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Panic attack

Terminology of psychiatry

This entry is made by Compilation and application of scientific encyclopedia entries of "Science Popularization China" to examine.

Panic attack It is a sudden panic experience. The onset of symptoms is often the manifestation of the patient's self perception. In some cases, the patient suddenly feels frightened, out of control, crazy, collapsed, as if death is coming, panicked, crying for help everywhere, accompanied by severe autonomic dysfunction, which starts and ends quickly, The symptoms will last for several minutes or tens of minutes, and the onset is self limited.

Chinese name: Panic attack
Foreign name: panicdisorder
Department: Psychiatry Department

Clinical: mental disease
Features: Autonomic symptoms accompanied by a sense of near death or loss of control
Treatment: Drug psychology and others

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definition

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pathogeny

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This disease is one of the most active fields in modern research, which can be summarized as follows:

First aspect

Panic disorder

Genetics Crowe et al. (1983), Harris et al. (1983), Crow et al. (1983) found that the incidence rate of this disease in the first degree relatives of panic disorder probands was 24.7% 20% and 17.3% respectively; The incidence rate of the first degree relatives in the normal control group was 2.3%, 4.8% and 1.8%; It shows that the disease has Family aggregation Torgersen (1983) reported a twin study, in which the comorbidity rate of MZ was 5 times higher than that of DZ; However, the co morbidity rate of MZ is only 31%, suggesting that non genetic factors play an important role in the occurrence of this disease.

Second aspect

Biochemistry has conducted various studies, which are described as follows:

⑴ Lactate: Cohen White (1950) first reported that the blood lactate content of patients with "nervous circulatory weakness" similar to anxiety disorder was higher than that of normal control group during moderate exercise Pitts and McClure (1967) It is believed that the increase of lactate content in blood may be related to anxiety attack, which is the result of intravenous infusion of 0.5mol of sodium lactate 10ml/kg to 14 anxiety patients and 16 normal people in a double-blind condition within 20 minutes. find Panic disorder 13 of the patients appeared during the infusion Panic attack Only 2 patients in the normal control group had similar symptoms. The mechanism of this phenomenon is not yet fully understood, and the possible explanation is that it caused metabolic alkalosis Hypocalcemia , abnormal aerobic metabolism, β- adrenaline Hyperactivity peripheral catecholamine Over release Central chemoreceptor Another explanation for the increased sensitivity is that lactic acid is metabolized to carbonic acid in the body, and then hydrolyzed to CO2 and water; CO2 changes the redox status of the medulla in the ventral part of the brain stem through the blood-brain barrier or leads to the firing of noradrenergic neurons in the locus coeruleus nucleus, which increases the positron emission tomography brain scan and regional cerebral blood flow, The increase of blood flow and oxygen metabolism rate in the right parahippocampal gyrus reflects the increase of activity in this region (Reiman et al., 1986).

⑵ CO2: Gorman et al. On the other hand, it shows that the brain stem Chemoreceptor It may be overly sensitive to CO2, which may increase the impulse emission of locus coeruleus.

⑶ Neurotransmitters: modern neurobiological research on anxiety focuses on Norepinephrine Energy, dopaminergic 5-hydroxytryptamine Can and γ - aminobutyric acid The adrenergic system of the four neurotransmitter systems, especially the locus coeruleus, plays an alert role, which can cause vigilance against danger. The dopamine system of the cerebral cortex in the anticipation mood is related to emotional behavior and expression. The 5-hydroxytryptamine system, especially the dorsal raphe nuclear energy, inhibits the adaptive behavior unique to anxiety; Central serotonin activity plays an important role in keeping alert and controlling anxiety. γ - aminobutyric acid is the main inhibitory neurotransmitter. These four neurotransmitter systems interact in different parts of the brain and at different levels. This complex signal interaction between cells is integrated at the subcellular level with the help of the second messenger, cAMP and Ca2+, which causes different changes in various parts of the brain and body to form various clinical manifestations of anxiety.

The locus coeruleus contains the entire central nervous system More than 50% Noradrenergic neurons There are nerve fibers projecting to the amygdaloid nucleus, marginal lobe and frontal lobe cortex of the hippocampus. It is found that electrical stimulation of locus coeruleus can cause obvious fear and anxiety responses in animals; At the same time, there is an increase in nerve impulse of locus coeruleus and central Norepinephrine Update acceleration. Drugs that can increase the distribution of locus coeruleus in humans, such as yohimbine, can stimulate anxiety, and drugs that can reduce the distribution of locus coeruleus, such as clonidine Propranolol (propranolol) benzodiazepine morphine, endorphin, tricyclic antidepressants, etc. have anti anxiety effects, indicating that locus coeruleus and noradrenergic system have an important impact on the onset of anxiety 5-hydroxytryptamine The recovered inhibitors have achieved good results in the treatment of panic disorder, indicating that the 5-hydroxytryptaminergic system plays a role in panic disorder.

⑷ Receptor: palpitations, tremors, sweating and other symptoms in patients with panic attacks are all β -- adrenaline can

Panic disorder

Signs of a large number of receptor excitations Some clinical observations found that β- Adrenergic receptor Blockers such as Propranolol , has the effect of reducing panic attacks and anxiety; However, these drugs cannot prevent spontaneous and sodium lactate induced panic attacks. Therefore, the role of β - adrenergic receptor in the pathogenesis of anxiety needs further research to clarify. Mohler and Okada (1977) Squires and Braestrup (1977) successively found benzodiazepine receptors in mammalian brain. This receptor and inhibitory neurotransmitter γ aminobutyric acid (GABA) receptors are adjacent to GABA, and there are two kinds of receptors: GABAA receptors and chloride ion (Cl -) channels couple GABAA receptors and GABA interact, which causes the Cl channel connected to them to open GABAB receptors may be coupled with calcium ion (Ca2+) and cAMP to help regulate the release of other neurotransmitters. Benzenediazepines and their receptors can promote the function of GABA and significantly slow down nerve conduction; However, blocking benzodiazepine receptors with drugs can cause acute anxiety symptoms in experimental animals. Therefore, some people speculate that anxiety patients may produce some substances that interfere with the function of benzodiazepine receptors, leading to anxiety symptoms.

