SECTION III Diseases of the Central Nervous System632 FIGURE 46-14 (Continued) FIGURE 46-15 Histiocytosis Sagittal T1-weighted image (A) demonstrates enlargement of the pituitary stalk (arrow) and absence of the posterior pitu- itary intrinsic T1 hyperintensity (arrowhead). Sagittal and coronal T1-weighted images post-gadolinium (B, C) demonstrate enhancement of the pituitary stalk and infundibulum (arrows).
633 FIGURE 46-16 CHAPTER 46 Atlas of Neuroimaging Middle cerebral artery stenosis (Chap. 21) Time-of-flight (TOF) MR angiography (MRA) (A, B) reveals narrowing within the left M1 segment that is likely secondary to atherosclerosis (arrows). FIGURE 46-17 Axial FLAIR MRI (B) demonstrates abnormal high signal Lacunar infarction (Chap. 21) involving the left anterior putamen and anterior limb of internal Axial noncontrast CT (A) demonstrates abnormal hypoden- capsule with ex-vacuo dilatation of the adjacent frontal horn sity involving the left anterior putamen and anterior limb of of the left lateral ventricle, suggestive of an old infarction internal capsule with ex-vacuo dilatation of the adjacent (arrow). A small area of slight hyperintensity is also seen in the frontal horn of the left lateral ventricle, suggestive of an old posterior limb of the right internal capsule that can corre- infarction (arrow). A small area of slight hypodensity is also spond to an acute lacunar infarct (arrowhead). seen in the posterior limb of the right internal capsule that can correspond to an acute infarct (arrowhead).
634 SECTION III Diseases of the Central Nervous System FIGURE 46-17 (Continued) strongly suggestive for an acute lacunar infarct (arrowhead). Diffusion-weighted image (C) and apparent diffusion coeffi- There is no evidence of restricted diffusion in the old infarct cient (ADC) map (D) demonstrate restricted water motion in (arrow). the lesion of the posterior limb of the right internal capsule, FIGURE 46-18 Axial T2-weighted MR images (A, B) demonstrate multiple Cerebral autosomal dominant arteriopathy with subcortical patchy areas of abnormal high signal in the periventricular infarcts and leukoencephalopathy (CADASIL) (Chap. 21) white matter (arrows).
635 FIGURE 46-18 (Continued) some of these areas, there are small areas of tissue loss CHAPTER 46 Atlas of Neuroimaging Coronal FLAIR MRI (C, D) demonstrates multiple patchy (encephalomalacia) (arrowheads). areas of abnormal high signal in the periventricular white matter bilaterally, including the temporal lobes (arrows). In FIGURE 46-19 Axial T2-weighted MRI (B) demonstrates a large hypointense CNS vasculitis intraparenchymal hematoma surrounded by hyperintense Axial noncontrast CT (A) demonstrates a large hyperdense vasogenic edema in the right parietal lobe. intraparenchymal hematoma surrounded by hypodense vasogenic edema in the right parietal lobe.
636 FIGURE 46-19 (Continued) Conventional angiography (C) demonstrates multiple seg- ments of intracranial arterial narrowing, some of which have associated adjacent areas of focal arterial dilatation. These abnormalities are suggestive of vasculitis. SECTION III Diseases of the Central Nervous System FIGURE 46-20 Axial T1-weighted MRI (B) demonstrates absence of flow Superior sagittal sinus thrombosis (Chap. 21) void in the superior sagittal sinus, suggestive of thrombosis. Noncontrast CT of the head (A) demonstrates increased den- sity in the superior sagittal sinus, suggestive of thrombosis (arrow), and small linear hyperdensities in some temporal lobe sulci, suggestive of subarachnoid hemorrhage (arrowheads).
637 FIGURE 46-20 (Continued) adjacent sulci. These findings are suggestive of vasogenic CHAPTER 46 Atlas of Neuroimaging Coronal FLAIR images (C, D) demonstrate areas of abnormal edema with subarachnoid hemorrhage (arrowheads). high signal involving the gray and the subcortical white mat- ter of the right frontal and left parietal lobes, as well as the FIGURE 46-20 (Continued)
SECTION III Diseases of the Central Nervous System638 FIGURE 46-20 (Continued) Diffusion-weighted images (E, F) and ADC maps (G, H) demonstrate restricted diffusion of the abnormal areas on FLAIR, suggestive of infarct. FIGURE 46-20 (Continued) Phase-contrast venography of the brain (I ) demonstrates absence of signal in the superior sagittal sinus down to the torcular herophili, and left transverse sinus and jugular vein.
639CHAPTER 46 Atlas of Neuroimaging FIGURE 46-20 (Continued) Axial (J) and coronal (K ) T1-weighted images post-gadolinium demonstrate a filling defect in the superior sagittal sinus, suggestive of thrombosis. FIGURE 46-21 Sagittal T1-weighted MR image (B) demonstrates pontine Multiple system atrophy (Chap. 26) atrophy and enlarged cerebellar fissures as a result of cere- Axial T2-weighted MR image ( A) reveals symmetric poorly bellar atrophy (arrows). circumscribed abnormal high signal in the middle cerebellar peduncles bilaterally (arrowheads).
640 SECTION III Diseases of the Central Nervous System FIGURE 46-22 Axial (B) and coronal (C) FLAIR images demonstrate bilateral Huntington’s disease (Chap. 25) symmetric abnormal high signal in the caudate and putamen. Axial noncontrast CT (A) demonstrates symmetric bilateral Coronal T1-weighted image (D) demonstrates enlarged severe atrophy involving the caudate nuclei, putamen, and frontal horns with abnormal configuration. Also note diffusely globus pallidi bilaterally with consequent enlargement of the decreased marrow signal, which could represent anemia or frontal horns of the lateral ventricles (arrows). There is also myeloproliferative disease. diffuse prominence of the sulci indicating generalized cortical atrophy.
641CHAPTER 46 Atlas of Neuroimaging FIGURE 46-23 Bell’s palsy (Chap. 29) Axial T1-weighted images post-gadolinium with fat suppres- sion (A–C) demonstrate diffuse smooth linear enhancement along the left facial nerve, involving the second and third segments (genus, tympanic, and mastoid) within the tempo- ral bone (arrows). Note that there is no evidence of a mass lesion. A potential pitfall for facial nerve enhancement in the stylomastoid foramen is the enhancement of the stylomas- toid artery that enters the foramen and supplies the tympanic cavity, the tympanic antrum, mastoid cells, and the semicir- cular canals. Coronal T1-weighted images post-gadolinium with fat sup- pression (D, E) demonstrate the course of the enhancing facial nerve (arrows). Although these findings are highly suggestive of Bell’s palsy, the diagnosis is established on clinical grounds.
642 SECTION III Diseases of the Central Nervous System FIGURE 46-24 T1-weighted MR image of the lumbar spine post-gadolinium Spinal cord infarction (Chap. 30) (B) demonstrates mild enhancement (arrow). Sagittal T2-weighted MR image of the lumbar spine (A) Sagittal diffusion-weighted MR image of the lumbar spine demonstrates poorly defined areas of abnormal high signal in (C) demonstrates restricted diffusion (arrow) in the areas of the conus medullaris and mild cord expansion (arrow). abnormal high signal on the T2-weighted image (A). FIGURE 46-25 Sagittal T1-weighted MR image post-gadolinium (B) demon- Acute transverse myelitis (Chap. 30) strates abnormal enhancement in the posterior half of the Sagittal T2-weighted MR image (A) demonstrates abnormal cord from C2 to T1 (arrows). high signal in the cervical cord extending from C1 to T1 with associated cord expansion (arrows).
643 CHAPTER 46 Atlas of Neuroimaging FIGURE 46-26 Following administration of gadolinium, corresponding axial Acute disseminated encephalomyelitis (ADEM) (Chap. 34) (C) and coronal (D) T1-weighted images demonstrate irregu- Axial T2-weighted (A) and coronal FLAIR (B) images demon- lar enhancement consistent with blood-brain barrier break- strate abnormal areas of high signal involving predominantly down and inflammation; some lesions show incomplete rim the subcortical white matter of the frontal lobe bilaterally, and enhancement, typical for demyelination. left caudate head.
644 SECTION III Diseases of the Central Nervous System FIGURE 46-27 Axial (B) and sagittal (C–E) T2-weighted MR images demon- Balo’s concentric sclerosis (a variant of multiple sclerosis) strate multiple areas of abnormal high signal in the supratentorial (Chap. 34) white matter bilaterally, as well as the involvement of the body Coronal FLAIR MRI (A) demonstrates multiple areas of and splenium of the corpus callosum and the callosal-septal abnormal high signal in the supratentorial white matter bilat- interface (arrowhead). Some of the lesions reveal concentric lay- erally. The lesions are ovoid in shape, perpendicular to the ers, typical of Balo’s concentric sclerosis (arrows). orientation of the lateral ventricles, and with little mass effect.
645 CHAPTER 46 Atlas of Neuroimaging FIGURE 46-27 (Continued) with some of the lesions demonstrating concentric ring Sagittal (F) and axial (G, H) T1-weighted MR images post- enhancement (arrows). gadolinium demonstrate abnormal enhancement of all lesions
SECTION III Diseases of the Central Nervous System646 FIGURE 46-28 Hashimoto’s encephalopathy Axial FLAIR (A) demonstrates focal area of abnormal high signal involving the gray and white matter in the left frontal lobe. There is also a small area of abnormal high signal in the precentral gyrus. Axial T1-weighted images (B, C) pre- and post-gadolinium demonstrate cortical/pial enhancement in the region of high signal on FLAIR.
647 CHAPTER 46 Atlas of Neuroimaging FIGURE 46-29 and C8 nerve roots, and the trunks and divisions that origi- Brachial plexopathy (Chap. 7) nate from these roots (arrows). Axial (A), sagittal (B), and coronal (C, D) short tau inversion recovery (STIR) MR images demonstrate abnormal enlarge- ment and abnormal high signal involving the right C6, C7,
SECTION III Diseases of the Central Nervous System648 FIGURE 46-29 (Continued) Diffusion-weighted MR imaging (E) demonstrates abnormal reduced diffusion within the right C6, C7, C8 nerve roots and their corresponding trunks and divisions (arrow). These findings are compatible with radiation-induced brachial plexopathy.
SECTION IV CHRONIC FATIGUE SYNDROME
CHAPTER 47 CHRONIC FATIGUE SYNDROME Stephen E. Straus† Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 Chronic fatigue syndrome (CFS) is the current name for a Estimates of the prevalence of CFS have depended on disorder characterized by debilitating fatigue and several the case definition used and the method of study. Chronic associated physical, constitutional, and neuropsychological fatigue itself is a common symptom, occurring in as many complaints (Table 47-1).This syndrome is not new; in the as 20% of patients attending general medical clinics; CFS past, patients diagnosed with conditions such as the vapors, is far less common. Community-based studies find that neurasthenia, effort syndrome, chronic brucellosis, epi- 100–300 individuals per 100,000 population in the demic neuromyasthenia, myalgic encephalomyelitis, hypo- United States meet the current CDC case definition. glycemia, multiple chemical sensitivity syndrome, chronic candidiasis, chronic mononucleosis, chronic Epstein-Barr PATHOGENESIS virus (EBV) infection, and postviral fatigue syndrome may have had what is now called CFS. A subset of ill veterans The diverse names for the syndrome reflect the many of military campaigns suffer from CFS. The U.S. Centers and controversial hypotheses about its etiology. Several for Disease Control and Prevention (CDC) has developed common themes underlie attempts to understand the diagnostic criteria for CFS based upon symptoms and the disorder: (1) it is often postinfectious; (2) it is associated exclusion of other illnesses (Table 47-2). with mild immunologic disturbances and sedentary behavior during childhood; and (3) it is commonly EPIDEMIOLOGY accompanied by neuropsychological complaints, somatic preoccupation, and/or depression. Patients with CFS are twice as likely to be women as men and are generally 25–45 years of age, although cases Many studies over the past quarter century sought to in childhood and in later life have been described. link CFS to acute and/or persisting infections with EBV, cytomegalovirus, human herpesvirus type 6, retroviruses, Cases are recognized in many developed countries. enteroviruses, Candida albicans, Mycoplasma spp., or Most arise sporadically, but many clusters have also Coxiella burnetii, among other microbial pathogens. been reported. Famous outbreaks of CFS occurred in Compared to findings in age-matched control subjects, Los Angeles County Hospital in 1934; in Akureyri, Ice- the titers of antibodies to some microorganisms are ele- land, in 1948; in the Royal Free Hospital, London, in vated in CFS patients. Reports that viral antigens and 1955; and in Incline Village, Nevada, in 1985. While nucleic acids could be specifically identified in patients these clustered cases suggest a common environmental with CFS, however, have not been confirmed. One study or infectious cause, none has been identified. from the United Kingdom failed to detect any associa- tion between acute infections and subsequent prolonged †Deceased. 650
TABLE 47-1 Changes in numerous immune parameters of uncertain 651 functional significance have been reported in CFS. Modest SPECIFIC SYMPTOMS REPORTED BY PATIENTS elevations in titers of antinuclear antibodies, reductions in WITH CHRONIC FATIGUE SYNDROME immunoglobulin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell SYMPTOM PERCENTAGE activity, disturbances in cytokine production, and shifts in lymphocyte subsets have been described. None of these Fatigue 100 immune findings appears in most patients, nor do any cor- Difficulty concentrating 90 relate with the severity of CFS. Comparison of monozy- Headache 90 gotic twin pairs discordant for CFS showed no substantive Sore throat 85 immunologic differences between affected and unaffected Tender lymph nodes 80 individuals. In theory, symptoms of CFS could result from Muscle aches 80 excessive production of a cytokine, such as interleukin 1, Joint aches 75 which induces asthenia and other flulike symptoms; how- Feverishness 75 ever, compelling data in support of this hypothesis are Difficulty sleeping 70 lacking. A recently published population-based study from Psychiatric problems 65 Wichita, Kansas, reported differences in gene expression Allergies 55 patterns and in candidate gene polymorphisms between Abdominal cramps 40 CFS patients and controls; these results are controversial Weight loss 20 and await confirmation. Rash 10 Rapid pulse 10 In some but not the more recent studies, patients Weight gain 5 with CFS commonly manifested sensitivity to sustained Chest pain 5 upright posture or tilting, resulting in hypotension and Night sweats 5 syncope, so as to suggest a form of dysautonomia. Source: From SE Straus: J Infect Diseases 157:405, 1988; with Disturbances in hypothalamic-pituitary-adrenal func- CHAPTER 47 Chronic Fatigue Syndrome permission. tion have been identified in several controlled studies of CFS, with some evidence for normalization in patients TABLE 47-2 whose fatigue abates. These neuroendocrine abnormali- ties could contribute to the impaired energy and CDC CRITERIA FOR DIAGNOSIS OF CHRONIC depressed mood of patients. FATIGUE SYNDROME Mild to moderate depression is present in one-half A case of chronic fatigue syndrome is defined by the to two-thirds of patients. Much of this depression may presence of: be reactive, but its prevalence exceeds that seen in other 1. Clinically evaluated, unexplained, persistent or chronic medical illnesses. Some propose that CFS is fundamentally a psychiatric disorder and that the vari- relapsing fatigue that is of new or definite onset; is not ous neuroendocrine and immune disturbances arise the result of ongoing exertion; is not alleviated by rest; secondarily. and results in substantial reduction of previous levels of occupational, educational, social, or personal MANIFESTATIONS activities; and 2. Four or more of the following symptoms that persist or Typically, CFS arises suddenly in a previously active recur during six or more consecutive months of illness individual. An otherwise unremarkable flulike illness or and that do not predate the fatigue: some other acute stress leaves unbearable exhaustion in • Self-reported impairment in short-term memory or its wake. Other symptoms, such as headache, sore throat, tender lymph nodes, muscle and joint aches, and fre- concentration quent feverishness, lead to the belief that an infection • Sore throat persists, and medical attention is sought. Over weeks to • Tender cervical or axillary nodes months, despite reassurances that “nothing serious is • Muscle pain wrong,” the symptoms persist and other features of the • Multijoint pain without redness or swelling syndrome become evident—disturbed sleep, difficulty in • Headaches of a new pattern or severity concentration, and depression (Table 47-1). • Unrefreshing sleep • Postexertional malaise lasting ≥24 h Depending on the dominant symptoms and the beliefs of the patient, additional consultations may be sought from Note: CDC, U.S. Centers for Disease Control and Prevention. allergists, rheumatologists, infectious disease specialists, psy- Source: Adapted from K Fukuda et al: Ann Intern Med 121:953, chiatrists, ecologic therapists, homeopaths, or other profes- 1994; with permission. sionals, frequently with unsatisfactory results. Once the fatigue. Another study found that chronic fatigue did not develop after typical upper respiratory infections but did in some individuals after infectious mononucleosis.Thus, while antecedent infections are associated with CFS, a direct microbial causality is unproven and unlikely.
