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The essential assumption of the biomedical model is that mental illness is basically a biological disease. In other words, the etiology of the mental disorder can be explained by physical causes, such as infections, genetics, neuroanatomic pathology or malfunctioning biochemistry. Evidence has accumulated, demonstrating that PD may be viewed as a biological disease.
The physical nature of the symptoms of panic attack also provides some reasons for the claim that PA/ PD involves biological modifications. The PA symptoms correspond to a great degree to symptoms of acute activation of the sympathetic branch of the autonomous nervous system, typical for the fight or flight reaction. Indeed, several authors argue that panic attack is, in fact, a fight or flight reaction of the body in absence of a real danger (Rosenhan & Seligman, 1989). When confronted with a real or perceived threat, the automatic "fight or flight" response may be triggered to prepare the body for immediate action. This response is accompanied by peripheral secretion of catecholamines, especially epinephrine and norepinephrine, and glucocorticoids (Carlson, 1992). These hormones increase the availability of the body's energy by glycogenolysis in liver and skeletal muscles thus raising the blood glucose and lactate, lipolysis in adipose tissue, mobilization of free fatty acids, and by increasing temperature. Both epinephrine and norepinephrine also dilate coronary blood vessels. As a consequence, the rate and strength of the heartbeat increases to supply more oxygen to the tissues. While norepinephrine produces vasoconstriction in skin, mucosa, skeletal muscles and most other organs, epinephrine dilates veins in skeletal muscles. These effects result in hypertension and consequently in reflex bradycardia. Other symptoms of a sympatho-adrenergic stimulation involve modifications of breathing, increased temperature, localized sweating, decreased motility and tone of stomach and intestine, constrictions of sphincters in stomach and intestine as well as piloerection. Breathing increases in rate and depth to exchange more oxygen to prepare for exertion. Breathlessness, dizziness, and pain or tightness in the chest may be experienced. Sweat glands are stimulated to prevent overheating. The pupils of the eye dilate to admit more light and increase peripheral vision to scan for danger. Sensitivity to bright light, and visual disturbances may occur. The digestive system shuts down to conserve blood for the muscles. A dry mouth, nausea and constipation may result. Muscles tense to prepare for flight, but may cause spasms and trembling when action is not taken. This complex response was developed through evolution in many organisms and normally serves for survival and protection. As mentioned above, symptoms of sympathetic activation and symptoms of panic attack share many common symptoms. Therefore, panic attack may be viewed as an emergency response which occurs in a situation where it is not appropriate (Barlow & Craske, 1994).
Clinically, a marked decrease of panic has been observed during pregnancy and lactation, with postlactational exacerbation of symptoms. These changes most likely reflect increased levels of progesterone, estrogen and oxytocin during pregnancy or lactation (Klein, 1993). The fact that the condition of PD patients improves during this time is a strong argument for the biological view of PD. As Klein points out, pregnancy and childbirth present an increased vulnerability, marked by heightened threatening endogenous stimuli. According to cognitive theories, which postulate that PA result from catastrophic interpretation of physiological changes, such states should make patients more prone to panic. Apparently this is not the case (Klein, 1994).
These procedures are a valuable tool for the experimental evaluation of neurochemical correlates of panic attack symptoms. They are capable of inducing experience that is phenomenologically similar to spontaneous panic attacks, as pointed out by panic patients. Therefore, a phenomenon which can be reproduced by pharmacological means must have biological bases.
The limbic system, especially the amygdala, has long been considered to be directly implicated in anxiety and other emotions. Amygdala receives projections from frontal cortex, association cortex, temporal lobe, olfactory system and other parts of the limbic system. It sends its afferents to frontal and prefrontal cortex, orbitofrontal cortex, hypothalamus, hippocampus as well as brain stem nuclei, such as locus ceruleus and raphé nucleus. Amygdala and its central nucleus thus communicate with many brain regions, including those that control breathing, motor function, autonomic response, release of hormones as well as processing of interoceptive and external information (Carlson, 1992). Amygdala is thus in a good position to modulate autonomic responses related to anxiety and panic because of its connections with the brain stem and the reticular formation, both of which control vegetative functions.
