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The treatment of anxiety disorders: a brief overview

The treatment of anxiety disorders has evolved considerably in the past 50 years. There was early use of alcohol and barbiturates to treat anxiety, but both were associated with significant problems. The situation changed in the 1950s and 60s, when the benzodiazepines were developed as effective anxiolytics; these agents are still commonly used today. The benzodiazepines work quickly and are generally well tolerated. Their primary disadvantages are initial sedation, ataxia, incoordination, impaired memory, and cognition and, after chronic adminstration, physiological dependence and the potential for withdrawal symptoms upon discontinuation. Some of these adverse effects occur more frequently in older patients. The current faculty has also observed occasional undesirable behavioral disinhibition in pediatric patients and in patients with a comorbid Cluster B Personality Disorder (Antisocial, Borderline, Histrionic, or Narcissistic). People with a history of or propensity for alcohol or drug abuse are at risk for abusing benzodiazepines. Due to their lack of significant antidepressant effects, these drugs are also not optimal for long-term monotherapy treatment of patients with generalized anxiety disorder (GAD) or other anxiety disorders. As a result, there has been a continued search for new anxiolytic agents. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) proved to be effective in the treatment of some anxiety disorders, but enthusiasm for their use is limited by side effects, especially during long term therapy. Over the past several years, the selective serotonin reuptake inhibitors (SSRIs) have become first-line monotherapy for the anxiety disorders, because they are generally better tolerated and have a broader spectrum of efficacy than older agents. Benzodiazepines are now recommended as adjunctive treatment for anxiety disorders, and as monotherapy for those intolerant of or unresponsive to other agents.
Venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), and paroxetine, an SSRI, were recently approved for the treatment of GAD and there is preliminary evidence that, like the SSRIs, the efficacy of venlafaxine may extend to other anxiety disorders.1 These newer agents represent a significant advance, but side effects in some patients, including weight gain, sexual dysfunction, and increases in anxiety upon initiation of treatment remain troublesome. With the currently available agents, the majority of patients with anxiety disorders can be successfully treated. Nevertheless, as many as one-third of patients in controlled studies are unresponsive to any one of these medications.2 Thus, there remains a need for new safe and effective anxiolytic agents.

The role of GABA in psychiatric disorders

The brain's principal inhibitory neurotransmitter, g-amino-butyric acid (GABA), along with serotonin and norepinephrine, is one of several neurotransmitters that appear to be involved in the pathogenesis of anxiety and mood disorders.

There are two principal subtypes of postsynaptic GABA receptor complexes, the GABA-A and GABA-B receptor complexes. Activation of the GABA-B receptor by GABA causes neuronal membrane hyperpolarization and a resultant inhibition of neurotransmitter release. In addition to binding sites for GABA, the GABA-A receptor has binding sites for benzodiazepines, barbiturates, and neurosteroids. GABA-A receptors are coupled to chloride ion channels; activation of the receptor induces increased inward chloride ion flux, resulting in membrane hyperpolarization and neuronal inhibition.3

After release into the synapse, free GABA that does not bind to either the GABA-A or GABA-B receptor complexes can be taken up by neurons and glial cells. Four different membrane transporter proteins, known as GAT-1, GAT-2, GAT-3, and BGT-1, which differ in their distribution in the CNS, are believed to mediate the uptake of synaptic GABA into neurons and glial cells.4

The GABA-A receptor subtype regulates neuronal excitability and rapid changes in fear arousal, such as anxiety, panic, and the acute stress response. Drugs that stimulate GABA-A receptors, such as the benzodiazepines and barbiturates, have anxiolytic and anti-seizure effects via GABA-A-mediated reduction of neuronal excitability, which effectively raises the seizure threshold.3 In support of the anticonvulsant and anxiolytic effects of the GABA-A receptor are findings that GABA-A antagonists produce convulsions in animals5 and the demonstration that there is decreased GABA-A receptor binding in a positron emission tomography (PET) study of patients with panic disorder.6 Low plasma GABA has been reported in some depressed patients and, in fact, may be a useful trait marker for mood disorders.7,8

GABA enhancement in psychiatric treatment: different mechanisms for different patients?

