Chapter 24. Fatigue, Asthenia, Anxiety, and Depression

In this chapter, we consider the clinically related phenomena of lassitude, fatigue, nervousness, irritability, anxiety, and depression. These complaints form the core of a group of "symptom-based" disorders that are a large part of medical practice. Although more abstruse than paralysis, sensory loss, seizures, or aphasia, they are no less important, if for no other reason than their frequency. In an audit of one neurologic practice, anxiety and depressive reactions were the main diagnosis in 20 percent of patients, second only to the symptom of headache (Digon et al). Similarly, in two primary care clinics in Boston and Houston, fatigue was the prominent complaint in 21 and 24 percent of patients, respectively. Some of these symptoms represent only slight aberrations of function or a heightening or exaggeration of normal reactions to environmental stress or to medical and neurologic diseases; others are integral features of the diseases themselves; and still others represent disturbances of neuropsychiatric function that are components of the diseases described in Chaps. 51, 52, and 53 on psychiatry.

Of the symptoms considered in this chapter, lassitude and fatigue are the most frequent, and the most vague. Fatigue refers to the universally familiar state of weariness or exhaustion resulting from physical or mental exertion. Lassitude has much the same meaning, although it connotes more of an inability or disinclination to be active, physically or mentally. More than half of all patients entering a general hospital register a complaint of fatigability or admit to it when questioned. During World War I, fatigue was such a prominent symptom in combat personnel as to be given a separate place in medical nosology, namely combat fatigue, a term that came to be applied to practically all acute psychiatric disorders occurring on the battlefield. In subsequent wars, it has become a key element of the posttraumatic stress disorders related to exposure to highly stressful circumstances. The common clinical antecedents and accompaniments of fatigue, its significance, and its physiologic and psychologic bases will be better understood if we first consider the effects of fatigue on the normal individual.

Effects of Fatigue on the Normal Person

Fatigue has three basic meanings: (1) biochemical and physiologic changes in muscles and a reduced capacity to generate force manifest as weakness, or asthenia; (2) a disorder in behavior, taking the form of a reduced output of work (work decrement) or a lack of endurance; and (3) a subjective feeling of tiredness and discomfort.

The decreased productivity and capacity for work, which is a direct consequence of fatigue, has been investigated by industrial psychologists. Their findings clearly demonstrate the importance of motivational factors on work output, whether the effort is of physical or mental type. Quite striking are individual constitutional differences in energy, which vary greatly, just as do differences in temperament. What should be emphasized is that in the majority of persons complaining of fatigue, one does not find true muscle weakness. This may be difficult to prove, for many such individuals are disinclined to exert full effort in tests of peak power of muscle contraction or in endurance of muscular activity.

The Clinical Significance of Fatigue

Patients experiencing lassitude and fatigue have a more or less characteristic way of expressing their symptoms. They say that they are "wiped, or burned out," "tired all the time," "weary," "exhausted," or "pooped out," or that they have "no pep," "no ambition," or "no interest." They manifest their condition by showing an indifference to the tasks at hand, by emphasizing how hard they are working, and how stressed they are by circumstances; they are inclined to sit around or lie down or to occupy themselves with trivial tasks. On closer analysis, one observes and hears that many such patients have difficulty in initiating activity and also in sustaining it; i.e., their endurance is diminished. This condition, of course, is the familiar aftermath of sleeplessness or prolonged mental or physical effort, and, under such circumstances, it is accepted as a normal physiologic reaction. When, however, similar symptoms appear without relation to such antecedents, they should be suspected of being the manifestations of disease.

The physician's task is initially to determine whether the patient is merely suffering from the common physical and mental effects of overwork. Overworked, overwrought people are observable everywhere in our society. In addition to fatigue, such persons frequently show irritability, restlessness, sleeplessness, and anxiety, sometimes to the point of panic attacks and a variety of somatic symptoms, particularly abdominal, thoracic, and cranial discomforts. Formerly, society accepted this state in responsible individuals and prescribed the obvious cure, a vacation. Even Charcot made time for regular "cures" during the year, in which he retired to a spa without family, colleagues, or the drain of work. Nowadays, the need to contain this type of stress, to which some individuals are more prone than others, has spawned an industry of meditation, yoga, and similar activities. Individuals with hobbies, nonwork interests, and athletic pursuits seem to be less subject to this problem. A common error in diagnosis, however, is to ascribe fatigue to overwork when actually it is a manifestation of anxiety or depression, as described below.

Fatigue as a Symptom of Psychiatric Illness

The majority of patients who seek medical help for unexplained chronic fatigue and lassitude are found to have some type of psychiatric illness. Formerly this state was called "neurasthenia," a term introduced by Beard, but because lassitude and fatigue rarely exist as isolated phenomena, the current practice is to label such cases according to the total clinical picture. The usual associated symptoms are anxiety, irritability, depression, insomnia, headaches, dizziness, difficulty in concentrating, reduced sexual drive, and loss (or sometimes increase) of appetite. In one series, 85 percent of persons admitted to a general hospital and seen in consultation by a psychiatrist for the chief complaint of chronic fatigue were diagnosed, finally, as having anxious depression or an anxiety state. In a subsequent study, Wessely and Powell found similarly that 72 percent of patients who presented to a neurologic center with unexplained chronic fatigue proved to have a psychiatric disorder, most often a depressive illness.

Several features are common to the psychiatric group with fatigue. Tests of peak muscle power on command, with the patient exerting full effort, reveal no weakness. The sense of fatigue may be worse in the morning. There is an inclination to lie down and rest, but sleep does not follow. The fatigue is worsened by mild exertion and relates more to some activities than to others. Inquiry may disclose that the symptom was first experienced in temporal relation to a grief reaction, a surgical procedure, physical trauma such as an automobile accident, or a medical illness such as myocardial infarction. The feeling of fatigue interferes with both mental and physical activities; the patient is easily worried, is "full of complaints," and finds it difficult to concentrate in attempting to solve a problem or to read a book, or in carrying on a complicated conversation. Also, sleep is disturbed, with a tendency to early morning waking, so that such persons are at their worst in the morning, both in spirit and in energy output. Their tendency is to improve as the day wears on, and they may even feel fairly normal by evening. It may be difficult to decide whether the fatigue is a primary manifestation of the disease or secondary to a lack of interest.

