Psychiatric Disorders/Anxiety disorders/Panic Disorder

Panic disorder is one of the anxiety disorders. It is characterized by the repeated occurrence of discrete panic attacks, associated with at least 1 month of persistent concern about having another panic attack. These attacks are discrete in that they have a recognizable beginning and end. In between the attacks, patients often no symptoms at all. However, with repeated episodes, they may experience some anticipatory anxiety. In addition, about half of panic disorder patients also experience Agoraphobia.

Phenomenology
The central feature of panic disorder is a panic attack. Panic attacks themselves are not a disease, but rather a cluster of symptoms that come on and depart relatively rapidly. Many diseases can cause panic attacks, including other anxiety disorders, and a number of medical disorders. These will be described later.

"Panic Disorder" is used to describe individuals who have recurrent panic attacks without an alternative explanation. By definition, the panic attacks have to be recurrent. For The Diagnostic and Statistical Manual of Mental Disorders, or DSM-IV this means two or more, however in practice most patients have many more attacks than that.

The attacks seem to come “out of the blue” and most often occur without clear precipitant or stressor. DSM-IV does not require that the panic attacks be spontaneous, and there can be situational triggers, however spontaneous attacks are probably the most common. Though, by definition, the attacks have a definable beginning and ending, there may be anticipatory and residual anxiety surrounding the attacks.

The attacks can occur any time, including while the patient is sleeping. In the case of nocturnal attacks, the panic seems to occur most often during non-REM sleep, and thus they are different from nightmares. Early on, patients may not recognize these symptoms as being anxiety based, and patients may end up in the emergency believing they are having a heart attack.

Epidemiology
In all, anxiety disorders are the most common psychiatric disorder. Panic is not the most common of these: the phobias have that honor. The lifetime prevalence of panic disorder is from 1 to 2%. It is more common in women than in men.

Etiology and Pathophysiology
Panic disorder appears to be genetic. It certainly runs in families and the risk of panic increases with the degree of consanguinity. However, sufficient twin and adoption studies are lacking to distinguish genetic from other familiar factors (for a discussion of why such studies are important in determining genetic versus environmental factors, see this article), and direct genetic studies have not shown clear linkages. This suggests that if the disorder is genetic, the pattern of inheritance is complicated.

One interesting clue is that several substances can precipitate panic in individuals who are predisposed. The best studied is sodium lactate infusion, and, to a lesser extent, carbon dioxide inhalation. These are of etiology interest, as both may represent, to the body, signs of suffocation. Other agents that can also induce panic include cholecystokinin, tetrapeptide, caffeine, yohimbine, isoproterenol, and the benzodiazepine antagonist, flumazenil. These findings help implicate several transmitter systems. The panic inducing effect of yohimbine and isoproterenol, along with studies showing a blunted growth hormone response to clonidine infusion helps suggests a noradrenergic role in the regulation of anxiety. Serotonin likely has a regulatory role as well; this is suggested, among other things, by the efficacy of serotonergic agents in treating panic.

The most direct affected neurotransmitter system is the GABA-ergic system. GABA, a major inhibitory transmitter system in the brain, is the major treatment site for all direct acting anxiolytics, such as benzodiazepines. The panic inducing effect of flumazenil lends further support. There is also some direct evidence suggesting that GABA levels are decreased in the area of the occipital cortex of patients with panic disorder. Some Functional MRI studies suggest that panic disordered patients show abnormal activation in the area of the hippocampus and parahippocampal gyrus.

How to put this all together? Some have suggested that panic disorder is really a “false suffocation alarm”, perhaps caused by oversensitivity to acid-base disturbances in the brain. This alarm, when triggered may activate certain areas of the brain responsible for our normal anxiety/arousal reactions, including the locus ceruleus—which is noradrenergic, or the dorsal raphe nucleus—which is serotonergic. Both structures help regulate limbic areas of the brain, including the hippocampus, parahippocampal gyrus and the amygdala. It is well known that stimulation of these limbic areas, all of which are rich in GABA receptors, can produce intense anxiety.

