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InternalMed_Harrison. In cases of hyperperfusion syndromes, treatment should commence urgently once the diagnosis is considered. Hypertension plays a key role commonly, and judicious lowering of the blood pressure with IV agents such as labetalol or nicardipine is advised along with continuous cardiac and blood pressure monitoring, often through an arterial line. It is reasonable to lower MAP by ~20% initially, as further FIGURE 463e-1 Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain in a patient taking cyclosporine after liver transplantation, who presented with seizures, headache, and cortical blindness. Increased signal is seen bilaterally in the occipital lobes predominantly involving the white matter, consistent with a hyperperfusion state secondary to calcineurin-inhibitor exposure.


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InternalMed_Harrison. lowering of the pressure may cause secondary ischemia and possibly infarction as pressure drops below the lower range of the patient’s autoregulatory capability. In cases where there is an identified cause of the syndrome, these etiologies should be treated promptly, including discontinuation of offending substances such as calcineurin inhibitors in toxic processes, treatment of immune-mediated disorders such as thrombotic thrombocytopenic purpura (TTP), and prompt delivery of the fetus in eclampsia. Seizures must be identified and controlled, often necessitating continuous EEG monitoring. Anticonvulsants are effective when seizure activity is identified, but in the special case of eclampsia, there is evidence to support the use of magnesium sulfate for seizure control.


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InternalMed_Harrison. Central nervous system (CNS) injuries following open heart or coronary artery bypass grafting (CABG) surgery are common and include acute encephalopathy, stroke, and a chronic syndrome of cognitive impairment. Hypoperfusion and embolic disease are frequently involved in the pathogenesis of these syndromes, although multiple mechanisms may be involved in these critically ill patients who are at risk for various metabolic and polypharmaceutical complications.


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InternalMed_Harrison. The frequency of hypoxic injury secondary to inadequate blood flow intraoperatively has been markedly decreased by the use of modern surgical and anesthetic techniques. Despite these advances, some patients still experience neurologic complications from cerebral hypoperfusion or may suffer focal ischemia from carotid or focal intra-cranial stenoses in the setting of regional hypoperfusion. Postoperative infarcts in the border zones between vascular territories commonly are blamed on systemic hypotension, although these infarcts can also result from embolic disease (Fig. 463e-2). Embolic disease is likely the predominant mechanism of cerebral injury during cardiac surgery as evidenced by diffusion-weighted MRI and intraoperative transcranial Doppler studies. It should be noted that some of the emboli that are found histologically in these


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InternalMed_Harrison. FIGURE 463e-2 Coronal fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain in a patient presenting with altered mental status after an episode of hypotension during coronary artery bypass grafting (CABG). Increased signal is seen in the border zones bilaterally between the middle cerebral artery and anterior cerebral artery territories. Diffusion-weighted MRI sequences demonstrated restricted diffusion in these same locations, suggesting acute infarction.


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InternalMed_Harrison. patients are too small to be detected by standard imaging sequences; therefore, a negative MRI after surgery does not exclude the diagnosis of emboli-related complications. Thrombus in the heart itself as well as atheromas in the aortic arch can become dislodged during cardiac surgeries, releasing a shower of particulate matter into the cerebral circulation. Cross-clamping of the aorta, manipulation of the heart, extracorporeal circulation techniques (“bypass”), arrhythmias such as atrial fibrillation, and introduction of air through suctioning have all been implicated as potential sources of emboli. Histologic studies indicate that literally millions of tiny emboli may be released, even using modern surgical techniques.


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InternalMed_Harrison. This shower of microemboli results in a number of clinical syndromes. Occasionally, a single large embolus leads to an isolated large-vessel stroke that presents with obvious clinical focal deficits. More commonly, the emboli released are multiple and smaller. When there is a high burden of these small emboli, an acute encephalopathy can occur postoperatively, presenting as either a hyperactive or hypoactive confusional state, the latter of which is frequently and incorrectly ascribed to depression or a sedative-induced delirium. When the burden of microemboli is lower, no acute syndrome is recognized, but the patient may suffer a chronic cognitive deficit. Cardiac surgery can be viewed, like delirium, as a “stress test for the brain.” Some patients with a low cerebral reserve due to underlying cerebrovascular disease or an early neurodegenerative process will develop a chronic, cognitive deficit, whereas others with higher reserves may remain asymptomatic despite a similar dose of


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InternalMed_Harrison. cerebrovascular disease or an early neurodegenerative process will develop a chronic, cognitive deficit, whereas others with higher reserves may remain asymptomatic despite a similar dose of microemboli. In this manner, cardiac surgery may serve to unmask the early manifestations of neurodegenerative disorders such as Alzheimer’s disease.


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InternalMed_Harrison. Since modern techniques have successfully minimized hypoperfusion complications during these surgeries, much attention is now focused on reducing this inevitable shower of microemboli. Off-pump CABG surgeries have the advantages of reducing length of stay and perioperative complications; however, off-pump CABG probably does not preserve cognitive function compared with on-pump CABG. Filters placed in the aortic arch may have some promise in capturing these emboli, although convincing evidence is lacking. Development of successful endovascular operative approaches may provide a reasonable alternative to conventional CABG procedures, especially for patients at high risk of developing cognitive dysfunction after surgery due to advanced age, previous stroke, underlying neurodegenerative disorders, or severe atheromatous disease of the carotid arteries or aortic arch.


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InternalMed_Harrison. Patients who have undergone solid organ transplantation are at risk for neurologic injury in the postoperative period and for months to years thereafter. Neurologic consultants should view these patients as a special population at risk for both unique neurologic complications as well as for the usual disorders found in any critically ill inpatient.


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InternalMed_Harrison. Immunosuppressive medications are administered in high doses to patients after solid organ transplant, and many of these compounds have well-described neurologic complications. In patients with headache, seizures, or focal neurologic deficits taking calcineurin inhibitors, the diagnosis of hyperperfusion syndrome should be considered, as discussed above. This neurotoxicity occurs mainly with cyclosporine and tacrolimus and can present even in the setting of normal serum drug levels. Treatment primarily involves lowering the drug dosage or discontinuing the drug. Sirolimus has very few recorded cases of neurotoxicity and may be a reasonable alternative for some patients. Other examples of immunosuppressive medications and their neurologic complications include OKT3-associated akinetic mutism and the leukoencephalopathy seen with methotrexate, especially when it is administered intrathecally or with concurrent radiotherapy. In any solid organ transplant patient with neurologic


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InternalMed_Harrison. mutism and the leukoencephalopathy seen with methotrexate, especially when it is administered intrathecally or with concurrent radiotherapy. In any solid organ transplant patient with neurologic complaints, a careful examination of the medication list is required to search for these possible drug effects.


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InternalMed_Harrison. Cerebrovascular complications of solid organ transplant are often first recognized in the immediate postoperative period. Border zone territory infarctions can occur, especially in the setting of systemic hypotension during cardiac transplant surgery. Embolic infarctions classically complicate cardiac transplantation, but all solid organ transplant procedures place patients at risk for systemic emboli. When cerebral embolization accompanies renal or liver transplantation surgery, a careful search for right-to-left shunting should include evaluation of the heart with agitated saline echocardiography (i.e., “bubble study”), as well as looking for intrapulmonary shunting. Renal and some cardiac transplant patients often have advanced atherosclerosis, providing yet another mechanism for stroke. Imaging with CT or MRI with diffusion is advised when cerebrovascular complications are suspected to confirm the diagnosis and to exclude intracerebral hemorrhage, which most often occurs in the


InternalMed_Harrison

InternalMed_Harrison. Imaging with CT or MRI with diffusion is advised when cerebrovascular complications are suspected to confirm the diagnosis and to exclude intracerebral hemorrhage, which most often occurs in the setting of coagulopathy secondary to liver failure or after cardiac bypass procedures.


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InternalMed_Harrison. Given that patients with solid organ transplants are chronically immunosuppressed, infections are a common concern (Chap. 169). In any transplant patient with new CNS signs or symptoms such as seizure, confusion, or focal deficit, the diagnosis of a CNS infection should be considered and evaluated through imaging (usually MRI) and possibly lumbar puncture. The most common pathogens responsible for CNS infections in these patients vary based on time since transplant. In the first month posttransplant, common pathogens include the usual bacterial organisms associated with surgical procedures and indwelling catheters. Starting in the second month posttransplant, opportunistic infections of the CNS become more common, including Nocardia and Toxoplasma species as well as fungal infections such as aspergillosis. Viral infections that can affect the brain of the immunosuppressed patient, such as herpes simplex virus, cytomegalovirus, human herpesvirus type 6 (HHV-6), and varicella, also


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InternalMed_Harrison. such as aspergillosis. Viral infections that can affect the brain of the immunosuppressed patient, such as herpes simplex virus, cytomegalovirus, human herpesvirus type 6 (HHV-6), and varicella, also become more common after the first month posttransplant. After 6 months posttransplant, immunosuppressed patients still remain at risk for these opportunistic bacterial, fungal, and viral infections but can also suffer late CNS infectious complications such as progressive multifocal leukoencephalopathy (PML) associated with JC virus and Epstein-Barr virus–driven clonal expansions of B cells resulting in posttransplant lymphoproliferative disorder or CNS lymphoma.


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InternalMed_Harrison. A wide variety of neurologic conditions can result from abnormalities in serum electrolytes, and consideration of electrolyte disturbances should be part of any inpatient neurologic consultation. A complete general discussion of fluid and electrolyte imbalance and homeostasis can be found in Chap. 63.


