Panic disorder is characterized by the spontaneous and unexpected occurrence of panic attacks, the frequency of which can vary from several attacks per day to only a few attacks per year. Panic attacks are defined as a period of intense fear in which 4 of 13 defined symptoms develop abruptly and peak rapidly less than 10 minutes from symptom onset. (See History.) Although such attacks can occur in other anxiety disorders, these attacks often occur without a discernible predictable precipitant in panic disorder. (See Diagnostic Considerations and Workup.)
To meet the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition (DSM-5)[1] criteria for panic disorder, panic attacks must be associated with longer than 1 month of subsequent persistent worry about: (1) having another attack or consequences of the attack, or (2) significant maladaptive behavioral changes related to the attack. To make the diagnosis of panic disorder, panic attacks cannot directly or physiologically result from substance use (intoxication or withdrawal), medical conditions, or another psychiatric disorder. (See History.) Other symptoms or signs may include headache, cold hands, diarrhea, insomnia, fatigue, intrusive thoughts, and ruminations. (See Physical Examination.)
Following exclusion of somatic disease, substance use disorders, and other psychiatric disorders, confirmation of the diagnosis of panic disorder with a brief mental status screening examination and initiation of appropriate treatment and referral is time- and cost-effective in patients with this condition, who have high rates of medical resource use. (See Mental Status Examination.)
Panic disorder can lead to a significant hindrance in lifestyle. Individuals with panic disorder also may face problems with employment and depression.[2]
In addition, persons with panic disorder have a much higher risk of alcohol abuse or dependence and suicidality than the general population.[2] However, some studies suggest that panic disorder itself is not a risk factor for suicide in the absence of other risks, such as affective disorders, substance use disorders, eating disorders, and personality disorders.[3]
For more information, see the Medscape Reference topics Anxiety Disorders; Specific Phobia; Separation Anxiety and School Refusal; and Phobic Disorders.
The apparent neurochemical dysfunction behind panic disorder may involve autonomic imbalance, decreased gamma-aminobutyric acid (GABA)–ergic tone,[13] allelic polymorphism of the catechol-O-methyltransferase (COMT) gene, increased adenosine receptor function, increased cortisol,[14] diminished benzodiazepine receptor function, and disturbances in serotonin,[15] serotonin transporter (5-HTTLPR)[16] and promoter (SLC6A4) genes,[17] norepinephrine, dopamine, cholecystokinin, and interleukin 1–beta.[18]
Some authors theorize that panic disorder may represent a state of chronic hyperventilation and carbon dioxide receptor hypersensitivity.[8] Some epileptic patients have panic as a manifestation of their seizures.
The serotonergic model suggests an exaggerated or inefficient postsynaptic receptor response to synaptic serotonin, potentially in the signal transduction cascade. Some studies report subsensitivity of serotonin 1A (5HT1A) receptors. The 5HT system or one of its subsystems may play a role in the pathophysiology of panic disorder, but further investigation is needed.
The catecholamine model postulates increased sensitivity to or improper processing of adrenergic CNS discharges, with potential hypersensitivity of presynaptic alpha-2 receptors.
Similarly, the locus coeruleus model explains that panic symptoms are due to increased local discharge resulting in adrenergic neuronal stimulation, similar to the more general catecholamine theory. Locus coeruleus activity also affects the hypothalamic-pituitary-adrenal (HPA) axis, which can respond abnormally to clonidine in patients with panic disorder.
The lactate model focuses on symptom production by postulated aberrant metabolic activity induced by lactate. The false suffocation carbon dioxide hypothesis explains panic phenomena by hypersensitive brainstem receptors. The GABA model postulates decreased inhibitory receptor sensitivity, with a resultant excitatory effect.
The neuroanatomic model suggests that panic attacks are mediated by a "fear network" in the brain that involves the amygdala, hypothalamus, and brainstem centers. More generally, the corticostriatal-thalamocortical (CSTC) circuitry is believed to mediate worry, interacting with the more fear-specific circuit in the amygdala. The sensation of fear occurs through reciprocal regulatory activity conceptually initiated in the amygdala and projected to the anterior cingulate cortex and/or orbitofrontal cortex. Projections from the amygdala to the hypothalamus then mediate endocrinologic responses to fear.
The cognitive theory suggests that patients with panic disorder have a heightened sensitivity to internal autonomic cues (e.g., tachycardia).
Panic disorder is a common psychiatric disorder that affects 3-5% of the population.[61] Studies of the association between psychiatric illness in first-degree relatives revealed a heredity of approximately 43% for panic disorder.[42] Patients with panic disorder also have a high rate (80%) of having other psychiatric disorders, many of which also have an important genetic basis.
Although panic disorder is a disease with a significant genetic basis, the exact nature of the basis is unclear. The present understanding suggests that panic disorder is a multifactorial condition, with multiple genes creating susceptibility to the condition coupled with influences from the environment.[54] The genetics of panic disorder is poorly understood relative to many psychiatric disorders in which genome-wide association studies (GWAS) have isolated numerous loci associated with susceptibility to disease.
Nonetheless, there are several loci that have been implicated in families with a strong history of panic disorder. Locus 13q22-32 has been linked to panic disorder and bladder conditions in families although the association was not found in families who had isolated panic disorder.[43] A locus at 9q31 was found to be associated with panic disorder (and likely generalized anxiety disorder) for an Icelandic cohort.[44]
In a study that performed a genome scan looking for regions of interest for anxiety disorders broadly defined in 219 US subjects in 19 extended pedigrees, investigators found an association at marker D4S413 on chromosome 4q31-q34, which is located near the NPY1R gene. This gene encodes the neuropeptide Y 1 receptor, and in an animal model, manipulation of this receptor was associated with anxiolysis.[45] A large GWAS that looked mainly at bipolar disorder but also psychosis, panic disorder, and suicidal behavior found an associated locus for panic disorder on 7q21.[47, 52]
Further study has implicated a few genes as likely contributors to panic disorder. Because monoamine oxidase inhibitors (MAOIs) have been used effectively in the treatment of panic disorder, the MAOA (monoamine oxidase A) gene is a logical consideration for contribution to panic disorder. In a study of a German and Italian population, patients with a longer repeat polymorphism in the MAOA promoter region had a higher incidence of panic disorder.[59] In recent years, the use of MAOIs has been in large part supplanted by newer agents.