Third aspect

Neuroanatomy German et al. (1989) provided the neuroanatomical hypothesis of panic disorder based on Klein's phenomenological model. Klein summarized three characteristics of panic disorder:

(1) Acute panic attack: because the patient has a significant autonomic nervous symptom outbreak during panic attack, and such attacks can be triggered by drugs acting on the brain stem, such as sodium lactate, CO2, yohimbine, etc., German and others believe that the brain stem, especially locus coeruleus, is closely related to acute panic attacks.

⑵ Anticipatory anxiety: The limbic lobe is the central animal experiment of human anger, vigilance, fear and other basic emotions, and the provocative lesions of the limbic structure can cause fear and panic reactions. Penciled also observed the same phenomenon in humans. Destructive lesions in this part can reduce anxiety. The marginal region of the human brain contains abundant benzodiazepine receptors. Intravenous injection of benzodiazepines is very effective in reducing expected anxiety, but the effect on controlling panic attacks is poor. These evidences suggest that expected anxiety may be related to the functional damage of the marginal lobe.

⑶ Terrorist avoidance: this is a learned behavior related to cognitive and conscious activities of the cerebral cortex. The nerve fibers from the frontal cortex to the brain stem can transfer the learned connections and cognitive activities originating from the prefrontal cortex to the brain stem, stimulate the neural nuclei of the brain stem, and cause panic attacks. Some anti panic attack drugs are effective in controlling panic attacks and expected anxiety, but their effects on terrorist avoidance are often inferior Cognitive behavioral therapy 。

Fourth aspect

The data of physiological EEG study showed that the α rhythm of anxiety patients was less than that of non anxiety patients, and the α activity was more in the higher frequency range; It indicates that anxiety patients are often in a high alert state. Hon Saric et al; However, the skin resistance response of the control group has a large change, which suggests that patients with frequent panic attacks have increased vascular alertness and decreased flexibility of skin resistance.

Fifth aspect

Psychoanalytic theory believes that neurotic anxiety is a reaction to an unrecognized danger. This danger is not recognized by patients due to the neurotic defense mechanism, and sometimes it is only symbolic. Neurotic anxiety Pan (1924) emphasized that birth injury was the source of all kinds of anxiety. Klein (1948) believed that anxiety originated from death instinct and was a reaction to hostility and aggression.

behaviorist theory It is believed that anxiety is a conditioned reflex formed by fear of certain environmental stimuli. Take the animal experiment as an example: if an animal presses the pedal to cause an electric shock, pressing the pedal will become a conditional stimulus before the electric shock. This conditional stimulus can cause the animal to produce a conditioned reflex of anxiety. This conditioned reflex led the experimental animals to avoid touching the pedal and avoid electric shock; The success of avoiding electric shock, an unconditional stimulus, strengthens the avoidance behavior of animals and reduces their anxiety level. This animal model can show that anxiety attacks are conditional responses to terrible situations obtained through learning.

Pathogenesis

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Neurobiology

Hypothesis German and other scholars put forward a neurobiological hypothesis about panic attacks and tried to

Panic disorder

Explain why drug therapy and cognitive behavioral psychotherapy are both effective treatments. It is believed that the stimulus response of animals to conditioned fear and the panic attack response of patients show surprising similarities between the physiological and behavioral consequences. That is, in animals, these reactions are transmitted by the "fear network" in the brain, which is centered on the amygdala and involves the interaction between the hypothalamus and the medial prefrontal cortex. The projections from the amygdala to the hypothalamus and brain stem explain many explicit signs of the conditioned fear response. Patients with panic attacks also have similar neural networks. One of the evidences is that genetic factors and stressful life events are related to the occurrence of panic disorder. Especially in early youth, antidepressants (especially drugs that affect the 5-HT system) can desensitize the projection network from the amygdala to the hypothalamus and brain stem, Effective psychosocial treatment can also reduce the fear and cognitive distortion related to the left prefrontal cortex and hypothalamus. Neuroimaging research will help to verify whether these hypotheses are correct.

Animal experiments have clarified that the brainstem pathway for acquiring conditioned fear and related neurotransmitters, namely the sensory input of conditioned stimuli, reach the lateral nucleus of the amygdala through the anterior part of the thalamus, and then pass to the central nucleus of the amygdala. The central nucleus of the amygdala is an information distribution center, which dominates autonomous and behavioral responses. The output of the central nucleus of the amygdala has many destinations: the parabrachial nucleus, which can accelerate the respiratory rate; Lateral hypothalamic nucleus, which can be activated Sympathetic nervous system And the discharge of autonomic arousal and sympathetic nerve; The locus coeruleus can lead to the increase of norepinephrine release and the increase of fear reaction of blood pressure, heart rate and behavior; And the hypothalamic paraventricular nucleus can cause Adrenocortical hormone Increase of release. In addition, there is an important correlation between the amygdala and the insula of the prefrontal cortex of the sensory thalamus, as well as the primary somatosensory cortex. Patients with panic attacks may have a neurocognitive deficit in these cortical processing pathways, which can lead to misinterpretation of sensory information. Through the misleading excitatory input to the amygdala, the "fear network" is improperly activated to produce related behaviors and autonomic nerves Neuroendocrine For example, during panic attacks, the heart rate and respiration of patients increased. Although patients with panic disorder showed more anxiety, panic and faster respiratory rate than normal volunteers or patients with other mental disorders, the most sensitive physiological indicator to inhale CO2 - ventilation change per minute/tidal concentration of terminal CO2 tended to have the opposite result. Although some scholars found evidence of high sensitivity of panic disorder patients to CO2, others also found that they were in the normal range in this measurement, and the cortisol level of panic disorder patients would increase only when the expected panic attack occurred. In short, there was evidence that some panic attacks were accompanied by autonomous and neuroendocrine activation.

