAA receptors that contain the alpha-1 subunit. The anxiolytic effect seems to be related to an allosteric modulation of receptors that contain the alpha-2 subunit.5 It is evident that GABA modulation is a determinant for both anxiety and seizures: in fact, GABAA antagonists produce convulsions in animals. A study using positron emission tomography showed that patients with panic disorder have a decrease in GABAA receptor binding.6
Not all classic GABA-ergic anticonvulsants exert helpful psychoactive properties. Although their pharmacological profile suggests anxiolytic properties, barbiturates, vigabatrin, and topiramate may have treatment-emergent psychiatric adverse effects. Agitation and hyperactivity have been described with barbiturates, especially in children, and it is well documented in the neurological literature that both vigabatrin and topiramate are associated with depression and psychoses.7 This may be a consequence of GABA-ergic neurotransmission. The emerging understanding of different roles for phasic or synaptic inhibition and tonic inhibition mediated by different subpopulations of GABAA receptors may lead to targeted compounds for anxiety disorders.
Calcium channel blockers
Calcium channel blockers represent another class of molecules that can be of relevance in anxiety. They have been shown to be of value in ameliorating symptoms in animal models of anxiety.8 In general terms, calcium channels can be categorized according to their biophysical and pharmacological properties in 2 main subfamilies: high-voltage–activated and low-voltage–activated channels. The former are differentiated into different subtypes: l-type (generating a long-lasting current); and N-, P/Q-, and R-types (expressed in nerve terminals and responsible for the calcium entry that triggers neurotransmitter release). On the other hand, low-voltage–activated calcium channels (T-type) generate transient currents, have a somatodendritic localization, and are critical to pacemaker activity and some patterns of burst firing.
Among the different subtypes, it seems that high-voltage calcium channels, in particular the N- and P/Q-types, may represent interesting molecular targets for antianxiety compounds because they regulate neurotransmitter release during synaptic neurotransmission, especially excitatory neurotransmission. The alpha-2-delta is a particular subunit of these channels, and it has been hypothesized that its modulation can be of value in controlling anxiety symptoms.4
In the case of gabapentin and pregabalin, N- and P/Q-type channels represent the main molecular target—in particular the alpha-2-delta subunit, type 1 and type 2. It has been suggested that the binding to this calcium channel subunit causes a channel conformational change, which lowers calcium influx and neuron depolarization and, therefore, firing. It also has been suggested that the expression of the alpha-2-delta subunit differs in different cell types in response to different conditions. For example, in chronic neuropathic pain, alpha-2-delta subunits may be up-regulated, which explains, at least in part, the efficacy of gabapentin and pregabalin in such a condition.5 It remains to be determined whether such plastic changes are also present in anxiety disorders.
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