InternalMed_Harrison

InternalMed_Harrison. The normal range of serum osmolality is around 275–295 mOsm/kg, but neurologic manifestations are usually seen only at levels >325 mOsm/kg. Hyperosmolality is usually due to hypernatremia, hyperglycemia, azotemia, or the addition of extrinsic osmoles such as mannitol, which is commonly used in critically ill neurologic patients. Hyperosmolality itself can lead to a generalized encephalopathy that is nonspecific and without focal findings; however, an underlying lesion such as a mass can become symptomatic under the metabolic stress of a hyperosmolar state, producing focal neurologic signs. Some patients with hyperosmolality from severe hyperglycemia can present, for unclear reasons, with generalized seizures or unilateral movement disorders, which usually respond to lowering of the serum glucose. The treatment of all forms of hyperosmolality involves calculation of apparent water losses and slow replacement so that the serum sodium declines no faster than 2 mmol/L (2 meq/L) per hour.


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InternalMed_Harrison. Hypernatremia leads to the loss of intracellular water, leading to cell shrinkage. In the cells of the brain, solutes such as glutamine and urea are generated under these conditions in order to minimize this shrinkage. Despite this corrective mechanism, when hypernatremia is severe (serum sodium >160 mmol/L [>160 meq/L]) or occurs rapidly, cellular metabolic processes fail and encephalopathy will result. There are many etiologies of hypernatremia including, most commonly, renal and extrarenal losses of water. Causes of neurologic relevance include central diabetes insipidus, where hyperosmolality is accompanied by submaximal urinary concentration due to inadequate release of arginine vasopressin (AVP) from the posterior pituitary, resulting often from pituitary injury in the setting of surgery, hemorrhage, infiltrative processes, or cerebral herniation.


InternalMed_Harrison

InternalMed_Harrison. Hyponatremia is commonly defined as a serum sodium <135 mmol/L (<135 meq/L). Neurologic symptoms occur at different levels of low sodium, depending not only on the absolute value but also on the rate of fall. In patients with hyponatremia that develops over hours, life-threatening seizures and cerebral edema may occur at values as high as 125 mmol/L. In contrast, some patients with more chronic hyponatremia that has slowly developed over months to years may be asymptomatic even with serum levels <110 mmol/L. Correction of hyponatremia, especially when chronic, must take place slowly in order to avoid additional neurologic complications. Cells in the brain swell in hypotonic hyponatremic states but may compensate over time by excreting solute into the extracellular space, leading to restoration of cell volume when water follows the solute out of the cells. If treatment of hyponatremia results in a rapid rise in serum sodium, cells in the brain may quickly shrink, leading to osmotic


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InternalMed_Harrison. of cell volume when water follows the solute out of the cells. If treatment of hyponatremia results in a rapid rise in serum sodium, cells in the brain may quickly shrink, leading to osmotic demyelination, a process that previously was thought to be limited exclusively to the brainstem (central pontine myelinolysis; see Fig. 330-6), but now has been described elsewhere in the CNS.


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InternalMed_Harrison. Treatment of hyponatremia is dependent on the cause. Hypertonic hyponatremia treatment focuses on correcting the underlying condition, such as hyperglycemia. Isovolemic hyponatremia (syndrome of inappropriate antidiuretic hormone [SIADH]) is managed with water restriction or administration of AVP antagonists. The management of choice for patients with hypervolemic hypotonic hyponatremia is free-water restriction and treatment of the underlying edematous disorder, such as hepatic failure, nephrotic syndrome, or congestive heart failure. Finally, in hypovolemic hypotonic hyponatremia, volume is replaced with isotonic saline while underlying conditions of the kidneys, adrenals, and gastrointestinal tract are addressed.


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InternalMed_Harrison. One neurologic cause of hypovolemic hypotonic hyponatremia is the cerebral salt-wasting syndrome that accompanies subarachnoid hemorrhage and, less commonly, other cerebral processes such as meningitis, stroke, or traumatic brain injury. In these cases, the degree of renal sodium excretion can be remarkable, and large amounts of saline, hypertonic saline, or oral sodium may need to be given in a judicious fashion in order to avoid complications from cerebral edema.


InternalMed_Harrison

InternalMed_Harrison. Hypokalemia, defined as a serum potassium level < 3.5 mmol/L (<3.5 meq/L), occurs either because of excessive potassium losses (from the kidneys or gut) or due to an abnormal potassium distribution between the intracellular and extracellular spaces. At very low levels (<1.5 mmol/L), hypokalemia may be life threatening due to the risk of cardiac arrhythmia and may present neurologically with severe muscle weakness and paralysis. Hypokalemic periodic paralysis is a rare disorder caused by excessive intracellular potassium uptake in the setting of a calcium or sodium channel mutation. Treatment of hypokalemia is dependent on the etiology but usually includes replacement of potassium through oral or IV routes as well as correcting the cause of potassium balance problems (e.g., eliminating β2-adrenergic agonist medications or treating the underlying cause of severe diarrhea).


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InternalMed_Harrison. Hyperkalemia is defined as a serum potassium level >5.5 mmol/L (>5.5 meq/L) and can neurologically present as muscle weakness with or without paresthesias. Hyperkalemia becomes life threatening when it produces electrocardiographic abnormalities such as peaked T waves or a widened QRS complex. In these cases, prompt treatment is essential and consists of strategies that protect the heart against arrhythmias (calcium gluconate administration); promote potassium redistribution into cells (with glucose, insulin, and β2-agonist medications); and increase potassium removal (through sodium polystyrene sulfonate, loop diuretics, or hemodialysis). Hypercalcemia usually occurs in the setting of either hyperparathyroidism or systemic malignancy. Neurologic manifestations include encephalopathy as well as muscle weakness due to reduced neuromuscular excitability. Seizures can occur but are more common in states of low calcium.


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InternalMed_Harrison. Hypocalcemia in adults often follows surgical treatment of the thyroid or parathyroid. Seizures and altered mental status dominate the neurologic picture and usually resolve with calcium repletion. Tetany is due to spontaneous, repetitive action potentials in peripheral nerves and remains the classic sign of symptomatic hypocalcemia. Disorders of magnesium are difficult to correlate with serum levels because a very small amount of total-body magnesium is located in the extracellular space. Hypomagnesemia presents neurologically with seizures, tremor, and myoclonus. When intractable seizures occur in the setting of hypomagnesemia, only administration of magnesium will lead to their resolution. High levels of magnesium, in contrast, lead to CNS depression. Hypermagnesemia usually only occurs in the setting of renal failure or magnesium administration and can lead to confusion and muscular paralysis when severe.


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InternalMed_Harrison. Polyneuropathy is a common cause of outpatient neurologic consultation (Chap. 459). In the inpatient setting, however, mononeuropathies are more frequent, especially the entrapment neuropathies that complicate many surgical procedures and medical conditions. Median neuropathy at the wrist (carpal tunnel syndrome) is the most frequent entrapment neuropathy by far, but it is rarely a cause for inpatient consultation. Mechanisms for perioperative mononeuropathy include traction, compression, and ischemia of the nerve. Imaging with MRI, including neurography, may allow these causes to be distinguished. In all cases of mononeuropathy, the diagnosis can be made through the clinical examination and then confirmed with electrodiagnostic studies in the subacute period, if necessary. Treatment consists mainly of avoidance of repetitive trauma but may also include surgical approaches to relieve pressure or repair the nerve.


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InternalMed_Harrison. Radial nerve injury classically presents with weakness of extension of the wrist and fingers (“wrist drop”) with or without more proximal weakness of extensor muscles of the upper extremity, depending on the site of injury. Sensory loss is in the distribution of the radial nerve, which includes the dorsum of the hand (Fig. 463e-3A). Compression at the level of the axilla, e.g., resulting from use of crutches, leads to weakness of the triceps, brachioradialis, and supinator muscles in addition to wrist drop. A more common site of compression occurs in the spiral groove of the upper arm in the setting of a humerus fracture or from sleeping with the arm draped over a bench or chair (“Saturday night palsy”). Sparing of the triceps is the rule when the nerve is injured in this location. Because extensors of the upper extremity are injured preferentially in radial nerve injury, these lesions may be mistaken for the pyramidal distribution of weakness that accompanies upper motor neuron


InternalMed_Harrison

InternalMed_Harrison. extensors of the upper extremity are injured preferentially in radial nerve injury, these lesions may be mistaken for the pyramidal distribution of weakness that accompanies upper motor neuron lesions from brain or spinal cord processes, prompting neuroimaging to exclude acute stroke or mass lesion.


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InternalMed_Harrison. Compression of the ulnar nerve is the second most common entrapment neuropathy after carpal tunnel syndrome. The most frequent site of compression is at the elbow where the nerve passes superficially in the ulnar groove. Symptoms usually begin with tingling in the ulnar distribution, including the fourth and fifth digits of the hand (Fig. 463e-3B). Sensory symptoms may be worsened by elbow flexion due to increased pressure on the nerve, hence the tendency of patients to complain of increasing paresthesias at night when the arm is flexed at the elbow during sleep. Motor dysfunction can be disabling and involves most of the intrinsic hand muscles, limiting dexterity and strength of grasp and pinch. Etiologies of ulnar entrapment include trauma to the nerve (hitting the “funny bone”), malpositioning during anesthesia for surgical procedures, and chronic arthritis of the elbow. When a perioperative ulnar nerve injury is considered, stretch injury or trauma to the lower trunk of the


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InternalMed_Harrison. malpositioning during anesthesia for surgical procedures, and chronic arthritis of the elbow. When a perioperative ulnar nerve injury is considered, stretch injury or trauma to the lower trunk of the brachial plexus should be entertained as well since its symptoms can mimic those of an ulnar neuropathy. If the clinical examination is equivocal, electrodiagnostic studies can definitively distinguish between plexus and ulnar nerve lesions a few weeks after the injury. Conservative methods of treatment are often the first step including bracing of the elbow to prevent flexion while sleeping. A variety of surgical approaches may also be effective in refractory or recurrent cases, including anterior ulnar nerve transposition and release of the flexor carpi ulnaris aponeurosis.