Differential Diagnosis
As already noted, panic attacks are not unique to panic disorder, and can be seen in almost any of the anxiety disorder. The difference in these cases it that the attacks are caused by the specific disorder: thus, a person with a phobia around heights may panic when forced to climb a ladder; similarly, a person with a social phobia may panic when having to give a public speech. In each case, the panic attack is directly associated with the person’s phobia or fear, and will not occur if the precipitants can be avoided.

Many medical conditions can produce symptoms that are similar or identical to panic attacks. Most common are medical conditions that affect the cardiopulmonary system, thus bringing on a sensation of shortness of breath or chest pain. Dramatic examples include pulmonary emboli, myocardial infarctions, and these should first be ruled out in an individual for which they represent a possibility. Chronic diseases, such as chronic obstructive pulmonary disease, or heart failure also can cause feelings of anxiety and panic. Paroxysmal supraventricular tachycardia (SVT) can be difficult to distinguish from panic attacks, but as distinguished by the very rapid onset of SVT, often peaking within seconds, and the positive response to a Valsalva maneuver. Hypoglycemia may cause anxiety, but is somewhat slower in onset, and predictably responds to sugar ingestion.

The list of other disorders that can cause anxiety is long. Some disorders typically cited include simple partial seizures, pheochromocytoma, mastocytosis, and carcinoid syndrome. Each of these disorders can cause seemingly paroxysmal anxiety, but each also has symptoms and laboratory findings that are unique to each disorder.

A number of medications and drugs can cause panic symptoms, either in ingestion or during withdrawal. Examples of drugs that typically can cause anxiety include levodopa, most stimulants and sympathomimetics. Alternately, drugs that usually produce anxiolytic or sedative effects, such as benzodiazepines or barbiturates, can cause anxiety during withdrawal.

In summary, differential list are quite long for panic, however we should not be overwhelmed by this list. A good history and physical, with proper supporting labs will rule out most of the possible mimics of anxiety. In fact, it is the very fact that the patient often looks and acts so healthy that distinguishes panic disorder from these other syndromes.

Comorbidity
The most common complication of panic disorder is agoraphobia. Agoraphobia, literally “fear of the marketplace” is often mistakenly thought to be a fear of open places. In reality, what occurs is that, for many individuals with panic disorder, the attacks are so unpredictable that the individual begins to restrict his or her traveling in order to be sure of being in a “safe place” such as home, when the attack occurs. Simply put, most of us would rather have these frightening attacks at home than in the mall, and the only way to be sure of this is to spend as much time at home as possible. One can imagine that this is a particularly disabling complication of the disorder; it can affect as many as half of Panic Disordered patients.

Drug and alcohol abuse is another serious complication, often beginning as an unsuccessful attempt to treat the symptoms, and sometimes then taking on a life of its own. Use of benzodiazepines or other tranquilizers are particularly problematic, as withdrawal symptoms may mimic, or even precipitate panic. Depression is common as well, and patients suffering from comorbid panic and major depression may have a higher risk for suicide than those with either disorder alone.

Though it may be surprising, patients with panic disorder alone are not at a higher risk for suicide than the general population.

Another commonly reported comorbidity is mitral valve prolapse. Though it is tempting to suggest an etiological role in either direction, the relationship between panic and mitral valve prolapse seems to stem from some shared abnormality, rather than any direct relationship.

Onset
Most often, there is no prodrome; instead, a panic full-blown panic attack is often the first sign of the disease. It can occur at any age, but most often begins during the late teens or the early twenties. It tends to be a disease of adolescence and adulthood: onset during childhood or geriatric years is much less common.

Long-term course
There appear to be at least two different potential courses. One group of patients experience waxing and waning of symptoms over the course of many years. During bad periods, the symptoms can be daily; at times that are more quiescent the patient may only have panic attacks once every few months, however they do not experience long attack free intervals. A second group experience a more episodic course, with a group of attacks being followed by long, symptoms free periods.