Persons who are homozygous for a polymorphism in the COMT gene (catechol-o-methyltransferase), in which a methionine substitutes for a valine at position 158, have been associated with a higher rate of panic disorder than persons who did not carry these polymorphisms.[46] Additionally, it has been suggested that people who were homozygous for this polymorphism also had a poorer response to treatment.[46] A different study of the same polymorphism found an increased benefit of exposure-based therapy for those who had the Val158Met polymorphism.[53]
More recently, studies have isolated additional genes of interest for panic disorder. A polymorphism on the HCRT (hypocretin) gene, in which isoleucine substitutes for valine at position 308 on 17q21.2, has been implicated in increased risk of panic disorder.[48] Additional GWAS have identified the neuropeptide S gene, the amiloride-sensitive cation channel gene, and the adenosine A(2A) genes as candidate genes.[49, 50, 51]
Lifetime prevalence estimates for panic disorder in US adults range from 2.0% to 6.0%.[61] The 12-month prevalence in adults is 2.7%, of which 44.8% are classified as “severe” cases.[61]
Panic disorder often coexists with mood disorders, and mood symptoms potentially follow the onset of panic attacks. Lifetime prevalence rates of major depression in panic disorder may be as high as 50-60%.[63] Other psychiatric disorders that occur comorbidity with panic disorder include schizophrenia, obsessive-compulsive disorder, specific phobias, social phobia, and agoraphobia.[60]
There are also medical conditions that apparently share significant comorbidity with panic disorder, such as COPD, irritable bowel syndrome, migraine headache, restless leg syndrome, and fatigue.[20, 21] Cardiovascular disorders (e.g., mitral valve prolapse, hypertension, cardiomyopathy, stroke) are also comorbid factors[22] ; panic patients are nearly twice as likely to develop coronary artery disease. Patients with both panic disorder and coronary disease can experience myocardial ischemia during their panic episodes[23, 24] ; thus, panic disorder is also associated with a higher risk of sudden death.[25] In addition, panic disorder is also present in 30% of patients with chest pain and normal findings on angiography, and individuals with panic disorder tend to have lower oxygen consumption and exercise tolerance than does the general population.[26]
Asthma is linked to a 4.5-fold increase in the risk of developing panic disorder, and people with panic disorder are 6 times as likely as those without anxiety disorders to develop asthma.[64] Patients with panic disorder can also have migraine headaches (12.7%), tension headaches (5.5%), and combined migraine and tension headaches (14.2%).[65] The lifetime prevalence of panic disorder in people with epilepsy is 6.6%.[66]
Approximately 10-20% of patients with anxiety disorder abuse alcohol and other drugs, and about 10-40% of alcoholics have a panic-related anxiety disorder.[67]
Pregnant mothers with panic disorder during pregnancy are more likely to have preterm labor and infants of smaller birth-weight for gestational age.[27]
Prevalence data for different racial groups are inconsistent. Symptom manifestations may differ, with black persons more often presenting with somatic symptoms and more likely to seek help in medical rather than psychiatric settings.
Women are 2-3 times more likely to be affected than men. Panic is also more common in women who have never been pregnant and during the postpartum period; it is less common during pregnancy.
Although panic can occur in people at any age, it usually develops between the ages of 18 and 45 years, with an average age of onset of 24 years.[61] Patients with late-onset panic disorder have a tendency toward less use of mental health resources, have lower comorbidity and hypochondriasis, and have better coping behavior.[28]
Panic disorder is a chronic disorder with a variable course. Appropriate pharmacologic therapy and cognitive-behavioral therapy (CBT), individually or in combination, are effective in more than 85% of cases. Patients with good premorbid functioning and a brief duration of symptoms tend to have a good prognosis.[68] About 10-20% of patients continue to have significant symptoms.[68]
Overall, the long-term prognosis is usually good, with almost 65% of patients with panic disorder achieving remission, typically within 6 months.[29] However, as discussed under History, trigger factors can lead to panic attacks— several of these triggers are associated with poor outcome, including severe illness at the time of the initial assessment, high interpersonal sensitivity, low social class, separation from a parent by death during early life, divorce, and unmarried status.[62]
The risk of coronary artery disease in patients with panic disorder is nearly doubled. In patients with coronary disease, panic can induce myocardial ischemia.[24] The risk of sudden death may also theoretically be increased due to reduced heart rate variability and increased QT interval variability.[25]
The suicide rate in individuals with panic disorder is also many times higher than the general population.[2]
Inform patients that the causes of panic disorder are likely biologic and psychosocial, and that panic symptoms are not life-threatening or uncommon.[55]
Educate patients about their diagnosis and treatment options, as well as about potential adverse effects of not only their treatment medications but also any comorbid substance use such as alcohol consumption and recreational drug use. These psychoactive substances can impact the course of panic disorder. Although some substances may seem to avert the anguish of an acute attack, they often compromise the long-term treatment plan.
Consider educating patients diagnosed with panic disorder about cognitive distortions that may help to amplify anxiety. Teach patients to recognize trigger stimuli so that they can contribute this to their psychological treatment approach.