The mechanism of selective 5-HT reuptake inhibitor (SSRI) drugs in panic disorder is related to the three transmission pathways of 5-HT norepinephrine: ① The projection of 5-HT neurons to the locus coeruleus is generally inhibited. For example, the greater the activity of 5-HT neurons in the raphe nucleus, the smaller the norepinephrine neurons in the locus coeruleus. Coplan believes that after 12 weeks of fluoxetine treatment, the level of 3-methoxy-4-hydroxyphenyleneglycol, the main metabolite of norepinephrine in plasma of panic disorder patients, decreases, which suggests that SSRI has the secondary effect of reducing norepinephrine activity by increasing the activity of 5-HT in the brain, which will lead to the relief of many cardiovascular symptoms related to panic attacks, including Tachycardia The projection from the raphe nucleus to the periaqueductal gray area can modify the defensive/escape behavior. Viana and colleagues found that stimulation of the dorsal raphe nucleus could dramatically increase the acute release of 5-HT in the dorsal area of the periaqueductal gray matter, which would lead to the elimination of activity in the periaqueductal gray matter area. This finding supports Deakin and Graeff's original hypothesis, That is to say, the projection of 5-HT from the dorsal raphe nucleus has the function of modifying the defense against escape reaction through the inhibitory effect on the periaqueductal gray matter. ③ Long term use of SSRI can reduce hypothalamic release Corticotropin releasing factor The level of CRF can promote the cascade reaction of events, thus leading to the production of cortisol, which is also a kind of adrenal cortical product central nervous system In many cases of preclinical models, the neurotransmitter of CRF has the effect of increasing fear. When directly applied to the brain, CRF will also increase the excitation rate of locus coeruleus. CRF antagonists reduce the physiological and behavioral consequences caused by CRF and stimulation. In fact, CRF antagonists are used in animals and Human body test Chinese medicine has been used as an anti anxiety drug.

genetics

Hypothesis A large number of studies suggest that rodents have more characteristic genetic loci on chromosomes

Panic disorder

Emotion is related to the formation of fear conditions. For example, Flint found that three loci on mouse chromosomes 1, 12 and 15 were associated with decreased activity and increased stool in a novel environment. They concluded that these loci are related to the increased "amorous" and speculated that there are convincing reasons for people to expect that the genetic basis of amorous is similar in other species, and it may be based on the psychological characteristics of human anxiety susceptibility.

A large number of studies have shown that if a first-degree relative has panic disorder, the probability of panic disorder is actually higher than the basic prevalence rate in the population. At least three studies have examined the consistency of panic disorder among twins, It is found that MZ has a higher prevalence consistency rate than DZ, which especially suggests that panic attacks have a higher prevalence consistency rate than the syndrome itself. However, no MZ panic disorder has a prevalence consistency rate close to 50% (ranging from 14% to 31%), which means that if genes are related to panic disorder, it is not the whole problem. 3. The environmental hypothesis of panic disorder has been suggested that the early breakdown of parental attachment is related to the subsequent formation of panic disorder. For example, the application of data from epidemiological research Tweed reports the diagnosis of panic disorder claustrophobia The probability of mother's death before the age of 10 is almost seven times that of adults without early family death history. The number of adults who separated from their parents or lived apart before the age of 10 is almost four times that of adults without early parental separation history. Stein found that parents with panic disorder reported more childhood sexual and physical abuse than healthy control group. The breakdown of emotional attachment between childhood and caregivers may be a risk factor for panic disorder. This view is consistent with the phenomenon that parents with panic disorder are clinically observed to be unusually sensitive to perceived, threatened or actual separation. In fact, panic patients are much less likely to have panic attacks when they have trusted companions around. A study shows that the presence of companions during CO2 inhalation can reduce the possibility of panic attacks.

There is evidence that patients with panic disorder who experience traumatic events or negative life events in childhood and adulthood are more sensitive to traumatic effects than barrier free individuals, especially events involving separation and attachment breakdown. Consistent with this pattern, recent traumatic stress can play a role in triggering panic attacks. This abnormality can take several forms, including increased or blocked nervous autonomic activity to properly interpret fear network signals and/or prevent cortical appropriate feedback that restricts anxiety and panic responses. Therefore, the interaction between life event stress and genetic susceptibility is the root cause of adult panic disorder.

Typical performance

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1. The typical manifestation of panic attack is that the patient is engaged in daily activities, such as reading, eating,

Panic disorder

When walking, meeting, or doing housework, I suddenly feel palpitations, as if my heart is going to jump out of my mouth; Chest tightness, chest pain, chest compression; or dyspnea The throat is blocked, as if suffocating. At the same time, there is a strong sense of fear, as if he will die or lose his reason. This nervousness makes the patient unbearable. So they cried out for help. Some people have hyperventilation, dizziness, unreality, sweating Facial flushing Or pale, unsteady gait, tremor Numbness of hands and feet , gastrointestinal discomfort and other symptoms of autonomic nervous overexcitement, as well as motor restlessness. The duration of this attack is very short, usually 5-20 minutes, rarely more than an hour. Symptoms can be relieved by themselves, or the attack can end with yawning, urination, and falling asleep.