Among chronically fatigued individuals without medical disease, not all deviate enough from normal to justify the diagnosis of anxiety or depression. Many persons, because of circumstances beyond their control, have little motivation and much idle time. They are bored with the monotony of their routine. Such circumstances are conducive to fatigue, just as the opposite, a strong emotion or a new enterprise that excites optimism and enthusiasm, will dispel fatigue. Some persons are born with low impulse and energy and become more so at times of stress; they have a lifelong inability to exercise vigorously, to compete successfully, to work hard without exhaustion, to withstand illness or recover quickly from it, or to assume a dominant role in a social group—a "constitutional asthenia" (Kahn's term). Most of these traits are evident from childhood. These difficulties are not currently framed in these terms because they sound judgmental, but disorders of this type have been known since antiquity and only vary in name and social context in each era.

Fatigue in Neurologic Diseases

Not unexpectedly, fatigue and intolerance of exercise (i.e., fatigue with mild exertion) are prominent manifestations of myopathic disease. Even in myasthenia gravis, the muscles exhibiting fatigue are usually weak, however, in the resting state. In addition to myasthenia gravis, the classes of myopathy in which weakness, inability to sustain effort, and excessive fatigue are notable features include the muscular dystrophies, congenital myopathies, other disorders of neuromuscular transmission (Lambert-Eaton syndrome), toxic myopathies (e.g., from cholesterol-lowering drugs), some of the glycogen storage myopathies, and mitochondrial myopathies. One type of glycogen storage disease, McArdle phosphorylase deficiency, is exceptional in that fatigue and weakness are accompanied by pain and sometimes by cramps and contracture. The first contractions after rest are of near-normal strength, but after 20 to 30 contractions, there occurs a deep ache and an increasing firmness and shortening of the contracting muscles. Another such process, acid maltase deficiency, is at times associated with disproportionate weakness and fatigue of respiratory muscles, which leads to dyspnea and retention of carbon dioxide. The characteristics of these diseases are presented in the chapters on muscle disease. Further comments on muscular fatigue can be found in Chap. 48.

Fatigue of varying degree is also a regular feature of all diseases that are marked by denervation of muscle and loss of muscle fibers. Fatigue in these cases is a result of the excessive work imposed on the remaining intact muscle (overwork fatigue). This is most characteristic of amyotrophic lateral sclerosis and the postpolio syndrome, but it also occurs in patients who are recovering from Guillain-Barré syndrome and in those with chronic polyneuropathy.

Not surprisingly, many neurologic diseases that are characterized by incessant muscular activity or by difficulty engaging the muscles (Parkinson disease, cerebral palsy, Huntington disease, hemiballismus) also induce fatigue. Muscles partially paralyzed by a stroke feel tired and may cause an overall fatigue state. The distinguished neuroanatomist A. Brodal gave an interesting account of his own stroke and its effects on muscle power. Fatigue is often a major complaint of patients with multiple sclerosis; its cause is unknown, although the effect of cytokines circulating in the cerebrospinal fluid has been postulated. The depression that follows stroke or myocardial infarction frequently presents with the complaint of fatigue rather than other signs of mood disorder. Inordinate fatigue is a common complaint among patients with postconcussive syndrome (see Chap. 35). Severe fatigue that causes the patient consistently to go to bed right after dinner and makes all mental activity effortful should suggest an associated depression. These central fatigue states and their possible mechanisms, almost all speculative, have been discussed by Chaudhuri and Behan.

Many states of disordered autonomic function in which static or orthostatic hypotension are features, are associated with a fatigue state. Whether there is in addition a type of central autonomic (hypothalamic) fatigue, aside from the endocrine changes discussed below, is uncertain, but such an entity seems plausible and has been included in models of the illness currently called chronic fatigue syndrome.

Fatigue in Medical Diseases

A wide variety of medications and other therapeutic agents, particularly when first administered, sometimes induce fatigue. The main offenders in this respect are antihypertensive drugs, especially beta-adrenergic blocking agents, antiepileptics, antispasticity drugs, anxiolytics, chemotherapy and radiation therapy and, paradoxically, many antidepressant and antipsychotic drugs. Introduction of these medications in gradually escalating doses may obviate the problem, but just as often, an alternative medicine must be chosen. The administration of beta-interferon for the treatment of multiple sclerosis (and alpha-interferon for other diseases) induces fatigue of varying degree. Surgeons and nurses can testify to fatigue that comes with exposure to anesthetics in inadequately ventilated operating rooms. Similarly, fatigue and headache may result from exposure to carbon monoxide or natural gas in homes with furnaces in disrepair or from leaking gas pipes, but this is also a frequent delusion in anxious, depressed, or demented patients.

The sleep apnea syndrome is an important and often overlooked cause of fatigue and daytime drowsiness. In overweight men who snore loudly and need to nap frequently, testing for sleep apnea is indicated (this subject was taken up in Chap. 19). Correcting the obstructive apnea that underlies this condition leads to a dramatic reduction in fatigue. The same holds for patients who have neuromuscular diseases that affect the diaphragm and other respiratory muscles.