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InternalMed_Harrison. The peroneal (also known as the fibular) nerve winds around the head of the fibula in the leg below the lateral aspect of the knee, and its superficial location at this site makes it vulnerable to trauma. Patients present with weakness of foot dorsiflexion (“foot drop”) as well as with weakness in eversion but not inversion at the ankle. Sparing of inversion, which is a function of muscles innervated by the tibial nerve, helps to distinguish peroneal neuropathies from L5 radiculopathies. Sensory loss involves the lateral aspect of the leg as well as the dorsum of the foot (Fig. 463e-3C). Fractures of the fibular head may be responsible for peroneal neuropathies, but in the perioperative setting, poorly applied braces exerting pressure on the nerve while the patient is unconscious, often in lithotomy position, are more often responsible. Tight-fitting stockings or casts of the upper leg can also cause a peroneal neuropathy, and thin individuals and those with recent weight loss are at


InternalMed_Harrison

InternalMed_Harrison. lithotomy position, are more often responsible. Tight-fitting stockings or casts of the upper leg can also cause a peroneal neuropathy, and thin individuals and those with recent weight loss are at increased risk.


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InternalMed_Harrison. Lateral cutaneous nerve of arm Sensory distribution of the radial nerve Posterior cutaneous nerve of arm Posterior cutaneous nerve of forearm FIGURE 463e-3 Sensory distribution of peripheral nerves commonly affected by entrapment neuropathies. A. Radial nerve. B. Ulnar nerve. C. Peroneal nerve. D. Femoral nerve. E. Lateral femoral cutaneous nerve. Sensory distribution of the peroneal nerve Lateral cutaneous nerve of calf Sensory distribution of the ulnar nerve of the femoral nerve Lateral femoral cutaneus nerve


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InternalMed_Harrison. Lesions of the proximal femoral nerve are relatively uncommon but may present dramatically with weakness of hip flexion, quadriceps atrophy, weakness of knee extension (often manifesting with leg-buckling falls), and an absent patellar reflex. Adduction of the thigh is spared as these muscles are supplied by the obturator nerve, thereby distinguishing a femoral neuropathy from a more proximal lumbosacral plexus lesion. The sensory loss found is in the distribution of the femoral nerve sensory branches including the anterior part of the thigh (Fig. 463e-3D). Compressive lesions from retroperitoneal hematomas or masses are common, and a CT of the pelvis should be obtained in all cases of femoral neuropathy to exclude these conditions. Bleeding into the pelvis resulting in hematoma can occur spontaneously, following trauma, or after intrapelvic surgeries such as renal transplantation. In intoxicated or comatose patients, stretch injuries to the femoral nerve are seen following prolonged,


InternalMed_Harrison

InternalMed_Harrison. spontaneously, following trauma, or after intrapelvic surgeries such as renal transplantation. In intoxicated or comatose patients, stretch injuries to the femoral nerve are seen following prolonged, extreme hip flexion or extension. Rarely, attempts at femoral vein or arterial puncture can be complicated by injury to this nerve.


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InternalMed_Harrison. The symptoms of lateral femoral cutaneous nerve entrapment, commonly known as “meralgia paresthetica,” include sensory loss, pain, and dysesthesia in part of the area supplied by the nerve (Fig. 463e-3E). There is no motor component to the nerve, and therefore weakness is not a part of this syndrome. Symptoms often are worsened by standing or walking. Compression of the nerve occurs where it enters the leg near the inguinal ligament, usually in the setting of tight-fitting belts, pants, corsets, or recent weight gain, including that of pregnancy. The differential diagnosis of these symptoms includes hip problems such as trochanteric bursitis.


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InternalMed_Harrison. Pregnancy and delivery place women at special risk for a variety of nerve injuries. Radiculopathy due to a herniated lumbar disc is not common during pregnancy, but compressive injuries of the lumbosacral plexus do occur secondary to either the fetal head passing through the pelvis or the use of forceps during delivery. These plexus injuries are more frequent with cephalopelvic disproportion and often present with a painless unilateral foot drop which must be distinguished from a peroneal neuropathy caused by pressure on the nerve while in lithotomy position during delivery. Other compressive mononeuropathies of pregnancy include meralgia paresthetica, carpal tunnel syndrome, femoral neuropathy when the thigh is abducted severely in an effort to facilitate delivery of the fetal shoulder, and isolated obturator neuropathy during lithotomy positioning. The latter presents with medial thigh pain that may be accompanied by weakness of thigh adduction. There is also a clear association


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InternalMed_Harrison. and isolated obturator neuropathy during lithotomy positioning. The latter presents with medial thigh pain that may be accompanied by weakness of thigh adduction. There is also a clear association between pregnancy and an increased frequency of idiopathic facial palsy (Bell’s palsy).


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InternalMed_Harrison. Chronic Fatigue Syndrome Gijs Bleijenberg, Jos W. M. van der Meer DEFINITION Chronic fatigue syndrome (CFS) is a disorder characterized by persis-tent and unexplained fatigue resulting in severe impairment in daily functioning. Besides intense fatigue, most patients with CFS report 464e SECTion 4 concomitant symptoms such as pain, cognitive dysfunction, and unrefreshing sleep. Additional symptoms can include headache, sore throat, tender lymph nodes, muscle aches, joint aches, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. Criteria for the diagnosis of CFS have been developed by the U.S. Centers for Disease Control and Prevention (Table 464e-1).


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InternalMed_Harrison. U.S. Centers for Disease Control and Prevention (Table 464e-1). CFS is seen worldwide, with adult prevalence rates varying between 0.2% and 0.4%. In the United States, the prevalence is higher among women (∼75% of cases), members of minority groups (African and Native Americans), and individuals with lower levels of education and occupational status. The mean age of onset is between 29 and 35 years. Many patients probably go undiagnosed and/ or do not seek help. There are numerous hypotheses about the etiology of CFS; there is no definitively identified cause. Distinguishing between predisposing, precipitating, and perpetuating factors in CFS helps to provide a framework for understanding this complex condition (Table 464e-2).


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InternalMed_Harrison. Predisposing Factors Physical inactivity and trauma in childhood tend to increase the risk of CFS in adults. Neuroendocrine dysfunction may be associated with childhood trauma, reflecting a biological correlate of vulnerability. Psychiatric illness and physical hyperactivity in adulthood raise the risk of CFS in later life. Twin studies suggest a familial predisposition to CFS, but no causative genes have been identified. Precipitating Factors Physical or psychological stress may elicit the onset of CFS. Most patients report an infection (usually a flulike illness or infectious mononucleosis) as the trigger of their fatigue. Relatively high percentages of CFS cases follow Q fever and Lyme disease.


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InternalMed_Harrison. Fatigue lasts for at least 6 months. Fatigue is of new or definite onset. Fatigue is not the result of an organic disease or of continuing exertion. Fatigue is not alleviated by rest. Fatigue results in a substantial reduction in previous occupational, educa tional, social, and personal activities. Four or more of the following symptoms are concurrently present for 6 months: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, pain in several joints, new headaches, unrefreshing sleep, or malaise after exertion. Medical condition explaining fatigue Major depressive disorder (psychotic features) or bipolar disorder Schizophrenia, dementia, or delusional disorder Anorexia nervosa, bulimia nervosa Alcohol or substance abuse Severe obesity (body mass index >40) TABLE 464e-2 PrEDiSPoSing, PrECiPiTATing, AnD PErPETuATing FACTorS in ChroniC FATiguE SynDromE


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InternalMed_Harrison. TABLE 464e-2 PrEDiSPoSing, PrECiPiTATing, AnD PErPETuATing FACTorS in ChroniC FATiguE SynDromE Childhood trauma (sexual, physical, emotional abuse; emotional and physical neglect) Physical inactivity during childhood Premorbid psychiatric illness or psychopathology Premorbid hyperactivity Somatic events: infection (e.g., mononucleosis, Q fever, Lyme disease), surgery, pregnancy Psychosocial stress, life events Fear of fatigue Lack of social support


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InternalMed_Harrison. Somatic events: infection (e.g., mononucleosis, Q fever, Lyme disease), surgery, pregnancy Psychosocial stress, life events Fear of fatigue Lack of social support However, no differences in Epstein-Barr virus load and immunologic reactivity were found between individuals who developed CFS and those who did not. While antecedent infections are associated with CFS, a direct microbial causality is unproven and unlikely. One study identified a murine leukemia virus–related retrovirus (XMRV); however, several subsequent studies have established this virus as a laboratory artifact. Patients also often report other precipitating somatic events such as serious injury, surgery, pregnancy, or childbirth. Serious life events, such as the loss of a loved one or a job, military combat, and other stressful situations, may also precipitate CFS. One-third of all patients cannot recall a trigger.


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InternalMed_Harrison. Perpetuating Factors Once CFS has developed, numerous factors may impede recovery. Physicians may contribute to chronicity by ordering unnecessary diagnostic procedures, by persistently suggesting psychological causes, and by not acknowledging CFS as a diagnosis. A patient’s focus on illness and avoidance of activities may perpetuate symptoms. A firm belief in a physical cause, a strong focus on bodily sensations, and a poor sense of control over symptoms may also prolong or exacerbate the fatigue and functional impairment. In most patients, inactivity is caused by negative illness perceptions rather than by poor physical fitness. Solicitous behavior of others may reinforce a patient’s illness-related perceptions and behavior. A lack of social support is another known perpetuating factor.


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InternalMed_Harrison. The pathophysiology of CFS is unclear. Neuroimaging studies have found that CFS is associated with reduced gray matter volume, which in turn is associated with a decline in physical activity; these changes have been partially reversed following cognitive behavioral therapy (CBT). In addition, functional MRI data have suggested that abnormal patterns of activation correlate with self-reported problems with information processing. Neurophysiologic studies have shown altered CNS activation patterns during muscle contraction. Evidence for immunologic dysfunction is inconsistent. Modest elevations in titers of antinuclear antibodies, reductions in immunoglobulin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell activity, disturbances How have you felt during the last two weeks? Please rate all four statements and per statement check the box that reflects your situation best.