SECTION IV Chronic Fatigue Syndrome652 pattern of illness is established, the symptoms may fluctu- that should not be simply dismissed as additional sub- ate somewhat. Many patients report that CFS symptoms, jective complaints. including cognitive problems, are exacerbated by intensive physical or other stressors, yet recent prospective studies Many symptoms of CFS respond to treatment. Nons- have not confirmed this impression. teroidal anti-inflammatory drugs alleviate headache, dif- Most patients remain capable of meeting family, work, fuse pain, and feverishness. Allergic rhinitis and sinusitis or community obligations despite their symptoms; discre- are common; when present, antihistamines or decon- tionary activities are abandoned first. Some feel unable to gestants may be helpful. Although the patient may be engage in any gainful employment. A minority of indi- averse to psychiatric diagnoses, depression and anxiety viduals requires help with the activities of daily living. are often prominent and should be treated. Expert psy- Econometric analyses conducted by the CDC have chiatric assessment is sometimes advisable. Nonsedat- confirmed that CFS exacts a significant toll on house- ing antidepressants improve mood and disordered hold and workforce productivity. sleep and may attenuate the fatigue. Even modest Ultimately, isolation, frustration, and pathetic resigna- improvements in symptoms can make an important dif- tion can mark the protracted course of illness. Patients ference in the patient’s degree of self-sufficiency and may become angry at physicians for failing to acknowl- ability to appreciate life’s pleasures. edge or resolve their plight. Fortunately, CFS does not appear to progress. On the contrary, many patients experi- Practical advice should be given regarding life-style. ence gradual improvement, and a minority recover fully. Sleep disturbances are common; consumption of heavy meals, alcohol, and caffeine at night can make sleep even DIAGNOSIS more elusive, compounding fatigue. Total rest leads to fur- ther deconditioning and the self-image of being an invalid, A thorough history, physical examination, and judicious whereas overexertion may worsen exhaustion and lead to use of laboratory tests are required to exclude other causes total avoidance of exercise. A carefully graded exercise reg- of the patient’s symptoms. Prominent abnormalities argue imen should be encouraged and has been proven to strongly in favor of alternative diagnoses. No laboratory relieve symptoms and enhance exercise tolerance. test, however, can diagnose this condition or measure its severity. In most cases, elaborate, expensive workups are not Controlled therapeutic trials have established that helpful. Early claims that MRI or single photon emission acyclovir, fludrocortisone, galantamine, modafinil, and IV CT can identify abnormalities in the brain of CFS patients immunoglobulin, among other agents, offer no signifi- have not withstood further study. The dilemma for patient cant benefit in CFS. Low doses of hydrocortisone provide and clinician alike is that CFS has no pathognomonic fea- modest benefit but may lead to adrenal suppression. tures and remains a constellation of symptoms and a diag- Countless anecdotes circulate regarding other tradi- nosis of exclusion. Often the patient presents with features tional and nontraditional therapies. It is important to that also meet criteria for other subjective disorders such as guide patients away from those therapeutic modalities fibromyalgia and irritable bowel syndrome. Questions have that are toxic, expensive, or unreasonable. been raised as to the relative merits of rendering a diagno- sis of CFS. Being diagnosed can provide validation of a The physician should promote the patient’s efforts to patient’s perceived symptoms but may also perpetuate or recover. Several controlled trials conducted in the United exacerbate them. Refusal to label a patient as having CFS, Kingdom, in Australia, and in the Netherlands showed however, can deny the patient the opportunity to under- cognitive-behavioral therapy to be helpful in adolescents take treatments that are of proven merit. and adults with CFS. This approach aims to dispel mis- guided beliefs and fears about CFS that can contribute to inactivity and despair. For CFS, as for many other condi- tions, a comprehensive approach to physical, psychologi- cal, and social aspects of well-being is in order. Treatment: FURTHER READINGS CHRONIC FATIGUE SYNDROME BAKER R, SHAW EJ: Diagnosis and management of chronic fatigue After other illnesses have been excluded, there are sev- syndrome or myalgic encephalitis (or encephalopathy): Summary eral points to address in the long-term care of a patient of NICE guidance. BMJ 335:446, 2007 with chronic fatigue. JONES JF et al: An evaluation of exclusionary medical/psychiatric The patient should be educated about the illness conditions in the definition of chronic fatigue syndrome. BMC and what is known of its pathogenesis; potential impact Med 7:57, 2009 on the physical, psychological, and social dimensions of life; and prognosis. Periodic reassessment is appropriate KILMAS NG, KONERU AO: Chronic fatigue syndrome: inflamma- to identify a possible underlying process that is late in tion, immune function, and neuroendocrine interactions. Curr declaring itself and to address intercurrent symptoms Rheumatol Rep 9:482, 2007 PRINS JB et al: Chronic fatigue syndrome. Lancet 367:346, 2006
SECTION V PSYCHIATRIC DISORDERS
CHAPTER 48 BIOLOGY OF PSYCHIATRIC DISORDERS Steven E. Hyman ■ Eric Kandel Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654 Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654 Challenges with Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . 656 Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661 Psychiatric disorders are a diverse group of brain disor- disorders, schizophrenia, and to some extent other psychi- ders with symptoms that primarily involve emotion, atric disorders constitute the most potent risk factors for higher cognitive function, and the ability to control suicide, a leading cause of death worldwide. complex behaviors. A compendium of psychiatric disor- ANATOMY ders can be found in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) of the Ameri- Progress in understanding the pathophysiology of psychi- can Psychiatric Association. This compendium illustrates atric disorders has been slow, despite its fundamental that the boundary between psychiatric and neurologic importance. Perhaps the most significant challenge is disorders, another heterogeneous group of brain disor- posed by the difficulties inherent in understanding the ders, is arbitrary and shifting. In areas of overlap such as high-level cognitive and affective functions of the brain autism, Tourette’s disorder, and Alzheimer’s disease, the that are disrupted in psychiatric disorders. As a result, disorder is often treated by either a psychiatrist or a neu- unlike many neurologic disorders, the common psychi- rologist.The term mental disorders, while still widely used, atric disorders appear to involve widely distributed neural fails to acknowledge the neural substrates of these distur- networks and lack an obvious, localized neuropathology, bances and their effects on physiology and behavior. which, if present, would help to narrow the hunt for cel- lular pathology and for underlying biochemical and mol- The major psychiatric disorders are common and ecular causes.Thus, the motor disturbances in Parkinson’s often run a chronic course.The chronic disorders include disease, Huntington’s disease, and amyotrophic lateral scle- anxiety disorders, attention deficit hyperactivity disorder, rosis result from discrete macroscopic lesions in different autism, obsessive-compulsive disorder, and schizophrenia. parts of the motor system. By contrast, in psychiatric dis- Other psychiatric disorders such as depressive disorders orders, when candidate regions have been identified, as in recur across the life span, but even bipolar disorder, classi- schizophrenia, depression, and autism, it has proven diffi- cally characterized as episodic, can run a chronic course. cult to differentiate convincingly, these abnormalities from normal variation partly because these target regions form The symptoms of psychiatric disorders often begin only one component of a disorder involving a much early, impairing the ability of children and adolescents to larger neural circuit (Chap. 15). learn and compromising the functioning of adults at work and in other life roles. As a result of their high prevalence, early onset, and persistence, psychiatric disorders con- tribute substantially to the burden of illness in all coun- GENETIC CONSIDERATIONS tries in which they have been studied. In the United Given the challenges of identifying relatively sub- States they are not only a leading cause of disability but tle neuropathology, it has long been hoped that the also a significant cause of premature death, because mood 654
identification of genetic variants conferring risk for psy- powerful tools to investigate the neural basis of the dis- 655CHAPTER 48 Biology of Psychiatric Disorders chiatric disorders would provide effective clues to those ease by putting the mutated gene into worms, flies, or underlying neural abnormalities that contribute to the mice in order to study the mechanisms of pathogenesis. psychiatric disorder in question. This hope is based on While such tools are only a beginning, and indeed have the significant body of data derived from family, twin, not yet led to development of therapies, gene identifica- and adoption studies demonstrating that heredity plays a tion and the study of its function have already created a significant role in the risk of major psychiatric disorders, strong platform for investigation. It permits, for example, including schizophrenia, bipolar disorder, depressive dis- the spatiotemporal characterization in the brain of the orders, and many others. For example, the rate of schiz- expression of disease-related genes, the generation of ophrenia in the general population is ~1%. However, antibodies against the normal and altered proteins, and when one member of a monozygotic twin pair is diag- the production by genetic engineering of worm, fly, and nosed with schizophrenia, the other twin, who is geneti- mouse models that could serve as assays for testing pos- cally identical, has nearly a 50% chance of also manifest- sible therapies. Moreover, the identification of rare, ing the disease. A first-degree relative of an affected Mendelian forms of Parkinson’s disease, Alzheimer’s dis- proband (who shares on average 50% of DNA ease, amyotrophic lateral sclerosis, and epilepsy has pro- sequences) has a 9% risk of schizophrenia. Adoption-at- vided significant insights into the more common forms birth studies provide additional strong support for a of these disorders. Thus far, however, no Mendelian genetic contribution to schizophrenia spectrum disor- form of any of the common early-onset psychiatric dis- ders; in one study from Finland, a schizophrenia-related orders of the brain has been identified convincingly. A illness was present in nearly one-quarter of adoptees small number of Mendelian disorders have symptoms whose biologic mother carried a similar diagnosis. that overlap with those of common psychiatric disor- ders. For example, Rett syndrome, which results from While there continue to be promising leads in the mutations in the methyl DNA binding protein MECP2, search for risk-conferring alleles, research over the past includes autistic-like symptoms but also many severe two decades has not succeeded in identifying with cer- symptoms that are not characteristic of autism. tainty risk genes for psychiatric disorders.There have been large efforts using a variety of strategies, including linkage In psychiatric disorders such as schizophrenia, genes studies and candidate gene studies, in attempts to identify are not, by themselves, causative; other factors, a “second genes responsible for schizophrenia, and more recently hit,” must contribute. Unfortunately, these potential envi- several groups have begun to undertake whole-genome ronmental factors, the “second hits,” have been difficult association studies. The strongest candidates include: dis- to identify. One interesting finding, documented in the rupted in schizophrenia (DISC1), a gene that was dis- Netherlands following World War II and in China, is that rupted by a balanced chromosomal translocation in a maternal famine during gestation is correlated with an Scottish family with schizophrenia-like symptoms; distro- increased incidence of schizophrenia, perhaps by con- brevin-binding protein 1 (DTNBP1); and neuroregulin 1 tributing to de novo germ-line mutations. Other poten- (NRG1), which encodes a protein involved in neuronal tial risk factors include urban birth, migration, increasing migration and in expression of N-methyl-D-aspartate paternal age, and intrauterine exposure to viral infection. (NMDA) glutamate receptors. Other potential candidates include DAOA, RGS4, and AKT1, but the evidence sup- New genetic technologies are now available for the porting them is weaker (Table 48-1). investigation of genetically complex disorders; these include more complete maps of human genetic variabil- One problem in identifying risk genes for psychiatric ity, high-density whole-genome association methods, and diseases has been the failure to replicate convincingly efficient high-throughput sequencing technologies using the discovery of putative risk genes.The failure stems in single nucleotide polymorphism (SNP) arrays.The use of large part from the complex nature of risk for psychi- these tools has already begun to yield significant results atric disorders, which appears to involve multiple genes for several common complex disorders, such as inflam- of small effect interacting with nongenetic factors. In matory bowel disease, age-related macular degeneration, addition, there appear to be different risk genes in dif- and type 2 diabetes mellitus. Psychiatric disorders are ferent population groups, perhaps reflecting new or well positioned to benefit from these new approaches. In recent mutations. addition, it is expected that additional emerging tech- nologies, including cost-efficient methods for whole- It is now relatively straightforward to identify genes genome sequencing, will soon be available, further that exert large causal effects on disease. Several less increasing the likelihood that risk-conferring alleles for common neurologic disorders result from deleterious psychiatric disorders will be identified within the next mutations within single genes. Thus, genes have been few years. To take full advantage of these new methods, identified that contribute to the muscular dystrophies, the psychiatric research community will need to collect triplet repeat disorders such as Huntington’s disease and very large populations for sufficiently powered genetic fragile X, and Down’s syndrome. The discovery of the studies, and identify (by high-resolution imaging, gene Huntington gene was followed by the development of
656 TABLE 48-1 SCHIZOPHRENIA CANDIDATE GENES SECTION V Psychiatric Disorders PROTEIN GENE CH LOCATION EVIDENCE FUNCTION DISC1 Disrupted in 1q42 Initially identified through Roles in microtubular schizophrenia a balanced translocation transport and neuronal in a single family with migration (via interactions schizophrenia and with Lis1 and NudEL); affective disorder; influences postsynaptic confirmed by linkage and responses (interactions with association in different Citron); activates populations. phosphodiesterase 4B, increasing cAMP (target of Dysbindin (dystrobrevin- DTNBP1 6p22 Linkage and association; antidepressant rolipram). binding protein 1) no coding region mutations; Wide distribution in CNS; no consistent allele or expression in synaptic Neuregulin 1 NRG1 8p12-21 haplotype implicated in terminals of hippocampus; different studies; negative in vitro, reduced levels D-Amino oxidase activator DAOA 13q32-34 symptoms of schizophrenia decrease glutamate in may associate with a specific neurons. haplotype of DTNBP1; expression decreased in Suppresses function of schizophrenia brain. NMDA receptors; role in Linkage and association; no neuronal differentiation coding region mutations; no and migration. consistent allele or haplotype implicated in different studies; Activates D-amino oxidase expression increased in which oxidies D-serine, an schizophrenia brain. agonist at NMDA receptors; Linkage and association; no reduced D-serine levels consistent allele or haplotype reported in blood and CSF implicated in different studies. in schizophrenia. Modulates postsynaptic Regulator of G-protein RGS4 1q21-22 Linkage and association; signal transduction, signaling 4 AKT1 14q22-32 susceptibility allele may including downregulation impair working memory and of 5HT1a (serotonin) V-akt murine thymoma regionally reduce brain receptors. viral oncogene volumes Phosphorylates and homologue 1 Inconsistent linkage, inactivates glycogen association, and brain synthase kinase (GSK) 3 beta. expression studies. Note: CH, chromosome; CNS, central nervous system; CSF, cerebrospinal fluid; NMDA, N-methyl-D-aspartate. expression patterns, or other markers) biologically mean- The diagnostic classification scheme (e.g., DSM-IV) upon ingful phenotypes for stratification of the genetic data. which both research and clinical practice rely is derived from expert consensus based on clusters of symptoms and CHALLENGES WITH PHENOTYPING signs and disease course. As a result, failure to delineate well-defined disease entities and to reliably assign individ- Psychiatric disorders have an additional obstacle to the uals, to affected versus nonaffected status have bedeviled identification of risk genes or pathophysiologic processes psychiatric research. that cannot be addressed simply by improving genetic technologies.There are at the moment no objective diag- The lack of objective tests for phenotyping presents nostic measures for any of the common psychiatric disor- enormous difficulties for genetic and other forms of inves- ders. There is not, as yet, a well-defined neuropathology tigation. While type 2 diabetes mellitus and hypertension, for psychiatric disorders nor are there biologic markers. for example, are both highly heterogeneous disorders, the measurement of glucose tolerance or of systolic and