Acute or chronic infection is an important cause of fatigue. Everyone has at some time or other sensed the abrupt onset of exhaustion, a tired ache in the muscles, or an inexplicable listlessness, only to discover later that he was "coming down with the flu." Chronic infections such as hepatitis, tuberculosis, brucellosis, infectious mononucleosis, HIV, and bacterial endocarditis may not be evident immediately but should be suspected when fatigue is a new symptom and disproportionate to other symptoms such as mood change, nervousness, and anxiety. Whether a chronic form of Lyme disease is responsible for chronic fatigue, as often imputed, is uncertain at best. Often, fatigue begins with an obvious infection (such as influenza, hepatitis, or infectious mononucleosis), but persists for several weeks after the overt manifestations of infection have subsided; it may then be difficult to decide whether the fatigue represents the lingering effects of the infection or is due to psychologic-asthenic symptoms during convalescence. This difficult problem is discussed below. Patients with systemic lupus, Sjögren syndrome, or polymyalgia rheumatica may complain of severe fatigue; in the last of these, fatigue may be the initial and a profound symptom.

Metabolic and endocrine diseases of various types may cause inordinate degrees of lassitude and fatigue. Sometimes there is, in addition, a true muscular weakness. In Addison, Sheehan, and Simmonds diseases, fatigue may dominate the clinical picture. Aldosterone deficiency is another established cause of chronic fatigue. In persons with hypothyroidism with or without frank myxedema, lassitude and fatigue are frequent complaints, as are muscle aches and joint pains. Fatigue may also be present in patients with hyperthyroidism, but it is usually less troublesome than nervousness. Uncontrolled diabetes mellitus is accompanied by excessive fatigability, as are hyperparathyroidism, hypogonadism, and Cushing disease. Fatigue as a feature of vitamin B12 deficiency, as stated in many textbooks, has not been evident in the cases with mild deficiency that we have observed.

Reduced cardiac output and diminished pulmonary reserve are important causes of breathlessness and fatigue, which are brought out by mild exertion. Anemia, when severe, is another cause, probably predicated on a similar inadequacy of oxygen supply to tissues. Mild grades of anemia are usually asymptomatic, and tiredness is still far too often ascribed to it. An occult malignant tumor, e.g., pancreatic, hepatic, or gastric carcinoma, may announce itself by inordinate fatigue. In patients with metastatic carcinoma, and especially lymphoma, leukemia, or multiple myeloma, fatigue is a usual and prominent symptom. Uremia is accompanied by fatigue; the associated anemia may play a role. Any type of nutritional deficiency may, when severe, cause lassitude; in its early stages, this may be the chief complaint. Weight loss and a history of alcoholism and dietary inadequacy provide the clues to the nature of the illness.

Pregnancy causes fatigue, which may be profound in the later months. To some extent the underlying causes, including the work of carrying excess weight and an anemia, are obvious; but if excessive weight gain and hypertension are associated, preeclampsia should be suspected.

Postviral and Chronic Fatigue Syndromes

A particularly difficult problem arises in the patient who complains of severe fatigue for many months or even years after a bout of infectious mononucleosis or some other viral illness. This has been appropriately called the postviral fatigue syndrome. The majority of patients are women between 20 and 40 years of age, but there are undoubtedly young men with the same illness. A few such patients had been found to have unusually high titers of antibody to Epstein-Barr virus (EBV), which suggested a causal relationship and gave rise to terms such as the chronic infectious mononucleosis or chronic EBV syndrome (Straus et al). However, subsequent studies made it clear that a majority of patients with complaints of chronic fatigue have neither a clear-cut history of infectious mononucleosis nor serologic evidence of this or another infection (Straus; Holmes et al). In some of these patients, the fatigue state has allegedly been associated with obscure immunologic abnormalities similar to those attributed (spuriously) to silicone breast implants or minor trauma. The currently fashionable designation for these abstruse states of persistent fatigue is the chronic fatigue syndrome.

Some perspective is provided by the recognition that a malady of this precise nature, under many different names, has long pervaded postindustrial western society, as described by Shorter in an informative history of the chronic fatigue syndrome. The attribution of fatigue to viral or Lyme infection and to ill-defined immune dysfunction are only the latest in a long line of putative explanations. At various times, even in our recent memory, colitis and other forms of bowel dysfunction, spinal irritation, hypoglycemia, brucellosis, and chronic candidiasis, "multiple chemical sensitivity," retroviral infection, or environmental allergies, among others, have been proposed without basis as causes. Unfortunately, these spurious associations have only served to marginalize the disease and patients who suffer from it.

The current criteria for the diagnosis of chronic fatigue syndrome are the presence of persistent and disabling fatigue for at least 6 months, coupled with an arbitrary number (6 or 8) of persistent or recurrent somatic and neuropsychologic symptoms including low-grade fever, cervical or axillary lymphadenopathy, myalgias, migrating arthralgias, sore throat, forgetfulness, headaches, difficulties in concentration and thinking, irritability, and sleep disturbances (Holmes et al). A number of such patients in our experience have complained of paresthesias in the feet or hands. On close questioning, many of these sensations prove to be odd, particularly numbness in the bones or muscles or fluctuating patches of numbness or paresthesia on the chest, face, or nose. Unusual descriptions may be given if the patient is allowed adequate time to describe the symptoms. A few have reported blurred or "close to" double vision; in neither case are there physical findings to corroborate the sensory experiences.

There is a common association with the similarly obscure entity of fibromyalgia, consisting of neck, shoulder, and paraspinal pain and point tenderness, as described in Chaps. 11 and 48. Despite these complaints, the patient may look surprisingly well and the neurologic examination is normal. The term for this same entity, myalgic encephalomyelitis, is preferred in Great Britain and captures the association between the two syndromes.