InternalMed_Harrison

InternalMed_Harrison. How have you felt during the last two weeks? Please rate all four statements and per statement check the box that reflects your situation best. No, 1. I feel tired Yes, that is not true that is true No, 2. I tire easily Yes, that is true that is not true No, 3. I feel fit Yes, that is true that is not true No, 4. Physically I feel exhausted Yes, that is true that is not true Scoring: Yes, 1, 2 and 4: 7 6 5 4 that is true FIGurE 464e-1 Shortened fatigue questionnaire.


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InternalMed_Harrison. No, 4. Physically I feel exhausted Yes, that is true that is not true Scoring: Yes, 1, 2 and 4: 7 6 5 4 that is true FIGurE 464e-1 Shortened fatigue questionnaire. in cytokine production, and shifts in lymphocyte subsets have been described. None of these immune findings appears in most patients, nor does any correlate with the severity of CFS. In theory, symptoms of CFS could result from excessive production of a cytokine, such as interleukin 1, that induces asthenia and other flulike symptoms; however, compelling data in support of this hypothesis are lacking. There is some evidence that CFS patients have mild hypocortisolism, the degree of which is associated with a poorer response to CBT. Discrepancies in perceived and actual cognitive performance are consistent findings in patients with CFS.


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InternalMed_Harrison. In addition to a thorough history, a systematic physical examination is warranted to exclude disorders causing fatigue (e.g., endocrine disorders, neoplasms, heart failure). The heart rate of CFS patients is often slightly above normal. Laboratory tests serve primarily to exclude other diagnoses; no test can diagnose CFS. The following laboratory screen usually suffices: complete blood count; erythrocyte sedimentation rate; C-reactive protein; serum creatinine, electrolytes, calcium, and iron; blood glucose; creatine kinase; liver function tests; thyroid-stimulating hormone; anti-gliadin antibodies; and urinalysis. Serology for viral or bacterial infections usually is not helpful. No specific abnormalities have been identified on MRI or CT scans. The decrease in gray matter volume observed at a population level by MRI is not useful for diagnosis in the individual patient. Extensive, unfocused, and expensive testing in a search for the “hidden” cause of the fatigue is not productive.


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InternalMed_Harrison. at a population level by MRI is not useful for diagnosis in the individual patient. Extensive, unfocused, and expensive testing in a search for the “hidden” cause of the fatigue is not productive. CFS is a constellation of symptoms with no pathognomonic features and remains a diagnosis of exclusion.


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InternalMed_Harrison. Bipolar disorders, schizophrenia, and substance abuse exclude a diagnosis of CFS, as do eating disorders, unless these issues have been resolved ≥5 years before symptom onset. In addition, CFS is excluded if the chronic fatigue developed immediately after a depressive episode. Depression developing in the course of the fatigue, however, does not preclude CFS. Concurrent psychiatric disorders, especially anxiety and mood disorders, are present in 30–60% of cases. In cases of suspected CFS, the clinician should acknowledge the impact of the patient’s symptoms on daily functioning. Disbelief or denial can provoke an exacerbation of genuine symptoms, which in turn strengthens the clinician’s disbelief, leading to an unfortunate cycle of miscommunication. The possibility of CFS should be considered if No, 3 2 1 3: Reversed that is not true a patient fulfils all criteria (Table 464e-1) and if other diagnoses have been excluded.


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InternalMed_Harrison. No, 3 2 1 3: Reversed that is not true a patient fulfils all criteria (Table 464e-1) and if other diagnoses have been excluded. The patient should be asked to describe the symptoms (fatigue and accompanying symptoms) and their duration as well as their consequences (reduction in daily activities). To assess symptom severity and the extent of daily-life impairment, the patient should describe a typical day, from waking to retiring, and, for comparison, an average day prior to symptom onset. Next, potential fatigue-precipitating factors are sought. The severity of fatigue is commonly difficult to assess quantitatively; a brief questionnaire is often helpful (Fig. 464e-1).


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InternalMed_Harrison. The patient should be informed of the current understanding of precipitating and perpetuating factors and effective treatments and should be offered general advice about disease management. If CBT for CFS is not available as an initial option (see below) and depression and anxiety are present, these symptoms should be treated. For patients with headache, diffuse pain, and feverishness, nonsteroidal anti-inflammatory drugs may be helpful. Even modest improvements in symptoms can make an important difference in the patient’s degree of self-sufficiency and ability to appreciate life’s pleasures. Controlled therapeutic trials have established that acyclovir, fludrocortisone, galantamine, modafinil, and IV immunoglobulin, among other agents, offer no significant benefit in CFS. Countless anecdotes circulate regarding other traditional and nontraditional therapies. It is important to guide patients away from those therapeutic modalities that are toxic, expensive, or unreasonable.


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InternalMed_Harrison. The patient should be encouraged to maintain regular sleep patterns, to remain as active as possible, and to gradually return to previous levels of exercise and other activity (work).


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InternalMed_Harrison. CBT and graded exercise therapy (GET) have been found to be the only beneficial interventions in CFS. Some patient groups argue against these approaches because of the implication that CFS is a purely mental disorder. CBT is a psychotherapeutic approach directed at changing unhealthy disease-perpetuating patterns of thoughts and behaviors. It includes educating the patient about the etiologic model, setting goals, restoring fixed bedtimes and wakeup times, challenging and changing fatigueand activity-related concerns, reducing a focus on symptoms, spreading activities evenly throughout the day, gradually increasing physical activity, planning a return to work, and resuming other activities. The intervention, which typically consists of 12–14 sessions spread over 6 months, helps CFS patients gain control over their symptoms.


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InternalMed_Harrison. GET targets deconditioning and exercise intolerance and usually involves a home exercise program that continues for 3–5 months. Walking or cycling is systematically increased, with set goals for maximal heart rates. Evidence that deconditioning is the basis for symptoms in CFS is lacking, however. CBT and GET appear to improve fatigue primarily by changing the patient’s perception of the fatigue and also by reducing the focus on symptoms. In general, CBT is the more multifaceted treatment, which may explain why CBT studies tend to yield better improvement rates than GET trials. Not all patients benefit from CBT or GET. Predictors of poor outcome are medical (including psychiatric) comorbidities, current disability claims, and severe pain. CBT offered in an early stage of the illness reduces the burden of CFS for the patient as well as for society in terms of decreased medical and disability-related costs.


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InternalMed_Harrison. Full recovery from untreated CFS is rare: the median annual recovery rate is 5% (range, 0–31%), and the median improvement rate is 39% (range, 8–63%). Patients with an underlying psychiatric disorder and those who continue to attribute their symptoms to an undiagnosed medical condition have poorer outcomes. Biology of psychiatric Disorders Robert O. Messing, Eric J. Nestler Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization.


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InternalMed_Harrison. Robert O. Messing, Eric J. Nestler Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization. They are highly heritable, with genetic risk comprising 20–90% of disease vulnerability. As a result of their prevalence, early onset, and persistence, they contribute substantially to the burden of illness world wide. All psychiatric disorders are broad heterogeneous syndromes markers. Therefore, diagnoses continue to be made solely from clini cal observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association, which is in its fifth edition as of 2013.


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InternalMed_Harrison. There is increasing agreement that the classification of psychiatric illnesses in DSM does not accurately reflect the underlying biology of these disorders. Uncertainties in diagnosis make it extremely difficult to study the neurobiologic and genetic basis of mental illness. This has led to the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoCs), which classifies mental illness on the basis of core abnormalities—e.g., psychosis (loss of reality) or anhedonia (decreased ability to experience pleasure), which are common symptoms of several illnesses—with the idea that such classifications will assist in defining the biologic basis of at least key symptoms. Other factors that have impeded progress in understanding mental illness include the lack of access to pathologic brain tissue except upon death and the inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations, delusions, guilt,


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InternalMed_Harrison. of access to pathologic brain tissue except upon death and the inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations, delusions, guilt, suicidality) that are inaccessible in animals.


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InternalMed_Harrison. Despite these limitations, the past decade has seen significant advances. Neuroimaging methods are beginning to provide evidence of brain pathology, genome-wide association studies and high-throughput sequencing are at last revealing genes that confer risk for severe forms of mental illness, and investigations using better validated animal models are offering new insight into the molecular, cellular, and circuit mechanisms of disease pathogenesis. There is also excitement in the potential utility of neuron-like cells induced in vitro from a patient’s peripheral tissues (e.g., fibroblasts) providing novel ways of studying disease pathophysiology and screening for new treatments. There is consequently justified optimism that the field of psychiatry will transition from behaviorally defined syndromes to true biologic disease entities and that such advances will drive the development of improved treatments and eventually cures and preventive measures. This chapter describes several


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InternalMed_Harrison. syndromes to true biologic disease entities and that such advances will drive the development of improved treatments and eventually cures and preventive measures. This chapter describes several examples of recent discoveries in basic neuroscience that have informed our current understanding of disease mechanisms in psychiatry.


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InternalMed_Harrison. Because the human brain can only be examined indirectly during life, genome analyses have been extremely important for obtaining molecular clues about the pathogenesis of psychiatric disorders. A wealth of new information has been made possible by recent technological developments that have permitted affordable, large-scale genome-wide association studies and fine-scale sequencing. As an example, significant progress has been made in the genetics of autism spectrum disorders (ASDs), which are a heterogeneous group of neurodevelopmental diseases that share clinical features of impaired reciprocal social communication and interaction and restricted, repetitive patterns of behavior. ASDs are highly heritable; concordance rates in monozygotic twins (~60–90%) are roughly 10-fold higher than in dizygotic twins and siblings, whereas first-degree relatives show about 50-fold increased risk compared with the general population. ASDs are also genetically heterogeneous. More than 100 known


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InternalMed_Harrison. in dizygotic twins and siblings, whereas first-degree relatives show about 50-fold increased risk compared with the general population. ASDs are also genetically heterogeneous. More than 100 known mutations account for up to 20% of cases, although none individually accounts for more than 1% (Table 465e-1). It appears that most cases result from complex genetic mechanisms, including inheritance of multiple genetic risk variants and epigenetic modifications. For example, up to 10% of patients with autism have large (>500 kb) de novo copy number variations scattered across the genome, suggesting that hundreds of different genes can influence autism risk.