diastolic blood pressure creates a strong framework within electroconvulsive therapy, had immediate and sustained 657 CHAPTER 48 Biology of Psychiatric Disorders which subtyping can occur, generally based on additional responses; however, due to the invasiveness, risk, and cost, objective measures. In contrast, it is not at all certain that this approach may not become a widespread treatment. the boundaries currently drawn around disorders in the Its significance lies in the putative identification of a cir- DSM-IV lead to an underlying and distinguishable set of cuit involved in mood regulation that can be manipu- neurobiologic factors. For example, there is much debate lated to produce therapeutic benefit. about the boundaries of schizophrenia. The DSM-IV lists three psychotic disorders as being independent—schizo- Treatment: phrenia, schizoaffective disorder, and schizophreniform PSYCHIATRIC DISORDERS disorder (American Psychiatric Association, 2000). Yet there is little agreement on whether the latter two are suf- The high prevalence and serious consequences of psy- ficiently homogeneous clinical entities to warrant inde- chiatric disorders make the availability of effective treat- pendent recognition. ments a matter of great importance for public health. Since the middle of the twentieth century, several Despite the problems with current disease classification classes of pharmacologic treatments (antipsychotic in psychiatry, there is agreement on the core symptoms drugs, antidepressant drugs, lithium, benzodiazepines, and strong cross-cultural similarity of disease manifesta- and anticonvulsants) and several standardized short- tion. In addition, there is a strong familial nature to major term psychotherapies have been developed and found psychiatric disorders and also a potent role for heredity, to be efficacious in clinical trials. The result is an arma- which can be inferred from twin and adoption studies. mentarium of useful treatments for many of the common These findings suggest that the central criteria for diag- disorders; however, as is the case for many common, nosing schizophrenia, bipolar disorder, autism, and other chronic medical disorders, there are no cures for psychi- major psychiatric disorders identify, however imperfectly, atric disorders. Residual symptoms and recurrences are distinctive, naturally occurring brain diseases. common, and many pharmacologic treatments have significant side effects. NEUROIMAGING This state of affairs is typified by schizophrenia, In parallel with improved classification and genetic stud- where a large number of drugs have been developed. ies, attempts are being made using neuroimaging to Initially these drugs were thought to be useful only in define anatomic abnormalities as objective, measurable the treatment of schizophrenia; however, they are now phenotypes of the disease. For example, new quantitative commonly used to treat any psychosis, irrespective of methods combined with structural MRI have suggested origin. In schizophrenia, in addition to the psychotic that, in schizophrenia, there may be disease-specific pat- symptoms of hallucinations and delusions, referred to terns of gray matter loss in frontal and temporal cerebral as positive symptoms, there are also negative symptoms cortex. Longitudinal studies of individuals with child- (social withdrawal, impoverished speech, lack of motiva- hood-onset schizophrenia have documented an acceler- tion) and cognitive symptoms (poor executive function). ated loss of gray matter. More recently, attempts have Both positive and negative symptoms are thought to be been made to associate specific DISC1 haplotypes with related to dopaminergic systems in the brain (Fig. 48-2). reduced frontal gray matter. While these approaches are The primary clinical benefit of antipsychotic drugs is the in their early stages, the effort to define objective brain- amelioration of the positive psychotic symptoms. With based phenotypes for genetic and clinical studies appears the exception of clozapine, often described as an atypi- very promising. cal antipsychotic drug, which produces improvement in some patients who do not respond to other drugs, all Functional imaging of individuals with depression the existing antipsychotic drugs have similar efficacy similarly has pinpointed abnormal activity in Brodman and differ primarily in their pattern of side effects. Cloza- area 25, the subgenual prefrontal cortex, a brain region pine and some other atypical drugs are thought to exert that connects to the amygdala and is thought to play a at least a modest therapeutic effect on the negative critical role in the processing of emotion-related infor- symptoms of schizophrenia. None of the drugs, how- mation (Fig. 48-1). Area 25 exhibits excessive metabolic ever, is effective against the symptoms that are central activity in major depression, which reverses with success- to the illness. Furthermore, their residual presence ful antidepressant treatment. This region is also activated throughout the course of the illness contributes sub- in normal subjects in whom sadness is induced by means stantially to the persistence of disability over the of emotion laden stimuli. This information serves as the patient’s lifetime. The search for new drugs to treat basis for an experimental approach to severe depression schizophrenia now focuses extensively on the ability to involving the use of deep-brain stimulation of the sub- modify its cognitive symptoms. All antipsychotic drugs genual prefrontal cortex using implanted electrodes. In an initial series, four of six patients with severe depression unresponsive to all currently proven treatments, including
658 x = –3 SECTION V Psychiatric Disorders Subgenual t value PFC 0 y = 31 –2.8 CC FIGURE 48-1 –5.5 Some patients with unipolar and bipolar disease show a functional abnormality in the prefrontal cortex ventral to the of Neural Science, 4th ed. New York, McGraw-Hill, 2000; genu of the corpus callosum. (From ER Kandel et al: Principles with permission.) in current use block or diminish the action of dopamine benefit at all. When pharmacologic modalities fail in at its D2 receptors (Fig. 48-3); they differ in their relative depression, electroconvulsive therapy continues to be an affinity at D2 receptors and by their actions at other effective treatment option. Lithium and several anticonvul- neurotransmitter receptors. These drugs represent sants dampen mood swings in bipolar disorder and also important progress, but safer and more effective treat- treat acute manic episodes; however, residual depressive ments are very much needed. symptoms, recurrences, and significant side effects are the rule. The exact mechanism of action of lithium is not Drugs useful in depression act by increasing synaptic known. At therapeutic levels, lithium interacts with two levels of serotonin, norepinephrine, or less commonly important signaling pathways: (1) it blocks inositol dopamine (Fig. 48-4). The term antidepressant is a mis- monophosphatase, thus influencing signaling via inositol nomer for this diverse class of drugs, however, because phosphates, such as IP3; and (2) it also blocks glycogen syn- their spectrum of action is much broader than depres- thase kinase 3 beta (GSK3beta). sion. These drugs are also effective in treating fear-based anxiety disorders such as panic disorder and generalized Unfortunately, there are currently very few promising anxiety disorder. In high doses, the selective serotonin drug targets that can be exploited to produce medica- uptake inhibitors are effective for obsessive-compulsive tions with truly novel mechanisms of action. Indeed, all disorder. The antidepressants are effective in the treat- of the major classes of drugs used to treat psychiatric ment of depression, but only moderately so. Many disorders were identified through empirical observa- patients require sequential trials with a number of differ- tions of drug effects in patient populations rather than ent drugs alone or in combination to achieve clinically as a result of understanding pathophysiology. The mole- meaningful benefit, and ~30% of patients derive no cular targets of these drugs were identified by the study
Neocortex Mesocortical system: 659 involved in the Nucleus negative symptoms CHAPTER 48 Biology of Psychiatric Disorders accumbens of schizophrenia (ventral striatum) Limbic Frontal forebrain cortex Mesolimbic and Midbrain Ventral Hippocampal mesocortical tegmental formation system area Mesolimbic Hippocampal Ventral system: formation tegmental involved in the area positive symptoms of schizophrenia A Midsagittal section B Coronal section FIGURE 48-2 The major dopaminergic tracts of the brain. (From ER Kandel et al: Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.) 1a Increase of synthesis Tyrosine Tyrosine Antipsychotic (L-DOPA) D3 DOPA Can produce Dopamine psychotic symptoms 1b Inhibition of synthesis (α-methyltyrosine) Inhibition of breakdown 6 (pargyline) 2 Interference with vesicular MAO Vesicular monoamine storage (reserpine, transporter tetrabenazine) Dopamine transporter Inhibition of reuptake 5 3 Stimulation of release of COMT (cocaine, amphetamine, DA at nerve terminal benztropine) (amphetamine, tyramide) Autoreceptor 4 Blocking of DA receptors and autoreceptors (antipsychotics: perphenazine, haloperidol) D2 D2 FIGURE 48-3 et al: Principles of Neural Science, 4th ed. New York, The key steps in the synthesis and degradation of McGraw-Hill, 2000.) dopamine and the sites of action of various psychoactive substances at the dopaminergic synapse. (From ER Kandel
660 Depressant Antidepressant SECTION V Psychiatric Disorders 1 Inhibition of synthesis Tryptophan (p-chlorophenylalanine, 5-OH-Tryptophan 5-HIAA p-propyldopacetamide) 2 5-HT 5-HT Inhibition of enzyme 5 Interference with 5-HT that oxidizes 5-HT MAO inhibitors vesicular storage (iproniazid, clorgyline) (reserpine, MAO tetrabenazine) 5-HT Inhibition of reuptake 4 3a Stimulation of 5-HT receptor (imipramine, Tricyclics and autoreceptor agonist amitryptyline, fluoxetine, selective serotonin 8-Hydroxy-dipropylamino- sertraline) reuptake inhibitors tetraline (8-OH-DPAT) 3b Stimulation of 5-HT receptors as partial agonist (lysergic acid diethylamide) A Serotonergic neurons 1a Inhibition of synthesis Tyrosine Deaminated (α-methyltyrosine) hydroxylase products 1b Inhibition of synthesis DOPA (FLA 63) Dopamine 2 NE Inhibition of enzyme 7 Interference with Receptor that oxidizes NE MAO inhibitors vesicular storage (pargyline) (reserpine, NE tetrabenazine) MAO 3 Stimulation of release of NM Inhibition of reuptake 6 NE at nerve terminals (desipramine) Tricyclics (amphetamine) COMT Inhibition of enzyme 5 4a Stimulation of receptors that inactivates NE Inactivation inhibitor (clonidine) (tropolone) 4b Blocking of receptors (phenoxybenzamine and phentolamine) B Noradrenergic neurons FIGURE 48-4 Actions of antidepressant and other drugs at serotonergic and noradrenergic synapses. (From ER Kandel et al: Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.) of efficacious drugs and then exploited to produce trials. Instruments such as the Depression Inventory and improved compounds within the same class. Suicide Intent Scale are now available for measuring mental illness; these have helped to objectify research Cognitive-behavioral psychotherapy designed to in psychopathology. focus on the management of specific symptoms has shown benefit in mild to moderately severe depression, New insights into the etiology of depression have fear-based anxiety disorders, and obsessive-compulsive also helped to guide therapy. Depressed patients have a disorder. A significant improvement in the treatment of systematic negative bias in their cognitive styles—in depression in the past decade has been the standard- the way they think about themselves and their future. ization of psychotherapy and its evaluation in clinical These distorted patterns of thinking reflect not simply
an unconscious conflict within the psyche but a disor- Medication therapy Post 661 der in cognitive style and behavior that is a key etiologic Pre agent in maintaining the disorder. Psychotherapy Post CHAPTER 48 Biology of Psychiatric Disorders An approach that focuses on distorted thinking, cog- Pre nitive therapy has been shown in randomized trials to be an effective psychological treatment for depression. FIGURE 48-5 This approach is based on increasing the patients’ Patients with obsessive-compulsive disorder tend to objectivity regarding their misinterpretations of every- show hyperactivity in the head of the caudate. (From ER day situations (their cognitive distortions), their miseval- Kandel et al: Principles of Neural Science, 4th ed. New York, uation of their internal processes (body sensations, McGraw-Hill, 2000.) intrusive thoughts and images), and their negative expectancies. A wide range of professionals can use the FURTHER READINGS methods with highly positive results. BORA E et al: Neurobiology of human affiliative behaviour: implica- Cognitive therapy has also proved beneficial in indi- tions for psychiatric disorders. Curr Opin Psychiatry 22:320, viduals at risk for suicide. Validated instruments exist to 2009 classify and assess suicidal behaviors, making it possible to identify high-risk individuals prospectively. Of partic- CANNON T et al: Association of DISC1/TRAX haplotypes with ular importance has been the identification of clinical schizophrenia, reduced prefrontal gray matter, and impaired and psychological variables that predict future suicide. short- and long-term memory. Arch Gen Psychiatry 62:1205, Hopelessness and consequent suicidal ideation, which 2005 are better predictors of suicide than clinical depression per se, can be quantified and substantially reduced by DORPH-PETERSEN KA et al: Primary visual cortex volume and total cognitive interventions. Several studies with individuals neuron number are reduced in schizophrenia. J Comp Neurol who had recently attempted suicide have demon- 501:290, 2007 strated that a short-term cognitive intervention can sig- nificantly reduce subsequent suicide attempts when HAHN CG et al: Altered neuregulin 1-erbB4 signaling contributes to compared to a control group. NMDA receptor hypofunction in schizophrenia. Nature Med 12: 824, 2006 This therapy has been extended to the treatment of other disorders including anxiety states and obsessive- HYMAN SE: Can neuroscience be integrated into the DSM-V? Nat compulsive disorder. With respect to obsessive-compul- Rev Neurosci 9:725, 2007 sive disorders, cognitive therapy has been shown to reverse a metabolic abnormality, identified by neuroimag- KANDEL ER et al: Principles of Neural Science, 4th ed. New York, ing, in parallel with the clinical improvement (Fig. 48-5). McGraw-Hill, 2000 Cognitive therapy has replaced psychoanalytically KENDLER KS et al: A Swedish national twin study of lifetime major based dynamic psychotherapy as the principal psycho- depression.Am J Psychiatry 163:107, 2006 logical treatment provided by specialists in certain countries. Its success has stimulated the development MCCLELLAN JM et al: Maternal famine, de novo mutations, and of other forms of short-term psychotherapy, including schizophrenia. JAMA 296: 582, 2006 O’DONOVAN MC et al: Interpersonal Psychiatry and Psychoanalytic-Oriented Genetics of psychosis; insights from views across the genome. Insight Therapy. These therapies are now also being Hum Genet. 126:3, 2009 tested in controlled clinical trials and have been found to be effective in a variety of clinical situations. RESSLER KJ, MAYBERG HS: Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Thus, paradoxically, one of the significant advances in Nat Neurosci 10:1116, 2007 the era of the new brain-based biologic psychiatry has been the development of evidence-based psychother- ROSS CA et al: Neurobiology of schizophrenia. Neuron 52:139, apy, a development based on the evidence that insofar 2006 as psychotherapy and other psychiatric treatments work, they do so by altering the functioning and per- haps even the structure of the brain.