Complaints of muscle weakness are also frequent among such patients, but Lloyd and coworkers, who studied their neuromuscular performance and compared them with control subjects, found no difference in maximal isometric strength or endurance in repetitive submaximal exercise and no change in intramuscular acidosis, serum creatine kinase (CK) levels, or depletion of energy substrates. These individuals share with depressed patients a subnormal response to cortical magnetic motor stimulation after exercise (Samii et al), which can be said to match their symptoms of reduced endurance but otherwise is difficult to interpret. In a small number of affected persons, a chronic but usually mild hypotension, elicited with tilt-table testing and reversed by mineralocorticoids, has been proposed as a cause of chronic fatigue (Rowe et al). Electromyography and nerve conduction studies are typically normal, as is the spinal fluid, but the electroencephalogram (EEG) may be mildly and nonspecifically slowed. Batteries of psychologic tests have disclosed variable impairments of cognitive function, misinterpreted by advocates of the "organic" nature of the syndrome as proof of some type of encephalopathy.

In a large group of patients who were studied 6 months after viral infections, Cope and colleagues found that none of the features of the original illness was predictive of the development of chronic fatigue; however, a previous history of fatigue or psychiatric problems, and an indefinite diagnosis were often associated with persistent disability. In one study of more than 1,000 patients who were observed for 6 months following an infective illness, the chronic fatigue syndrome was no more frequent than in the general population (Wessely et al). One thing is clear to the authors: that applying the label of chronic fatigue syndrome in susceptible individuals tends to perpetuate this state.

Having oriented the above discussion to imply that many cases of chronic fatigue have a psychologic, or asthenic basis, it should be emphasized that previously healthy individuals, for years after a severe febrile viral infection may have persistent fatigue; the best-characterized situation follows mononucleosis, but other febrile illnesses have been implicated as well. These cases, in our experience, have arisen suddenly, mostly in adolescents and young men, and less often women, who experience overwhelming fatigue during a well-documented and prolonged viral infection. They continue to take interest in activities in which they are able to participate, do not show anxiety or major depressive symptoms, and have the best prognosis, although complete recovery may take up to 3 to 5 years. Often these patients are able to define the date on which the illness began. The term postviral fatigue state is most appropriate for this group. Impressive in some of our cases have been severe headaches and orthostatic hypotension, with wide swings in blood pressure resulting in syncope as well as intermittent hypertension. Alcohol intolerance may develop. It would seem that the more ambiguous and less-severe cases of chronic fatigue, particularly those with fibromyalgia, may have a different basis, but this cannot be stated with certainty.

At the present time, the status of the chronic fatigue syndrome is undetermined. The possibility of an obscure metabolic or immunologic derangement secondary to a viral infection cannot be dismissed, as discussed by Swartz, but the majority of cases lack such a history. Certainly, high levels of cytokines, such as occur after many types of illness and with cancer, and some of the numerous endocrine aberrations are capable of causing fatigue and lethargy. From a neurologic perspective, the hypothalamus is the structure most implicated by the loss of endurance and the presence of associated symptoms such as orthostatic intolerance, tachycardia and some of the endocrine changes enumerated later in the chapter. Treatment is discussed further on.

Differential Diagnosis of Fatigue

If one looks critically at patients who seek medical help because of incapacitating exhaustion, lassitude, and fatigability, it is evident that the most commonly overlooked diagnoses are anxiety and depression as described in Chap. 52. The correct conclusion can usually be reached by keeping these illnesses in mind as one elicits the history from patient and family. Difficulty arises when symptoms of the psychiatric illness are so inconspicuous as not to be appreciated; one comes then to suspect the diagnosis only by having eliminated the common medical causes. Repeated observation may bear out the existence of an anxiety state or gloomy mood. Reassurance in combination with a therapeutic trial of antidepressant drugs may suppress symptoms of which the patient was barely aware, thus clarifying the diagnosis. The best that can be done is to assist the patient in adjusting to the adverse circumstances that have brought him under medical surveillance.

In intractable cases, tuberculosis, brucellosis, Lyme disease, hepatitis, bacterial endocarditis, mycoplasmal pneumonia, HIV, EBV, cytomegalovirus (CMV), coxsackie B, and other viral infections, and malaria, hookworm, giardiasis, and other parasitic infections need to be considered in the differential diagnosis, and an inquiry made for their characteristic symptoms, signs, and when appropriate, laboratory findings; however, such infections are infrequently found. There should also be a search for anemia, renal failure, chronic inflammatory disease such as temporal arteritis and polymyalgia rheumatica (sedimentation rate); an endocrine survey (thyroid, calcium, and cortisol levels) and an evaluation for an occult tumor are also in order in obscure cases. It must be remembered that chronic intoxication with alcohol, barbiturates, or other sedative drugs, some of which are given to suppress nervousness or insomnia, may contribute to fatigability. The rapid and recent onset of fatigue should always suggest the presence of an infection, a disturbance in fluid balance, gastrointestinal bleeding, or rapidly developing circulatory failure of either peripheral or cardiac origin. The features that suggest sleep apnea have been mentioned above and are discussed further in Chap. 19.

Finally, it bears repeating that lassitude and fatigue must be distinguished from genuine muscular weakness. The demonstration of reduced power, reflex changes, fasciculations, and atrophy sets the case analysis along different lines, bringing up for particular consideration diseases of the peripheral nervous system or of the musculature. Rare, difficult-to-diagnose diseases that cause inexplicable muscle weakness and exercise intolerance are otherwise inevident hyperthyroidism, hyperparathyroidism, ossifying hemangiomas with hypophosphatemia, some of the periodic paralyses, hyperinsulinism, disorders of carbohydrate and lipid metabolism, and the mitochondrial myopathies, all of which are discussed in later chapters of the book on disease of muscle.