Indeed, numerous studies have demonstrated an implication of limbic system, and amygdala in particular, in PD. Halgren et al. (1978) electrically stimulated the amygdala and hippocampus in humans which resulted in somatic and emotional symptoms of panic attack. In animals, Iwata et al. (1987) observed increases in heart rate and blood pressure, symptoms of sympathetic activation that are also present during a panic attack, after injections of excitatory amino acids into central nucleus of amygdala. Microinjections of benzodiazepines into amygdala had "anti-conflict" properties that are correlated with anxiolytic effects in humans (Hodges et al., 1987; Kuhar, 1986). In addition to this, microinjections of CCK8 (both sulfated and non-sulfated) into the amygdaloid nucleus produce fear-motivated behavior in rats, such as facilitation of extinction of active avoidance behavior and retention of passive avoidance (Fekete et al., 1984).
Locus ceruleus is a particularly important region related to anxiety. This region is a metencephalic nucleus located in the caudal pontine central grey. It contains 50% of all brain noradrenergic neurons and is composed almost exclusively of 12 000 noradrenergic neurons on each side of brain. It also produces a major portion of norepinephrine in the central nervous system. Collateral branches of axons of noradrenergic neurons project to most regions of the brain. Of those numerous projections, there are many that have been associated with panic disorder or panic attacks: with the limbic system, especially the amygdala, hippocampus, septum, and cingulate cortex, all cortices, brain stem, reticular formation, cerebellum and spinal cord (Cooper et al., 1991).
Evidence from lesion, electrical and chemical stimulation, and single-unit recording studies suggests that locus ceruleus seems to be implicated in the sleep-wake cycle, arousal, anxiety and fear (Redmond & Huang, 1979; Redmond et al., 1976). In addition, most agents that alleviate anxiety (benzodiazepines, alcohol, opiates, barbiturates) act also to lower the activity of locus ceruleus (Nybäck et al., 1975; Geyer & Lee, 1984; Huang, 1979). Locus ceruleus also contains benzodiazepine receptors, as well as receptors for endogenous opiates. During syndrome of withdrawal from benzodiazepines, opiates and alcohol, anxiety increases as does the activity of locus ceruleus, both lasting as long as the withdrawal symptoms persist.
Other important brain regions appear to be implicated in modulation of anxiety. Hypothalamus, pituitary gland, especially anterior pituitary gland are involved in synthesis and release of numerous stress-related hormones. Numerous brain stem regions, namely pons, medulla oblongata, cerebellum, reticular formation, periaqueductal gray matter, are also involved, especially in functions such as perception of somatic and sensory stimuli, fear-related reflexes, arousal, and neuro-vegetative functions. Cerebral cortex is implicated in anxiety control and development in terms of storage of memory, cognitive processes and control of motor movement (Carlson, 1992; Taylor & Arnow, 1988).
Studies with twins who grew up together can also provide us with a useful piece of information. In Slater and Shields' study (1969), monozygotic twins had concordance rate of 41% for anxiety states, whereas the concordance among dizygotic was only 4%. Torgersen (1983, 1990) investigated concordance rates for anxiety disorders with panic attacks and found that 31% of the monozygotic twins had a similar diagnosis compared to 0% of the dizygotic twins. When he narrowed down the comparison to PD with agoraphobia, the concordance rate between monozygotic twins was 15%. Even though the differences in concordance rates might appear important, they might be misleading. First of all, the number of subjects was small, such that, for example, the concordance rate of 31% in monozygotic twins was based on 4 out of 13 pairs of twins, which is obviously not enough to generalize. Secondly, the higher concordance in monozygotic twins could be potentially explained by other non-genetic factors. For instance, monozygotic twins may be treated differently by their parents, extended families and peers. They might have more profound identity crisis than the one that teenagers usually go through. Often they are dealt with as an entity rather than two separate individuals. In addition to this, they might tend to develop mutual dependency and have more experiences of separation anxiety, a state that seems to be related to agoraphobia and panic disorder.