CHAPTER 49 MENTAL DISORDERS Victor I. Reus I Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672 Panic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 Generalized Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . 664 Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676 Phobic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 I Somatoform Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678 Stress Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669 I Personality Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679 Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . 670 I Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680 I Assessment and Evaluation of Violence . . . . . . . . . . . . . . . . 684 I Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 I Mental Health Problems in the Homeless . . . . . . . . . . . . . . . 684 Depression in Association with Medical Illness . . . . . . . . . . . 671 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684 Mental disorders are common in medical practice and the clinician into targeted assessment. Prime MD (and a may present either as a primary disorder or as a comor- self-report form, the PHQ) and the Symptom-Driven bid condition. The prevalence of mental or substance Diagnostic System for Primary Care (SDDS-PC) are use disorders in the United States is approximately 30%. inventories that require only 10 min to complete and Only one-third of these individuals are currently receiv- link patient responses to the formal diagnostic criteria ing treatment. Global burden of disease statistics indicate of anxiety, mood, somatoform, and eating disorders and that 4 out of the 10 most important causes of disease to alcohol abuse or dependence. worldwide are psychiatric in origin. A physician who refers patients to a psychiatrist The revised fourth edition for use by primary care should know not only when doing so is appropriate physicians of the Diagnostic and Statistical Manual of Mental but also how to refer, since societal misconceptions and Disorders (DSM-IV-PC) provides a useful synopsis of the stigma of mental illness impede the process. Pri- mental disorders most likely to be seen in primary care mary care physicians should base referrals to a psychia- practice.The current system of classification is multiaxial trist on the presence of signs and symptoms of a men- and includes the presence or absence of a major mental tal disorder and not simply on the absence of a physical disorder (axis I), any underlying personality disorder explanation for a patient’s complaint. The physician (axis II), general medical condition (axis III), psychoso- should discuss with the patient the reasons for request- cial and environmental problems (axis IV), and overall ing the referral or consultation and provide reassurance rating of general psychosocial functioning (axis V). that he or she will continue to provide medical care and work collaboratively with the mental health pro- Changes in health care delivery underscore the need fessional. Consultation with a psychiatrist or transfer of for primary care physicians to assume responsibility for care is appropriate when physicians encounter evi- the initial diagnosis and treatment of the most common dence of psychotic symptoms, mania, severe depres- mental disorders. Prompt diagnosis is essential to ensure sion, or anxiety; symptoms of posttraumatic stress that patients have access to appropriate medical services disorder (PTSD); suicidal or homicidal preoccupation; and to maximize the clinical outcome. Validated or a failure to respond to first-order treatment. The patient-based questionnaires have been developed that pathogenesis of psychiatric and addictive disorders are systematically probe for signs and symptoms associated discussed in Chap. 48. with the most prevalent psychiatric diagnoses and guide 662
ANXIETY DISORDERS feelings of unreality are also common. Diagnostic crite- 663 CHAPTER 49 Mental Disorders ria require at least 1 month of concern or worry about Anxiety disorders, the most prevalent psychiatric ill- the attacks or a change in behavior related to them.The nesses in the general community, are present in 15–20% lifetime prevalence of panic disorder is 1–3%. Panic of medical clinic patients. Anxiety, defined as a subjec- attacks have a sudden onset, developing within 10 min tive sense of unease, dread, or foreboding, can indicate a and usually resolving over the course of an hour, and primary psychiatric condition or can be a component they occur in an unexpected fashion.The frequency and of, or reaction to, a primary medical disease. The pri- severity of panic attacks vary, ranging from once a week mary anxiety disorders are classified according to their to clusters of attacks separated by months of well-being. duration and course and the existence and nature of The first attack is usually outside the home, and onset is precipitants. typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and When evaluating the anxious patient, the clinician results in a generalized fear and a progressive avoidance must first determine whether the anxiety antedates or of places or situations in which a panic attack might postdates a medical illness or is due to a medication side recur. Agoraphobia, which occurs commonly in patients effect. Approximately one-third of patients presenting with panic disorder, is an acquired irrational fear of with anxiety have a medical etiology for their psychi- being in places where one might feel trapped or unable atric symptoms, but an anxiety disorder can also present to escape (Table 49-2).Typically, it leads the patient into with somatic symptoms in the absence of a diagnosable a progressive restriction in lifestyle and, in a literal sense, medical condition. in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of PANIC DISORDER others to go out into the world and do not volunteer this information; thus physicians will fail to recognize the Clinical Manifestations syndrome if direct questioning is not pursued. Panic disorder is defined by the presence of recurrent TABLE 49-2 and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a DIAGNOSTIC CRITERIA FOR AGORAPHOBIA variety of physical symptoms, including palpitations, sweating, trembling, shortness of breath, chest pain, 1. Anxiety about being in places or situations from which dizziness, and a fear of impending doom or death escape might be difficult (or embarrassing) or in which (Table 49-1). Paresthesias, gastrointestinal distress, and help may not be available in the event of having an unexpected or situationally predisposed panic attack TABLE 49-1 or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that DIAGNOSTIC CRITERIA FOR PANIC ATTACK include being outside the home alone; being in a crowd or standing in a line; being on a bridge; and A discrete period of intense fear or discomfort, in which traveling in a bus, train, or automobile. four or more of the following symptoms developed abruptly and reached a peak within 10 min: 2. The situations are avoided (e.g., travel is restricted) or 1. Palpitations, pounding heart, or accelerated heart rate else are endured with marked distress or with anxiety 2. Sweating about having a panic attack or panic-like symptoms, 3. Trembling or shaking or require the presence of a companion. 4. Sensations of shortness of breath or smothering 5. Feeling of choking 3. The anxiety or phobic avoidance is not better 6. Chest pain or discomfort accounted for by another mental disorder, such as 7. Nausea or abdominal distress social phobia (e.g., avoidance limited to social situa- 8. Feeling dizzy, unsteady, lightheaded, or faint tions because of fear of embarrassment), specific 9. Derealization (feelings of unreality) or depersonaliza- phobia (e.g., avoidance limited to a single situation tion (being detached from oneself) like elevators), obsessive-compulsive disorder (e.g., avoidance of dirt in someone with an obsession about 10. Fear of losing control or going crazy contamination), posttraumatic stress disorder (e.g., 11. Fear of dying avoidance of stimuli associated with a severe stres- 12. Paresthesias (numbness or tingling sensations) sor), or separation anxiety disorder (e.g., avoidance of 13. Chills or hot flushes leaving home or relatives). Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 2000. Washington, DC, American Psychiatric Association, 2000.
SECTION V Psychiatric Disorders664 Differential Diagnosis Treatment: PANIC DISORDER A diagnosis of panic disorder is made after a medical eti- ology for the panic attacks has been ruled out. A variety Achievable goals of treatment are to decrease the fre- of cardiovascular, respiratory, endocrine, and neurologic quency of panic attacks and to reduce their intensity. conditions can present with anxiety as the chief com- The cornerstone of drug therapy is antidepressant med- plaint. Patients with true panic disorder will often focus ication (Tables 49-3, 49-4, and 49-5). Selective sero- on one specific feature to the exclusion of others. For tonin reuptake inhibitors (SSRIs) benefit the majority of example, 20% of patients who present with syncope as a panic disorder patients and do not have the adverse primary medical complaint have a primary diagnosis of effects of tricyclic antidepressants (TCAs). Fluoxetine, a mood, anxiety, or substance-abuse disorder, the most paroxetine, and sertraline have received approval from common being panic disorder. The differential diagnosis the U.S. Food and Drug Administration (FDA) for this of panic disorder is complicated by a high rate of indication. SSRIs should be started at one-third to one- comorbidity with other psychiatric conditions, espe- half of their usual antidepressant dose (e.g., 5–10 mg cially alcohol and benzodiazepine abuse, which patients fluoxetine, 25–50 mg sertraline, 10 mg paroxetine). initially use in an attempt at self-medication. Some 75% Monoamine oxidase inhibitors (MAOIs) are also effective of panic disorder patients will also satisfy criteria for and may specifically benefit patients who have comor- major depression at some point in their illness. bid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, When the history is nonspecific, physical examination and the need to maintain a low-tyramine diet (avoid- and focused laboratory testing must be used to rule out ance of cheese and wine) have limited their use, how- anxiety states resulting from medical disorders such as ever. Antidepressants typically take 2–6 weeks to pheochromocytoma, thyrotoxicosis, or hypoglycemia. become effective, and doses may need to be adjusted Electrocardiogram (ECG) and echocardiogram may based upon the clinical response. detect some cardiovascular conditions associated with panic, such as paroxysmal atrial tachycardia and mitral Because of anticipatory anxiety and the need for valve prolapse. In two studies, panic disorder was the immediate relief of panic symptoms, benzodiazepines primary diagnosis in 43% of patients with chest pain are useful early in the course of treatment and sporadi- who had normal coronary angiograms and was present cally thereafter (Table 49-6). For example, alprazolam, in 9% of all outpatients referred for cardiac evaluation. starting at 0.5 mg qid and increasing to 4 mg/d in Panic disorder has also been diagnosed in many patients divided doses, is effective, but patients must be moni- referred for pulmonary function testing or with symp- tored closely, as some develop dependence and begin toms of irritable bowel syndrome. to escalate the dose of this medication. Clonazepam, at a final maintenance dose of 2–4 mg/d, is also helpful; its Etiology and Pathophysiology longer half-life permits twice-daily dosing, and patients appear less likely to develop dependence on this agent. The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic respon- Early psychotherapeutic intervention and education sivity, and social learning. Panic disorder shows familial aimed at symptom control enhances the effectiveness aggregation; the disorder is concordant in 30–45% of of drug treatment. Patients can be taught breathing monozygotic twins, and genome-wide screens have iden- techniques, educated about physiologic changes that tified suggestive risk loci. Acute panic attacks appear to be occur with panic, and learn to expose themselves volun- associated with increased noradrenergic discharges in the tarily to precipitating events in a treatment program locus coeruleus. Intravenous infusion of sodium lactate spanning 12–15 sessions. Homework assignments and evokes an attack in two-thirds of panic disorder patients, as monitored compliance are important components of do the α2-adrenergic antagonist yohimbine, cholecys- successful treatment. Once patients have achieved a tokinin tetrapeptide (CCK-4), and carbon dioxide inhala- satisfactory response, drug treatment should be main- tion. It is hypothesized that each of these stimuli activates a tained for 1–2 years to prevent relapse. Controlled trials pathway involving noradrenergic neurons in the locus indicate a success rate of 75–85%, although the likeli- coeruleus and serotonergic neurons in the dorsal raphe. hood of complete remission is somewhat lower. Agents that block serotonin reuptake can prevent attacks. Panic-disorder patients have a heightened sensitivity to GENERALIZED ANXIETY DISORDER somatic symptoms, which triggers increasing arousal, set- ting off the panic attack; accordingly, therapeutic interven- Clinical Manifestations tion involves altering the patient’s cognitive interpretation of anxiety-producing experiences as well as preventing the Patients with generalized anxiety disorder (GAD) have attack itself. persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic
TABLE 49-3 665 ANTIDEPRESSANTS NAME USUAL DAILY DOSE, mg SIDE EFFECTS COMMENTS CHAPTER 49 Mental Disorders SSRIs Fluoxetine (Prozac) 10–80 Headache; nausea and Once daily dosing, usually in other GI effects; jitteriness; A.M.; fluoxetine has very long Sertraline (Zoloft) 50–200 insomnia; sexual dysfunction; half-life; must not be combined can affect plasma levels of other with MAOIs Paroxetine (Paxil) 20–60 meds (except sertraline); akathisia rare Fluvoxamine (Luvox) 100–300 Citalopram (Celexa) 20–60 Escitalopram (Lexapro) 10–30 TCAs Amitriptyline (Elavil) 150–300 Anticholinergic (dry mouth, Once daily dosing, usually qhs; tachycardia, constipation, blood levels of most TCAs Nortriptyline (Pamelor) 50–200 urinary retention, blurred vision); available; can be lethal in O.D. sweating; tremor; postural (lethal dose = 2 g); nortriptyline Imipramine (Tofranil) 150–300 hypotension; cardiac conduction best tolerated, especially by delay; sedation; weight gain elderly Desipramine (Norpramin) 150–300 Doxepin (Sinequan) 150–300 Clomipramine (Anafranil) 150–300 Mixed norepinephrine/ serotonin reuptake inhibitors Venlafaxine (Effexor) 75–375 Nausea; dizziness; dry mouth; Bid-tid dosing (extended release headaches; increased blood available); lower potential for Duloxetine (Cymbalta) 40–60 pressure; anxiety and insomnia drug interactions than SSRIs; contraindicated with MAOI Mirtazapine (Remeron) 15–45 Nausea, dizziness, headache, May have utility in treatment of 250–450 insomnia, constipation neuropathic pain and stress Mixed-action drugs incontinence Bupropion (Wellbutrin) Somnolence; weight gain; Once daily dosing neutropenia rare Trazodone (Desyrel) 200–600 Jitteriness; flushing; seizures in Tid dosing, but sustained at-risk patients; anorexia; release also available; fewer Nefazodone (Serzone) 300–600 tachycardia; psychosis sexual side effects than SSRIs or TCAs; may be useful for Amoxapine (Asendin) 200–600 Sedation; dry mouth; ventricular adult ADD irritability; postural hypotension; Useful in low doses for sleep priapism rare because of sedating effects with no anticholinergic side Sedation; headache; dry mouth; effects nausea; constipation Discontinued sale in United States and several other Sexual dysfunction countries due to risk of liver failure Lethality in overdose; EPS possible MAOIs 45–90 Insomnia; hypotension; May be more effective in Phenelzine (Nardil) 20–50 anorgasmia; weight gain; patients with atypical features Tranylcypromine hypertensive crisis; toxic or treatment-refractory 20–60 reactions with SSRIs depression (Parnate) 6–12 Local skin reaction; hypertension No dietary restrictions with Isocarboxazid (Marplan) 6-mg dose Transdermal selegiline (Emsam) Note: ADD, attention deficit disorder; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepres- sant; EPS, extrapyramidal symptoms. arousal, feeling “on edge” or restless, and insomnia diagnosis. Interestingly, family studies indicate that GAD (Table 49-7). Onset is usually <20 years, and a history and panic disorder segregate independently. Over 80% of childhood fears and social inhibition may be present. of patients with GAD also suffer from major depression, The lifetime prevalence of GAD is 5–6%; the risk is dysthymia, or social phobia. Comorbid substance abuse higher in first-degree relatives of patients with the is common in these patients, particularly alcohol and/or
666 TABLE 49-4 MANAGEMENT OF ANTIDEPRESSANT SIDE EFFECTS SECTION V Psychiatric Disorders SYMPTOMS COMMENTS AND MANAGEMENT STRATEGIES Gastrointestinal Usually short-lived and dose-related; consider temporary dose reduction or Nausea, loss of appetite administration with food and antacids Famotidine, 20–40 mg/d Diarrhea Wait for tolerance; try diet change, stool softener, exercise; avoid laxatives Constipation Consider dose reduction; drug holiday Sexual dysfunction Bethanechol, 10–20 mg, 2 h before activity, or cyproheptadine, 4–8 mg 2 h Anorgasmia/impotence; before activity, or bupropion, 100 mg bid or amantadine, 100 mg bid/tid impaired ejaculation Tolerance unlikely; increase fluid intake, use calf exercises/support hose; Orthostasis fludrocortisone, 0.025 mg/d Wait for tolerance Anticholinergic Maintain good oral hygiene; use artificial tears, sugar-free gum Dry mouth, eyes Antiparkinsonian drugs not effective; use dose reduction/slow increase; lorazepam, 0.5 mg bid, or propranolol, 10–20 mg bid Tremor/jitteriness Schedule all doses for the morning; trazodone, 50–100 mg qhs Caffeine; schedule all dosing for bedtime; bupropion, 75–100 mg in Insomnia afternoon Sedation Evaluate diet, stress, other drugs; try dose reduction; amitriptyline, 50 mg/d Decrease carbohydrates; exercise; consider fluoxetine Headache Related to tolerance? Increase dose or drug holiday; Weight gain add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2.5 mg bid Loss of therapeutic benefit over time TABLE 49-5 Etiology and Pathophysiology POSSIBLE DRUG INTERACTIONS WITH SELECTIVE Anxiogenic agents share in common the property of alter- SEROTONIN REUPTAKE INHIBITORS ing the binding of benzodiazepines to the γ-aminobutyric acid (GABA)A receptor/chloride ion channel complex, AGENT EFFECT implicating this neurotransmitter system in the patho- genesis of anxiety and panic attacks. Benzodiazepines are Monoamine oxidase Serotonin syndromea— thought to bind two separate GABAA receptor sites: inhibitors absolute contraindication type I, which has a broad neuroanatomic distribution, Serotonergic agonists, e.g., Potential serotonin and type II, which is concentrated in the hippocampus, tryptophan, fenfluramine syndrome striatum, and neocortex. The antianxiety effects of the Drugs that are metabolized Delayed metabolism various benzodiazepines and side effects such as sedation by P450 isoenzymes: resulting in increased and memory impairment are influenced by their relative tricyclics, other SSRIs, blood levels and potential binding to type I and type II receptor sites. Serotonin antipsychotics, beta toxicity—possible fatality [5-hydroxytryptamine (5HT)] and 3α-reduced neurac- blockers, codeine, secondary to QT tive steroids (allosteric modulators of GABAA) also triazolobenzodiazepines, prolongation with appear to have a role in anxiety, and buspirone, a partial calcium channel blockers terfenadine or astemizole 5HT1A receptor agonist, and certain 5HT2A and 5HT2C Drugs that are bound tightly Increased bleeding receptor antagonists (e.g., nefazodone) may have benefi- to plasma proteins, e.g., secondary to cial effects. warfarin displacement Drugs that inhibit the Increased SSRI side Treatment: metabolism of SSRIs by effects GENERALIZED ANXIETY DISORDER P450 isoenzymes, e.g., quinidine A combination of pharmacologic and psychotherapeu- tic interventions is most effective in GAD, but complete aSee Rx Depressive Disorders, later. symptomatic relief is rare. A short course of a benzodi- Note: SSRI, selective serotonin reuptake inhibitor. azepine is usually indicated, preferably lorazepam, oxazepam, or temazepam. (The first two of these agents 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 relatively rare.