Obtain verbal informed consent for psychotropic medications, and document the discussion of the risks and benefits of treatment medications. Promote healthy behaviors, including exercise and good sleep hygiene. Advise patients to avoid anxiogenic substances, such as caffeine, energy drinks, and other OTC stimulants.[55]
Talk to the patient’s family about the importance of minimizing any avoidance behaviors by the patient and ensuring pharmacologic compliance and adherence to therapy appointments. Help the family to understand the nature of the anxiety symptoms and to provide reasonable accommodation (without enabling dysfunctional behaviors or alcohol/prescription drug use). Family members can be particularly important in helping the patient to overcome unrealistic fears and ingrained avoidance behaviors, in the context of ongoing cognitive-behavioral therapy (CBT) in which the patient learns the coping skills to manage anxiety.
Although dietary modification (eg, 5-hydroxytryptophan or inositol[30] supplementation) may be effective in preventing recurrence, there is much more evidence for the effectiveness of CBT and medications. Herbal supplementation should be deferred until after the patient has discussed it with his or her psychiatrist or primary care provider.
For more information, see Anxiety Center, as well as Anxiety, Panic Attacks, and Hyperventilation.
A general medical evaluation is important to rule out medical causes of panic symptoms.[55, 56] History, collateral information, and physical examination, as well as a mental status examination remain the diagnostic cornerstones for panic disorder. It is crucial to assess the specific features of the individual patient’s panic disorder, such as whether agoraphobia is present, the extent of situational fear and avoidance, and whether there are comorbid psychiatric conditions, all of which can affect the course, treatment, and prognosis of panic disorder.[55, 56]
DSM-5 criteria for panic disorder include 4 or more attacks in a 4-week period, or 1 or more attacks followed by at least 1 month of fear of another panic attack.[1]
The following are potential symptom manifestations of a panic attack[1] :
During the episode, patients have the urge to flee or escape and have a sense of impending doom (as though they are dying from a heart attack or suffocation).
Patients with panic disorder have recurring episodes of panic, with the fear of recurrent attacks resulting in significant behavioral changes (e.g., avoiding certain situations or locations) and worry about the implications or consequences of the attack (e.g., losing control, going crazy, dying). Panic disorder may result in changes in personality traits, characterized by the patient becoming more passive, dependent, or withdrawn.
Unexpected panic attacks have no known precipitating cue. Situationally-bound (cued) panic attacks recur predictably in temporal relationship to the trigger; these panic attacks usually implicate the diagnosis of a specific phobia. Situationally predisposed panic attacks are more likely to occur in relation to a given trigger, but they do not always occur.
A variant of panic disorder unrelated to fear (nonfearful panic disorder [NFPD]) is associated with high rates of medical resource use (32-41% of patients with panic disorder seeking treatment for chest pain) and a poor prognosis.[4]
Triggers of panic can include the following:
Assess precipitating events (e.g., major life events), phobias, agoraphobia, obsessive-compulsive behavior, and suicidal ideation and/or plan. In one study, lifetime rates of suicide attempts in patients with uncomplicated panic disorder were consistently higher (7%) than in individuals without a psychiatric disorder (1%).[69] Also assess whether there is a family history of panic or other psychiatric illness.
Exclude involvement of alcohol, nicotine, illicit drugs (e.g., cocaine, amphetamine, phencyclidine, amyl nitrate, lysergic acid diethylamide [LSD], yohimbine, 3,4-methylenedioxymethamphetamine [MDMA, ecstasy]), cannabis, and medications (e.g., caffeine, theophylline, sympathomimetics, anticholinergics), including OTC agents.
In experimental settings, symptoms can be elicited in people with panic disorder by hyperventilation, inhalation of carbon dioxide,[8] caffeine consumption, or intravenous infusions of hypertonic sodium lactate or hypertonic saline,[9] cholecystokinin, isoproterenol, flumazenil, or naltrexone.[10] The carbon dioxide inhalation challenge is especially provocative of panic symptoms in smokers.[11]
There are no physical signs specific for panic disorder. If the patient presents in an acute state of panic, he or she can physically manifest any anticipated sign of an increased sympathetic state. These nonspecific signs may include hypertension, tachycardia, mild tachypnea, mild tremors, and cool, clammy skin. Blood pressure and temperature may be within the reference range. A panic attack normally lasts 20-30 minutes from onset, although in rare cases it can go on for more than an hour. Somatic concerns of death from cardiac or respiratory problems may be a major focus of patients during an attack. Patients may end up in an emergency department.
Hyperventilation may be difficult to detect by observing breathing, because respiratory rate and tidal volume may appear normal. Patients may sigh frequently or have difficulty with breath-holding. Reproduction of symptoms with overbreathing is unreliable. Chvostek sign, Trousseau sign, or overt carpopedal spasm may be present.
The remaining physical examination findings are typically normal in panic disorder. However, remember that panic disorder is largely a diagnosis of exclusion, and attention should be focused on the exclusion of other disorders.
No results on the mental status examination are specific for panic disorder. The patient may or may not appear anxious at the time of interview, and the results on his or her Mini-Mental Status Examination, including cognitive performance, memory, serial-7, and proverb interpretation, should appear intact and consistent with the patient’s educational level and apparent baseline intellectual functioning.
During a panic attack, a mental status examination may reveal extreme anxiety, fear, and a sense of impending death or doom. The patient may have difficulty speaking as well as appear sweaty and confused. The patient’s speech may reflect anxiety or urgency, or it may sound normal, and the individual’s mood may be described as similar to "anxious," with congruent affect. Incongruent affect should raise consideration of other diagnostic possibilities.