2. Anticipatory anxiety Most patients often worry about the recurrence of panic attacks in the interval after repeated panic attacks, so they are nervous. They may also have some symptoms of hyperactivity of autonomic nervous system, fearing that they will not get help when they get sick.

3. When help seeking and avoidance behavior panic attacks, due to strong fear, patients can't bear it and often immediately request emergency help. During the interval between attacks, 60% of patients, fearing that they would not get help when they got sick, actively avoided some activities, such as not going out alone, not going to crowded places, not traveling by car, etc., or asking others to accompany them when they went out; Immediate secondary Agoraphobia 。

clinical manifestation

Panic disorder refers to repeated, sometimes unpredictable attacks of anxiety or panic that suddenly occur, causing extreme pain and lasting for a few minutes or more. Some attacks in panic disorder are not limited to specific predictable situations. After a panic attack, you will continue to worry about another attack.

symptom

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1. The typical manifestation of panic attack is that the patient is engaged in daily activities, such as reading, eating, walking, and meeting

Panic disorder

Or suddenly feel short of breath, dizziness or mild headache, syncope, tremor or tremor when doing housework, unreal feeling, dry mouth, difficulty in concentrating or talking, blurred vision, chest tightness, chest pain, chest compression or pain, or dyspnea, throat blockage, as if suffocation is imminent, heart palpitations, heart beats, as if the heart is about to jump out of the mouth; Hand numbness, foot numbness, suffocation, sweating, hot flashes or chills, eager to escape nausea, muscle tension, fear of death to lose control or go crazy. At the same time, there is a strong sense of fear, as if he is about to die or lose his reason. This nervousness makes the patient unbearable. As a result, some people cry for help, and some of them have hyperventilation, dizziness, unreality, sweating Facial flushing Or pale gait instability, tremor, numbness of hands and feet, gastrointestinal discomfort and other autonomic hyperexcitability symptoms, as well as motor restlessness. In panic attacks, patients generally try to avoid the situation of a special function to expect panic stop, or seek help to prevent collapse, heart attack or madness. This kind of attack is sudden, with clear consciousness at the time of attack. It lasts for a short time, usually 5~20min (peak within 10min), and rarely more than 1h, it can relieve itself; Or to yawn, urinate and fall asleep and end the mental state between attacks. After the attack, the patient realizes that everything is normal, and can recall the process of the attack, but it can suddenly recur soon. The patient can have frequent attacks for more than three times in a month. 2. Anticipatory anxiety. Most patients often worry about reoccurrence of panic attacks in the interval after repeated panic attacks, so nervousness can also cause some symptoms of hyperactivity of autonomic nervous system, called Anticipatory anxiety It can last for more than one month. Attention should be paid to distinguish it from generalized anxiety.

3. Help seeking and avoidance behavior When panic attacks occur, patients can't bear the strong sense of fear. They often immediately ask for emergency help. During the interval between attacks, 60% of patients, because they are afraid of not getting help when they get sick, take the initiative to avoid some activities, such as not going out alone, not going to crowded places, not traveling by car, or asking others to accompany them when they go out; Immediate secondary Agoraphobia Panic attacks sometimes (but not always) lead to fearful avoidance of squares in certain situations, in which it is difficult or embarrassing to avoid, or feel unable to get help from others immediately. Therefore, it can be divided into two types: panic disorder with agoraphobia and panic disorder without agoraphobia. Occasional panic attacks (that is, the frequency of panic attacks is not enough to make a diagnosis of panic disorder) can also occur in other mental disorders, especially in other mental disorders Anxiety disorder Medium.

complication

The increase of suicidal tendency in patients with panic disorder often accompanied by depressive symptoms should be paid attention to clinically.

diagnosis

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This disease often has no obvious inducement. Sudden onset has a variety of autonomic nervous symptoms, especially palpitations, tightness of breath, dizziness and sweating; In a short period of time, the symptoms develop rapidly and reach the peak with strong fear; It can relieve itself after a short duration. In addition to the expected anxiety and fear of reoccurrence, there can be no discomfort. The recurrence interval can be long or short. Frequent attacks and anticipation anxiety are easily misdiagnosed as extensive Anxiety disorder Many cases secondary Agoraphobia DSM-IV classifies the disease into panic disorder accompanied by Square horror And panic disorder without agoraphobia with severe depression should be diagnosed separately.

According to the diagnostic criteria of ICD-10, the diagnosis basis of panic attacks is that there are at least three attacks within one month, and each attack does not exceed 2h. The interval between two attacks that significantly affect daily activities has no obvious symptoms except fear of reoccurrence. It has the following characteristics:

1. There is no real danger in the attack situation.

2. Not limited to known or predictable situations (see specific phobia or social phobia).

3. There is almost no anxiety symptoms during the interval between panic attacks (although they often worry about the next panic attack).

4. It is not the result of physical diseases (such as hyperthyroidism) or substance abuse due to physiological fatigue.

main points

The visitor has at least one panic attack and continues to worry about the recurrence or consequences, or the attack leads to obvious behavior change, which lasts at least one month

Judge whether it is accompanied Square horror

Exclude panic attacks caused by substance use and physical diseases

Exclude Others Psychological disorders Secondary panic attack

identify

Panic attack, as a group of syndromes, can be seen in a variety of mental diseases and somatic diseases. The diagnosis of panic disorder can be made only after the exclusion of such diseases. The mental diseases that need to be differentiated include extensive anxiety disorder and Depressive disorder In addition, pay attention to Schizophrenia , depersonalization disorder, somatoform disorder and other medical diseases need to be identified: Hyperthyroidism , hyperparathyroidism, arrhythmia, coronary insufficiency, pheochromocytoma hypoglycemia, true vertigo, drug withdrawal and alcohol withdrawal symptoms are particularly confusing Mitral valve prolapse Mitral valve prolapse is also a sudden occurrence of palpitations, chest pain, as well as tightness, fatigue and even syncope, but there is no dizziness, sweating, tremor, facial fever or chills, and depersonalization, near death or loss of control Echocardiography It can be identified, but there are research reports, and the two may be combined; It is believed that panic disorder may lead to mitral valve prolapse. If panic disorder is controlled, mitral valve prolapse may disappear (German et al. 1981).