TABLE 49-6 667 ANXIOLYTICS EQUIVALENT PO ONSET OF ACTION HALF-LIFE, h COMMENTS CHAPTER 49 Mental Disorders NAME DOSE, mg Fast 20–70 Active metabolites; quite sedating Benzodiazepines 5 Fast 30–100 Flurazepam is a pro-drug; metabolites Diazepam (Valium) 15 Intermediate 1.5–5 Flurazepam are active; quite sedating 0.25 Intermediate 10–20 No active metabolites; can induce (Dalmane) confusion and delirium, especially in Triazolam (Halcion) Intermediate 12–15 elderly No active metabolites; direct hepatic Lorazepam (Ativan) 1 Intermediate 5–30 glucuronide conjugation; quite Slow 5–15 sedating Alprazolam (Xanax) 0.5 Active metabolites; not too sedating; Slow 9–12 may have specific antidepressant and Chlordiazepoxide 10 Slow 18–50 antipanic activity; tolerance and (Librium) 15 dependence develop easily Oxazepam (Serax) 2 weeks 2–3 Active metabolites; moderately Temazepam 15 sedating (Restoril) 0.5 No active metabolites; direct Clonazepam glucuronide conjugation; not too (Klonopin) 7.5 sedating Non-benzodiazepines No active metabolites; moderately Buspirone (BuSpar) sedating No active metabolites; moderately sedating Active metabolites; tid dosing—usual daily dose 10–20 mg tid; nonsedating; no additive effects with alcohol; useful for agitation in demented or brain- injured patients TABLE 49-7 DIAGNOSTIC CRITERIA FOR GENERALIZED ANXIETY DISORDER A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). B. The person finds it difficult to control the worry. C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 months): 1. restlessness or feeling keyed up or on edge 2. being easily fatigued 3. difficulty concentrating or mind going blank 4. irritability 5. muscle tension 6. sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep) D. The focus of the anxiety and worry is not confined to features of an Axis I disorder, e.g., the anxiety or worry is not about having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having a serious illness (as in hypochondriasis), and the anxiety and worry do not occur exclusively during posttraumatic stress disorder. E. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. F. The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a gen- eral medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder, or a pervasive developmental disorder. Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 2000.
SECTION V Psychiatric Disorders668 are metabolized via conjugation rather than oxidation doses that are comparable to their efficacy in major depression. Benzodiazepines are contraindicated dur- and thus do not accumulate if hepatic function is ing pregnancy and breast-feeding. altered.) Administration should be initiated at the lowest dose possible and prescribed on an as-needed basis as Anticonvulsants with GABAergic properties may also symptoms warrant. Benzodiazepines differ in their mil- be effective against anxiety. Gabapentin, oxcarbazepine, ligram per kilogram potency, half-life, lipid solubility, tiagabine, pregabalin, and divalproex have all shown metabolic pathways, and presence of active metabo- some degree of benefit in a variety of anxiety-related lites. Agents that are absorbed rapidly and are lipid solu- syndromes. Agents that selectively target GABAA recep- ble, such as diazepam, have a rapid onset of action and a tor subtypes are currently under development, and it higher abuse potential. Benzodiazepines should gener- is hoped that these will lack the sedating, memory- ally not be prescribed for >4–6 weeks because of the impairing, and addicting properties of benzodiazepines. development of tolerance and the risk of abuse and dependence. Withdrawal must be closely monitored as PHOBIC DISORDERS relapses can occur. It is important to warn patients that concomitant use of alcohol or other sedating drugs may Clinical Manifestations be neurotoxic and impair their ability to function. An optimistic approach that encourages the patient to clar- The cardinal feature of phobic disorders is a marked and ify environmental precipitants, anticipate his or her reac- persistent fear of objects or situations, exposure to which tions, and plan effective response strategies is an essen- results in an immediate anxiety reaction. The patient tial element of therapy. avoids the phobic stimulus, and this avoidance usually impairs occupational or social functioning. Panic attacks Adverse effects of benzodiazepines generally parallel may be triggered by the phobic stimulus or may occur their relative half-lives. Longer-acting agents, such as spontaneously. Unlike patients with other anxiety disor- diazepam, chlordiazepoxide, flurazepam, and clon- ders, individuals with phobias usually experience anxiety azepam, tend to accumulate active metabolites, with only in specific situations. Common phobias include resultant sedation, impairment of cognition, and poor fear of closed spaces (claustrophobia), fear of blood, and psychomotor performance. Shorter-acting compounds, fear of flying. Social phobia is distinguished by a specific such as alprazolam and oxazepam, can produce day- fear of social or performance situations in which the time anxiety, early morning insomnia, and, with discon- individual is exposed to unfamiliar individuals or to pos- tinuation, rebound anxiety and insomnia. Although sible examination and evaluation by others. Examples patients develop tolerance to the sedative effects of include having to converse at a party, use public benzodiazepines, they are less likely to habituate to the restrooms, and meet strangers. In each case, the affected adverse psychomotor effects. Withdrawal from the individual is aware that the experienced fear is excessive longer half-life benzodiazepines can be accomplished and unreasonable given the circumstance. The specific through gradual, stepwise dose reduction (by 10% content of a phobia may vary across gender, ethnic, and every 1–2 weeks) over 6–12 weeks. It is usually more dif- cultural boundaries. ficult to taper patients off shorter-acting benzodi- azepines. Physicians may need to switch the patient to a Phobic disorders are common, affecting ~10% of the benzodiazepine with a longer half-life or use an adjunc- population. Full criteria for diagnosis are usually satisfied tive medication, such as a beta blocker or carba- first in early adulthood, but behavioral avoidance of mazepine, before attempting to discontinue the benzo- unfamiliar people, situations, or objects dating from early diazepine. Withdrawal reactions vary in severity and childhood is common. duration; they can include depression, anxiety, lethargy, diaphoresis, autonomic arousal, and, rarely, seizures. In one study of female twins, concordance rates for agoraphobia, social phobia, and animal phobia were Buspirone is a nonbenzodiazepine anxiolytic agent. found to be 23% for monozygotic twins and 15% for It is nonsedating, does not produce tolerance or depen- dizygotic twins. A twin study of fear conditioning, a dence, does not interact with benzodiazepine recep- model for the acquisition of phobias, demonstrated a tors or alcohol, and has no abuse or disinhibition heritability of 35–45%, and a genome-wide linkage potential. However, it requires several weeks to take scan identified a risk locus on chromosome 14 in a effect and requires thrice-daily dosing. Patients who region previously implicated in a mouse model of fear. were previously responsive to a benzodiazepine are Animal studies of fear conditioning have indicated that unlikely to rate buspirone as equally effective, but processing of the fear stimulus occurs through the lat- patients with head injury or dementia who have symp- eral nucleus of the amygdala, extending through the toms of anxiety and/or agitation may do well with this central nucleus and projecting to the periaqueductal agent. Escitalopram, paroxetine, and venlafaxine are gray region, lateral hypothalamus, and paraventricular FDA approved for the treatment of GAD, usually at hypothalamus.
Treatment: TABLE 49-8 669 PHOBIC DISORDERS DIAGNOSTIC CRITERIA FOR POSTTRAUMATIC CHAPTER 49 Mental Disorders Beta blockers (e.g., propranolol, 20–40 mg orally 2 h STRESS DISORDER before the event) are particularly effective in the treat- ment of “performance anxiety” (but not general social A. The person has been exposed to a traumatic event in phobia) and appear to work by blocking the peripheral which both of the following were present: manifestations of anxiety, such as perspiration, tachycar- dia, palpitations, and tremor. MAOIs alleviate social pho- 1. The person experienced, witnessed, or was con- bia independently of their antidepressant activity, and fronted with an event or events that involved actual paroxetine, sertraline, and venlafaxine have received or threatened death or serious injury, or a threat to FDA approval for treatment of social anxiety. Benzodi- the physical integrity of self or others azepines can be helpful in reducing fearful avoidance, but the chronic nature of phobic disorders limits their 2. The person’s response involved intense fear, help- usefulness. lessness, or horror Behaviorally focused psychotherapy is an important B. The traumatic event is persistently reexperienced in component of treatment, as relapse rates are high when one (or more) of the following ways: medication is used as the sole treatment. Cognitive- 1. Recurrent and intrusive distressing recollections behavioral strategies are based upon the finding that of the event, including images, thoughts, or distorted perceptions and interpretations of fear-pro- perceptions ducing stimuli play a major role in perpetuation of pho- 2. Recurrent distressing dreams of the event bias. Individual and group therapy sessions teach the 3. Acting or feeling as if the traumatic event were patient to identify specific negative thoughts associated recurring (includes a sense of reliving the experi- with the anxiety-producing situation and help to reduce ence, illusions, hallucinations, and dissociative the patient’s fear of loss of control. In desensitization flashback episodes, including those that occur on therapy, hierarchies of feared situations are constructed awakening or when intoxicated) and the patient is encouraged to pursue and master 3. Intense psychological distress at exposure to inter- gradual exposure to the anxiety-producing stimuli. nal or external cues that symbolize or resemble an aspect of the traumatic event Patients with social phobia, in particular, have a high 4. Physiologic reactivity on exposure to internal or rate of comorbid alcohol abuse, as well as of other psy- external cues that symbolize or resemble an aspect chiatric conditions (e.g., eating disorders), necessitating of the traumatic event the need for parallel management of each disorder if anxiety reduction is to be achieved. C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not STRESS DISORDERS present before the trauma), as indicated by three or more of the following: Clinical Manifestations 1. Efforts to avoid thoughts, feelings, or conversations Patients may develop anxiety after exposure to extreme associated with the trauma traumatic events such as the threat of personal death or injury or the death of a loved one. The reaction may 2. Efforts to avoid activities, places, or people that occur shortly after the trauma (acute stress disorder) or be arouse recollections of the trauma delayed and subject to recurrence (PTSD) (Table 49-8). In both syndromes, individuals experience associated 3. Inability to recall an important aspect of the trauma symptoms of detachment and loss of emotional respon- 4. Markedly diminished interest or participation in sivity.The patient may feel depersonalized and unable to recall specific aspects of the trauma, though typically it is significant activities reexperienced through intrusions in thought, dreams, or 5. Feeling of detachment or estrangement from others flashbacks, particularly when cues of the original event 6. Restricted range of affect (e.g., unable to have are present. Patients often actively avoid stimuli that pre- cipitate recollections of the trauma and demonstrate a loving feelings) resulting increase in vigilance, arousal, and startle 7. Sense of a foreshortened future (e.g., does not response. Patients with stress disorders are at risk for the development of other disorders related to anxiety, mood, expect to have a career, marriage, children, or a and substance abuse (especially alcohol). Between 5 and normal life span) D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following: 1. Difficulty falling or staying asleep 2. Irritability or outbursts of anger 3. Difficulty concentrating 4. Hypervigilance 5. Exaggerated startle response E. Duration of the disturbance (symptoms in criteria B, C, and D) is >1 month. F. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 2000.
SECTION V Psychiatric Disorders670 10% of Americans will at some time in their life satisfy everyday functioning. Fears of contamination and germs criteria for PTSD, with women more likely to be are common, as are handwashing, counting behaviors, affected than men. and having to check and recheck such actions as Risk factors for the development of PTSD include a whether a door is locked. The degree to which the dis- past psychiatric history and personality characteristics of order is disruptive for the individual varies, but in all high neuroticism and extroversion. Twin studies show a cases obsessive-compulsive activities take up >1 h/d and substantial genetic influence on all symptoms associated are undertaken to relieve the anxiety triggered by the with PTSD, with less evidence for an environmental core fear. Patients often conceal their symptoms, usually effect. because they are embarrassed by the content of their thoughts or the nature of their actions. Physicians must Etiology and Pathophysiology ask specific questions regarding recurrent thoughts and behaviors, particularly if physical clues such as chafed It is hypothesized that in PTSD there is excessive release and reddened hands or patchy hair loss (from repetitive of norepinephrine from the locus coeruleus in response hair pulling, or trichotillomania) are present. Comorbid to stress and increased noradrenergic activity at projec- conditions are common, the most frequent being depres- tion sites in the hippocampus and amygdala. These sion, other anxiety disorders, eating disorders, and tics. changes theoretically facilitate the encoding of fear- OCD has a lifetime prevalence of 2–3% worldwide. based memories. Greater sympathetic responses to cues Onset is usually gradual, beginning in early adulthood, associated with the traumatic event occur in PTSD, but childhood onset is not rare.The disorder usually has a although pituitary adrenal responses are blunted. waxing and waning course, but some cases may show a steady deterioration in psychosocial functioning. Treatment: Etiology and Pathophysiology STRESS DISORDERS A genetic contribution to OCD is suggested by twin Acute stress reactions are usually self-limited, and treat- studies. Family studies show an aggregation with Tourette’s ment typically involves the short-term use of benzodi- disorder. OCD is also more common in males and in first- azepines and supportive/expressive psychotherapy. The born children. chronic and recurrent nature of PTSD, however, requires a more complex approach employing drug and behav- The anatomy of obsessive-compulsive behavior is ioral treatments. PTSD is highly correlated with peritrau- thought to include the orbital frontal cortex, caudate matic dissociative symptoms and the development of nucleus, and globus pallidus.The caudate nucleus appears an acute stress disorder at the time of the trauma. TCAs to be involved in the acquisition and maintenance of such as imipramine and amitriptyline, the MAOI habit and skill learning, and interventions that are suc- phenelzine, and the SSRIs can all reduce anxiety, symp- cessful in reducing obsessive-compulsive behaviors also toms of intrusion, and avoidance behaviors, as can pra- decrease metabolic activity measured in the caudate. zosin, an α1 antagonist. Propranolol given during the acute stress period may have beneficial effects in pre- Treatment: venting the development of PTSD. Trazodone, a sedating OBSESSIVE-COMPULSIVE DISORDER antidepressant, is frequently used at night to help with insomnia (50–150 mg qhs). Carbamazepine, valproic Clomipramine, fluoxetine, fluvoxamine, and sertraline acid, or alprazolam have also independently produced are approved for the treatment of OCD. Clomipramine improvement in uncontrolled trials. Psychotherapeutic is a TCA that is often tolerated poorly owing to anti- strategies for PTSD help the patient overcome avoid- cholinergic and sedative side effects at the doses ance behaviors and demoralization and master fear of required to treat the illness (25–250 mg/d). Its efficacy recurrence of the trauma; therapies that encourage the in OCD is unrelated to its antidepressant activity. Fluox- patient to dismantle avoidance behaviors through step- etine (5–60 mg/d), fluvoxamine (25–300 mg/d), and ser- wise focusing on the experience of the traumatic event traline (50–150 mg/d) are as effective as clomipramine are the most effective. and have a more benign side-effect profile. Only 50–60% of patients with OCD show adequate improve- OBSESSIVE-COMPULSIVE DISORDER ment with pharmacotherapy alone. In treatment- resistant cases, augmentation with other serotonergic Clinical Manifestations agents, such as buspirone, or with a neuroleptic or ben- zodiazepine may be beneficial. When a therapeutic Obsessive-compulsive disorder (OCD) is characterized by obsessive thoughts and compulsive behaviors that impair
response is achieved, long-duration maintenance ther- sometimes be necessary to undertake an empirical trial 671 CHAPTER 49 Mental Disorders apy is usually indicated. Recent studies are beginning to of an alternative medication. explore the efficacy of deep brain stimulation (DBS) for refractory, severe OCD. Between 20 and 30% of cardiac patients manifest a depressive disorder; an even higher percentage experi- For many individuals, particularly those with time- ence depressive symptomatology when self-reporting consuming compulsions, behavior therapy will result in scales are used. Depressive symptoms following unstable as much improvement as that afforded by medication. angina, myocardial infarction, cardiac bypass surgery, or Effective techniques include the gradual increase in heart transplant impair rehabilitation and are associated exposure to stressful situations, maintenance of a diary with higher rates of mortality and medical morbidity. to clarify stressors, and homework assignments that Depressed patients often show decreased variability in substitute new activities for compulsive behaviors. heart rate (an index of reduced parasympathetic nervous system activity); this has been proposed as one mecha- MOOD DISORDERS nism by which depression may predispose individuals to ventricular arrhythmia and increased morbidity. Depres- Mood disorders are characterized by a disturbance in sion also appears to increase the risk of developing coro- the regulation of mood, behavior, and affect. Mood dis- nary heart disease; increased serotonin-induced platelet orders are subdivided into (1) depressive disorders, aggregation has been implicated as a possible cause. (2) bipolar disorders, and (3) depression in association TCAs are contraindicated in patients with bundle with medical illness or alcohol and substance abuse branch block, and TCA-induced tachycardia is an addi- (Chaps. 50, 51, and 52). Depressive disorders are differ- tional concern in patients with congestive heart failure. entiated from bipolar disorders by the absence of a SSRIs appear not to induce ECG changes or adverse manic or hypomanic episode. The relationship between cardiac events and thus are reasonable first-line drugs for pure depressive syndromes and bipolar disorders is not patients at risk for TCA-related complications. SSRIs well understood; depression is more frequent in families may interfere with hepatic metabolism of anticoagu- of bipolar individuals, but the reverse is not true. In the lants, however, causing increased anticoagulation. Global Burden of Disease Study conducted by the World Health Organization, unipolar major depression In patients with cancer, the mean prevalence of ranked fourth among all diseases in terms of disability- depression is 25%, but depression occurs in 40–50% of adjusted life-years and was projected to rank second by patients with cancers of the pancreas or oropharynx. the year 2020. In the United States, lost productivity This association is not due to the effect of cachexia directly related to mood disorders has been estimated at alone, as the higher prevalence of depression in patients $55.1 billion per year. with pancreatic cancer persists when compared to those with advanced gastric cancer. Initiation of antidepressant DEPRESSION IN ASSOCIATION WITH medication in cancer patients has been shown to MEDICAL ILLNESS improve quality of life as well as mood. Psychotherapeu- tic approaches, particularly group therapy, may have Depression occurring in the context of medical illness is some effect on short-term depression, anxiety, and pain difficult to evaluate. Depressive symptomatology may symptoms. reflect the psychological stress of coping with the dis- ease, may be caused by the disease process itself or by Depression occurs frequently in patients with neurologic the medications used to treat it, or may simply coexist in disorders, particularly cerebrovascular disorders, Parkinson’s time with the medical diagnosis. disease, dementia, multiple sclerosis, and traumatic brain injury. One in five patients with left-hemisphere stroke Virtually every class of medication includes some agent involving the dorsolateral frontal cortex experiences that can induce depression. Antihypertensive drugs, anti- major depression. Late-onset depression in otherwise cholesterolemic agents, and antiarrhythmic agents are cognitively normal individuals increases the risk of a common triggers of depressive symptoms. Among the subsequent diagnosis of Alzheimer’s disease. Both TCA antihypertensive agents, β-adrenergic blockers and, to a and SSRI agents are effective against these depressions, lesser extent, calcium channel blockers are the most as are stimulant compounds and, in some patients, likely to cause depressed mood. Iatrogenic depression MAOIs. should also be considered in patients receiving gluco- corticoids, antimicrobials, systemic analgesics, antiparkin- The reported prevalence of depression in patients sonian medications, and anticonvulsants. To decide with diabetes mellitus varies from 8–27%, with the sever- whether a causal relationship exists between pharmaco- ity of the mood state correlating with the level of logic therapy and a patient’s change in mood, it may hyperglycemia and the presence of diabetic complica- tions. Treatment of depression may be complicated by effects of antidepressive agents on glycemic control. MAOIs can induce hypoglycemia and weight gain.TCAs can produce hyperglycemia and carbohydrate craving.