Treatment of Fatigue

It has been our impression that most patients with ongoing complaints of very low energy without a clearly preceding febrile infection from the outset and without one of the medical illnesses associated with fatigue, have elements of depression. They are probably best treated with gradually increasing exercise levels and perhaps with antidepressant medication, although this regimen has not always been successful. There are reports of success in treating these patients with mineralocorticoids (predicated on the above-mentioned orthostatic intolerance), estradiol patches, hypnosis, and a variety of other medical and nonmedical treatments. Cognitive and behavioral therapies have been summarized in the Effective Health Care report by Bagnall and colleagues from the National Health Service Centre for Reviews and Dissemination and in the extensive review by Chambers and colleagues, neither of which came to a firm conclusion about the effects of treatment, but acknowledged that cognitive behavioral therapy and graded exercise therapy may be of value. A few patients with chronic fatigue exhibit the psychologic disorder related to litigation ("compensation neurosis"). Noteworthy is the frequency with which a similar syndrome has become the basis of court action against employers or claims against the government, as in the "building-related illness" (formerly "sick-building syndrome"). As alluded to earlier, attribution of fatigue to Lyme disease and obscure infections or allergies should be made cautiously if there is no firm evidence.

The world is full of nervous, tense, apprehensive, and worried people. The stresses of contemporary society are often blamed for their plight. The poet W.H. Auden referred to his era as "the age of anxiety," and little has changed since then. Medical historians have identified comparable periods of pervasive anxiety dating back to the time of Marcus Aurelius and Constantine, when societies were undergoing rapid and profound changes, and individuals were assailed by an overwhelming sense of insecurity, personal insignificance, and fear of the future (Rosen).

Like lassitude and fatigue, nervousness, irritability, and anxiety are among the most frequent symptoms encountered in office and hospital practice. A British survey found that more than 40 percent of the population, at one time or another, experienced symptoms of severe anxiety, and approximately 5 percent suffered from lifelong anxiety states (Lader). The vast amount of antianxiety medication and alcohol that is consumed in our society would tend to corroborate these figures. Of course, any person facing a challenging or threatening task for which he may feel unprepared and inadequate experiences some degree of nervousness and anxiety. Anxiety is then not abnormal, and the alertness and attentiveness that accompany it may actually improve performance up to a point. Barratt and White found that mildly anxious medical students performed better on examinations than those lacking in anxiety. As anxiety increases, so does the standard of performance, but only to a point, after which increasing anxiety causes a rapid decline in performance (Yerkes-Dodson law).

If worry or depression stands in clear relation to serious economic reverses or loss of a loved one, the symptom is also usually accepted as normal, but no less worthy of emotional support. Only when it is excessively intense or prolonged or when accompanying visceral derangements are prominent do anxiety and depression become matters of medical concern. Admittedly, the line that separates normal emotional reactions and pathologic ones is not sharp. Chapter 52 deals with these matters more fully.

Here we are concerned with nervousness, irritability, stress, anxiety, and depression as symptoms, together with current views of their origins and biologic significance.

Anxiety Reactions and Panic Attacks

There is no unanimity among psychiatrists as to whether symptoms of nervousness, irritability, anxiety, and fear comprise a single emotional reaction, varying only in its severity or duration, or a group of discrete reactions, each with distinctive clinical features. In some writings, anxiety is classified as a form of subacute or chronic fear but there is reason to question this assumption. Anxious patients, when frightened under experimental conditions, state that the fear reaction differs in being more overwhelming. The exceedingly frightened person is "frozen," unable to act or to think clearly, and his responses are automatic and sometimes irrational. The fear reaction is characterized by overactivity of both the sympathetic and parasympathetic nervous systems, and the parasympathetic effects (bradycardia, sphincteric relaxation) may predominate, unlike anxiety, in which sympathetic effects are the more prominent ones. Long ago, Cicero distinguished between an acute and transient attack of fear provoked by a specific stimulus (angor) and a protracted state of fearfulness (anxietas). This distinction was elaborated by Freud, who regarded fear as an appropriate response to a sudden, unexpected external threat and anxiety as a neurotic maladjustment.

Less readily distinguishable from anxiety is the complaint of nervousness. By this vague term, the layperson usually refers to a state of restlessness, inner tension, uneasiness, apprehension, irritability, or hyperexcitability. Unfortunately, the term may have a wide range of other connotations, such as a distressing hallucination or paranoid idea, a frankly hysterical outburst, or even tics or tremulousness. Obviously, a careful inquiry as to what the patient means in complaining of nervousness is always a necessary first step in the analysis.

Most often nervousness represents no more than a transient psychic and behavioral state in which the person is maximally challenged or threatened by difficult personal problems. Some persons claim to have been nervous throughout life or to be nervous periodically for no apparent reason. In these instances, the symptoms blend imperceptibly with those of anxiety disorder or depression, described below.

We use the term anxiety to denote an emotional state characterized by subjective feelings of nervousness, irritability, uneasy anticipation, and apprehension, often but by no means always with a definite topical content and the physiologic accompaniments of strong emotion, i.e., one or more of the symptoms of breathlessness, tightness in the chest, choking sensation, palpitation, increased muscular tension, dizziness, trembling, sweating, and flushing. The vasomotor and visceral accompaniments are mediated through the autonomic nervous system, particularly its sympathetic part, and involve also the thyroid and adrenal glands.

Panic Attacks

The symptoms of anxiety may be manifest either in acute episodes, each lasting several minutes or up to an hour, or as a protracted state that may last for weeks, months, or years. In the panic attack, the patient is suddenly overwhelmed by feelings of apprehension, or a fear that he may lose consciousness and die, have a heart attack or stroke, lose his reason or self-control, become insane, or commit some horrible crime. These experiences are accompanied by a series of physiologic reactions, mainly sympathoadrenal hyperactivity, resembling the "fight-or-flight" reaction. Breathlessness, a feeling of suffocation, dizziness, sweating, trembling, palpitation, and precordial or gastric distress are typical but not invariable physical accompaniments. As a persistent and less-severe state, the patient experiences fluctuating degrees of nervousness, palpitation or excessive cardiac impulse, shortness of breath, light-headedness, faintness, easy fatigue, and intolerance of physical exertion.