When diagnosing this disease, routine medical evaluation should be made first to exclude whether it is anxiety symptoms caused by somatic diseases (such as heart disease and hyperthyroidism). Patients with panic disorder have already seen a physician first, and are basically excluded Organic disease The possibility of. Table 1 briefly lists the differentiation between panic attacks and heart attacks.

Panic attacks may occur in other phobias, such as social phobia (when talking to a group of people) or specific phobias (such as when seeing spiders). Panic attacks in these phobias can be predicted, and can not be diagnosed only in specific stimuli or situations, Only unpredictable panic attacks can make a diagnosis of panic disorder.

stay Depressive disorder Repeated panic attacks may also occur during the course of the disease and fear of reoccurrence. In some patients, depression can be secondary to panic disorder (that is, the experience of panic disorder makes patients become depressed). It is important to remember that panic attacks are relatively short. Patients who describe themselves as "panicking all day long" are in a very anxious mood rather than panic attacks in clinical manifestations. [1]

inspect

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laboratory

There is no specific laboratory test index for this disease

Other auxiliary

The alpha rhythm of electroencephalogram in anxiety patients decreased and alpha activity was mostly in the higher frequency range; It indicates that anxiety patients are often in a high alert state.

treatment

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The aim is to control panic attacks as soon as possible to prevent recurrence and square terror.

1. When dealing with the first panic attack, early treatment should explain to the patient that the somatic symptoms caused by anxiety seem terrible, but actually harmless, and explain the patient's "fear of losing self-control or dying" The idea is that cognitive impairment caused by anxiety will make anxiety enter a vicious circle to prevent the further formation of panic disorder. Patients should be told the importance of avoidance behavior. Avoiding places where panic disorder occurs will lead to square fear

2. The following drugs can be selected for drug treatment:

⑴ Tricyclic antidepressants: some antidepressants have the effect of anti panic attack when used in large doses. Therefore, it is often used as a first-line drug. The daily dose of imipramine is 50~300mg. It can be started from a small dose of 10mg or 25mg. Gradually, the daily dose of most patients is at least 150mg. Clomipramine （ Chlorpromazine ）(25-200mg/d) can also be used. Those who cannot tolerate anticholinergic side effects can use desipramine (dememipramine) instead; Nortriptyline can be selected for the elderly who are prone to hypotension amitriptyline It is similar to benzodiazepines in reducing panic attacks, and rarely causes dependence and withdrawal reactions. However, the drug has a slow onset and many adverse reactions, and the initial effect of amitriptyline on panic disorder is to improve the level of arousal, including anxiety, insomnia and sympathetic excitement. Therefore, about 2/3 of the patients who are effective for benzodiazepines or amitriptyline need to start using the drug from a small dose and relapse after 6 weeks of drug withdrawal, and need further treatment.

⑵ 5-hydroxytryptamine recovery inhibitor: it can be used as a first-line drug, especially for those who cannot tolerate tricyclic side effects; Patients with obsessive-compulsive symptoms or social phobia can be the first choice. Common drugs include: paroxetine (20 ～ 60mg/d), fluoxetine (5 ～ 20mg/d), sertraline (50 ～ 150mg/d) and Fluvoxamine (150mg/d) Taking SSRI (such as fluoxetine, paroxetine, fluvoxamine), SNRI (venlafaxine and its sustained release agents), NaSSA (mirtazapine) and other new antidepressants in the morning can also control the symptoms of panic attacks, with the same effect as amitriptyline Equivalent. The drug has no anticholinergic effect of amitriptyline and adverse reactions of cardiovascular system, but its specific adverse reactions can make some patients unable to tolerate and stop taking the drug.

⑶ Monoamine oxidase inhibitor : Applicable to those who cannot tolerate other antidepressants; merge Atypical depression Or social phobia can be used as the first choice of commonly used drugs: phenethylhydrazine (15-60-90mg/d) and Tranamphetamine (10 ～ 80mg/d) in the morning.

⑷ Highly effective benzodiazepines: applicable to those who cannot tolerate various antidepressants; The first choice is for the cases with prominent anticipation anxiety or phobic avoidance and the need for quick results. Commonly used drugs are: alprazolam and clonazepam. The latter has a longer action time and less withdrawal reaction. Benzodiazepines must be used in large doses for several months when controlling panic attacks, but will cause dependence and withdrawal reactions. Conventional drugs are Alprazolam In the treatment dose, the potency of this drug is higher than diazepam, but the sedative effect is relatively weak. It usually takes 6mg/d to control panic attacks (equivalent to 60mg diazepam). Adding the drug takes 2-3 weeks, and withdrawal is slow, generally more than 6 weeks.

⑸ Other drugs: venlafaxine (50-75mg/d) and nefazodone (200-600mg/d) can be used for patients with poor efficacy of other drugs.

Because the disease is easy to recur, the treatment period should not be shorter than half a year; Some cases need to maintain medication for 3-5 years to fully alleviate.