Treatment
As with most therapeutics in psychiatry, there are two types of treatment for panic: acute treatment and preventive treatment. Acute treatment refers to relieving symptoms that are occurring now: in this case, the acute panic attack. Preventative treatment refers to decreasing the frequency and severity of future attacks.

Both treatment strategies have several options, including pharmacologic and psychotherapy options. Neither strategy is good or bad in itself, but represent two approaches that have their own advantages and limitations.

Acute Treatment
Acute treatment of panic attacks is very difficult, as the attacks may begin and end before treatment has time to take effect. Treatment is more likely to be effective in cases where these is some warning, or way to predict that panic will occur, or in patients who have an unusually long time until the peak of symptoms. Obviously, in cases where panic attacks are not caused by panic disorder, but by a more predictable problem, for example a phobia, treatment is more likely to be effective. For example, a patient who has fear of flying may take a medication before getting on a plane. Patients, during a panic attack feel very desperate, and will take anything to relieve their anxiety. That said, often the treatments are more effective at diminishing the subsequent anticipatory and secondary anxiety than in treating the panic attack itself.

Pharmacological treatment
Acute treatment of panic, or really any type of acute anxiety, usually involves the use of fast acting medications. These typically have short half lives, and rapid times to onset. The most common medications used for acute treatment of anxiety are the benzodiazepines. They all work through potentiation of GABA action at GABA-A receptors in the CNS. Because of their indirect effect on the GABA receptor, the benzodiazepines are relatively safe compared with other sedatives.

There are three classes of benzodiazepines: 2-keto, 3-hydroxy, and triazolo. 2-keto drugs include chlordiazepoxide, diazepam, prazepam, clorazepate, halazepam, clonazepam, and flurazepam. Many of these are pro-drugs; they are oxidized in the liver (usually to active metabolites). They therefore tend to have long half-lives and are more susceptible to drug interactions and age effects. The 3-hydroxy drugs include oxazepam, lorazepam, and temezepam. These are conjugated in the liver (to inactive substances); thus, they have shorter half-lives, and are less affected by age and other drugs. The triazolo class includes alprazolam, triazolam and adinazolam. These are oxidized, but with more limited active metabolites. Thus, they are somewhat shorter-acting than the 2-keto drugs. The mechanism of action relates to specific receptors on GABA receptors.

The most commonly used benzodiazepines for acute anxiety, at least in the US, are alprazolam, clonazepam, lorazepam and diazepam. All have a relatively quick onset, and, except for diazepam, short to medium half lives. The advantage of benzodiazepines is that they can be effective, if administered in time. Indeed, there are few other medications that can be used in a “as needed” or PRN basis. In addition, they are relatively safe, even in overdose. There are downsides of using benzodiazepines. Though they are relatively safe, they still can cause respiratory depression, even coma or death in overdose. The chance of this is much higher in individuals who already have respiratory or cardiac problems. The risk is also greatly increased if the benzodiazepines are taken along with another CNS depressant, such as alcohol. In addition, there is a risk of tolerance and withdrawal. Tolerance is a pharmacodynamic neuroadaption, in which an individual becomes “used to” a given medication, and begins needing more medication to achieve the same effect. Tolerance mainly occurs with repeated use, thus the risk of tolerance increases if benzodiazepines are used frequently. Withdrawal is also common with repeated and continuous use of benzodiazepines. The symptoms of withdrawal are often virtually identical to the original anxiety symptoms. For this reason, benzodiazepines can, at times, create a vicious circle in which an individual begins to experience rebound anxiety as soon as they stop using their medication.

Addiction is another concern. Addiction refers to the compulsive use of a medication, usually for the psychic effects of the medication, such as in order to “get high.” While tolerance and withdrawal are common with repeat use of benzodiazepines, addiction is much less common. The greatest predictor of benzodiazepine addiction is a prior history of substance dependence, either to alcohol or some other substance. It should never be assumed that addiction is an inevitable, or even common result of benzodiazepine use; it is not. Often physicians need to spend time educating their patients about this, and the difference between true addiction and physical dependence/tolerance or withdrawal.