SECTION V Psychiatric Disorders672 SSRIs, like MAOIs, may reduce fasting plasma glucose, TABLE 49-9 but they are easier to use and may also improve dietary and medication compliance. CRITERIA FOR MAJOR DEPRESSIVE EPISODE Hypothyroidism is frequently associated with features of depression, most commonly depressed mood and A. Five (or more) of the following symptoms have been memory impairment. Hyperthyroid states may also pre- present during the same 2-week period and represent sent in a similar fashion, usually in geriatric populations. a change from previous functioning; at least one of the Improvement in mood usually follows normalization of symptoms is either (1) depressed mood or (2) loss of thyroid function, but adjunctive antidepressant medica- interest or pleasure. Note: Do not include symptoms tion is sometimes required. Patients with subclinical that are clearly due to a general medical condition, or hypothyroidism can also experience symptoms of mood-incongruent delusions or hallucinations. depression and cognitive difficulty that respond to thy- 1. Depressed mood most of the day, nearly every day, roid replacement. as indicated by either subjective report (e.g., feels The lifetime prevalence of depression in HIV-positive sad or empty) or observation made by others (e.g., individuals has been estimated at 22–45%. The relation- appears tearful) ship between depression and disease progression is mul- 2. Markedly diminished interest or pleasure in all, or tifactorial and likely to involve psychological and social almost all, activities most of the day, nearly every factors, alterations in immune function, and central ner- day (as indicated by either subjective account or vous system disease. Chronic hepatitis C infection is also observation made by others) associated with depression, which may worsen with 3. Significant weight loss when not dieting or weight interferon-α treatment. gain (e.g., a change of >5% of body weight in a Some chronic disorders of uncertain etiology, such as month), or decrease or increase in appetite nearly chronic fatigue syndrome (Chap. 47) and fibromyalgia, every day are strongly associated with depression and anxiety; 4. Insomnia or hypersomnia nearly every day patients may benefit from antidepressant treatment, usu- 5. Psychomotor agitation or retardation nearly every ally at lower than normal dosing. day (observable by others, not merely subjective feelings of restlessness or being slowed down) DEPRESSIVE DISORDERS 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or excessive or inappropri- Clinical Manifestations ate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) Major depression is defined as depressed mood on a daily 8. Diminished ability to think or concentrate, or indeci- basis for a minimum duration of 2 weeks (Table 49-9). siveness, nearly every day (either by subjective An episode may be characterized by sadness, indiffer- account or as observed by others) ence, apathy, or irritability and is usually associated with: 9. Recurrent thoughts of death (not just fear of dying), changes in sleep patterns, appetite, and weight; motor recurrent suicidal ideation without a specific plan, agitation or retardation; fatigue; impaired concentration or a suicide attempt or a specific plan for commit- and decision-making; feelings of shame or guilt; and ting suicide thoughts of death or dying. Patients with depression have a profound loss of pleasure in all enjoyable activi- B. The symptoms do not meet criteria for a mixed episode. ties, exhibit early morning awakening, feel that the dys- C. The symptoms cause clinically significant distress or phoric mood state is qualitatively different from sadness, and often notice a diurnal variation in mood (worse in impairment in social, occupational, or other important morning hours). areas of functioning D. The symptoms are not due to the direct physiologic Approximately 15% of the population experiences a effects of a substance (e.g., a drug of abuse, a major depressive episode at some point in life, and 6–8% medication) or a general medical condition (e.g., of all outpatients in primary care settings satisfy diagnostic hypothyroidism) criteria for the disorder. Depression is often undiag- E. The symptoms are not better accounted for by nosed, and, even more frequently, it is treated inade- bereavement; i.e., after the loss of a loved one, the quately. If a physician suspects the presence of a major symptoms persist for >2 months or are characterized depressive episode, the initial task is to determine by marked functional impairment, morbid preoccupa- whether it represents unipolar or bipolar depression or is tion with worthlessness, suicidal ideation, psychotic one of the 10–15% of cases that are secondary to gen- symptoms, or psychomotor retardation eral medical illness or substance abuse. Physicians should also assess the risk of suicide by direct questioning, as Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. patients are often reluctant to verbalize such thoughts Washington, DC, American Psychiatric Association, 2000. without prompting. If specific plans are uncovered or if significant risk factors exist (e.g., a past history of suicide attempts, profound hopelessness, concurrent medical ill- ness, substance abuse, or social isolation), the patient must be referred to a mental health specialist for imme- diate care. The physician should specifically probe each of these areas in an empathic and hopeful manner, being
sensitive to denial and possible minimization of distress. are anergy, fatigue, weight gain, hypersomnia, and episodic 673CHAPTER 49 Mental Disorders The presence of anxiety, panic, or agitation significantly carbohydrate craving. The prevalence increases with dis- increases near-term suicidal risk. Approximately 4–5% of tance from the equator, and improvement may occur by all depressed patients will commit suicide; most will altering light exposure. have sought help from a physician within 1 month of their death. Etiology and Pathophysiology In some depressed patients, the mood disorder does Although evidence for genetic transmission of unipolar not appear to be episodic and is not clearly associated depression is not as strong as in bipolar disorder, mono- with either psychosocial dysfunction or change from the zygotic twins have a higher concordance rate (46%) individual’s usual experience in life. Dysthymic disorder than dizygotic siblings (20%), with little support for any consists of a pattern of chronic (at least 2 years), ongo- effect of a shared family environment. There is some ing, mild depressive symptoms that are less severe and evidence that a functional polymorphism in the sero- less disabling than those found in major depression; the tonin transporter (5-HTT) gene may interact with two conditions are sometimes difficult to separate, how- stressful life events to markedly increase risk of depression ever, and can occur together (“double depression”). and suicide. Positron emission tomography (PET) stud- Many patients who exhibit a profile of pessimism, disin- ies show decreased metabolic activity in the caudate terest, and low self-esteem respond to antidepressant nuclei and frontal lobes in depressed patients that returns treatment. Dysthymic disorder exists in ~5% of primary to normal with recovery. Single-photon emission com- care patients. The term minor depression is used for indi- puted tomography (SPECT) studies show comparable viduals who experience at least two depressive symp- changes in blood flow. toms for 2 weeks but who do not meet the full criteria for major depression. Despite its name, minor depression Postmortem examination of brains of suicide victims is associated with significant morbidity and disability indicate altered noradrenergic activity, including increas- and also responds to pharmacologic treatment. ed binding to α1-, α2-, and β-adrenergic receptors in the cerebral cortex and decreased numbers of noradrenergic Depression is approximately twice as common in neurons in the locus coeruleus. Involvement of the sero- women as in men, and the incidence increases with age tonin system is suggested by findings of reduced plasma in both sexes. Twin studies indicate that the liability to tryptophan levels, a decreased cerebrospinal fluid level of major depression in adult women is largely genetic in 5-hydroxyindolacetic acid (the principal metabolite of origin. Negative life events can precipitate and con- serotonin in brain), and decreased platelet serotonergic tribute to depression, but genetic factors influence the transporter binding.An increase in brain serotonin recep- sensitivity of individuals to these stressful events. In most tors in suicide victims and decreased expression of the cases, both biologic and psychosocial factors are involved cyclic AMP response element-binding (CREB) protein in the precipitation and unfolding of depressive episodes. are also reported. Depletion of blood tryptophan, the The most potent stressors appear to involve death amino acid precursor of serotonin, rapidly reverses the of a relative, assault, or severe marital or relationship antidepressant benefit in depressed patients who have problems. been successfully treated. However, a decrement in mood after tryptophan reduction is considerably less robust in Unipolar depressive disorders usually begin in early untreated patients, indicating that, if presynaptic seroton- adulthood and recur episodically over the course of a ergic dysfunction occurs in depression, it likely plays a lifetime. The best predictor of future risk is the number contributing rather than a causal role. of past episodes; 50–60% of patients who have a first episode have at least one or two recurrences. Some Neuroendocrine abnormalities that reflect the neu- patients experience multiple episodes that become more rovegetative signs and symptoms of depression include severe and frequent over time. The duration of an (1) increased cortisol and corticotropin-releasing hor- untreated episode varies greatly, ranging from a few mone (CRH) secretion, (2) an increase in adrenal size, months to ≥1 year. The pattern of recurrence and clini- (3) a decreased inhibitory response of glucocorticoids to cal progression in a developing episode are also variable. dexamethasone, and (4) a blunted response of thyroid- Within an individual, the nature of episodes (e.g., spe- stimulating hormone (TSH) level to infusion of thyroid- cific presenting symptoms, frequency and duration) may releasing hormone (TRH). Antidepressant treatment be similar over time. In a minority of patients, a severe leads to normalization of these pituitary-adrenal abnor- depressive episode may progress to a psychotic state; in malities. Major depression is also associated with an elderly patients, depressive symptoms may be associated upregulation of proinflammatory cytokines, which nor- with cognitive deficits mimicking dementia (“pseudo- malizes with antidepressant treatment. dementia”). A seasonal pattern of depression, called sea- sonal affective disorder, may manifest with onset and remis- Diurnal variations in symptom severity and alter- sion of episodes at predictable times of the year. This ations in circadian rhythmicity of a number of neuro- disorder is more common in women, whose symptoms chemical and neurohumoral factors suggest that biologic
SECTION V Psychiatric Disorders674 differences may be secondary to a primary defect in reg- Determine whether there is a history of good response to a medication ulation of biologic rhythms. Patients with major depres- in the patient or a first-degree relative; if yes, consider treatment with sion show consistent findings of a decrease in rapid eye this agent. movement (REM) sleep onset (REM latency), an increase in REM density, and, in some subjects, a decrease in If not, evaluate patient characteristics and match to drug; consider stage IV delta slow-wave sleep. health status, side-effect profile, convenience, cost, patient preference, Although antidepressant drugs inhibit neurotransmit- drug interaction risk, suicide potential, and medication compliance ter uptake within hours, their therapeutic effects typi- history. cally emerge over several weeks, implicating adaptive changes in second messenger systems and transcription Begin new medication at 1/3 to 1/2 target dose if drug is a TCA, factors as possible mechanisms of action. Antidepressant bupropion, venlafaxine, or mirtazapine, or full dose as tolerated if drug drugs have been shown to regulate neural plasticity and is an SSRI. cell survival by increasing the expression of brain- derived neurotrophic factor (BDNF) through upregula- If problem side effects occur, evaluate possibility of tolerance; consider tion of the CREB protein and to alter stress responsivity temporary decrease in dose or adjunctive treatment. through an increase in glucocorticoid receptor tran- scription. Secondary effects on activation of the mitogen- If unacceptable side effects continue, taper drug over 1 week and activated protein (MAP) kinase and phosphoinositol-3 initiate new trial; consider potential drug interactions in choice. kinase/AKT pathways and increased expression of the antiapoptotic protein, Bcl-2, are also thought to be criti- Evaluate response after 6 weeks at target dose; if response is cal to antidepressant actions. inadequate, increase dose in stepwise fashion as tolerated. Treatment: If inadequate response after maximal dose, consider tapering and DEPRESSIVE DISORDERS switching to a new drug vs. adjunctive treatment; if drug is a TCA, obtain plasma level to guide further treatment. Treatment planning requires coordination of short-term strategies to induce remission combined with longer FIGURE 49-1 term maintenance designed to prevent recurrence. The A guideline for the medical management of major depres- most effective intervention for achieving remission and sive disorder. SSRI, selective serotonin reuptake inhibitor; preventing relapse is medication, but combined treat- TCA, tricyclic antidepressant. ment, incorporating psychotherapy to help the patient cope with decreased self-esteem and demoralization, profile of the drug (Tables 49-4 and 49-5). A previous improves outcome (Fig. 49-1). Approximately 40% of response, or a family history of a positive response, to a primary care patients with depression drop out of treat- specific antidepressant often suggests that that drug be ment and discontinue medication if symptomatic tried first. Before initiating antidepressant therapy, the improvement is not noted within a month, unless addi- physician should evaluate the possible contribution of tional support is provided. Outcome improves with comorbid illnesses and consider their specific treat- (1) increased intensity and frequency of visits during the ment. In individuals with suicidal ideation, particular first 4–6 weeks of treatment, (2) supplemental educa- attention should be paid to choosing a drug with low tional materials, and (3) psychiatric consultation as indi- toxicity if taken in overdose. The SSRIs and other newer cated. Despite the widespread use of SSRIs and other antidepressant drugs are distinctly safer in this regard; second-generation antidepressant drugs, there is no nevertheless, the advantages of TCAs have not been convincing evidence that this class of antidepressant is completely superseded. The existence of generic equiv- more efficacious than TCAs. Between 60 and 70% of all alents make TCAs relatively cheap, and for several tri- depressed patients respond to any drug chosen, if it is cyclics, particularly nortriptyline, imipramine, and given in a sufficient dose for 6–8 weeks. There is no ideal desipramine, well-defined relationships among dose, antidepressant; no current compound combines rapid plasma level, and therapeutic response exist. The onset of action, moderate half-life, a meaningful rela- steady-state plasma level achieved for a given drug tionship between dose and blood level, a low side-effect dose can vary more than tenfold between individuals. profile, minimal interaction with other drugs, and safety Plasma levels may help in interpreting apparent resis- in overdose. tance to treatment and/or unexpected drug toxicity. The principal side effects of TCAs are antihistamine A rational approach to selecting which antidepres- (sedation) and anticholinergic (constipation, dry sant to use involves matching the patient’s preference mouth, urinary hesitancy, blurred vision). Cardiac toxic- and medical history with the metabolic and side effect ity due to conduction block or arrhythmias can also occur but is uncommon at therapeutic levels. TCAs are