3. Psychotherapy After controlling panic attacks with medication, it is often necessary to cooperate with psychotherapy to eliminate expected anxiety and phobic avoidance.

(1) Supportive psychotherapy: explain the nature of the disease to patients to reduce the mental burden of patients, encourage patients to adhere to the treatment plan, organize similar patients to participate in group treatment, and help each other to achieve better results.

⑵ Cognitive behavioral therapy ： Cognitive Therapy It is a professional treatment conducted by a clinical psychologist or psychiatrist. The short-term effect of cognitive therapy is similar to that of drug therapy and has a lower recurrence rate. However, this treatment needs to be carried out by specialists, and it takes time. Generally, drug treatment should be carried out before cognitive therapy.

① The following methods can be selected: patients with chronic hyperventilation during the intermittent period of attacks and acute hyperventilation during spontaneous or induced panic attacks can lead to hypocapnia and alkalosis, thus reducing cerebral blood flow and causing dizziness, confusion and Depersonalization And other symptoms. The use of anti panic drugs to control panic attacks, or through respiratory behavior training, to teach patients to adjust their breathing rate and not to hyperventilate, can significantly reduce panic attacks

② Exposure therapy : Let the patient be exposed to the somatic feelings during panic attacks through meditation, so as to eliminate the fear of various autonomic nervous responses of the patient. For patients with phobic avoidance behavior or secondary square phobia, on-site exposure should be adopted so that patients can gradually adapt to the situation of fear.

③ Relaxation training: the muscles of head and face, chest and abdomen of upper limbs and lower limbs can be contracted and relaxed in order from top to bottom to reduce anxiety. It can also let patients learn health Qigong, relax the muscles of the whole body, regulate breathing, and guard the elixir field to eliminate distractions.

④ Cognitive reconstruction: give reasonable explanations to patients' physical feelings and emotional experiences at the time of onset, so that patients can realize that such feelings and experiences are benign and will not cause serious damage to health.

Recuperate

The disease usually starts in late adolescence or early adulthood, and there is another peak of the disease at the age of 35-40. It is found that this disease can also occur in childhood. Some cases can be completely alleviated in a few weeks, and those whose disease duration exceeds 6 months are easy to enter the chronic fluctuation course. Patients without concomitant agoraphobia had better therapeutic effect. The prognosis of secondary square terrorists is poor. About 7% of the cases have attempted suicide. More than half of the patients have severe cases Depressive episode It increases the risk of suicide and deserves special attention.

prevention

Due to the late development of psychiatry in the whole medicine and the complexity of the basic theory of the specialty itself, the etiology and pathogenesis of a considerable number of common mental diseases have not yet been clarified. In addition, the influence of old ideas on the cause of mental illness has been considered mysterious and neglected for a long time, thus hindering the development of mental disease prevention. In fact, preventing the occurrence of mental illness is not only an important subject in medical science, but also the development of social culture and success Social welfare It is an important work of.

Relevant statistics

It is estimated that the lifetime prevalence of panic disorder is about 2% - 4%. A large-scale epidemiological survey of adults in the United States in the 1980s showed that the lifetime prevalence of panic disorder was about 1.5%, and the lifetime prevalence of panic attacks was 3.6%, while 9% - 10% of people experienced a panic attack. Another survey in the 1990s showed that the lifetime prevalence rate of the American population was 3.5%, of which the ratio of male to female was 2:5 (Kessler, et al., 1994). There is no corresponding survey data in China. Panic disorder mostly occurs in early adulthood. The age range is 15-40 years old, and the average age of onset is 25 years old. However, the disease can occur at all ages. Its occurrence has nothing to do with socio-economic conditions. [1]

Research progress

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summary

Panic disorder is a serious anxiety that occurs repeatedly. There are many hypotheses to explain its etiology and mechanism. Neurobiochemical hypotheses include classical neurotransmitter GABA, 5-HT, DA, Ach and other functional abnormality hypotheses, and neuropeptide CCK and DA imbalance hypothesis. Genetic factors may also play a role in the occurrence of panic disorder, because it is found in the investigation of human stove pedigree that the incidence of this disease among relatives of anxiety patients is 15%, which is three times that of general residents [1]; The survey of twins found that the comorbidity rate of monozygotic twins was 50%, the anxiety quality was 65%, while the comorbidity rate of twins was only 4%, and the anxiety quality was only 13% [1]; These studies show that panic disorder has an obvious genetic tendency, and its etiology is at least partly due to genes.

along with molecular genetics With the development of technology, many studies have been carried out on the etiology of panic disorder at the gene level.

GABAA receptor gene

γ - aminobutyric acid (GABA) receptors are divided into two subtypes: GABAA and GABAB. The GABAA subtype receptor, chlorpheniramine value and diazepam receptor form a complex, which is a tetramer composed of α, β, γ and δ subunits, and controls the chlorpheniramine value. The α subunit has a stable binding point; There are GABA binding sites on the β subunit; The γ subunit cannot bind to benzodiazepines or GABA, but it is necessary for oligomeric receptors to have high affinity with benzodiazepines; The δ subunit has no binding site, and its function is still unclear. α. The peptide chains of β, γ and δ subunits all cross the cell membrane four times [2,3].