The patient’s thought processes should be logical, linear, and goal directed. Thought content is particularly important to specifically assess in order to ensure that a patient has no suicidal or homicidal thoughts. Acute anxiety, as a form of acute mental anguish, can lead to unsafe or self-injurious behavior. Abnormalities in thought process or thought content (aside from impulsive suicidal thoughts) should prompt reconsideration of other etiologies. Insight and judgment are usually present and intact.
Standardized mental status screening tests include the following:
No invasive procedures are required to diagnose panic disorder, although they may be useful in eliminating other conditions in the differential diagnosis. As previously mentioned, history, collateral information, physical examination, and a mental status examination remain the diagnostic cornerstones for panic disorder.
Use electrocardiography (ECG) to assess for signs of ventricular preexcitation (short PR and delta wave), for short or long QT interval in patients with palpitations, and for ischemia, infarction, or pericarditis patterns in patients with chest pain. Outpatient Holter monitoring or transtelephonic event recording is rarely necessary but should be considered in patients with palpitations associated with syncope or near-syncope.
Patients who may be at risk for pulmonary embolism require appropriate testing (e.g., determination of D-dimer level, spiral CT scanning, ventilation-perfusion [V/Q] scanning, duplex Doppler/ultrasonography, or pulmonary angiography).
Laboratory studies that can exclude medical disorders other than panic disorder include the following:
Room air pulse oximetry values are usually within the reference range or at the upper limit of the reference range. End-tidal capnography values are typically less than 30 torr during hyperventilation.
Arterial blood gas analysis is useful in confirming hyperventilation (respiratory alkalosis) and excluding hypoxemia or metabolic acidosis. The presence of hypoxemia with hypocapnia or a widened alveolar-arterial (A-a) gradient should increase the suspicion of pulmonary embolus.
Electrolyte analysis is unnecessary, although several abnormalities may be present in the setting of hyperventilation. Serum phosphorus and ionized calcium may be diminished in patients with hyperventilation and carpopedal spasm, Chvostek sign, or Trousseau sign. The serum calcium level may be within the reference range.
Human subjects with panic anxiety have elevated levels of orexin in the cerebrospinal fluid. Orexin, also known as hypocretin, is thought to play an important role in the pathogenesis of panic in rat models[31] ; it is also a potential gene of risk for panic disorder.
No imaging study findings are currently specific for panic disorder, although they are performed to evaluate anatomic evidence of other diagnostic possibilities. Studies may include an electroencephalogram (EEG) to exclude partial complex seizures.
Investigational functional neuroimaging is not used in routine clinical practice for diagnosis or for monitoring treatment response. However, positron emission tomography (PET) scanning has demonstrated increased flow in the right parahippocampal region and reduced serotonin type 1A receptor binding in the anterior and posterior cingulate and raphe of patients with panic disorder.[15] Magnetic resonance imaging (MRI) has demonstrated smaller temporal lobe volume, despite normal hippocampal volume, in patients with panic disorder.[19]
All patients with panic disorder should be referred to a psychiatrist, psychologist, or other mental health professional. Psychiatric treatment has a demonstrated effect on decreasing medical costs associated with emergency department and nonpsychiatric outpatient care.[32] Free information is available to patients and physicians from the National Institute of Mental Health (NIMH) and the National Alliance on Mental Illness (NAMI) (which has a separate section on panic disorder that may be useful for patients and their families).
Pharmacotherapy, cognitive- behavioral therapy (CBT), and other psychological treatment modalities are used to manage panic disorder. The American Psychiatric Association (APA) recommends treating patients with panic disorder when symptoms cause dysfunction (e.g., work, family, social, leisure activities) or significant distress.[55] Treatment goals include the following[55] :
For more information, see the Medscape Reference topics Anxiety Disorders; Separation Anxiety and School Refusal; and Phobic Disorders.
Psychotherapy is recommended for patients with panic disorder who prefer nonpharmacologic management and who are able and willing to take the time and effort to participate in weekly (or sometimes alternate weekly) sessions and between-session practices.[55] The strongest available evidence is for CBT.[55, 56]
CBT, with or without pharmacotherapy, is the treatment of choice for panic disorder, and it should be considered for all patients.[33] This therapeutic modality has higher efficacy and lower cost, dropout rates, and relapse rates than do pharmacologic treatments. CBT may include countering anxious beliefs, exposure to fear cues, changing anxiety-maintaining behaviors, and preventing relapse.[55]
It is important to identify the frequency and nature of the panic disorder symptoms as well as the triggers of panic symptoms for effective management.[55] The patient’s symptomatic status should be monitored at each session, such as with the use of rating scales, and patients can also self-monitor by keeping a daily diary of panic symptoms.[55]
Providing a few doses of a benzodiazepine as needed (prn) can enhance patient confidence and compliance. Limit the total tablet dispensation to ensure that patients understand that they have a limited supply of the drug and that this medicine represents a temporary or emergency use option.
Educate the patient regarding the importance of longer-term management with selective serotonin reuptake inhibitor (SSRI) medication and psychotherapeutic techniques (e.g., CBT). Avoid prescribing benzodiazepine in patients with a known history of substance misuse or alcoholism.
Outpatient care is the general setting for uncomplicated panic disorder. Patients may be hospitalized if they display any evidence of dangerous behavior, have safety concerns, and/or report suicidal or homicidal ideation—as may occur in context of acute anxiety, fear of anxiety, or its consequences.
Considerations for admission include intoxication or withdrawal from sedative/hypnotics such as alcohol or alprazolam, which are sometimes ingested or abused in patients’ attempts to medicate or manage the anxiety. Patients may also be hospitalized if they become so incapacitated by their anxiety that they are unable to adhere to outpatient care. Inpatient treatment is also necessary in patients when the differential diagnosis includes other medical disorders that warrant admission (e.g., unstable angina, acute myocardial ischemia).