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InternalMed_Harrison. Amid this genetic heterogeneity, however, some common themes have emerged that inform pathogenesis of ASDs. For instance, many identified mutations are in genes that encode proteins involved in synaptic function and early transcriptional regulation (Table 465e-1) and have a clear relationship to activity-dependent neural responses that can affect the development of neural systems underlying cognition and social behaviors. Mutations in these genes may be detrimental by altering the balance of excitatory versus inhibitory synaptic signaling in local and extended circuits and by altering mechanisms that control brain growth. Some mutations affect genes (e.g., PTEN, TSC1, and TSC2) that negatively regulate signaling from several types of extracellular stimuli, including those transduced by receptor tyrosine kinases. Their dysregulation can alter neuronal growth as well as synaptic development and function.


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InternalMed_Harrison. With further understanding of pathogenesis and the definition of specific ASD subtypes, there is reason to believe that effective therapies will be identified. Work in mouse models has already demonstrated that some autism-like behaviors can be reversed, even in fully developed adult animals, by modifying the underlying pathology; these results encourage hope for many affected individuals. Treatments that target excitation-inhibition imbalance or altered mRNA translation appear to offer early promise. For example, the genes TSC1, TSC2, and PTEN are negative regulators of signaling through the target of rapamycin complex 1 (TORC1), which regulates protein synthesis. Rapamycin, a selective inhibitor of TORC1, can reverse several behavioral and synaptic defects in mice carrying null mutations in these genes. Another example is fragile X syndrome, which is the leading cause of inherited autism and mental disability and is due to mutations in FMR1 that result in loss of the encoded fragile


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InternalMed_Harrison. in these genes. Another example is fragile X syndrome, which is the leading cause of inherited autism and mental disability and is due to mutations in FMR1 that result in loss of the encoded fragile X mental retardation protein (FMRP). FMRP is a polyribosome-associated mRNA-binding protein that represses the translation of a subset (~5%) of all mRNAs, several of which encode proteins that comprise the postsynaptic density, including the metabotropic glutamate receptor 5 (mGluR5). Treatment of Fmr1 knockout mice with mGluR5 antagonists reduces several behavioral and morphologic abnormalities in these mice; these promising preclinical results have led to ongoing trials of mGluR5 antagonists in humans with fragile X syndrome.


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InternalMed_Harrison. The ability to catalog common genetic variants and assay them on array-based platforms and, more recently, to carry out whole-exome sequencing has allowed investigators to collect sample sizes sufficient to detect genetic risk loci for schizophrenia with genome-wide significance. Several of the identified genes are parts of molecular complexes, such as voltage-gated calcium channels (in particular, CACNA1C and CACNB2) and the postsynaptic density of excitatory synapses. As in ASDs, copy number variants, single-nucleotide polymorphisms, and small insertions and deletions are common in schizophrenia. Genes that promote risk for drug addiction have also begun to emerge from large family and population studies. The best-established susceptibility loci are regions on chromosomes 4 and 5 containing GABAA receptor gene clusters linked to alcoholism and the CHRNA5-A3-B4 nicotinic acetylcholine receptor gene cluster on chromosome 15 associated with nicotine and alcohol addiction.


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InternalMed_Harrison. A recurrent theme that has emerged from genetic studies of psychiatric disorders is pleiotropy, namely, that many genes are associated Chapter 465e Biology of Psychiatric Disorders Sodium channel, voltage-gated, type I, alpha subunit Sodium channel, voltage-gated, type II, alpha subunit exchanger Glutamate receptor, ionotropic, N-methyl-Daspartate 2B


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InternalMed_Harrison. T-box, brain 1 Signal transduction Synaptic function Signal transduction Translation and protein stability Synaptic function Signal transduction Translation and protein stability Synaptic function Signal transduction with multiple psychiatric syndromes. For example, mutations in MECP2, FMR1, and TSC1 and TSC2 (see Table 465e-1 for abbreviations) can cause mental retardation without ASD, others in MECP2 can cause obsessive-compulsive and attention-deficit hyperactivity disorders, some alleles of NRXN1 are associated with symptoms of both ASD and schizophrenia, and common polymorphisms in CACNA1C are strongly associated with both schizophrenia and bipolar disorder. Likewise, duplication of chromosome 16p is associated with both schizophrenia and autism, whereas DiGeorge’s (velocardiofacial) syndrome region deletions and the DISC1 (disrupted in schizophrenia 1) locus on chromosome 22 are associated with schizophrenia, autism, and bipolar disorder. The association of genes with multiple


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InternalMed_Harrison. syndrome region deletions and the DISC1 (disrupted in schizophrenia 1) locus on chromosome 22 are associated with schizophrenia, autism, and bipolar disorder. The association of genes with multiple syndromes attests to the complexity of psychiatric disorders and the influence of additional factors that combine to specify the ultimate phenotype, including regulatory variants that determine cell-type specificity and timing of gene expression, protective variants, and epigenetic effects.


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InternalMed_Harrison. Studies of signal transduction have revealed numerous intracellular signaling pathways that are perturbed in psychiatric disorders, and such research has provided insight into development of new therapeutic agents. For example, lithium is a highly effective drug for bipolar disorder and competes with magnesium to inhibit numerous magnesium-dependent enzymes, including the enzyme GSK3β and several enzymes involved in phosphoinositide signaling that lead to activation of protein kinase C. These findings have led to discovery programs focused on developing GSK3β or protein kinase C inhibitors as potential novel treatments for mood disorders.


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InternalMed_Harrison. The observations that tricyclic antidepressants (e.g., imipramine) inhibit serotonin and/or norepinephrine reuptake and that monoamine oxidase inhibitors (e.g., tranylcypromine) are effective antidepressants initially led to the view that depression is caused by a deficiency of these monoamines. However, this hypothesis has not been substantiated. A cardinal feature of these drugs is that longterm administration is needed for their antidepressant effects. This means that their short-term actions, namely promotion of serotonin or norepinephrine function, are not per se antidepressant but rather induce a cascade of adaptations in the brain that underlie their clinical effects. The nature of these therapeutic drug-induced adaptations has not been identified with certainty. One theory holds that, in a subset of depressed patients who display upregulation of the hypothalamic-pituitary-adrenal (HPA) axis characterized by increased secretion of corticotropin-releasing factor (CRF) and


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InternalMed_Harrison. that, in a subset of depressed patients who display upregulation of the hypothalamic-pituitary-adrenal (HPA) axis characterized by increased secretion of corticotropin-releasing factor (CRF) and glucocorticoids, excessive glucocorticoids cause atrophy of hippocampal neurons, which is associated with reduced hippocampal volumes seen clinically. Chronic antidepressant administration might reverse this atrophy by increasing brain-derived neurotrophic factor (BDNF) in hippocampus. A role for stress-induced decreases in the generation of newly born hippocampal granule cell neurons, and its reversal by antidepressants through BDNF and other growth factors, has also been suggested.


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InternalMed_Harrison. A major advance in recent years has been the identification of several rapidly acting antidepressants with non–monoamine-based mechanisms of action. The best established is ketamine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors, which exerts rapid (hours) and robust antidepressant effects in severely depressed patients who have not responded to other treatments. Ketamine, which at higher doses is psychotomimetic and anesthetic, exerts these antidepressant effects at low doses with minimal side effects. However, the response to ketamine is transient, which has led to several approaches to maintain treatment response, such as repeated ketamine delivery. The mechanism underlying ketamine’s antidepressant action is not known, but its striking clinical efficacy has stimulated animal research on the role of glutamate neurotransmission and synaptic plasticity in key limbic regions. Recent evidence supports a role for TORC1 activation because administration


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InternalMed_Harrison. has stimulated animal research on the role of glutamate neurotransmission and synaptic plasticity in key limbic regions. Recent evidence supports a role for TORC1 activation because administration of rapamycin blocks the antidepressant-like effects of ketamine in animal models. Mechanisms by which ketamine activates TORC1 are currently an active area of investigation.


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InternalMed_Harrison. A major goal in the field of drug abuse has been to identify neuroadaptive mechanisms that lead from recreational use to addiction. Such research has determined that repeated intake of abused drugs induces specific changes in cellular signal transduction, leading to changes in synaptic strength (long-term potentiation or depression) and neuronal structure (altered dendritic branching or cell soma size) within the brain’s reward circuitry. These modifications are mediated in part by changes in gene expression, achieved by drug regulation of transcription factors (e.g., CREB [cAMP response element-binding protein] and ΔFosB [a Fos family protein]) and their target genes. Such alterations in gene expression are associated with lasting alterations in epigenetic modifications, including histone acetylation and methylation and DNA methylation. These adaptations provide opportunities for developing treatments targeted to drug-addicted individuals. The fact that the spectrum of these


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InternalMed_Harrison. histone acetylation and methylation and DNA methylation. These adaptations provide opportunities for developing treatments targeted to drug-addicted individuals. The fact that the spectrum of these adaptations partly differs depending on the particular addictive substance used creates opportunities for treatments that are specific for different classes of addictive drugs and that may, therefore, be less likely to disturb basic mechanisms that govern normal motivation and reward.