Enhancement of GABA function can theoretically be effected through several mechanisms, including direct receptor agonism (benzodiazepines), inhibition of the extraneuronal enzymatic breakdown of GABA (vigabatrin), modulation of GABA-coupled ion channels (topiramate), and inhibition of the reuptake of synaptic GABA by neurons and glial cells (tiagabine). In a review article by one of the program faculty (Terence Ketter) and colleagues, two categories of anticonvulsant drugs were identified on the basis of their clinical psychotropic profiles.7 These categories provide a theoretical model for the potential usefulness of GABA-enhancing agents in the treatment of anxiety and other neuropsychiatric disorders. Two important mechanisms of anticonvulsant drugs are: (1) enhancement of GABA inhibitory action and (2) attenuation of glutamatergic excitatory action. Drugs that enhance GABA receptor-mediated inhibitory neurotransmission include benzodiazepines, tiagabine, valproate, vigabatrin, and gabapentin; all of these agents have "sedating" clinical profiles. In addition to anxiolytic effects, they can also cause fatigue and impaired cognition. Valproate has known anti-manic properties, while others in this group show promise in this therapeutic area. Agents that attenuate glutamatergic excitatory neurotransmission, such as felbamate or lamotrigine, have "activating" clinical profiles; they tend to improve alertness and, in some patients, may have anxiogenic and possibly antidepressant effects. Table 1 shows the GABAergic and antiglutamatergic actions of several drugs with distinctive GABA-enhancing activity: tiagabine, gabapentin, vigabatrin, and valproate. Ketter et al note that patients with seizure disorders often exhibit a variety of mood and anxiety symptoms. The authors suggested that it may be clinically useful to select a drug with a side effect profile that may actually benefit the patient. For example, a "sedating" GABA-enhancing agent may be better tolerated or even beneficial in a patient who manifests seizure-related symptoms of chronic anxiety.7

The faculty concurred that GABA-enhancing agents have shown early evidence of efficacy in several neuropsychiatric disorders. The benzodiazepines, valproate, carbamazepine, tiagabine, gabapentin and vigabatrin, all have GABAergic mechanisms, and produce anxiolytic effects in preclinical models of anxiety, and varying degrees of clinically relevant anxiolytic effects.7,9-15 Several GABAergic agents (tiagabine, topiramate, valproate, and carbamazepine) have shown evidence of efficacy in post-traumatic stress disorder (PTSD). One of the cardinal features of PTSD is nocturnal awakening associated with vivid and very frightening nightmares. Two of the faculty (EK and TAK) have found that tiagabine normalizes sleep architecture or sleep disturbance in many patients with PTSD and, in addition, reduced arousal, agitation, anxiety, and the frequency of flashbacks.

EK made a clinical distinction between PTSD patients who develop PTSD following a single episode of trauma, such as victims of violent crimes, and those who experience repetitive trauma, such as incest victims or combat veterans. Patients who experience a single traumatic episode appear to respond to SSRIs, while those with repetitive trauma tend not to respond well to SSRIs. The latter patients may benefit from treatment with GABAergic mood stabilizers. GABA-enhancing agents (carbamazepine, valproate, and vigabatrin) have also been shown to have activity in the behavioral despair model of depression16 and, in a recently completed study, valproate also appears to be effective in impulsive-aggressive or agitated patients.17 There are promising preliminary reports of the clinical utility of the GABA-enhancing agents gabapentin and tiagabine in the treatment of anxiety disorders. Gabapentin increases GABA primarily by enhancing release of GABA from glia.7 Although the structure of gabapentin is similar to that of GABA, it does not directly act on GABA receptors.7 Gabapentin has shown promise in neuropathic pain syndromes,18 and anxiety.19-23 It has also demonstrated potential usefulness for the treatment of bipolar disorder,24 and intermittent explosive disorder.25

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