The APA recommends clinicians carefully assess the risk for suicide in patients with panic disorder as these individuals have an increased risk of suicidal ideation and behavior, regardless of whether comorbid conditions are present (e.g., major depression).[55]
In rare cases of severe panic disorder in which outpatient management is ineffective or impractical, hospitalization or partial hospitalization may be necessary.[55] Transfer to an acute psychiatric facility may be necessary for suicidal or homicidal patients.
Patients with chest pain, dyspnea, palpitations, or near-syncope should be placed on oxygen and in a supine or Fowler position. Monitor the patients with pulse oximetry, electrocardiography (ECG), and frequent determination of vital signs (including one set of orthostatic vital signs, when possible).
A major component of therapy involves educating the patient that their symptoms are neither from a serious medical condition nor from a psychotic disorder, but rather from a chemical imbalance in the fight-or-flight response. This alone may account for the significant placebo response rate noted in clinical trials.[34]
Patients with panic disorder may require frequent reassurance and explanation. Many may benefit from social service intervention, which may provide supportive discussions and explore resources for outpatient care. The emergency department staff must listen effectively and remain empathic and nonargumentative. Statements made by healthcare staff, such as, "It's nothing serious" and "It's related to stress" are frequently misinterpreted by the patient as implying a lack of understanding and concern.
Instituting treatment for panic disorder in the emergency department is appropriate in a very limited subset of patients who are highly motivated and cooperative, who possess an understanding of the psychological nature of their disorder, and whose symptomatology is elicited as a response to a temporary stress. In such cases, pharmacotherapy with an oral benzodiazepine for a brief duration (approximately 1 wk) may be appropriate.
Intravenous (IV) medication (e.g., lorazepam at 0.5 mg IV q20min) may be necessary in patients with panic disorder who, as a result of subsequent poor impulse control, pose a risk to themselves or to those around them. However, patients with panic disorder are probably best served by referral to a psychiatrist before beginning anxiolytic medications. A psychiatrist can establish a constructive rapport with patients and follow their needs on a long-term basis.
Cognitive-behavioral therapy (CBT) helps patients to understand how automatic thoughts and false beliefs/distortions lead to exaggerated emotional responses, such as anxiety, and how they can lead to secondary behavioral consequences. CBT can be used alone or in addition to pharmacotherapy. However, the combination approach yields superior results for most patients, compared with results from the use of either modality alone,[33, 36] by enhancing long-term outcomes through reduction in the likelihood of relapse when pharmacologic therapy is stopped.[55] Combination therapy should be considered for patients in whom standard monotherapies have not been successful.[55]
CBT is most effective when started early after symptom onset and in patients with few psychological comorbidities.[38] Therapy is generally limited to 10-15 weekly sessions and can be conducted either individually or in a group.[55] The National Collaborating Centre for Mental Health recommends CBT take the form of weekly sessions of 1-2 hours and be completed within a maximum of 4 months of commencement.[56]
Cognitive restructuring involves substituting positive thoughts (e.g., patients can tell themselves that they are only feeling a little uneasiness or that their feelings will soon be gone) for the maladaptive thoughts that accompany panic (e.g., feeling that they are going to die or are having a heart attack).
Behavioral therapy involves sequentially greater exposure of the patient to anxiety-provoking stimuli. Over time, the patient becomes desensitized to the experience. Relaxation techniques also help to control patients' levels of anxiety.[37, 38]
Data from 3 national epidemiologic surveys as well as the Cross-National Collaborative Panic Study suggest the existence of 2 subtypes of panic disorder, respiratory and nonrespiratory.[58] The nonrespiratory subtype was typified by general somatic symptoms, whereas the respiratory subtype was not only thought to be a more severe form of the disorder but also associated with a significantly greater likelihood of lifetime major depression.[58]
Respiratory training can help patients to control hyperventilation during panic attacks and to control anxiety with controlled breathing. In addition, capnometry feedback-assisted breathing training can be used to prevent hypocapnia and stabilize the respiratory rate.
Interoceptive exposure involves encouraging patients to induce internal sensations (e.g., dizziness, increased heart rate, lightheadedness) by spinning, exercising, or rapid breathing and to interpret these as normal bodily sensations. Guided imagery and hypnotic suggestion may also be beneficial.
The American Psychiatric Association (APA) found insufficient evidence to either recommend any pharmacologic intervention as superior to others for panic disorder or to routinely recommend combination therapy over monotherapy.[55] However, pharmacotherapy is recommended for patients who prefer to be managed with medication or those who don’t have the time or other resources to participate in psychosocial therapy.[55] Keep in mind that patients with panic disorder are twice as likely as the population to use alternative therapies. The use of dietary supplements (e.g., herbs) should be discussed to avoid drug interactions.
It is important to inform patients of the potential adverse effects of specific pharmacotherapies, as well as a realistic time frame for expecting results and the likely duration of treatment.[55, 56]
Selective serotonin reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, sertraline, paroxetine and paroxetine controlled release, fluvoxamine) are generally used as first-line pharmacologic agents in panic disorder, followed remotely by tricyclic antidepressant agents (TCAs) (e.g., imipramine, desipramine, nortriptyline, clomipramine).[55, 56]
The National Collaborating Centre for Mental Health practice guidelines indicate that TCAs such as imipramine or clomipramine may be considered for the management of panic disorder if an SSRI is not suitable or if there is no improvement after a 12-week course of SSRI treatment.[56] (Prior to the use of SSRIs for panic disorder, the TCAs and the monoamine oxidase inhibitors [MAOIs] were used much more commonly for this condition.) In addition to SSRIs, the APA reported that there is strong support from randomized controlled trials for the effective use of serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine) as the initial treatment of panic disorder.[55]
Citalopram (Celexa) and escitalopram (Lexapro) are likely to cause fewer hepatic enzyme interactions than other SSRIs and may be appropriate initial choices for patients with complicated medical regimens or for those who are concerned about drug interactions.