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InternalMed_Harrison. Increasingly, causal relationships are being established between individual molecular and cellular adaptations and specific behavioral abnormalities that characterize the addicted state. For example, acute activation of μ-opioid receptors by morphine or other opiates activates Gi/o proteins, leading to inhibition of adenylyl cyclase, resulting in reduced cyclic AMP (cAMP) production, protein kinase A (PKA) activation, and activation of the transcription factor CREB. Repeated administration of these drugs (Fig. 465e-1) evokes a homeostatic response involving upregulation of adenylyl cyclases and PKA and increased activation of CREB. Such upregulation of cAMP-CREB signaling has been identified in the locus coeruleus, periaqueductal gray, ventral tegmental area (VTA), nucleus accumbens, and several other CNS regions, and contributes to opiate craving and signs of opiate withdrawal. The fact that endogenous opioid peptides do not produce tolerance and dependence, while morphine and heroin


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InternalMed_Harrison. other CNS regions, and contributes to opiate craving and signs of opiate withdrawal. The fact that endogenous opioid peptides do not produce tolerance and dependence, while morphine and heroin do, may relate to the observation that, unlike endogenous opioids, morphine and heroin are weak inducers of μ-opioid receptor desensitization and endocytosis. Therefore, these drugs cause prolonged receptor activation and inhibition of adenylyl cyclases, which provides a powerful stimulus for the upregulation of cAMP-CREB signaling that characterizes the opiate-dependent state.


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InternalMed_Harrison. The study of interconnected brain circuits that drive behavior has been greatly advanced through newer methods in brain imagining that have documented abnormalities in neural function and connectivity in psychiatric disorders. The past decade has also witnessed the development of revolutionary new techniques—optogenetics and designer receptors and ligands—that provide unprecedented temporal and spatial control of neural circuits and permit detection of neural activity in real time in awake, behaving animals.


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InternalMed_Harrison. Positron emission tomography (PET), diffusion tensor imaging (DTI), and functional magnetic resonance imaging (fMRI) have identified neural circuits that contribute to psychiatric disorders, for example, defining the neural circuitry of mood within the brain’s limbic system (Fig. 465e-2). Integral to this system are the nucleus accumbens (important also for brain reward—see below), amygdala, hippocampus, and regions of prefrontal cortex. Recent optogenetic research in animals, where the activity of specific types of neurons in defined circuits can be controlled with light, has confirmed the importance of this limbic circuitry in controlling depression-related behavioral abnormalities. Given that many symptoms of depression (so-called neurovegetative symptoms) involve physiologic functions, a key role for the hypothalamus is also presumed. A subset of depressed individuals shows a small reduction in hippocampal size, as noted above. In addition, brain imaging investigations have


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InternalMed_Harrison. a key role for the hypothalamus is also presumed. A subset of depressed individuals shows a small reduction in hippocampal size, as noted above. In addition, brain imaging investigations have revealed increased activation of the amygdala by negative stimuli and reduced activation of the nucleus accumbens by rewarding stimuli. There is also evidence for altered activity in prefrontal cortex, such as hyperactivity of subgenual area 25 in anterior cingulate cortex. Such findings


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InternalMed_Harrison. FIGURE 465e-1 Opiate action in the locus coeruleus (LC). Binding of opiate agonists to μ-opioid receptors catalyzes nucleotide exchange on Gi and Go proteins, leading to inhibition of adenylyl cyclase, neuronal hyperpolarization via activation of K+ channels, and inhibition of neurotransmitter release via inhibition of Ca2+ channels. Inhibition of adenylyl cyclase (AC) reduces protein kinase A (PKA) activity and phosphorylation of several PKA substrate proteins, thereby altering their function. For example, opiates reduce phosphorylation of the cAMP response element-binding protein (CREB), which appears to initiate longer term changes in neuronal function. Chronic administration of opiates increases levels of AC isoforms, PKA catalytic (C) and regulatory (R) subunits, and the phosphorylation of several proteins, including CREB (indicated by red arrows). These changes contribute to the altered phenotype of the drug-addicted state. For example, the excitability of LC neurons is


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InternalMed_Harrison. of several proteins, including CREB (indicated by red arrows). These changes contribute to the altered phenotype of the drug-addicted state. For example, the excitability of LC neurons is increased by enhanced cAMP signaling, although the ionic basis of this effect remains unknown. Activation of CREB causes upregulation of AC isoforms and tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis.


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InternalMed_Harrison. have led to trials of deep brain stimulation (DBS) of either the nucleus accumbens or subgenual area 25, which appears to be therapeutic in some severely depressed individuals.


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InternalMed_Harrison. In schizophrenia, structural and functional imaging studies have identified a 3% loss of brain volume, most of which is in gray matter. This loss is progressive, and cortical gray matter appears to be particularly affected over time. The temporal lobes, particularly the left superior temporal gyrus, Heschl gyrus, and planum temporale, are often the most severely affected. The rate of loss in these regions as well as in frontal and parietal lobes appears to be greatest early in the course of the disease. Functional imaging studies provide evidence of reduced metabolic (presumably neural) activity in the dorsolateral prefrontal cortex at rest and when performing tests of executive function, including working memory. There is also evidence for impaired structural and task-related functional connectivity, mainly in frontal and temporal lobes. These neuroimaging findings in schizophrenia have been confirmed in pathologic studies that show enlargement of the ventricular


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InternalMed_Harrison. These neuroimaging findings in schizophrenia have been confirmed in pathologic studies that show enlargement of the ventricular Chapter 465e Biology of Psychiatric Disorders the rewards (nucleus accumbens), memories of reward-related cues (amygdala, hippocampus), and executive control of obtaining rewards (prefrontal cortex).


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InternalMed_Harrison. Drugs of abuse alter neurotransmission through initial actions at different classes of ion channels, neurotransmitter receptors, or neurotransmitter transporters (Table 465e-2). Studies in animal models have demonstrated that although the initial targets differ, the actions of these drugs converge on the brain’s reward circuitry by promoting dopamine neurotransmission in the nucleus accumbens and other limbic targets of the VTA. In addition, some drugs promote activation of opioid and cannabinoid receptors, which modulate this reward circuitry. By these mechanisms, drugs of abuse produce powerful rewarding signals, which, after repeated drug administration, corrupt a vulnerable brain’s reward circuitry in ways that promote addiction. Three major pathologic adaptations have been described. First, drugs produce tolerance and dependence in reward circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal that promotes relapse. Second,


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InternalMed_Harrison. described. First, drugs produce tolerance and dependence in reward circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal that promotes relapse. Second, sensitization to the


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InternalMed_Harrison. FIGURE 465e-2 Neural circuitry of depression and addiction. The figure shows a simplified rewarding effects of the drugs and associ summary of a series of limbic circuits in brain that regulate mood and motivation and are impli ated cues is seen during prolonged absti cated in depression and addiction. Shown in the figure are the hippocampus (HP) and amyg nence and also triggers relapse. Third, dala (Amy) in the temporal lobe, regions of prefrontal cortex, nucleus accumbens (NAc), and executive function is impaired in such a hypothalamus (Hyp). Only a subset of the known interconnections among these brain regions is way as to increase impulsivity and com- shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons. pulsivity, both of which promote relapse. The ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures.


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InternalMed_Harrison. pulsivity, both of which promote relapse. The ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures. Norepinephrine (from the locus coeruleus [LC]) and serotonin (from the dorsal raphe [DR] and that addictive drugs, as well as craving for other raphe nuclei) innervate all of the regions shown. In addition, there are strong connections them, activate the brain’s reward circuitry. between the hypothalamus and the VTA-NAc pathway. Important peptidergic projections from In addition, patients who abuse alcohol the hypothalamus include those from the arcuate nucleus that release β-endorphin and melano cortin and from the lateral hypothalamus that release orexin.


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InternalMed_Harrison. system and reduction of cortical and subcortical gray matter in frontal and temporal lobes and in the limbic system. The reduction in cortical thickness is associated with increased cell packing density and reduced neuropil (defined as axons, dendrites, and glial cell processes) without an apparent change in neuronal cell number. Specific classes of inter-neurons in prefrontal cortex consistently show reduced expression of the gene encoding the enzyme glutamic acid decarboxylase 1 (GAD1), which synthesizes γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. Neuregulin 1 (NRG1), a member of the epidermal growth factor (EGF) family of growth factors, and its receptor ERBB4, have been implicated in schizophrenia, and they serve important roles in the maturation of GABAergic interneurons in cerebral cortex; loss of NRG1-ERBB4 in mice leads to a reduced neuropil, thus phenocopying a pathologic finding in schizophrenia. These findings are consistent with one


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InternalMed_Harrison. of GABAergic interneurons in cerebral cortex; loss of NRG1-ERBB4 in mice leads to a reduced neuropil, thus phenocopying a pathologic finding in schizophrenia. These findings are consistent with one working hypothesis of schizophrenia as a developmental neurodegenerative disorder due in part to loss of cortical interneurons in frontal and temporal lobes.


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InternalMed_Harrison. Work in rodent and nonhuman primate models of addiction has established the brain’s reward regions as key neural substrates for the acute actions of drugs of abuse and for addiction induced by repeated drug administration (Fig. 465e-2). Midbrain dopamine neurons in the VTA function normally as rheostats of reward: they are activated by natural rewards (food, sex, social interaction) or even by the expectation of such rewards, and many are suppressed by the absence of an expected reward or by aversive stimuli. These neurons thereby transmit crucial survival signals to the rest of the limbic brain to promote reward-related behavior, including motor responses to seek and obtain matter in the prefrontal cortex as well as reduced activity in anterior cingulate and orbitofrontal cortex during tasks of attention and inhibitory control. It is thought that damage to these cortical areas contributes to addiction by impairing decision-making and increasing impulsivity.


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InternalMed_Harrison. There is increasing evidence for the involvement of inflammatory mechanisms in a subset of depressed patients. These individuals display elevated blood levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and other cytokines. Moreover, rodents exposed to chronic stress exhibit similar increases in peripheral cytokines, and peripheral or central delivery of those cytokines to normal rodents increases their susceptibility to chronic stress. These findings have led to the novel idea of using peripheral cytokines as biomarkers of a subtype of depression and the potential utility of developing new antidepressants that oppose cytokine action.