GABAA receptor chloride channel diazepam receptor complex plays an important role in anti anxiety; GABAA receptor is coupled with the chlorine channel and controls the chlorine channel. GABAA receptor agonists (such as GABA) can activate the GABAA receptor, open the chlorine channel, increase the extracellular CI inward flow and chlorine conduction, cause the postsynaptic membrane hyperpolarization, produce the inhibitory effect on neurons, and therefore produce the anti focal effect; Benzenediazepines Antianxiety drug (such as diazepam) acting on diazepam receptors can up regulate GABAA receptors, thus increasing the affinity of GABAA receptors for GABA and their binding with GABA, thus increasing the frequency of GABAA receptors opening chlorine channels and enhancing the Postsynaptic inhibition Effect, showing anti anxiety effect; Barbiturates It directly acts on the chlorine channel, prolongs the opening time of the chlorine channel, and also has anti anxiety effect. In conclusion, GABAA receptor agonists, diazepam receptor agonists and Barbiturates Because they act on GABAA receptor, diazepam receptor and chlorine channel respectively, they all have anti anxiety effects. On the contrary, diazepam binding inhibitor (DBI) is an endogenous diazepam binding inhibitor, which can down regulate the GABAA receptor, reduce the binding of GABAA with ligands, and cause anxiety; β - carblin can bind to diazepam receptor, weaken the effect of GABA, and also cause anxiety; The India prevents already the toxin to cause the chlorine channel to close, the antagonism GABA function, may cause the convulsion. Therefore, the GABAA receptor chloride channel diazepam receptor complex plays a very important role in the occurrence and treatment of anxiety [2].

The subunit of the GABAA receptor chloride channel diazepam receptor complex has great polymorphism. There are 13 variants of the human GAGAA receptor complex subunit, including 7 variants of the α subunit (α 1~α 7), 3 variants of the β subunit (β 1~β 3), and 2 variants of the γ subunit (γ 1~γ 2), while no variants of the δ subunit have been found at present [3]. There is a hypothesis that the susceptibility to panic disorder and the responsiveness of drug therapy are related to the differences of GAGAA receptor complex subunit variants. Since each subunit variant is encoded by a unique gene and transcribed by its corresponding mRNA, this hypothesis further believes that the susceptibility to panic disorder and the responsiveness of drug therapy are related to the genetic polymorphism of GAGAA receptor complex MRNA level. Tanay (1996) [4] found that chronic administration of anti panic drugs such as imipramine, phenethylhydrazine, and diazepam to rats can change the mRNA levels of brainstem GABAA receptor complex α 1, β 2, and γ 2 subunits, and then change the expression of specific GABAA receptor complex subunits gene expression The changes of Antianxiety drug (Busperon), which strongly supports the above hypothesis. Crowe (1997) [5] further detected the genes encoding eight subunit variants of GABAA receptor complex (α 1~α 5 β1、β3、γ2）， Linkage studies were conducted among 104 strictly defined panic disorder patients and 134 generalized panic disorder or subsyndromic panic disorder patients. However, the results showed that there was a linkage, which did not support the above hypothesis. It was believed that panic disorder was not caused by the mutation of any one of the eight GABAA receptor complex subunit genes detected.

5-HT1D receptor gene

The anti anxiety effect of drugs also involves other neurotransmitter systems, such as NE system, especially the central locus coeruleus, which is the awakening center of expected danger; DA system may be related to emotional behavior and anxiety performance; The 5-HT system, especially in the dorsal nucleus, inhibits the adaptive behavior of anxiety. The above neurotransmitter systems are interconnected and work together at different levels of the brain [6].

The increase of plasma corticosteroid content can feedback the acceleration of T-HT renewal rate and overactivity of 5-HT function, which may be related to the occurrence of anxiety [7]; 5-HT can also promote the secretion of ACTH, thus regulating and influencing the anxiety reaction [1]. Antianxiety drugs benzodiazepines can reduce the activity of 5-HT, inhibit the renewal rate of 5-HT in the brain, and slow the consumption rate of 5-HT, which may be related to their anti anxiety effects [1-7]; The antianxiety drug buspiron can reduce the activity of 5-HTergic neurons, and its antianxiety effect is also related to this [8]. In conclusion, the 5-HT system is closely related to the occurrence and treatment of anxiety disorder, and the 5-HT receptor gene has therefore become one of the candidate genes for panic disorder.

5-HT is subject to 14 subtypes of this sub division, in which the 5-HT1D receptor can also be subdivided into the 1080 base of the gene of the 5-HT1D α receptor, and C and T conversion can occur, forming a 080 polymorphism [9]; The 276th base of the gene encoding 5HT1D β receptor can have A and C conversion, forming A276G polymorphism [9]; These two polymorphisms are static polymorphisms, which do not directly change the amino acid structure encoded, but they may indirectly affect the expression level of 5-HT1D receptor, thereby affecting the susceptibility to panic disorder. Therefore, Ohara (1996) [9] studied a group of panic disorder patients and normal controls, and sequenced their 5-HT1D α and β receptor genes. However, the results showed that there was no significant difference between the two groups in the above two polymorphisms, which does not support the theory that the 5-HT1D receptor gene affects the susceptibility to panic disorder.

D4 receptor gene

Dopamine D4 receptor is mainly distributed in the frontal cortex. Because the gene encoding D4 receptor is highly polymorphic, these polymorphisms may affect the function of D4 receptor, making it one of the candidate genes for evaluating panic disorder. Ten polymorphisms of D4 receptor gene were found, including three static polymorphisms and seven dynamic polymorphisms. D4 receptor gene Initial codon The first 31 base C on the upstream codon 11 can be converted to T, thus forming a polymorphism C-31T. The frequency of allele A1 (that is, the first 31 base is C) is 0.93, and the frequency of A2 is 0.07 [10]; The 31st base G in the 11th codon downstream of the start codon of the D4 receptor gene can be converted to C, so that the 11th amino acid Gly on the encoded D4 receptor is replaced by the amino acid Arg, thus forming a polymorphic Gly11Arg. The frequency of allele A1 (that is, the 31st base G) is 0.99, and the frequency of A2 is 0.11 [10]; A 21bp long base sequence on codons 36 to 42 of D4 receptor gene can be deleted, and the resulting polymorphism allele A1 has no 21bp deletion, while allele A1 has 21bp deletion [10]. Cichon (1995) [10] studied 148 normal German people, 256 Schizophrenia Patients, 99 affective disorder patients and a group of panic disorder patients found that all patients had polymorphisms of C-31T There is no significant difference between Gly11Arg and normal people. No 21bp deletion was found in schizophrenic patients, affective disorder patients and normal people, but this rare substitution mutation was found in one panic disorder patient, which may mean that the deletion mutation is involved in the occurrence of panic disorder, but it may also be opportunistic False positive results 。