However, the FDA issued a Drug Safety Communication in August 2011 stating that citalopram (Celexa) should not be used at doses greater than 40 mg per day, owing to the potential for dangerous abnormalities in cardiac electrical activity.[57] Citalopram 20 mg per day is the maximum recommended dose in patients with hepatic impairment, who are older than 50 years, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (Tagamet) or another CYP 2C19 inhibitor. Such individuals can have higher blood levels of citalopram, leading them to have an increased risk of prolonged QT interval and torsade de pointes.[57]
Additional warnings as of March 2012 discourage the use of citalopram at any dose in patients with certain conditions (congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure) due to potentially dangerous prolongation of the QT interval.[57]
Escitalopram seems to be well tolerated in preliminary studies, but costs more than citalopram and does not appear to offer any significant advantage. Fluoxetine (Prozac) can be used, especially if panic disorder occurs with depression. Patients may have poor tolerance for it at the start because the drug may initially increase anxiety, except at very low starting doses. Fluoxetine has a long half-life, making it a good choice in marginally compliant patients. However, this agent alters the metabolism of cytochrome P-450 2D6-cleared agents.
Sertraline (Zoloft) represents a similar SSRI option with a slightly different pharmacodynamic profile, including sigma-receptor effects, although it has some P450 3A4 interactions.
Paroxetine (Paxil), mirtazapine, and TCAs are usually prescribed for use before bedtime to help improve sleep. Caution patients to avoid operating a motor vehicle or machinery directly after the dose or if they are feeling sedated.
Paroxetine is also available in a controlled release preparation (Paxil CR), which may improve tolerability, but it still inhibits P450 2D6. Paroxetine is a category D drug during pregnancy (ie, human studies have shown a risk to the fetus, but the drug’s benefits may outweigh the risk in pregnant women). Use of this medication requires patient counseling as well as documentation of the potential risks in women of reproductive age.
Mirtazapine (Remeron), a noradrenergic and specific serotonergic antidepressant (NaSSA), has a much more sedating effect, generally reducing its potential to aggravate initial anxiety.[35] Mirtazapine acts distinctly as an alpha-2 antagonist, consequently increasing synaptic norepinephrine and serotonin, while it also blocks some postsynaptic serotonergic receptors that conceptually mediate excessive anxiety when stimulated with serotonin. Note that mirtazapine may cause residual morning sedation that often improves with continued therapy, and it may also cause an increase in appetite or weight gain.
Most patients are started on long-term (e.g., 6 mo) therapy with SSRIs, TCAs, or MAOIs only after consultation with their primary physician or psychiatrist.
Benzodiazepines (e.g., alprazolam, clonazepam, lorazepam) can achieve long-term control of panic disorder, but these agents should be reserved for patients with refractory panic disorder. Patients started on benzodiazepines for panic disorder should receive a psychiatric referral for review of pharmacologic management and, potentially, a psychotherapist for any additional nonpharmacologic treatment options. Benzodiazepines should not be used as monotherapy in panic disorder unless there is no co-occurring mood disorder.[55]
Benzodiazepines act quickly but carry the liability of physiologic and psychological dependence. Benzodiazepines can be reasonably used as an initial adjunct while SSRIs are titrated to an effective dose; that is, these agents can then be tapered over 4-12 weeks while the SSRI is continued. This approach can improve short-term tolerability, although it may increase the risk of sedation and requires warnings for the patient to not operate motor vehicles after taking benzodiazepines or if they’re feeling sedated.
Alprazolam (Xanax) has been widely used for panic disorder, but its use is currently discouraged because of its higher abuse/dependence potential. This agent has a short half-life, which makes it particularly prone to rebound anxiety and psychological dependence. Clonazepam (Klonopin) has become a favored replacement, because it has a longer half-life and empirically elicits fewer withdrawal reactions upon discontinuation relative to alprazolam.
Complications of benzodiazepine use
Because panic disorder is usually a chronic disorder, sole reliance on habituating drugs is discouraged. Benzodiazepine dependence can occur in 30% of patients who are on therapy that lasts longer than 8 weeks.[30] It is less likely to occur in patients without a history of chemical or emotional dependence. Benzodiazepine abuse is suggested by escalating dose consumption over time.
Note that benzodiazepine withdrawal can precipitate panic. The primary physician should gradually taper doses over several weeks or months.
Treatment is working if the patient’s key symptoms (e.g., frequency/intensity of panic attacks, level of anticipatory anxiety, degree of agoraphobic avoidance, severity of functional interference and distress related to the disorder) decrease.[55] Be aware that changes may occur more quickly in some domains than others.
Regularly evaluate the severity of any co-occurring psychiatric conditions, such as major depression and other anxiety disorders. Useful adjunctive tools for evaluating treatment outcome include rating scales on an ongoing basis.[55]
First-line treatments for panic disorder may result in a partial response or no response. In such cases, reevaluate the patient as early as possible for any untreated underlying medical conditions that could cause the patient’s symptoms, as well as the presence of any co-occurring general medical or psychiatric conditions (e.g., depression, substance abuse), treatment noncompliance, problems with the collaboration between therapist and patient, psychosocial stressors, motivational factors, and treatment intolerance.[55, 56] Clinicians goals should be toward remission whenever feasible, rather than accepting partial improvements as satisfactory outcomes.
Consider a change in treatment strategy when the treatment outcome remains unsatisfactory despite an adequate trial, particularly when significant panic symptoms persist despite a long course of a specific treatment.[55, 56] The types of changes must be personalized for each individual.