One of the most intriguing hypotheses postulates an abnormality of the noradrenergic and adrenergic systems. Increased plasmatic and urinary concentrations of epinephrine (EPI) and norepinephrine (NE) in panic disorder patients have been shown in some but not all studies (Braune et al., 1994; Butler et al., 1992; Villacres et al., 1987; Nesse et al., 1985a; Appleby et al., 1981; Wyatt et al., 1971; Cameron et al., 1984). In addition, augmentations of plasma 3-methoxy-4-hydroxyphenylethylene (MHPG), a metabolite of NE, have been documented in patients with frequent and severe panic attacks (Charney et al., 1984b). Panic patients confronted with anxiogenic situations have increased plasma free MHPG and NE levels (Braune et al., 1994; Ko et al., 1983; Uhde et al., 1982; Nesse et al., 1985b). Stimulation of the noradrenergic system by alpha2-adrenoceptor antagonist yohimbine and beta-adrenoceptor agonist isoproterenol produces panic-like symptoms in PD patients and some healthy subjects (Charney et al., 1987; Charney et al., 1990; Pohl et al., 1990). Pathological changes in the alpha or/and beta-receptors have been demonstrated (Charney & Heninger, 1986; Rainey et al., 1984; Nesse et al., 1984; Pohl et al., 1985).
Another plausible hypothesis concerns serotonergic system, especially in terms of interaction with noradrenergic system (Zacharko et al., 1995). Raphé nucleus, a midbrain structure with high concentration of serotonergic neurons, projects to locus ceruleus, and has an inhibitory influence on the activity of noradrenergic neurons (Meltzer, 1987). Pharmacological agents that decrease serotonergic activity have anxiolytic effect in animals (Briley et al., 1990). Serotonin and its metabolite 5-HIAA are reduced in anxious dogs (Guttmacher et al., 1983). In humans, alleviation of symptoms is achieved by administration of selective serotonin reuptake inhibitors. Murphy & Pigott (1990) have presented evidence suggesting that the anxiolytic effects of benzodiazepines might also be related to serotonergic activity. In addition to it, panic disorder patients reported an exacerbation of symptoms when they received serotonin precursors tryptophan and 5-HTP, serotonin receptors' agonist m-chlorophenylpiperazine and flenfluramine, a drug that increases the synaptic availability of serotonin (Murphy & Pigott, 1990, Den Boer & Westenberg, 1990, Targum, 1990, Kahn & Van Praag, 1988). It is thus possible that an altered serotonergic transmission is one of the elements that are implicated in anxiety and panic.
Another major hypothesis for PD etiology involves benzodiazepine receptors and their natural ligands. The anxiolytic action of benzodiazepines is mediated through benzodiazepine receptor complex, potentiating the inhibitory effects of GABA (Lima, 1991; Paul & Skolnick, 1981; Skolnick & Paul, 1982). Sensitivity of central and peripheral benzodiazepine receptors have been shown to be modified by aversive life events and social variables (Trullas & Skolnick, 1993). Studies have demonstrated that animals with low exploratory behavior (anxious) have lower density of brain benzodiazepine receptors (Rago et al., 1991). Also, stimulation of benzodiazepine receptors by their inverse agonists, beta-carbolines, produces anxiety and panic-like symptoms in PD patients and healthy subjects (Zacharko et al., 1995).
Adenosine system also appears to be implicated in PD. Numerous studies have demonstrated that PD patients are hypersensitive to the effects of caffeine, adenosine antagonist, and often spontaneously reduce intake. In large doses, caffeine can produce panic-like symptoms in PD patients and healthy subjects, especially those with low regular consumption of caffeine (Boulenger et al., 1984; Uhde, 1990). Caffein-induced panic is typically accompanied by increases in plasma lactate, glucose and cortisol (Orlikov & Ryuzov, 1991).
Other neurotransmitters and neuromodulators appear to be implicated in PD. For example, dopamine-containing mesocorticolimbic system appears to be implicated in anticipation, conditioning and motivation, and contains neurons with high concentrations of various neuropeptides, including those associated with arousal (enkephalines), anxiogenesis (beta-carbolines) and anxiolysis (Zacharko et al., 1995). Most or some central dopaminergic systems respond to MAO inhibitors, stress and anxiogenic beta-carbolines (Cooper et al., 1991). Recently, numerous neuropeptides have been linked to mediation and control of anxiety. Cholecystokinin peptides, neuropeptide Y, beta-carbolines, enkephalines, substance P, corticotropin releasing factor might have modulatory effects on panic and anxiety, to name just a few. (Zacharko et al., 1995)