CHRNA4 gene

The central neurotransmitter NE inhibits the hypothalamus pituitary adrenal response induced by stress, and acetylcholine (Ach) can promote the secretion of ACTH, and then regulate and affect the emotional reaction of anxiety [1]; Another study found that choline in anxiety patients cholinesterase The activity is significantly low, which suggests that anxiety is related to the low activity of cholinesterase [1]. In conclusion, Ach ergic system is closely related to the occurrence of anxiety disorder.

Ach receptors are divided into N and M subtypes. N-type Ach receptors (CHRN) are widely distributed in the central nervous system, including the cerebral cortex, hippocampus, amygdala, and striatum of the limbic system. The CHRN receptor consists of four subgenes, each of which is a transmembrane glycoprotein with a molecular weight of about 55kD. They constitute the CHRN receptor according to the ratio of α 2 β γ δ, with a total molecular weight of about 275kD; The five subunits are arranged in a pentagon shape, and together form the ion channel wall of the CHRN receptor, which is generally asymmetrical dumbbell shaped. Each CHRN receptor has two Ach binding sites on the outside of the cell, which are located on the hemigliate residues at positions 192 and 193 of the two α subunits. They have the ability to recognize and bind Ach; When Ach ions (mainly Na+) enter the cell through ion channels, potential changes occur in the postsynaptic membrane, producing physiological effects [3].

The subunits that make up the CHRN receptor have a variety of variants [3], of which the α subunit has six variants (α 2~α 7), and the β subunit has three variants (β 2~β 4). These variants can change the function of the CHRN receptor. Each variant is encoded by its own unique code. The gene encoding the α 4 subunit (CHRNA4 gene) is located at 20q13.3 locus [11]. It has been found that anxiety disorder is associated with EEG low voltage (LVEEG), and about 1/3 of VLEEG cases are linked to 20q13.3 locus [1], so there is a hypothesis that the susceptibility of panic disorder may also be related to the CHRNA4 receptor gene. In order to explore the relationship between the two, Steinlein (1997) [11] detected three different CHRA4 gene polymorphisms in a group of panic disorder patients and normal people Allele frequency The results showed that there was no significant difference. This study does not support the association between CHRNA4 gene and panic disorder.

CCKB gene

Cholecystokinin (cholystokinin, CCK) is a neuropeptide, which is mainly synthesized in the cell body. Its precursor is composed of 130 amino acids. After post translation processing, it can produce active peptide fragments such as CCK39, CCK33, CCK8 and CCK4 [12]. Low dose of CCK4 can induce panic attacks in patients with panic disorder, so CCK may be involved in the occurrence of panic disorder.

CCK receptors are divided into two subtypes, namely CCKA and CCKB receptors. CCKA receptors are distributed in the periphery, while CCKB receptors are distributed in the cerebral cortex, striatum, etc., so the gene encoding CCKB receptors is a candidate gene for panic disorder. Kato (1996) [13] screened the mutations of CCKB gene in 22 probands of panic disorder families by SSCP method, and found two polymorphisms: a polymorphism 2491C → A was found in the intron between exons 4 and 5 in 10 patients, and a missense mutation (1550G → A, Val125 → Ile) was found in the extracellular ring of exon 2 in one proband; The missense mutation was detected in 34 unrelated panic disorder patients and 112 normal controls, and 8.8% (3/34) patients and 4.4% (5/112) normal people had the mutation. However, there is no significant difference in these mutations between patients and normal people, so it is considered that these mutations have no pathophysiological significance in panic disorder.^[1]

epilogue

Phobic molecular genetics Many studies have been carried out, mainly focusing on the relationship between panic disorder and GABAA, 5-HT1D, D4, CHRNA4 receptor genes and CCKB genes. In these studies, except that a 21bp deletion mutation in D4 receptor gene may be involved in the occurrence of panic disorder, other studies were negative. However, this does not make us lose confidence in finding the susceptible genes of panic disorder, because there are still shortcomings in previous studies: ① The investigation of subtypes and polymorphism types of candidate genes is incomplete: for example, only 8 of the 13 subunit genes of GABAA receptor complex have been investigated, and there are still 5 that have not been investigated; Only one of the 14 subtypes of 5-HT receptor gene was investigated, and 13 were not yet investigated; Only 3 of the 10 polymorphisms of D4 receptor gene were investigated, and 7 were not yet investigated; Only one of the 11 subunit genes of CHRN receptor was investigated, and there are still 10 genes not investigated. ② Small sample size: panic disorder may be a Genetic heterogeneity The disease is caused by the superposition of small genetic effects of multiple genes. Therefore, to investigate the relationship between each gene and panic disorder, it often requires Lin Da's sample to find positive results. The sample size of previous studies is not large, so it is difficult to rule out the possibility of false negative results. In addition, the only study that found positive results may also be because the sample size is too small, It is difficult to rule out that it is caused by chance False positive results 。 Therefore, the molecular genetic research on panic disorder is equal to further expanding the sample size and carrying out in-depth and comprehensive research. [1]

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