If, after any key clinical issues have been addressed, and a change in treatment is still desired: (1) The current treatment strategy can be augmented with either another medication or treatment modality, if some significant benefits were noted with the current treatment, or (2) the patient can switch to another treatment strategy with different drug or modality, if the initial therapy did not provide any significant relief of the patient’s symptoms.[55]
The following are some recommendations from the American Psychiatric Association (APA)[55] :
In general, pharmacologic management is continued for at least 1 year following an acute response to increase the potential for further reductions in the patient’s panic symptoms as well as to lower the risk for recurrence.[55] Monthly “booster” sessions that target prevention of relapse may also be used.[55]
The decision to taper or discontinue an effective pharmacotherapy must be tailored to the patient and discussed between the patient and clinician, based upon factors including the duration of the patient’s symptom stability, whether current/impeding psychosocial stressors are present, the extent of the patient’s motivation, as well as the potential outcomes following medication taper or discontinuation.[55, 56]
Despite the effectiveness of standard management for panic disorder in a majority of affected patients, some individuals with good treatment responses may have persistent or recurrent symptoms following remission.[55] Symptomatic fluctuations are not uncommon during treatment and symptoms may recur following remission. Provide patients with response plans in such situations.[55]
Cognitive-behavioral therapy (CBT) with cognitive restructuring, relaxation techniques, breathing exercises, hypnotic suggestion, and interoceptive exposure may prevent recurrence. Pharmacotherapy and dietary modification (e.g., 5-hydroxytryptophan or inositol supplementation[38] ) may also prevent recurrence, as may exercise.[39]
A study suggested that patients who give a high importance to religion and religious practices have improved panic symptoms and fewer recurrences.[40] Internet-based CBT and virtual reality exposure therapy are promising possibilities for recurrence prevention.[41]
Patients with panic disorder are reluctant to believe their symptoms are not life-threatening and have a high rate of emergency department use. Moreover, because of a reluctance to use medications (related to a fear of losing control), patients with panic disorder are frequently noncompliant. Psychiatrists need to not only assess and identify potential barriers to treatment compliance but also work with the patient to minimize or overcome these roadblocks.[55]
Patients with panic disorder also have a 4-fold increase in the risk of adverse medication effects, which can result in noncompliance and temporarily increased anxiety. Psychiatrists should encourage patients to discuss such concerns as well as provide realistic expectations at various points in their treatment.[55]
Refer all patients with panic disorder for psychiatric or mental health follow-up care and to support groups. Consult a cardiologist for patients with abnormal electrocardiogram (ECG) findings, ventricular dysrhythmia, abnormal cardiac examination, or risk factors for ischemic heart disease,[26] and consult an addiction treatment specialist in cases of significant intoxication or withdrawal.
Initial follow-up care should occur within 2 weeks, because selective serotonin reuptake inhibitors (SSRIs) can cause an initial exacerbation of panic symptoms. For this reason, begin with the lowest dose—with the understanding that the dose must be increased at the initial follow-up visit.
Assess potential suicide risk at all appointments. Ensure continuing treatment of any concurrent substance use disorders. Follow-up care by a chemical dependence treatment specialist is recommended when indicated.
Patients with ventricular dysrhythmias, abnormal findings on electrocardiography (ECG), abnormal findings on cardiac examination, or significant risk factors for heart disease should be referred to a cardiologist.[23]
First-line pharmacologic therapies for panic disorder include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).[55] These 3 classes of agents are preferred over benzodiazepines as monotherapies for patients with co-occurring depression or substance use disorders.
The FDA issued a Drug Safety Communication in August 2011 stating that the SSRI, citalopram (Celexa), should not be used at doses greater than 40 mg per day, owing to the potential for dangerous abnormalities in cardiac electrical activity.[57] Citalopram 20 mg per day is the maximum recommended dose in patients with hepatic impairment, who are older than 60 years, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (Tagamet) or another CYP 2C19 inhibitor. Such individuals can have higher blood levels of citalopram, leading to an increased risk of prolonged QT interval and torsade de pointes.[57]
Additional warnings as of March 2012 discourage the use of citalopram at any dose in patients with certain conditions (congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure) due to potentially dangerous prolongation of the QT interval.[57]
For patients requiring rapid symptom control, benzodiazepines can be used as adjuncts with antidepressant agents to treat residual anxiety symptoms, and they may be preferred (as monotherapies or in combination with antidepressants).[55] Clinicians must carefully assess the benefit of more rapid response against the potential complications of benzodiazepine therapy.
The American Psychiatric Association (APA) recommends avoiding TCAs for patients with panic disorder who also have acute narrow-angle glaucoma or clinically significant prostatic hypertrophy.[55] TCAs may increase the risk of falls and fractures, particularly in elderly patients. In addition, owing to the potential for significant or fatal arrhythmia in patients with preexisting cardiac conduction abnormalities, it is important to obtain an electrocardiogram (ECG) in these individuals before starting TCA treatment. Use TCAs with caution in suicidal patients as overdoses with these drugs can cause cardiac toxicity and death.[55]
Clinical Context: Lorazepam is a sedative hypnotic with a short onset of effects and a relatively intermediate half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, lorazepam may depress all levels of the CNS, including the limbic and reticular formations.
Clinical Context: Clonazepam is a sedative hypnotic that is a long-acting benzodiazepine with a half-life of approximately 36 hours and an intermediate onset of action. This agent facilitates inhibitory GABA neurotransmission and other inhibitory transmitters.
Clinical Context: Alprazolam is used for the management of anxiety attacks. It is a short-acting anxiolytic with an intermediate onset of effects. This agent binds to receptors at several sites within the CNS, including the limbic system and the reticular formations. The effects of alprazolam may be mediated through the GABA receptor system. Alprazolam has been widely reviewed in the literature, although its use is currently discouraged because of its higher potential to elicit dependency.