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InternalMed_Harrison. Recent evidence has also linked proinflammatory signaling in the brain to addiction, particularly to alcohol. Human alcoholism is associated with impaired innate immunity, increases in circulating proinflammatory cytokines, and an increase in brain levels of the cytokine monocyte chemotactic protein-1 (MCP-1, also referred to as CCL2). Many of these cytokines are produced by astrocytes and microglia, and by neurons under certain pathologic conditions, where they play important roles in modifying neuronal function and plasticity. For example MCP-1 modulates the release of certain neurotransmitters and, when administered into the VTA, increases neuronal excitability, promotes dopamine release, and increases locomotor activity. Recent gene expression array studies of alcohol drinking in mice have Opiates Endorphins, enkephalins Psychostimulants Dopamine (cocaine, amphetamine, methamphetamine) Marijuana Endocannabinoids (anandamide, 2arachidonoylglycerol)


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InternalMed_Harrison. Opiates Endorphins, enkephalins Psychostimulants Dopamine (cocaine, amphetamine, methamphetamine) Marijuana Endocannabinoids (anandamide, 2arachidonoylglycerol) Dopamine transporter (antagonist—cocaine; reverse transport—amphetamine, methamphetamine) identified a network of regulated cytokines in brain, and a role in regu-465e-5 lation of alcohol consumption has been recently validated for several of them, including IL-6. A major focus of current research is to define the site and mechanism by which proinflammatory cytokines impair brain function to elicit a depressive episode or promote drug abuse. This brief narrative illustrates the substantial progress that is being made in understanding the genetic and neurobiologic basis of mental illness. It is anticipated that biologic measures will be used increasingly to diagnosis and subtype a psychiatric disorder and that targeted therapeutics will become available to treat them. Chapter 465e Biology of Psychiatric Disorders


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InternalMed_Harrison. Chapter 465e Biology of Psychiatric Disorders Victor I. Reus Mental disorders are common in medical practice and may present either as a primary disorder or as a comorbid condition. The prevalence of mental or substance use disorders in the United States is approximately 30%, but only one-third of affected individuals are currently receiving treatment. Global burden of disease statistics indicate that 4 of the 10 most important causes of morbidity and attendant health care costs worldwide are psychiatric in origin.


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InternalMed_Harrison. Changes in health care delivery underscore the need for primary care physicians to assume responsibility for the initial diagnosis and treatment of the most common mental disorders. Prompt diagnosis is essential to ensure that patients have access to appropriate medical services and to maximize the clinical outcome. Validated patient-based questionnaires have been developed that systematically probe for signs and symptoms associated with the most prevalent psychiatric diagnoses and guide the clinician into targeted assessment. The Primary Care Evaluation of Mental Disorders (PRIME-MD; and a self-report form, the Patient Health Questionnaire) and the Symptom-Driven Diagnostic System for Primary Care (SDDS-PC) are inventories that require only 10 min to complete and link patient responses to the formal diagnostic criteria of anxiety, mood, somatoform, and eating disorders and to alcohol abuse or dependence.


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InternalMed_Harrison. A physician who refers patients to a psychiatrist should know not only when doing so is appropriate but also how to refer, because societal misconceptions and the stigma of mental illness impede the process. Primary care physicians should base referrals to a psychiatrist on the presence of signs and symptoms of a mental disorder and not simply on the absence of a physical explanation for a patient’s complaint. The physician should discuss with the patient the reasons for requesting the referral or consultation and provide reassurance that he or she will continue to provide medical care and work collaboratively with the mental health professional. Consultation with a psychiatrist or transfer of care is appropriate when physicians encounter evidence of psychotic symptoms, mania, severe depression, or anxiety; symptoms of posttraumatic stress disorder (PTSD); suicidal or homicidal preoccupation; or a failure to respond to first-order treatment. This chapter reviews the clinical


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InternalMed_Harrison. depression, or anxiety; symptoms of posttraumatic stress disorder (PTSD); suicidal or homicidal preoccupation; or a failure to respond to first-order treatment. This chapter reviews the clinical assessment and treatment of some of the most common mental disorders presenting in primary care and is based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the framework for categorizing psychiatric illness used in the United States. Eating disorders are discussed later in this chapter, and the biology of psychiatric and addictive disorders is discussed in Chap. 465e.


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InternalMed_Harrison. The DSM-5 and the tenth revision of the International


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InternalMed_Harrison. Classification of Diseases (ICD-10), which is used more com monly worldwide, have taken somewhat differing approaches to the diagnosis of mental illness, but considerable effort has been expended to provide an operational translation between the two nosologies. Both systems are in essence purely descriptive and emphasize clinical pragmatism, in distinction to the Research Domain Criteria (RDOC) proposed by National Institute of Mental Health, which aspires to provide a causal framework for classification of behavioral disturbance. None of these diagnostic systems has as yet achieved adequate validation. The Global Burden of Disease Study 2010, using available epidemiologic data, nevertheless has reinforced the conclusion that, regardless of nosologic differences, mental and substance abuse disorders are the major cause of life-years lost to disability among all medical illnesses. There is general agreement that high-income countries will need to build capacity in professional training


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InternalMed_Harrison. disorders are the major cause of life-years lost to disability among all medical illnesses. There is general agreement that high-income countries will need to build capacity in professional training in lowand middle-income countries in order to provide an adequate balanced care model for the delivery of evidence-based therapies for mental disorders. Recent surveys that indicate a dramatic increase in mental disorder prevalence in rapidly developing countries, such as China, may reflect both an increased recognition of the issue, but also the consequence of social turmoil, stigma, and historically inadequate resources. The need for improved prevention strategies and for more definitive and effective interventional treatments remains a global concern.


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InternalMed_Harrison. Anxiety disorders, the most prevalent psychiatric illnesses in the general community, are present in 15–20% of medical clinic patients. Anxiety, defined as a subjective sense of unease, dread, or foreboding, can indicate a primary psychiatric condition or can be a component of, or reaction to, a primary medical disease. The primary anxiety disorders are classified according to their duration and course and the existence and nature of precipitants. When evaluating the anxious patient, the clinician must first determine whether the anxiety antedates or postdates a medical illness or is due to a medication side effect. Approximately one-third of patients presenting with anxiety have a medical etiology for their psychiatric symptoms, but an anxiety disorder can also present with somatic symptoms in the absence of a diagnosable medical condition.


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InternalMed_Harrison. PANIC DISORDER Clinical Manifestations Panic disorder is defined by the presence of recurrent and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, shortness of breath, chest pain, dizziness, and a fear of impending doom or death. Paresthesias, gastrointestinal distress, and feelings of unreality are also common. Diagnostic criteria require at least 1 month of concern or worry about the attacks or a change in behavior related to them. The lifetime prevalence of panic disorder is 2–3%. Panic attacks have a sudden onset, developing within 10 min and usually resolving over the course of an hour, and they occur in an unexpected fashion. Some may occur when waking from sleep. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset


InternalMed_Harrison

InternalMed_Harrison. sleep. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and results in a generalized fear and a progressive avoidance of places or situations in which a panic attack might recur. Agoraphobia, which occurs commonly in patients with panic disorder, is an acquired irrational fear of being in places where one might feel trapped or unable to escape. It may, however, be diagnosed even if panic disorder is not present. Typically, it leads the patient into a progressive restriction in lifestyle and, in a literal sense, in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus, physicians will fail to recognize the


InternalMed_Harrison

InternalMed_Harrison. patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus, physicians will fail to recognize the syndrome if direct questioning is not pursued.


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InternalMed_Harrison. Differential Diagnosis A diagnosis of panic disorder is made after a medical etiology for the panic attacks has been ruled out. A variety of cardiovascular, respiratory, endocrine, and neurologic conditions can present with anxiety as the chief complaint. Patients with true panic disorder will often focus on one specific feature to the exclusion of others. For example, 20% of patients who present with syncope as a primary medical complaint have a primary diagnosis of a mood, anxiety, or substance abuse disorder, the most common being panic disorder. The differential diagnosis of panic disorder is complicated by a high rate of comorbidity with other psychiatric conditions, especially alcohol and benzodiazepine abuse, which patients initially use in an attempt at self-medication. Some 75% of panic disorder patients will also satisfy criteria for major depression at some point in their illness.


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InternalMed_Harrison. When the history is nonspecific, physical examination and focused laboratory testing must be used to rule out anxiety states resulting from medical disorders such as pheochromocytoma, thyrotoxicosis, or hypoglycemia. Electrocardiogram (ECG) and echocardiogram may detect some cardiovascular conditions associated with panic such as paroxysmal atrial tachycardia and mitral valve prolapse. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome.


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InternalMed_Harrison. Etiology and Pathophysiology The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30–45% of monozygotic twins, and genome-wide screens have identified suggestive risk loci. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the α2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. Patients with panic disorder have a heightened sensitivity to somatic symptoms, which triggers increasing arousal,


InternalMed_Harrison

InternalMed_Harrison. in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. Patients with panic disorder have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic intervention involves altering the patient’s cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself.


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InternalMed_Harrison. Achievable goals of treatment are to decrease the frequency of panic attacks and to reduce their intensity. The cornerstone of drug therapy is antidepressant medication (Tables 466-1 through 466-3). Selective serotonin reuptake inhibitors (SSRIs) benefit the majority of panic disorder patients and do not have the adverse effects of tricyclic antidepressants (TCAs). Fluoxetine, paroxetine, sertraline, and the selective serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine have received approval from the U.S. Food and Drug Administration (FDA) for this indication. These drugs should be started at one-third to one-half of their usual antidepressant dose (e.g., 5–10 mg fluoxetine, 25–50 mg sertraline, 10 mg paroxetine, venlafaxine 37.5 2709 mg). Monoamine oxidase inhibitors (MAOIs) are also effective and may specifically benefit patients who have comorbid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, and the need to


InternalMed_Harrison

InternalMed_Harrison. are also effective and may specifically benefit patients who have comorbid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, and the need to maintain a low-tyramine diet (avoidance of cheese and wine) have limited their use, however. Antidepressants typically take 2–6 weeks to become effective, and doses may need to be adjusted based on the clinical response.