Psychological Treatments
There are a number of psychological treatments aimed at curbing anxiety once it begins. Most of the symptomatic treatments are rooted in behavioral therapy. Most commonly used are the relaxation therapies, which, as the name implies, are geared towards promoting relaxation and lessening anxiety. Common examples include progressive muscle relaxation and deep breathing exercises. Both are easily taught, and become more effective the more they are practiced. Thus, when instructing patients in their use, they should be encouraged to practice them often, so that panic does occur, the behavioral strategies can be done almost automatically.

Preventive Treatment
Preventive treatment refers to treatment strategies aimed at decreasing the frequency and severity of future attacks. Ideally, one wishes to eliminate the attacks altogether, and sometimes this is possible, but even if it is not, any alleviation in the severity of the disorder will likely be of great benefit to the patient. For example, a patient who is afraid to go to work for fear of having a panic attack there may feel sufficiently safe to resume working if the attacks begin to seem more minor.

Pharmacological treatment
In practice, benzodiazepines are sometimes used preventive as well as symptomatic treatment. In this case, instead of being used as needed, they are given continually, usually in divided doses, so that there is a constant blood level throughout the day. Some of the short acting benzodiazepines have come out with longer acting versions that can be taken once a day: alprazolam is an example. Despite the common use of these agents, the continuous use of benzodiazepines is controversial for the reasons discussed above: mainly those of tolerance and dependence. Though, admittedly there are different opinions and some conflicting data, it is the opinion here that these are not first line treatments for prevention of panic, or any anxiety disorder. Antidepressants have largely supplanted benzodiazepines as first line treatment for the prevention of panic. Most currently available antidepressants likely have some effect on anxiety. However, the SSRIs are likely the most popular, and a number of studies have demonstrated them to be as good or better than the benzodiazepines in treating anxiety. The dose and treatment strategy for the use of antidepressants in panic is similar to that for depression: similar doses are required, and a similar time course is used. For that reason, antidepressant treatment will not be discussed in detail here, and the reader (listener) is referred to the section on the treatment of depression. It is notable, however, that some clinicians suggest a slow titration for fear that the antidepressants may cause some anxiety or agitation if administered too aggressively.

Other medications have also shown efficacy in treating panic disorder. Propranolol has been used to prevent panic, though it is generally thought to be less consistently effective than antidepressants or benzodiazepines. Inositol has also shown promise, though it is little used in clinical populations currently. Buspirone, which has proved effective in some types of anxiety, most notably generalized anxiety disorder, is NOT effective for panic disorder. Cognitive-behavior therapy, used either independently or in conjunction with medical treatment, should also be considered, especially in light of the fact that in addition to reducing the frequency of panic attacks, it is also an effective treatment for agoraphobia.

Psychological treatments
There are a number of psychological treatments aimed at preventing anxiety. Much of psychoanalysis and dynamic therapy was aimed as reducing anxiety in the sense that anxiety itself wasn’t seen as the problem, but as a signal of ongoing conflicts and stresses which, once attended to would lessen the resulting anxiety. That said, the long term dynamic therapies such as psychoanalysis are no longer considered the treatment of choice for preventing panic disorder. Most commonly used now are the cognitive-behavioral therapies or CBT. CBT is based on learning theory; the idea is that people learn to develop automatic responses of fear or dread in relation to a stimulus. What is learned can be unlearned, and much of CBT is spent teaching the patient to tolerate the triggers of anxiety. In the case of phobias, the triggers are clear; in the case of panic disorder, the trigger is, in a sense, the anxiety itself, and the patient learns to tolerate their anxiety.

CBT treatment has been shown in some studies to be as effective as medication treatment. It has the additional advantage of alleviating the concomitant agoraphobia, which medications are generally less effective in treating. Indeed, agoraphobia left to itself may persist long after panic is prevented, and in those cases CBT may be the only treatment with will address with lingering and disabling complication.