Clinical Context: Diazepam is an anxiolytic benzodiazepine and has a rapid onset of effects. This medication depresses all levels of the CNS (eg, the limbic and reticular formations), possibly by increasing the activity of GABA.
By binding to specific receptor sites, benzodiazepines appear to potentiate the effects of gamma-aminobutyrate (GABA) and facilitate inhibitory GABA neurotransmission and other inhibitory transmitters. These agents are effective on standing-dose and as-needed (prn) schedules
Clinical Context: Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on reuptake of norepinephrine or dopamine. It has a long half-life and therefore a lower risk of withdrawal symptoms. However, fluoxetine does require slower titration and has CNS stimulating effects.
Clinical Context: Paroxetine is the least stimulating SSRI. This agent is a potent selective inhibitor of neuronal serotonin reuptake. Paroxetine also has a very weak effect on norepinephrine and dopamine neuronal reuptake. It does not significantly bind to muscarinic, alpha-adrenergic, or histamine receptors and therefore has fewer adverse effects than do tricyclic antidepressants (TCAs).
Clinical Context: Sertraline selectively inhibits presynaptic serotonin reuptake. It also has a very weak inhibitory effect on norepinephrine and dopamine neuronal reuptake.
Clinical Context: Fluvoxamine is a potent selective inhibitor of neuronal serotonin reuptake. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and therefore has fewer adverse effects than do tricyclic antidepressants.
Clinical Context: Citalopram enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. SSRIs are the antidepressants of choice due to minimal anticholinergic effects.
Clinical Context: Escitalopram is an SSRI and an S-enantiomer of citalopram. Its mechanism of action is thought to be potentiation of serotonergic activity in the CNS resulting from the inhibition of CNS neuronal reuptake of serotonin.
Selective serotonin reuptake inhibitors (SSRIs) are first-line agents for the long-term management of anxiety disorders. Control is gradually achieved over a 2- to 4-week course, depending on the required dosage increases.
All commonly used SSRIs appear to have a role in the treatment of panic disorder. Fluoxetine is covered here, because it has a very long half-life; this makes it well suited for patients who have difficulty remembering to take all of their medications each day. The longer half-life also minimizes the risk and severity of SSRI withdrawal that can occur when patients exhaust or abruptly discontinue their SSRI.
Clinical Context: The mechanism of action of imipramine is not fully known. However, the clinical effect is hypothesized as being due to the inhibition of the reuptake of norepinephrine and serotonin (5-hydroxytryptamine [5-HT]) at presynaptic neurons.
Clinical Context: Desipramine may increase the synaptic concentration of norepinephrine in the CNS by inhibiting the reuptake by the presynaptic neuronal membrane. It may have effects in the desensitization of adenyl cyclase, downregulation of beta-adrenergic receptors, and downregulation of serotonin receptors.
Clinical Context: Clomipramine affects serotonin uptake. This agent also affects norepinephrine uptake when converted into its metabolite, desmethylclomipramine.
Tricyclic antidepressants (TCAs) have the advantages of once-daily dosing, low risk of dependence, and no dietary restrictions. However, these drugs are discontinued in 35% of patients because of adverse effects, such as blurred vision, dry mouth, dizziness, weight gain, gastrointestinal disturbance, agitation, insomnia, headache, and decreased libido or ability to orgasm.
TCAs must be started in low doses to avoid amphetamine-like stimulation and can require up to 8-12 weeks for treatment response.
Clinical Context: Nardil is the MAOI that is most commonly used for managing panic disorder. It has demonstrated clear superiority over placebo in double-blind trials for treating specific symptoms of panic disorder. This drug is usually reserved for patients who do not tolerate or whose condition does not have a response to traditional cyclic or second-generation antidepressants.
Clinical Context: Tranylcypromine is also effective against panic disorder. It binds irreversibly to MAO, thereby reducing monoamine breakdown and enhancing synaptic availability.
Monoamine oxidase inhibitors (MAOIs) are effective in patients with social phobia and refractory anxiety disorders, including panic disorder. Advantages of MAOIs include a low risk of dependence and less anticholinergic effect than tricyclic antidepressants (TCAs). Disadvantages include the higher number of adverse effects, including sexual difficulty, hypotension, weight gain, dry mouth, tachycardia, insomnia, drowsiness, headache, weakness, and constipation.
Clinical Context: Venlafaxine is a serotonin/norepinephrine reuptake inhibitor. It may treat depression by inhibiting neuronal serotonin and norepinephrine reuptake. In addition, it causes beta-receptor down-regulation.
Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants inhibit serotonin reuptake receptors and, unlike the pure selective serotonin reuptake inhibitors (SSRIs), inhibit the reuptake of norepinephrine as well.
Clinical Context: Trazodone is useful in the treatment of panic disorder and agoraphobia with panic attacks. It is an antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. Trazodone also has a negligible affinity for cholinergic and histaminergic receptors.
In animals, this drug selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan.
Clinical Context: Mirtazapine is an alpha-2 adrenergic antagonist that increases synaptic norepinephrine and serotonin, while also blocking some postsynaptic serotonergic receptors that conceptually mediate excessive anxiety when stimulated with serotonin. This agent causes significant sedation which generally reduces its potential to aggravate initial anxiety and may cause residual morning sedation that often improves with continued therapy.
Sedating antidepressants such as mirtazapine are usually prescribed for use only at night before bed to help improve sleep, but they should include a warning for patients not to operate a motor vehicle or machinery if they are feeling sedated or directly after the dose.
Mirtazapine may also cause an increase in appetite or weight gain.
Other antidepressants are those that are unique and not categorized into the classification of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SSNIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).