Attacks tend to occur during periods of relative calm and in nonthreatening circumstances. Usually, the apprehension and physical symptoms escalate over a period of minutes to an hour and then abate over 20 to 30 min, leaving the patient tired, weak, and perplexed. The dramatic symptoms of the panic attack have usually abated by the time the patient reaches a doctor's office or an emergency department, but the blood pressure may still be elevated, and there may be tachycardia. Otherwise, the patient looks remarkably collected. Often, discrete anxiety attacks and persistent states of anxiety merge with one another. The fear of further attacks leads many patients, particularly women, to become agoraphobic and homebound, fearing public places, especially if alone.

Because panic is a common disorder, affecting 2 to 4 percent of the population at some time in their lives as cited by Roy-Byrne and colleagues, and the symptoms mimic acute neurologic disease, the neurologist is often called upon to distinguish panic attacks from temporal lobe seizures or from vertiginous disorders. Except for the occasional inability of the patient to think or articulate clearly during a panic attack, the manifestations of epilepsy are quite different. Practically never is consciousness lost during a panic attack. If dizziness predominates in the attacks, there may be concern about vertebrobasilar ischemia or labyrinthine dysfunction (see Chap. 15). Vertigo from any cause is accompanied by many of the autonomic symptoms displayed during a panic attack, but careful questioning in the latter will elicit the characteristic apprehension, breathlessness, and palpitations, and the absence of ataxia or other neurologic signs.

Recurrent panic attacks and chronic anxiety have a familial aspect, with one-fifth of first-degree relatives affected and a high degree of concordance in monozygotic twins. The panic symptoms tend to be periodic, beginning in the patient's twenties; a later onset is more usually coupled with depression, treatment of which is discussed in Chap. 52. Most often, panic in younger persons is a component of a generalized anxiety disorder, but it may stand alone as the only mental symptom or be an opening feature of schizophrenia.

Persistent Anxiety and Anxious Depression

Episodic or sustained anxiety without a disorder of mood (i.e., without depression) is classified as generalized anxiety disorder, or formerly, anxiety neurosis. The term neurocirculatory asthenia (among many others) had been applied to the chronic form when accompanied by prominent fatigue and exercise intolerance, in which case it blends into the fatigue states discussed earlier. The symptoms of anxiety may, however, be part of several other psychiatric disorders; it may be combined with other somatic symptoms in hysteria and is the most prominent feature of phobic disorder. Symptoms of persistent anxiety with insomnia, lassitude, and fatigue should always raise the suspicion of a depressive illness, especially when they begin in middle adult life or beyond. Also, unexplained anxiety or panic attacks may sometimes herald the onset of a schizophrenic illness. As with fatigue, the symptoms of both anxiety and depression are prominent features of the postconcussion syndrome, and of posttraumatic stress syndrome (see Chap. 35). These disorders highlight the difficulty in separating generalized anxiety disorder as a unique psychiatric entity. When visceral symptoms predominate or the psychic counterparts of fear and apprehension are absent, the presence of thyrotoxicosis, Cushing disease, pheochromocytoma, hypoglycemia, and menopausal symptoms should be considered.

Posttraumatic Stress Disorder (Ptsd)

This state has been alluded to previously in several contexts, but in the past decades it has come to have specific connotation and to stand as a separate disorder. An extremely stressful, or traumatic event that causes fear and helplessness, triggers a persistent psychological state in which the patient reexperiences the event, avoids reminders of it, and is in a constant state of hyperarousal. Current diagnostic criteria require that this condition persist for over a month, prior to that time the condition is termed "acute stress disorder." Even proponents of posttraumatic stress disorder (PTSD) as a separate medical condition acknowledge that there is considerable overlap with anxious depression, the critical difference being the existence of a triggering traumatic event. They make the point that the original event may not be initially articulated by the patient but symptoms such as palpitations, dyspnea, dysphoria, and unexplained pains and other physical symptoms may be prominent, just as in depression.

The biologic distinctions that have been made between anxious depression and PTSD include lower-than-normal cortisol levels, an attenuated increase of these levels in the immediate aftermath of the event, and an exaggerated suppression in response to dexamethasone. However, elevated circulating levels of norepinephrine and increased sensitivity of alpha2-adrenergic receptors that are found in the posttraumatic syndrome are shared with all other anxiety states (Southwick et al). Many of these studies have been poorly controlled.

It is apparent that there is a wide range of human vulnerability to prolonged difficulties after traumatic events. In all probability, this parallels to some extent an endogenous susceptibility to PTSD. Examples of this are the elicitation of symptoms by events not even witnessed personally, such as national disasters that are shared by large populations but produce symptoms in only a very few individuals, and the wide variation of responses to witnessing death and destruction during wartime.

The authors' view is in agreement with the consensus that PTSD represents a special type of induced anxiety state with fairly stereotyped psychologic aspects, often with an accompanying depression and somatic symptoms. Separating it by highlighting the triggering event serves a useful nosologic purpose and draws attention to the need for treatment in individuals such as those returning from battle or after rape or violent attack.

Selective serotonin reuptake inhibitors have been suggested for initial treatment but the other classes of antidepression drugs are also effective. Limiting anxiolytics such as benzodiazepines is recommended, but there are few data on which to make these judgments. A sympathetic psychiatrist is helpful in reassuring affected individuals and giving them perspectives to cope with the trauma. The review by Yehuda is very informative on this subject and many of the comments above are taken from her summary. An emerging notion is that sedatives or narcotics administered immediately after the inciting event may reduce the incidence and severity of PTSD, for example in battlefield conditions.