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InternalMed_Harrison. Because of anticipatory anxiety and the need for immediate relief of panic symptoms, benzodiazepines are useful early in the course of treatment and sporadically thereafter (Table 466-4). For example, alprazolam, starting at 0.5 mg qid and increasing to 4 mg/d in divided doses, is effective, but patients must be monitored closely, as some develop dependence and begin to escalate the dose of this medication. Clonazepam, at a final maintenance dose of 2–4 mg/d, is also helpful; its longer half-life permits twice-daily dosing, and patients appear less likely to develop dependence on this agent.


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InternalMed_Harrison. Early psychotherapeutic intervention and education aimed at symptom control enhance the effectiveness of drug treatment. Patients can be taught breathing techniques, be educated about physiologic changes that occur with panic, and learn to expose themselves voluntarily to precipitating events in a treatment program spanning 12–15 sessions. Homework assignments and monitored compliance are important components of successful treatment. Once patients have achieved a satisfactory response, drug treatment should be maintained for 1–2 years to prevent relapse. Controlled trials indicate a success rate of 75–85%, although the likelihood of complete remission is somewhat lower.


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InternalMed_Harrison. GENERALIZED ANXIETY DISORDER Clinical Manifestations Patients with generalized anxiety disorder (GAD) have persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic arousal, feeling “on edge” or restless, and insomnia (Table 466-5). Onset is usually before age 20 years, and a history of childhood fears and social inhibition may be present. The lifetime prevalence of GAD is 5–6%; the risk is higher in first-degree relatives of patients with the diagnosis. Interestingly, family studies indicate that GAD and panic disorder segregate independently. More than 80% of patients with GAD also suffer from major depression, dysthymia, or social phobia. Comorbid substance abuse is common in these patients, particularly alcohol and/or sedative/hypnotic abuse. Patients with GAD worry excessively over minor matters, with life-disrupting effects; unlike in panic disorder, complaints of shortness of breath, palpitations, and tachycardia are


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InternalMed_Harrison. abuse. Patients with GAD worry excessively over minor matters, with life-disrupting effects; unlike in panic disorder, complaints of shortness of breath, palpitations, and tachycardia are relatively rare.


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InternalMed_Harrison. Etiology and Pathophysiology All anxiogenic agents act on the γ-aminobutyric acid (GABA)A receptor/chloride ion channel complex, implicating this neurotransmitter system in the pathogenesis of anxiety and panic attacks. Benzodiazepines are thought to bind two separate GABAA receptor sites: type I, which has a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety effects of the various benzodiazepines are influenced by their relative binding to alpha 2 and 3 subunits of the GABAA receptor, and sedation and memory impairment to the alpha 1 subunit, Serotonin (5-hydroxytryptamine [5-HT]) and 3α-reduced neuroactive steroids (allosteric modulators of GABAA) also appear to have a role in anxiety, and buspirone, a partial 5-HT1A receptor agonist, and certain 5-HT2A and 5-HT2C receptor antagonists (e.g., nefazodone) may have beneficial effects.


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InternalMed_Harrison. A combination of pharmacologic and psychotherapeutic interventions is most effective in GAD, but complete symptomatic relief is rare. A short course of a benzodiazepine is usually indicated, preferably lorazepam, oxazepam, or alprazolam. (The first two of these agents are metabolized via conjugation rather than oxidation and thus do not accumulate if hepatic function is impaired; the latter Once-daily dosing, usually qhs; blood levels of most TCAs available; can be lethal in overdose (lethal dose = 2 g); nortriptyline best tolerated, especially by elderly Nausea, dizziness, insomnia Nausea, dizziness, headache, insomnia, constipation Somnolence, weight gain; neutropenia rare Nausea, diarrhea, headache; dosage adjustment if given with CYP3A4 inhibitor/stimulator Nausea, diarrhea, sweating, headache; low incidence of sedation or weight gain Nausea, constipation, sweating; rare increase in blood pressure/pulse


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InternalMed_Harrison. Nausea, diarrhea, sweating, headache; low incidence of sedation or weight gain Nausea, constipation, sweating; rare increase in blood pressure/pulse Bid-tid dosing (extended release available); lower potential for drug interactions than SSRIs; contraindicated with MAOIs Primary metabolite of venlafaxine; no increased efficacy with higher dosing May have utility in treatment of neuropathic pain and stress incontinence No specific p450 effects; 5-HT3a and 5-HT7 receptor antagonist, 5-HT1b partial agonist, and 5-HT1a agonist Most noradrenergic of SNRIs Sedation; dry mouth; ventricular irritability; postural hypotension; priapism rare Daytime somnolence, dizziness, nausea Sexual dysfunction Tid dosing, but sustained release also available; fewer sexual side effects than SSRIs or TCAs; may be useful for adult ADD Useful in low doses for sleep because of sedating effects with no anticholinergic side effects


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InternalMed_Harrison. Useful in low doses for sleep because of sedating effects with no anticholinergic side effects Insomnia; hypotension; edema; anorgasmia; weight gain; neuropathy; hypertensive crisis; toxic reactions with SSRIs; narcotics Local skin reaction hypertension May be more effective in patients with atypical features or treatment-refractory depression Less weight gain and hypotension than phenelzine No dietary restrictions with 6 mg dose Abbreviations: ADD, attention deficit disorder; EPS, extrapyramidal symptoms; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; MAOIs, monoamine oxidase inhibitors; OCD, obsessive-compulsive disorder; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.


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InternalMed_Harrison. also has limited active metabolites.) Treatment should be initiated at the lowest dose possible and prescribed on an as-needed basis as symptoms warrant. Benzodiazepines differ in their milligram per kilogram potency, half-life, lipid solubility, metabolic pathways, and presence of active metabolites. Agents that are absorbed rapidly and are lipid soluble, such as diazepam, have a rapid onset of action and a higher abuse potential. Benzodiazepines should generally not be prescribed for >4–6 weeks because of the development of tolerance and the risk of abuse and dependence. Withdrawal must be closely monitored as relapses can occur. It is important to warn patients that concomitant use of alcohol or other sedating drugs may exacerbate side effects and impair their ability to function. An optimistic approach that encourages the patient to clarify environmental precipitants, anticipate his or her reactions, and plan effective response strategies is an essential element of therapy.


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InternalMed_Harrison. Adverse effects of benzodiazepines generally parallel their relative half-lives. Longer-acting agents, such as diazepam, chlordiazepoxide, flurazepam, and clonazepam, tend to accumulate active metabolites, with resultant sedation, impairment of cognition, and poor psychomotor performance. Shorter-acting compounds, such as alprazolam, lorazepam, and oxazepam, can produce daytime anxiety, early morning insomnia, and, with discontinuation, rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely to habituate to the adverse psychomotor effects. Withdrawal from the longer half-life benzodiazepines can be accomplished through gradual, stepwise dose reduction (by 10% every 1–2 weeks) over 6–12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Physicians may need to switch the patient to a benzodiazepine with a longer half-life or use an


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InternalMed_Harrison. Nausea, loss of Usually short-lived and dose-related; consider appetite temporary dose reduction or administration with food and antacids Diarrhea Famotidine, 20–40 mg/d Constipation Wait for tolerance; try diet change, stool softener, exercise; avoid laxatives Anorgasmia/ Bethanechol, 10–20 mg, 2 h before activity, or impotence; impaired cyproheptadine, 4–8 mg 2 h before activity, or ejaculation bupropion, 100 mg bid, or amantadine, 100 mg Orthostasis Tolerance unlikely; increase fluid intake, use calf exercises/support hose; fludrocortisone, 0.025 mg/d Dry mouth, eyes Maintain good oral hygiene; use artificial tears, sugar-free gum Tremor/jitteriness Antiparkinsonian drugs not effective; use dose reduction/slow increase; lorazepam, 0.5 mg bid, or propranolol, 10–20 mg bid Insomnia Schedule all doses for the morning; trazodone, 50–100 mg qhs Sedation Caffeine; schedule all dosing for bedtime; bupropion, 75–100 mg in afternoon


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InternalMed_Harrison. Insomnia Schedule all doses for the morning; trazodone, 50–100 mg qhs Sedation Caffeine; schedule all dosing for bedtime; bupropion, 75–100 mg in afternoon Headache Evaluate diet, stress, other drugs; try dose reduction; amitriptyline, 50 mg/d Loss of therapeutic ben-Related to tolerance? Increase dose or drug holiefit over time day; add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2.5 mg bid adjunctive medication such as a beta blocker or carbamazepine, before attempting to discontinue the benzodiazepine. Withdrawal reactions vary in severity and duration; they can include depression, anxiety, lethargy, diaphoresis, autonomic arousal, and, rarely, seizures. Serotonergic agonists, e.g., tryptophan, fenfluramine, tryptans Drugs that are metabolized by P450 isoenzymes: tricyclics, other SSRIs, antipsychotics, beta blockers, codeine, triazolobenzodiazepines, calcium channel blockers Drugs that are bound tightly to plasma proteins, e.g., warfarin


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InternalMed_Harrison. Drugs that are bound tightly to plasma proteins, e.g., warfarin Drugs that inhibit the metabolism of SSRIs by P450 isoenzymes, e.g., quinidine Serotonin syndrome—absolute contraindication Increased bleeding secondary to displacement Abbreviation: SSRIs, selective serotonin reuptake inhibitors.