Serotonin in anxiety

What exactly is an anxiety disorder?

The DSM-IV defines generalized anxiety disorder based on diagnostic categories using signs and symptoms. Thus, generalized anxiety disorder (GAD) has the key component of worry, with associated symptoms of restlessness, fatigue, impaired concentration, irritability, muscle tension, and sleep disturbance. Diagnostic categories that share core symptoms are grouped as disorders. The core symptom in anxiety disorders is the excessive experience of anxiety, which can manifest itself in different forms such as panic, avoidance, intrusive experiences, or patterns of cognition. Anxiety, however, is not unique to anxiety disorders. The majority of patients with major depression experience pathological anxiety as a symptom. Confusion arises as terms like anxiety can encompass different experiences and observed behaviors. Thus nervousness, tension, irritability, agitation, restlessness, worry, and somatization all describe overlapping or equivalent experiences for individuals.

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How Does Anxiety Manifest Itself in the Brain?

Several neurotransmitters mediate the different components of anxiety, including excitatory amino acids such as glutamate, inhibitory amino acids such as gamma-aminobutyric acid (GABA), and monoaminergic neurotransmitters such as catecholamines and indoleamines. Different aspects of the anxiety response are mediated by various neurotransmitters in anatomically distinct areas. Thus, imprinting of emotionally traumatic memories is mediated, in part, by norepinephrine's action through the beta-adrenergic receptors in the amygdala. The development of conditioned fear is mediated by dopamine-1 receptors in the amygdala, leading to facilitation of declarative memory associatons through the hippocampus (Ninan, 1999).

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Serotonin and Anxiety

The neurons located in the dorsal and median raphe nuclei of the brain stem are the primary source of serotonin production in the brain. The serotonergic system has been implicated in the alterations in appetite, energy, sleep, mood, libido, and cognitive functioning seen in anxiety and affective disorders. Additionally, serotonin is important in regulating anxiety as well as impulsiveness in suicidal and other violent acts. The role of serotonin in anxiety is supported by its modulatory effects on the locus coeruleus and its dense projections to the amygdala. Decreased serotonin activity is associated with depression, and the most effective antidepressants have been shown to enhance the functioning of serotonin. Low activity of serotonin may permit the dysregulation of other neurotransmitters, including norepinephrine. These two systems are linked so closely that notable changes in one are reflected in the other; interactions between these systems appear to be reciprocal. The precise nature of the reciprocal interaction can vary, and the activity of norepinephrine at presynaptic serotonergic terminals may lead to a decreased release of serotonin, whereas its activity at postsynaptic adrenoreceptors may lead to an increase in the release of serotonin (Ninan P, 1999).

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What’s the Functional Anatomy of Anxiety?

It is important to consider environmental and physiological anxiogenic stimuli to obtain an understanding of how the placebo effect might alter the serotonergic system. So then, what might cause one to be anxious and what is the functional anatomy of anxiety? Fear might be a good starting point for this discussion, because fear is a normal response to threat. Anxiety may be explained in terms of unwarranted or inappropriate fear. The protective response to threat is an evolutionarily maintained, unconditioned response "hard wired" in the brain. The fear/anxiety response does not have to be learned and includes defensive behaviors, autonomic arousal, hyperalgesia, potentiation of somatic reflexes, and activation of the stress axis through the hypothalamic pituitary-adrenal axis. An amygdala-based neurocircuit has been proposed to mediate the fear and anxiety response. The amygdala is central to registering the emotional significance of stimuli and the development of emotional memories (Johnson et.al., 1995).

Life-threatening challenges result in the permanent imprinting of the experience in the emotional circuits through the amygdala, capturing the full emotional memory of the experience. Associated cues are stored through the declarative memory circuits involving the hippocampus. This allows for associated cues to trigger the emotional memory of trauma, bringing it to conscious awareness (conditioned fear).

The medial prefrontal cortex is reciprocally connected with the amygdala, allowing for self-imposed regulation of affect and modulation of autonomic and neuroendocrine function. This allows for the cognitive control of the anxiety response. New memories with more benign associations can result in the extinction of emotionally traumatic memory. The potential cues for triggering the anxiety response include psychological threat, novelty, social or performance situations, cognitive mechanisms, and conditioned associative memories. Thus, in panic attacks, the fear is of imminent death; in social phobia, the concern is with embarrassment; in PTSD, the emotional memory of the trauma; in OCD, the intrusive obsessional ideas; and in GAD, anxiety, there are not conditioned specific triggers (considered free-floating)(Johnson et. al.,1995).