contraindicated in patients with serious cardiovascular difficulty in achieving orgasm. Sexual dysfunction fre- 675 risk factors. Overdoses of tricyclic agents can be lethal, quently results in noncompliance and should be asked with desipramine carrying the greatest risk. It is judi- about specifically. Sexual dysfunction can sometimes be CHAPTER 49 Mental Disorders cious to prescribe only a 10-day supply when suicide is ameliorated by lowering the dose, by instituting week- a risk. Most patients require a daily dose of 150–200 mg end drug holidays (two or three times a month), or by of imipramine or amitriptyline or its equivalent to treatment with amantadine (100 mg tid), bethanechol achieve a therapeutic blood level of 150–300 ng/mL (25 mg tid), buspirone (10 mg tid), or bupropion and a satisfactory remission; some patients show a par- (100–150 mg/d). Paroxetine appears to be more anti- tial effect at lower doses. Geriatric patients may require cholinergic than either fluoxetine or sertraline, and ser- a low starting dose and slow escalation. Ethnic differ- traline carries a lower risk of producing an adverse drug ences in drug metabolism are significant; Hispanic, interaction than the other two. Rare side effects of SSRIs Asian, and African-American patients generally require include angina due to vasospasm and prolongation of lower doses than whites to achieve a comparable the prothrombin time. Escitalopram is the most specific blood level. P450 profiling using genetic chip technol- of currently available SSRIs and appears to have no spe- ogy may be clinically useful in predicting individual cific inhibitory effects on the P450 system. sensitivity. Venlafaxine and duloxetine block the reuptake of Second-generation antidepressants include amoxap- both norepinephrine and serotonin but produce rela- ine, maprotiline, trazodone, and bupropion. Amoxapine tively little in the way of traditional tricyclic side effects. is a dibenzoxazepine derivative that blocks norepineph- Unlike the SSRIs, venlafaxine has a relatively linear dose- rine and serotonin reuptake and has a metabolite that response curve. Patients should be monitored for a pos- shows a degree of dopamine blockade. Long-term use sible increase in diastolic blood pressure, and multiple of this drug carries a risk of tardive dyskinesia. Maproti- daily dosing is required because of the drug’s short half- line is a potent noradrenergic reuptake blocker that has life. An extended-release form is available and has a little anticholinergic effect but may produce seizures. somewhat lower incidence of gastrointestinal side Bupropion is a novel antidepressant whose mechanism effects. Mirtazapine is a tetracyclic antidepressant that of action is thought to involve enhancement of nora- has a unique spectrum of activity. It increases noradren- drenergic function. It has no anticholinergic, sedating, or ergic and serotonergic neurotransmission through a orthostatic side effects and has a low incidence of blockade of central α2-adrenergic receptors and postsy- sexual side effects. It may, however, be associated with naptic 5HT2 and 5HT3 receptors. It is also strongly anti- stimulant-like side effects, may lower seizure threshold, histaminic and, as such, may produce sedation. and has an exceptionally short half-life, requiring frequent dosing. An extended-release preparation is available. With the exception of citalopram and escitalopram, each of the SSRIs may inhibit one or more cytochrome SSRIs such as fluoxetine, sertraline, paroxetine, citalo- P450 enzymes. Depending on the specific isoenzyme pram, and escitalopram cause a lower frequency of anti- involved, the metabolism of a number of concomitantly cholinergic, sedating, and cardiovascular side effects but administered medications can be dramatically affected. a possibly greater incidence of gastrointestinal com- Fluoxetine and paroxetine, for example, by inhibiting plaints, sleep impairment, and sexual dysfunction than 2D6, can cause dramatic increases in the blood level of do TCAs. Akathisia, involving an inner sense of restless- type 1C antiarrhythmics, while sertraline, by acting on ness and anxiety in addition to increased motor activity, 3A4, may alter blood levels of carbamazepine, or may also be more common, particularly during the first digoxin. week of treatment. One concern is the risk of “serotonin syndrome,” thought to result from hyperstimulation of The MAOIs are highly effective, particularly in atypi- brainstem 5HT1A receptors and characterized by cal depression, but the risk of hypertensive crisis follow- myoclonus, agitation, abdominal cramping, hyper- ing intake of tyramine-containing food or sympath- pyrexia, hypertension, and potentially death. Serotoner- omimetic drugs makes them inappropriate as first-line gic agonists taken in combination should be monitored agents. Transdermal selegiline may avert this risk at low closely for this reason. Considerations such as half-life, dose. Common side effects include orthostatic hypoten- compliance, toxicity, and drug-drug interactions may sion, weight gain, insomnia, and sexual dysfunction. guide the choice of a particular SSRI. Fluoxetine and its MAOIs should not be used concomitantly with SSRIs, principal active metabolite, norfluoxetine, for example, because of the risk of serotonin syndrome, or with TCAs, have a combined half-life of almost 7 days, resulting in a because of possible hyperadrenergic effects. delay of 5 weeks before steady-state levels are achieved and a similar delay for complete drug excretion once its Electroconvulsive therapy is at least as effective as use is discontinued. All the SSRIs may impair sexual medication, but its use is reserved for treatment-resis- function, resulting in diminished libido, impotence, or tant cases and delusional depressions.Transcranial mag- netic stimulation (TMS) is an investigational treatment of depression that has been shown to have efficacy in
SECTION V Psychiatric Disorders676 several controlled trials; it is uncertain whether the TABLE 49-10 observed benefits were clinically meaningful, however. CRITERIA FOR A MANIC EPISODE Vagus nerve stimulation (VNS) has recently been approved for treatment-resistant depression, but its A. A distinct period of abnormally and persistently ele- degree of efficacy is controversial. vated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary) Regardless of the treatment undertaken, the response should be evaluated after ~2 months. Three-quarters of B. During the period of mood disturbance, three (or more) patients show improvement by this time, but if remission of the following symptoms have persisted (four if the is inadequate the patient should be questioned about mood is only irritable) and have been present to a sig- compliance and an increase in medication dose should nificant degree: be considered if side effects are not troublesome. If this 1. Inflated self-esteem or grandiosity approach is unsuccessful, referral to a mental health spe- 2. Decreased need for sleep (e.g., feels rested after cialist is advised. Strategies for treatment then include only 3 hours of sleep) selection of an alternative drug, combinations of antide- 3. More talkative than usual or pressure to keep talking pressants, and/or adjunctive treatment with other 4. Flight of ideas or subjective experience that classes of drugs, including lithium, thyroid hormone, and thoughts are racing dopamine agonists. A large randomized trial (STAR-D) 5. Distractibility (i.e., attention too easily drawn to was unable to show preferential efficacy. Patients whose unimportant or irrelevant external stimuli) response to an SSRI wanes over time may benefit from 6. Increase in goal-directed activity (either socially, at the addition of buspirone (10 mg tid) or pindolol work or school, or sexually) or psychomotor agitation (2–5 mg tid) or small amounts of a TCA such as 7. Excessive involvement in pleasurable activities that desipramine (25 mg bid or tid). Most patients will show have a high potential for painful consequences some degree of response but aggressive treatment (e.g., engaging in unrestrained buying sprees, sex- should be pursued until remission is achieved, and drug ual indiscretions, or foolish business investments) treatment should be continued for at least 6–9 more months to prevent relapse. In patients who have had C. The symptoms do not meet criteria for a mixed episode. two or more episodes of depression, indefinite mainte- D. The mood disturbance is sufficiently severe to cause nance treatment should be considered. marked impairment in occupational functioning or in It is essential to educate patients both about depres- usual social activities or relationships with others, or to sion and the benefits and side effects of medications necessitate hospitalization to prevent harm to self or they are receiving. Advice about stress reduction and others, or there are psychotic features. cautions that alcohol may exacerbate depressive symp- E. The symptoms are not due to the direct physiologic toms and impair drug response are helpful. Patients effects of a substance (e.g., a drug of abuse, a med- should be given time to describe their experience, their ication, or other treatment) or a general medical condi- outlook, and the impact of the depression on them and tion (e.g., hyperthyroidism). their families. Occasional empathic silence may be as helpful for the treatment alliance as verbal reassurance. Note: Manic-like episodes that are clearly caused by somatic antide- Controlled trials have shown that cognitive-behavioral pressant treatment (e.g., medication, electroconvulsive therapy, light and interpersonal therapies are effective in improving therapy) should not count toward a diagnosis of bipolar I disorder. psychological and social adjustment and that a com- Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. bined treatment approach is more successful than med- Washington, DC, American Psychiatric Association, 2000. ication alone for many patients. thinking indistinguishable from schizophrenia. Half of BIPOLAR DISORDER patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, Clinical Manifestations anxiety, and irritability. It may be difficult to distinguish mixed mania from agitated depression. In some bipolar Bipolar disorder is characterized by unpredictable swings patients (bipolar II disorder), the full criteria for mania are in mood from mania (or hypomania) to depression. lacking, and the requisite recurrent depressions are sepa- Some patients suffer only from recurrent attacks of rated by periods of mild activation and increased energy mania, which in its pure form is associated with (hypomania). In cyclothymic disorder, there are numerous increased psychomotor activity; excessive social extro- hypomanic periods, usually of relatively short duration, version; decreased need for sleep; impulsivity and alternating with clusters of depressive symptoms that impairment in judgment; and expansive, grandiose, and fail, either in severity or duration, to meet the criteria of sometimes irritable mood (Table 49-10). In severe major depression. The mood fluctuations are chronic mania, patients may experience delusions and paranoid and should be present for at least 2 years before the diagnosis is made. Manic episodes typically emerge over a period of days to weeks, but onset within hours is possible, usually in the early morning hours. An untreated episode of either depression or mania can be as short as several weeks or
last as long as 8–12 months, and rare patients have an TABLE 49-11 677 unremitting chronic course.The term rapid cycling is used CLINICAL PHARMACOLOGY OF MOOD STABILIZERS for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs AGENT AND DOSING SIDE EFFECTS AND OTHER CHAPTER 49 Mental Disorders in 15% of all patients, almost all of whom are women. In Lithium EFFECTS some cases, rapid cycling is linked to an underlying thy- roid dysfunction and, in others, it is iatrogenically trig- Starting dose: 300 mg Common side effects: Nausea/ gered by prolonged antidepressant treatment. Approxi- bid or tid anorexia/diarrhea, fine tremor, mately half of patients have sustained difficulties in work Therapeutic blood level: thirst, polyuria, fatigue, weight performance and psychosocial functioning. 0.8–1.2 meq/L gain, acne, folliculitis, neu- trophilia, hypothyroidism Bipolar disorder is common, affecting ~1.5% of the Valproic acid population in the United States. Onset is typically Starting dose: Blood level is increased by between 20 and 30 years of age, but many individuals 250 mg tid thiazides, tetracyclines, and report premorbid symptoms in late childhood or early Therapeutic blood NSAIDs adolescence. The prevalence is similar for men and level: 50–125 μg/mL women; women are likely to have more depressive and Blood level is decreased by men more manic episodes over a lifetime. Carbamazepine/ bronchodilators, verapamil, oxcarbazepine and carbonic anhydrase Differential Diagnosis Starting dose: 200 mg inhibitors bid for carbamazepine, The differential diagnosis of mania includes toxic effects 150 bid for Rare side effects: Neurotoxic- of stimulant or sympathomimetic drugs as well as sec- oxcarbazepine ity, renal toxicity, hypercal- ondary mania induced by hyperthyroidism, AIDS, or Therapeutic blood level: cemia, ECG changes neurologic disorders, such as Huntington’s or Wilson’s 4–12 μg/mL for disease, or cerebrovascular accidents. Comorbidity with carbamazepine Common side effects: Nausea/ alcohol and substance abuse is common, either because Lamotrigine anorexia, weight gain, seda- of poor judgment and increased impulsivity or because Starting dose: 25 mg/d tion, tremor, rash, alopecia of an attempt to self-treat the underlying mood symp- toms and sleep disturbances. Inhibits hepatic metabolism of other medications Etiology and Pathophysiology Rare side effects: Pancreatitis, Genetic predisposition to bipolar disorder is evident hepatotoxicity, Stevens- from family studies; the concordance rate for monozy- Johnson syndrome gotic twins approaches 80%. Multiple genes are likely to be involved. Common side effects: Nausea/ anorexia, sedation, rash, The pathophysiologic mechanisms underlying the dizziness/ataxia profound and recurrent mood swings of bipolar disorder remain unknown. Neuroimaging studies have reported Carbamazepine, but not anatomic changes in amygdala volume as well as oxcarbazepine, induces increases in white matter hyperintensities. Molecular hepatic metabolism of other studies have implicated changes in membrane Na+- and medications K+-activated ATPase and disordered signal transduction involving the phosphoinositol system and GTP-binding Rare side effects: Hypona- proteins as possible contributing mechanisms. Patients tremia, agranulocytosis, with bipolar disorder also appear to have altered circa- Stevens-Johnson syndrome dian rhythmicity, and lithium may exert its therapeutic Common side effects: Rash, benefit through a resynchronization of intrinsic rhythms dizziness, headache, tremor, keyed to the light/dark cycle. sedation, nausea Rare side effect: Stevens- Treatment: Johnson syndrome BIPOLAR DISORDER Note: NSAID, nonsteroidal anti-inflammatory drug; ECG, electrocar- (Table 49-11) Lithium carbonate is the mainstay of diogram. treatment in bipolar disorder, although sodium val- proate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressed phase. The response rate to lithium carbonate is 70–80% in acute mania, with beneficial effects appearing in 1–2 weeks. Lithium also has a prophylactic effect in prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression. A simple cation, lithium is rapidly absorbed from the gastrointestinal tract and remains unbound to plasma or tissue proteins. Some 95% of a given dose is excreted unchanged through the kidneys within 24 h. Serious side effects from lithium are rare, but minor complaints such as gastrointestinal discomfort, nausea,
678 diarrhea, polyuria, weight gain, skin eruptions, alopecia, TABLE 49-12 and edema are common. Over time, urine-concentrat- CONSENSUS GUIDELINES FOR DRUG TREATMENT ing ability may be decreased, but significant nephrotox- OF ACUTE MANIA AND BIPOLAR DEPRESSION icity does not usually occur. Lithium exerts an antithy- SECTION V Psychiatric Disorders roid effect by interfering with the synthesis and release CONDITION PREFERRED AGENTS of thyroid hormones. More serious side effects include Euphoric mania tremor, poor concentration and memory, ataxia, Mixed/dysphoric mania Lithium dysarthria, and incoordination. There is suggestive, but Mania with psychosis Valproic acid not conclusive, evidence that lithium is teratogenic, Valproic acid with olanzapine, inducing cardiac malformations in the first trimester. Hypomania conventional antipsychotic, or risperidone In the treatment of acute mania, lithium is initiated Severe depression with Lithium, lamotrigine, or at 300 mg bid or tid, and the dose is then increased by psychosis valproic acid alone 300 mg every 2–3 days to achieve blood levels of Venlafaxine, bupropion, or 0.8–1.2 meq/L. Because the therapeutic effect of lithium Severe depression paroxetine plus lithium plus may not appear until after 7–10 days of treatment, without psychosis olanzapine, or risperidone; adjunctive usage of lorazepam (1–2 mg every 4 h) or consider ECT clonazepam (0.5–1 mg every 4 h) may be beneficial to Mild to moderate Bupropion, paroxetine, control agitation. Antipsychotics are indicated in depression sertraline, venlafaxine, or patients with severe agitation who respond only par- citalopram plus lithium tially to benzodiazepines. Patients using lithium should Lithium or lamotrigine alone; be monitored closely, since the blood levels required to add bupropion if needed achieve a therapeutic benefit are close to those associ- ated with toxicity. Note: ECT, electroconvulsive therapy. Source: From GS Sachs et al: Postgrad Med, April, 2000. Valproic acid may be better than lithium for patients who experience rapid cycling (i.e., more than four In such situations, an alternative agent or combina- episodes a year) or who present with a mixed or dys- tion therapy is usually helpful. phoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis Consensus guidelines for the treatment of acute mania are rare toxicities. and bipolar depression are described in Table 49-12. Carbamazepine and oxcarbazepine, although not for- SOMATOFORM DISORDERS mally approved by the FDA for bipolar disorder, have clinical efficacy in the treatment of acute mania. Clinical Manifestations Second-generation antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole) Patients with multiple somatic complaints that cannot have also been shown to be effective, either alone or in be explained by a known medical condition or by the combination with a mood stabilizer. An increased risk of effects of alcohol or of recreational or prescription drugs weight gain and other metabolic abnormalities is a con- are commonly seen in primary care practice; one survey cern with these agents. indicated a prevalence of such complaints of 5%. In som- atization disorder, the patient presents with multiple phys- The recurrent nature of bipolar mood disorder ical complaints referable to different organ systems necessitates maintenance treatment. A sustained (Table 49-13). Onset is usually <30 years, and the dis- blood lithium level of at least 0.8 meq/L is important order is persistent. Formal diagnostic criteria require the for optimal prophylaxis and has been shown to recording of at least four pain, two gastrointestinal, one reduce risk of suicide, a finding not yet apparent for sexual, and one pseudoneurologic symptom. Patients other mood stabilizers. Compliance is frequently an with somatization disorder often present with dramatic issue and often requires enlistment and education of complaints, but the complaints are inconsistent. Symp- concerned family members. Efforts to identify and toms of comorbid anxiety and mood disorder are com- modify psychosocial factors that may trigger mon and may be the result of drug interactions due to episodes are important, as is an emphasis on lifestyle regimens initiated independently by different physicians. regularity. Antidepressant medications are some- Patients with somatization disorder may be impulsive times required for the treatment of severe break- and demanding and frequently qualify for a formal through depressions, but their use should generally comorbid psychiatric diagnosis. In conversion disorder, the be avoided during maintenance treatment because symptoms focus on deficits that involve motor or sen- of the risk of precipitating mania or accelerating the sory function and on psychological factors that initiate cycle frequency. Loss of efficacy over time may be observed with any of the mood-stabilizing agents.