Stress and Stress Syndromes

The psychologic phenomenon of stress is closely allied to nervousness, fatigue, and anxiety and all of them are pervasive features of modern life. In general terms, stress has been defined as a feeling of self-doubt about being able to cope with some situation over a period of time. The term stress syndrome refers to perturbations of behavior and accompanying physiologic changes that are ascribable to environmental challenges of such intensity and duration as to overwhelm the individual's adaptive capacity. The biologic effects of this phenomenon can be recognized in many species; chickens laying fewer eggs when moved to a new coop and cows giving less milk when put in a new barn, or monkeys going berserk when repeatedly frustrated by threats that they cannot control. Human beings forced to work under confined conditions and constant danger and cultural groups removed from their home and traditional way of life lose their coping skills and suffer anxiety and stress reactions.

Hans Selye, influenced by Pavlov's concepts of stress, produced lesions in the visceral organs by exposing animals to life-threatening stressors combined with corticosteroids. Cardiac contraction-band necrosis and the shallow hemorrhagic gastrointestinal tract lesion (Cushing ulcer) are two examples of such catecholamine-mediated organ damage that is precipitated by acutely stressful circumstances. The dramatic syndrome of ballooning of the left ventricular apex, or takotsubo-like cardiomyopathy (so-named for the shape of the Japanese octopus trapping pot), is a manifestation of catecholamine excess caused by acute stress.

There is also equivocal epidemiologic evidence that chronic stress in certain individuals, captured in the type A personality, raises the risk of cardiac disease, but the mechanism here, if it indeed exists, is likely to be through a physiologic intermediary such as systemic hypertension or perhaps inflammation that leads to atherosclerosis. Presumably, they have an increased output of "stress hormones" (cortisol and adrenaline).

Such psychologic disorders, bearing a direct relationship to environmental stressors, are among the most common occupational health problems. Stress syndromes are distinguished from anxiety disorders, in which the psychologic disturbance arises from within the individual and has no definite relationship to environmental stimuli. Whether certain individuals are by nature hyperresponsive to such stimuli is not known. The only therapeutic approach is to attempt to alter the patient's perception of stress—for example, with psychotherapy and meditation exercises—and to remove him, if possible, from recognizable environmental stressors. (See "Editorial" in references.)

Irritable Mood and Aggressive Behavior

The phenomenon of irritability, or an irritable mood, must be familiar to almost everyone, exposed as we are to all of the noise, niggling inconveniences, and annoyances of daily life. It is, nevertheless, a difficult symptom to interpret in the context of psychopathology. Freud used the term Reisbarkeit in a restricted sense to denote an undue sensitivity to noise—and considered it a manifestation of anxiety, but obviously, this symptom has a much broader connotation and significance. For one thing, some people are by nature irritable throughout life. Also, irritability is an almost expected reaction in overworked, overwrought individuals, who become irritable by force of circumstances. An irritable mood or feeling may be present without observed manifestations (inward irritability), or there may be an overt loss of control of temper, with irascible verbal and behavioral outbursts, provoked by trivial but frustrating events.

Irritability in the foregoing circumstances can hardly be considered a departure from normal. However, when it becomes a recurrent event in a person of normally placid temperament, it assumes significance, for it may then signify an ongoing anxiety state or depression. Irritability is also a common symptom of obsessive–compulsive disorders. Here the irritability tends to be directed inward, indicating perhaps a sense of frustration with personal disability (Snaith and Taylor). Depressed patients are frequently irritable; as a corollary, this symptom should always be sought in patients suspected of being depressed. The days preceding menses and the mother's common postnatal mood disorder are characterized by high levels of outwardly directed irritability. Short-temperedness and irritability are also common features of the manic state. The most extreme degrees of irritability, exemplified by repeated quarrelsome and assaultive behavior (irritable aggression), are rarely observed in anxiety disorders and endogenous depression but are usually the mark of sociopathy and conventional brain disease (in the past, general paresis). Such irritable aggression is also observed in some patients with Alzheimer disease and other types of dementia, particularly of the frontotemporal type, and following traumatic contusions or encephalitis of the temporal and frontal lobes.

Cause, Mechanism, and Biologic Significance of Nervousness and Anxiety

These have been the subjects of much biologic and psychologic speculation, and completely satisfactory explanations are not available. As noted above, some individuals go through life in a chronic state of low-grade anxiety, the impetus for which may or may not be apparent. Spontaneous episodes of anxiety demand another explanation. Some psychologists regard anxiety as anticipatory behavior, i.e., a state of uneasiness about something that may happen in the future. William McDougall spoke of it as "an emotional state arising when a continuing strong desire seems likely to miss its goal." The primary emotion, somewhat muted perhaps, may be one of fear, and its arousal under conditions that are not overtly threatening may be explained as a conditioned response to some recondite component of a formerly threatening stimulus. The James-Lange theory of emotion, which is dated but should not be dismissed, suggests that the dominant feature of the experience of anxiety is simply the physical experience of the associated autonomic discharge.

Infusions of lactic acid can make the symptoms of anxiety worse and, in susceptible individuals, may elicit a panic attack. The patient seems not to tolerate the work or exercise needed to build up stamina. The urinary excretion of epinephrine was found to be elevated in some patients with panic disorder; in others, there is an increased urinary excretion of norepinephrine and its metabolites. During periods of intense anxiety, aldosterone excretion is increased to 2 or 3 times normal.

There is evidence that corticosteroids and corticotropin-releasing hormone (CRH) have a role in the genesis of anxiety. A systemic release of corticosteroid accompanies all states of stress, and the administration of corticosteroids may give rise to anxiety and panic in some patients and to depression in others, suggesting a linkage between steroid stimulation of the limbic system activities that generate these states. In animal models, stress elicited by predators or electric shock as well as by withdrawal of alcohol and other drugs precipitates activity in CRH pathways (amygdala to hypothalamus, raphe nuclei, nucleus ceruleus, and other regions of the brainstem); blocking such activity by drugs or by destruction of the amygdala eliminates anxiety and fear-like behavior. Admittedly, the concepts of fear, stress, and anxiety are used interchangeably in these models, but repeated stimuli that produce fear and stress may eventually induce a state akin to anxiety, and the amygdala appears to be involved in the perpetuation of this anxiety state. The meaning of these effects, i.e., whether they are primary or secondary, is not certain, but it is evident that prolonged and diffuse anxiety is associated with certain biochemical abnormalities of the blood and probably of the brain.