The large available data base on the physiology and pathophysiology of anxiety has led to the development of several neuroanatomic models of anxiety disorders. One of the most well known models was proposed by Gray, who postulated the presence of several distinct neuroanatomic circuits modulating different aspects of the anxiety reaction. In this model, anticipatory anxiety is proposed to be analogous to the state of behavioral inhibition seen in animals who are presented with a threat. In this state, the animal stops what it is doing and becomes vigilant for any sign of danger. He summarized data from animal studies to conclude that this state is activated in the presence of stimuli associated with punishment or non-reward or in the presence of novel stimuli. The actual experience of punishment or non-reward activates a different system, he called the "fight or flight" system, in which the animal responds with species-specific defensive reactions such as biting, striking, hissing, or attempting escape. This system is proposed to be most similar to the panic reaction. Evidence was presented from animal studies suggesting that the primary anatomic elements of this system include the septohippocampal areas, the locus coeruleus, and the median raphe nucleus. The theory was that the primary function of the septohippocampal formation is to act as a comparator, which assesses stimuli for the presence of danger. This comparator function is continually working at a low level when the organism is not in the presence of threat, but when threat is detected the septohippocampal system will activate the behavioral inhibition circuit, which reciprocally will cause increased monitoring of sensory stimuli for evidence of threat as well as inhibition of ongoing behavioral programs. Activation of the raphe nucleus would, in part, initiate enhanced serotonergic inputs to the hippocampus that allows an increase flow of information through this system (Johnson et. al., 1995).

The hippocampus has the densest concentration of GABA receptors and it is speculated that this may be the site of anxiolytic action for the benzodiazepines in general anxiety states. Anxiolytic drugs that affect the behavioral inhibition system might then act by either reducing the serotonergic inputs into the hippocampal septal formation. This action would have the effect of lowering hippocampal activation.

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How Can Anxiety Be Treated?

GAD has been shown to respond to treatment with benzodiazepines, and there are is some data available that examines the function of this system in patients with this anxiety disorder. Patients with GAD have been found to have abnormally low levels of peripheral lymphocyte benzodiazepine receptors, which normalize after treatment with benzodiazepines. This suggests that GAD might be associated with an abnormal down regulation of benzodiazepine receptors, although the expected decrease in response to benzodiaepines has not been found (Johnson et. al., 1995).

The neurotransmitters of interest are those tied to currently available pharmacologic treatments - benzodiazepines, serotonin-1A agonists such as buspirone, and antidepressant medications affecting norepinephrine and serotonin. The response to pharmacologic treatments and their time course in relieving symptoms through a reverse engineering approach indicate the relevance of these neurotransmitters in anxiety (Cowely, 1991).

The recognition of the anxiolytic potency of barbiturates and subsequently benzodiazepines has led to the benzodiazepine receptor mediated model of anxiety. The benzodiazepines act mainly through the GABA-A receptor subtype by potentiating GABA transmission. GABA is a ubiquitous neurotransmitter, involved in the majority of inhibitory synapses in the brain. Thus, GABA suppresses neural firing, inhibiting or regulating other neurotransmitters including serotonin, norepinephrine, and dopamine. It accomplishes this by decreasing their turnover in limbic areas - the amygdala as well as the locus ceruleus and raphe nuclei (Cowely, 1991). The following is an example of how neurotransmitter control may have an anxiolytic effect:

Benzodiazepines provide powerful and rapid relief from the symptoms of anxiety. High-potency benzodiazepines, in particular, have also demonstrated syndromal benefits in GAD, panic disorder, and social phobia. Most studies have limited their use to durations from several weeks to a few months. However, benzodiazepines are not effective in major depression, which is a relevant issue given the high comorbidity of major depression in all the anxiety disorders. There is some suggestion that benzodiazepines may even potentiate or aggravate depression. The usefulness of the benzodiazepines has been limited by their potential for tolerance, dependence, and psychomotor and cognitive impairment. Patients who are treated for periods longer than two weeks or so may experience a withdrawal syndrome if therapy is discontinued abruptly. This syndrome is characterized by anxiety, dysphoria, depersonalization, hyperacusis, and unsteadiness. The risk of physical dependence increases with higher doses and longer durations of treatment (Ninan, 1999).

Cognitive impairment associated with benzodiazepine therapy may be problamatic in older patients, and it may be magnified when these agents are used in combination with other sedatives, such as alcohol. Buspirone is a partial agonist of the serotonin receptor and the only one in its class available in the United States. It has demonstrated efficacy in GAD, but not in other anxiety disorders, nor does it have a powerful antidepressant effect profile.