TABLE 49-13 poor relationships with physicians stemming from their 679 CHAPTER 49 Mental Disorders sense that they have been evaluated and treated inappro- DIAGNOSTIC CRITERIA FOR SOMATIZATION priately or inadequately. Hypochondriasis can be dis- DISORDER abling in intensity and is persistent, with waxing and waning symptomatology. A. A history of many physical complaints beginning <30 years that occur over a period of several years and In factitious illnesses, the patient consciously and volun- result in treatment being sought or significant impair- tarily produces physical symptoms of illness. The term ment in social, occupational, or other important areas Munchausen’s syndrome is reserved for individuals with par- of functioning. ticularly dramatic, chronic, or severe factitious illness. In true factitious illness, the sick role itself is gratifying. A B. Each of the following criteria must have been met, with variety of signs, symptoms, and diseases have been either individual symptoms occurring at any time during the simulated or caused by factitious behavior, the most com- course of the disturbance: mon including chronic diarrhea, fever of unknown ori- 1. Four pain symptoms: a history of pain related to at gin, intestinal bleeding or hematuria, seizures, and hypo- least four different sites or functions (e.g., head, glycemia. Factitious disorder is usually not diagnosed until abdomen, back, joints, extremities, chest, rectum, 5–10 years after its onset, and it can produce significant during menstruation, during sexual intercourse, or social and medical costs. In malingering, the fabrication during urination) derives from a desire for some external reward, such as a 2. Two gastrointestinal symptoms: a history of at least narcotic medication or disability reimbursement. two gastrointestinal symptoms other than pain (e.g., nausea, bloating, vomiting other than during Treatment: pregnancy, diarrhea, or intolerance of several differ- SOMATOFORM DISORDERS ent foods) 3. One sexual symptom: a history of at least one Patients with somatization disorders are frequently sub- sexual or reproductive symptom other than pain jected to many diagnostic tests and exploratory surg- (e.g., sexual indifference, erectile or ejaculatory eries in an attempt to find their “real” illness. Such an dysfunction, irregular menses, excessive menstrual approach is doomed to failure and does not address the bleeding, vomiting throughout pregnancy) core issue. Successful treatment is best achieved through 4. One pseudoneurologic symptom: a history of at least behavior modification, in which access to the physician is one symptom or deficit suggesting a neurologic con- tightly regulated and adjusted to provide a sustained dition not limited to pain (conversion symptoms such and predictable level of support that is less clearly con- as impaired coordination or balance, paralysis or tingent on the patient’s level of presenting distress. Visits localized weakness, difficulty swallowing or lump can be brief and should not be associated with a need in throat, aphonia, urinary retention, hallucinations, for a diagnostic or treatment action. Although the litera- loss of touch or pain sensation, double vision, blind- ture is limited, some patients with somatization disorder ness, deafness, seizures; dissociative symptoms may benefit from antidepressant treatment. such as amnesia; or loss of consciousness other than fainting) Any attempt to confront the patient usually creates a sense of humiliation and causes the patient to abandon C. Either of the following: treatment from that caregiver. A better strategy is to 1. After appropriate investigation, each of the symp- introduce psychological causation as one of a number toms in criterion B cannot be fully explained by a of possible explanations and to include factitious illness known general medical condition or the direct as an option in the differential diagnoses that are dis- effects of a substance (e.g., a drug of abuse, a cussed. Without directly linking psychotherapeutic inter- medication) vention to the diagnosis, the patient can be offered a 2. When there is a related general medical condition, face-saving means by which the pathologic relationship the physical complaints or resulting social or occu- with the health care system can be examined and alter- pational impairment are in excess of what would be native approaches to life stressors developed. expected from the history, physical examination, or laboratory findings D. The symptoms are not intentionally produced or feigned (as in factitious disorder or malingering). Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 2000. or exacerbate the medical presentation. Like somatiza- PERSONALITY DISORDERS tion disorder, the deficit is not intentionally produced or simulated, as is the case in factitious disorder (malinger- Clinical Manifestations ing). In hypochondriasis, the essential feature is a belief of serious medical illness that persists despite reassurance Personality disorders are characteristic patterns of think- and appropriate medical evaluation. As with somatization ing, feeling, and interpersonal behavior that are relatively disorder, patients with hypochondriasis have a history of inflexible and cause significant functional impairment or
SECTION V Psychiatric Disorders680 subjective distress for the individual. The observed dyscontrol, and/or rejection hypersensitivity. Anxious or behaviors are not secondary to another mental disorder, fearful cluster C patients often respond to medications nor are they precipitated by substance abuse or a general used for axis I anxiety disorders (see earlier). It is impor- medical condition. This distinction is often difficult to tant that the physician and the patient have reasonable make in clinical practice, as personality change may be expectations vis-à-vis the possible benefit of any med- the first sign of serious neurologic, endocrine, or other ication used and its side effects. Improvement may be medical illness. Patients with frontal lobe tumors, for subtle and observable only over time. example, can present with changes in motivation and personality while the results of the neurologic examina- SCHIZOPHRENIA tion remain within normal limits. Individuals with per- sonality disorders are often regarded as “difficult Clinical Manifestations patients” in clinical medical practice because they are seen as excessively demanding and/or unwilling to fol- Schizophrenia is a heterogeneous syndrome character- low recommended treatment plans. Although DSM-IV ized by perturbations of language, perception, thinking, portrays personality disorders as qualitatively distinct social activity, affect, and volition. There are no pathog- categories, there is an alternative perspective that per- nomonic features. The syndrome commonly begins in sonality characteristics vary as a continuum between late adolescence, has an insidious (and less commonly normal functioning and formal mental disorder. acute) onset, and, often, a poor outcome, progressing Personality disorders have been grouped into three from social withdrawal and perceptual distortions to overlapping clusters. Cluster A includes paranoid, schi- recurrent delusions and hallucinations. Patients may pre- zoid, and schizotypal personality disorders. It includes sent with positive symptoms (such as conceptual disor- individuals who are odd and eccentric and who main- ganization, delusions, or hallucinations) or negative tain an emotional distance from others. Individuals have symptoms (loss of function, anhedonia, decreased emo- a restricted emotional range and remain socially isolated. tional expression, impaired concentration, and dimin- Patients with schizotypal personality disorder frequently ished social engagement) and must have at least two of have unusual perceptual experiences and express magical these for a 1-month period and continuous signs for at beliefs about the external world. The essential feature of least 6 months to meet formal diagnostic criteria. As paranoid personality disorder is a pervasive mistrust and individuals age, positive psychotic symptoms tend to suspiciousness of others to an extent that is unjustified attenuate and some measure of social and occupational by available evidence. Cluster B disorders include antiso- function may be regained. “Negative” symptoms pre- cial, borderline, histrionic, and narcissistic types and dominate in one-third of the schizophrenic population describe individuals whose behavior is impulsive, exces- and are associated with a poor long-term outcome and a sively emotional, and erratic. Cluster C incorporates poor response to drug treatment. However, marked vari- avoidant, dependent, and obsessive-compulsive personal- ability in the course and individual character of symp- ity types; enduring traits are anxiety and fear. The toms is typical. boundaries between cluster types are to some extent artificial, and many patients who meet criteria for one The four main subtypes of schizophrenia are cata- personality disorder also meet criteria for aspects of tonic, paranoid, disorganized, and residual. Many indi- another.The risk of a comorbid major mental disorder is viduals have symptoms of more than one type. Catatonic- increased in patients who qualify for a diagnosis of per- type describes patients whose clinical presentation is sonality disorder. dominated by profound changes in motor activity, nega- tivism, and echolalia or echopraxia. Paranoid-type describes Treatment: patients who have a prominent preoccupation with a spe- PERSONALITY DISORDERS cific delusional system and who otherwise do not qualify as having disorganized-type disease, in which disorganized Dialectical behavior therapy (DBT) is a cognitive-behav- speech and behavior are accompanied by a superficial or ioral approach that focuses on behavioral change while silly affect. In residual-type disease, negative symptomatol- providing acceptance, compassion, and validation of the ogy exists in the absence of delusions, hallucinations, or patient. Several randomized trials have demonstrated motor disturbance. The term schizophreniform disorder the efficacy of DBT in the treatment of personality disor- describes patients who meet the symptom requirements ders. Antidepressant medications and low-dose antipsy- but not the duration requirements for schizophrenia, chotic drugs have some efficacy in cluster A personality and schizoaffective disorder is used for those who manifest disorders, while anticonvulsant mood-stabilizing agents symptoms of schizophrenia and independent periods and MAOIs may be considered for patients with cluster B of mood disturbance. Prognosis depends not on symptom diagnoses who show marked mood reactivity, behavioral severity but on the response to antipsychotic medication.
A permanent remission without recurrence does occa- synapses, and DISC1 is a scaffolding protein that partici- 681 CHAPTER 49 Mental Disorders sionally occur. About 10% of schizophrenic patients pates in a variety of protein-protein interactions impor- commit suicide. tant in neuronal development. One group has reported risk variants in the α7 nicotinic acetylcholine receptor Schizophrenia is present in 0.85% of individuals world- subunit gene and linked it to a specific auditory process- wide, with a lifetime prevalence of ~1–1.5%. An estimated ing deficit. 300,000 episodes of acute schizophrenia occur annually in the United States, resulting in direct and indirect costs of Schizophrenia is also associated with gestational and $62.7 billion. perinatal complications, including Rh factor incompati- bility, fetal hypoxia, prenatal exposure to influenza during Differential Diagnosis the second trimester, and prenatal nutritional deficiency. Studies of monozygotic twins discordant for schizophre- The diagnosis is principally one of exclusion, requiring nia have reported neuroanatomic differences between the absence of significant associated mood symptoms, any affected and unaffected siblings, supporting a “two- relevant medical condition, and substance abuse. Drug strike” etiology involving both genetic susceptibility and reactions that cause hallucinations, paranoia, confusion, or an environmental insult. The latter might involve local- bizarre behavior may be dose-related or idiosyncratic; ized hypoxia during critical stages of brain development. parkinsonian medications, clonidine, quinacrine, and pro- caine derivatives are the most common prescription med- A number of structural and functional abnormalities ications associated with these symptoms. Drug causes have been identified in schizophrenia, including (1) cor- should be ruled out in any case of newly emergent psy- tical atrophy and ventricular enlargement; (2) specific chosis. The general neurologic examination in patients volume losses in the amygdala, hippocampus, right pre- with schizophrenia is usually normal, but motor rigidity, frontal cortex, fusiform gyrus, and thalamus; (3) progres- tremor, and dyskinesias are noted in one-quarter of sive reduction in cortical volume over time; (4) reduced untreated patients. metabolism in the thalamus and prefrontal cortex; (5) abnormalities of the planum temporale; and (6) changes Epidemiology and Pathophysiology in the size, orientation, and density of cells in the hippocam- pus and prefrontal cortex, and decreased numbers of cortical Epidemiologic surveys identify several risk factors for interneurons.These observations have suggested that schizo- schizophrenia including genetic susceptibility, early devel- phrenia may result from a disturbance in a cortical opmental insults, winter birth, and increasing parental age. striatal–thalamic circuit resulting in abnormalities in sensory Genetic factors are involved in at least a subset of individ- filtering and attention. uals who develop schizophrenia. Schizophrenia is observed in ~6.6% of all first-degree relatives of an Schizophrenic individuals are highly distractible and affected proband. If both parents are affected, the risk for demonstrate deficits in perceptual-motor speed, ability offspring is 40%. The concordance rate for monozygotic to shift attention, and filtering out of background stim- twins is 50%, compared to 10% for dizygotic twins. uli. Event-related evoked potential studies of schizo- Schizophrenia-prone families are also at risk for other phrenia have defined a reduction in P300 amplitude to a psychiatric disorders, including schizoaffective disorder novel stimulus, which implicates an impairment in cog- and schizotypal and schizoid personality disorders, the latter nitive processing. Impaired information processing is terms designating individuals who show a lifetime pattern also found in unaffected family members. of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccen- The dopamine hypothesis of schizophrenia is based on tric behavior, and mild perceptual distortions. the discovery that agents that diminish dopaminergic activity also reduce the acute symptoms and signs of psy- Despite evidence for a genetic causation, the results chosis, specifically agitation, anxiety, and hallucinations. of molecular genetic linkage studies in schizophrenia are Amelioration of delusions and social withdrawal is less inconclusive. Major gene effects appear unlikely. Possible dramatic. Thus far, however, evidence for increased susceptibility genes include: neuregulin-1 (chromosome dopaminergic activity in schizophrenia is indirect, 8p21); dysbindin (6p22.3); proline dehydrogenase although decreased D2 receptor occupancy by dopamine (22q11); D-amino-acid oxidase activator (13q34); dis- has been shown in drug-naïve patients. An increase in rupted in schizophrenia 1, (DISC1), (1q42); and catechol- the activity of nigrostriatal and mesolimbic systems and a O-methyl transferase (COMT). Neuregulin-1, dysbindin, decrease in mesocortical tracts innervating the prefrontal and D-amino-acid oxidase activator appear to be cortex is hypothesized, although it is likely that other involved in glutamatergic function, increasing interest in neurotransmitters, including serotonin, acetylcholine, glu- N-methyl-D-aspartate (NMDA)–mediated glutamate tamate, and GABA, also contribute to the pathophysiol- signaling as a possible therapeutic target for treatment. ogy of the illness. Possible involvement of excitatory COMT is involved in the removal of dopamine from amino acids is supported by the genetic data cited above and findings that NMDA receptor antagonists and chan- nel blockers, such as phencyclidine (PCP) and ketamine,
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