In addition to the role of the amygdala, animal studies have related acute anxiety to a disturbance of function of the locus ceruleus and the septal and hippocampal areas, the principal norepinephrine-containing nuclei. The locus ceruleus is involved in rapid eye movement (REM) sleep and drugs such as the tricyclic antidepressants and monoamine oxidase inhibitors, which suppress REM sleep, also decrease anxiety. Certain of the serotonin receptors in the brain, different from those implicated in depression, have been related to anxiety. Other parts of the brain must also be involved; bifrontal orbital leukotomy diminishes anxiety, possibly by interrupting the medial forebrain connections with the limbic parts of the brain. Positron emission tomography (PET) studies in subjects who anticipate an electric shock show enhanced activity in the temporal lobes and insula, implicating these regions in the experience of acute anxiety (see also "Physiology of the Limbic System" in Chap. 25). Other credible studies have demonstrated a role for the anterior cingulate gyrus in eliciting many of the autonomic features (particularly increased heart rate) of excessive arousal and anxiety.

Several other alterations in neurotransmitter function have been implicated in the anxious state. The finding that a small proportion of the inherited personality trait of anxiety can be accounted for by one polymorphism of the serotonin transporter gene is provocative (Lesch et al) but requires confirmation.

There are few persons who do not at some time experience periods of severe discouragement and despair. As with nervousness, irritability, and anxiety, depression of mood that is appropriate to a given situation in life (e.g., grief reaction) is seldom the basis of medical concern. Persons in these situations tend to seek help only when their grief or unhappiness is persistent and beyond control. However, there are numerous instances in which the symptoms of depression assert themselves for reasons that are not apparent. Often the symptoms are interpreted as a medical illness, bringing the patient first to the internist or neurologist. Sometimes another disease is found (such as cancer, chronic hepatitis, or other infection or postinfectious asthenia) in which chronic fatigue is confused with depression; more often the opposite pertains, i.e., an endogenous depression is the essential problem even when there has been evidence earlier of a viral or bacterial infection.

From the patient and the family it is learned that the patient has been "feeling unwell," "low in spirits," "blue," "down," "unhappy," or "morbid." There has been a change in his emotional reactions of which the patient may not be fully aware. Activities that were formerly found pleasurable are no longer so. Often, however, change in mood is less conspicuous than reduction in psychic and physical energy, and it is in this type of patient that diagnosis is most difficult. A complaint of fatigue is almost invariable; not uncommonly, it is worse in the morning after a night of restless sleep. The patient complains of a "loss of energy," "weakness," "tiredness," "having no energy," that his job has become more difficult. His outlook is pessimistic. The patient is irritable and preoccupied with uncontrollable worry over trivialities. With excessive worry, the ability to think with accustomed efficiency is reduced; the patient complains that his mind is not functioning properly, and he is forgetful and unable to concentrate. If the patient is naturally of suspicious nature, paranoid tendencies may assert themselves.

Particularly troublesome may be the patient's tendency to hypochondriasis. Indeed, most cases formerly diagnosed as hypochondriasis are now regarded as depression with superimposed anxiety. Pain from whatever cause, a stiff joint, a toothache, fleeting chest or abdominal pains, muscle cramps, or other disturbances such as constipation, frequency of urination, insomnia, pruritus, burning tongue, or weight loss may lead to obsessive complaints. The patient passes from doctor to doctor, seeking relief from symptoms that would not trouble the normal person, and no amount of reassurance relieves his state of mind. The anxiety and depressed mood of these persons may be obscured by their preoccupation with visceral functions.

When the patient is examined, his facial expression is often plaintive, troubled, pained, or anguished. The patient's attitude and manner betray a prevailing mood of depression, hopelessness, and despondency. In other words, the affect, which is the outward expression of feeling, is consistent with the depressed mood. During the interview, the patient may be tearful and may cry openly. In some, there is a kind of immobility of the face that mimics parkinsonism, though others are restless and agitated (pacing, wringing their hands, etc.). Occasionally the patient will smile, but the smile impresses one as more a social gesture than a genuine expression of feeling.

The stream of speech is slow. Sighing is frequent. There may be long pauses between questions and answers. The latter are brief and may be monosyllabic. There is a paucity of ideas. The impediment extends to all topics of conversation and affects movement of the limbs as well. The most extreme forms of decreased motor activity, rarely seen in the office or clinic, border on muteness and stupor ("anergic depression"). Conversation is replete with pessimistic thoughts, fears, and expressions of unworthiness, inadequacy, inferiority, hopelessness, and sometimes guilt. In severe depressions, bizarre ideas and bodily delusions may be expressed ("blood drying up," "bowels are blocked with cement," "I am half dead").

Several theories have emerged concerning the cause of the pathologic depressive state, but none can be confirmed with confidence except for a heritable aspect. These views are elaborated on in Chap. 52.

It is the authors' belief that depressive states are among the most commonly overlooked diagnoses in clinical medicine. Part of the trouble is with the word itself, which implies being unhappy about something. Endogenous depression should be suspected in all states of chronic ill health, hypochondriasis, disability that exceeds the manifest signs of a medical disease, neurasthenia and ongoing fatigue, and chronic pain syndromes. Inasmuch as recovery is the rule, suicide is a tragedy for which the medical profession must sometimes share responsibility. In extreme circumstances, however, the patient is impelled to suicide and efforts on the part of the physician cannot be considered as a failure.

Depressive illnesses and theories of their causation and management are considered extensively in Chap. 52.