Schizophrenia is the most common chronic psychotic disorder, affecting approximately one percent of the population worldwide.Because the onset of schizophrenia generally occurs early in life and results in serious chronic impairment of cognition, emotional state, and behavior, schizophrenia represents a major social problem not only in terms of cost but also in terms of lost human potential and family stress. For the general physician, the medical care of schizophrenic patients presents a substantial challenge because schizophrenic patients often are unable to supply an accurate medical history. Schizophrenic patients often have difficulty complying with medical treatment, not only because of their illness but also because many of them are homeless or live alone without financial support. It is estimated that the mortality of schizophrenic patients is double that of the general population.Epidemiology and Genetics There is remarkable cross-cultural consistency in the prevalence of schizophrenia. Numerous studies have corroborated that the lifetime risk of schizophrenia is between 0.4 and 2.7 percent, with a mean risk of one percent. Family and genetic studies of schizophrenia have been hampered by the heterogeneity of schizophrenia and by the uncertainties surrounding diagnosis. A further difficulty for family and genetic studies is the decreased fertility of schizophrenic individuals; pedigrees are small, and therefore, genetic studies have less power. In one study, individuals with schizophrenia reproduced at a rate about one quarter that of control subjects. Nonetheless, in most adequately designed studies, familial aggregation of schizophrenia is observed. Adoption studies and twin studies provide strong evidence that familial transmission of schizophrenia has a genetic component. However, twin studies demonstrate that environmental factors are also important: the maximum concordance rate for schizophrenia in monozygotic (genetically identical) twin pairs is approximately 50 percent. Thus, genetic factors cannot, by themselves, explain the occurrence of schizophrenia.Many family studies have produced findings that are consistent with the hypothesis that genes predisposing to schizophrenia may also predispose to related forms of psychopathology. A person with a first-degree relative who is schizophrenic is at increased risk not only for schizophrenia but also for schizotypal personality disorder and schizoaffective disorder. Some studies suggest a link between the genetic predisposition to schizophrenia and mood disorders with psychotic features, though the evidence is inconclusive. Pathophysiology Schizophrenia is characterized both by gross anatomic pathology and by microscopic neuropathology of the prefrontal cerebral cortex, the hippocampus, and related limbic structures.9-11 In vivo neuroradiological studies and postmortem brain analyses demonstrate enlargement of the ventricular system and loss of tissue in temporal lobes of schizophrenic patients. Tissue loss seems to be more pronounced in the left temporal lobe than in the right temporal lobe.12,13 Many quantitative studies of brain morphology have suffered from the wide variations in normal control populations. One study addressed this problem by using a cohort of 15 monozygotic twin pairs who were discordant for schizophrenia.13 In 14 of the pairs, the schizophrenic co-twin had a smaller anterior hippocampus on the left; in 13 of the pairs, the schizophrenic co-twin had a smaller anterior hippocampus on the right. Compared with their normal co-twins, 14 of the twins with schizophrenia had enlarged left lateral ventricles and 13 had enlarged right lateral ventricles. The third ventricle was also larger in 13 of the 15 schizophrenic twins. Such differences were not found in either hippocampal size or ventricular volume in seven sets of monozygotic twins without schizophrenia who served as control subjects. This study demonstrates an important role for nongenetic factors in the pathogenesis of schizophrenia, in that affected and unaffected co-twins showed significant differences in brain morphology despite being genetically identical. Whether these gross anatomic abnormalities bear a cause-and-effect relation to the primary disease process remains unclear. It is significant that there does not appear to be a correlation between ventricular volume and either duration of illness or use of medication; this suggests that the anatomic abnormalities antedate the onset of symptoms of schizophrenia. Moreover, neither gliosis nor inflammatory cells have been found in neuropathological studies,9,10 which rules out an active neurodegenerative process. Taken together, these data are consistent with a brain lesion that occurs early in life and acts in conjunction with a genetic predisposition to schizophrenia to produce symptoms that appear at a later time. The possible causes of the observed tissue loss are currently the subject of intensive research. Some studies suggest that the tissue loss results from a disruption of neuronal migration during morphogenesis of the cerebral cortex. Neuropsychological studies and neuroradiological findings also indicate clear abnormalities of frontal lobe function in schizophrenic patients. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) of schizophrenic patients have revealed decreased frontal lobe metabolism (so-called hypofrontality) that is independent of medication status. When schizophrenic patients are given tasks that require frontal lobe activation, such as the Wisconsin Card Sort, they perform poorly. This impaired performance correlates with the failure of their frontal lobe neurons to activate normally in response to the task. The prefrontal cortex and the limbic structures implicated by these anatomic and functional studies are richly innervated by dopamine-mediated pathways. This finding helps explain the efficacy of antipsychotic drugs that act as dopamine receptor antagonists , although the precise mechanism by which they ameliorate the symptoms of schizophrenia remains unknown.New dopamine receptor subtypes have been identified by molecular cloning. One of these, the D4 dopamine receptor, appears to be a critical site of action of the atypical antipsychotic drug clozapine [see Subsection VIII]. Indirect evidence from postmortem examination indicates that there may be a sixfold increase in the density of D4 dopamine receptors in the brains of schizophrenic individuals.20 Although this finding has yet to be replicated, it does suggest that dopamine receptor abnormalities play a role not only in the treatment of schizophrenia but also in its pathogenesis. Diagnosis As defined by the diagnostic criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) published by the American Psychiatric Association,21 the essential features of schizophrenia are the presence of psychotic symptoms during some phase of the illness, a chronic course, and deterioration in functioning combination of symptoms or signs by itself is pathognomonic of schizophrenia; the course of illness must be taken into account as well Differential Diagnosis, below. For a diagnosis of schizophrenia, DSM-IV requires a duration of illness of at least six months and a deterioration in functioning from the highest level achieved before illness. Although the six-month criterion is arbitrary, the requirement for chronicity markedly improves the validity of the diagnosis as determined by stability of diagnosis at long-term follow-up.22 Few believe that the DSM-IV criteria and the similar DSM-III-R criteria identify a homogeneous diagnostic entity; however, the criteria have proved to be fairly reliable in clinical use and have permitted clinical researchers to identify somewhat purer populations for family, diagnostic, treatment, and outcome studies. DSM-IV describes four subtypes of schizophrenia: catatonic, disorganized, paranoid, and undifferentiated. These traditional subtypes appear to have little diagnostic validity; they have only modest stability over time23 and do not breed true.24 Psychotic symptoms that characterize schizophrenia include disturbances in perception, abnormalities in the content of thought, and abnormalities in the form of thought. Perceptual disturbances consist of hallucinations and illusions. Hallucinations are false perceptions that occur in the absence of an appropriate stimulus. In schizophrenia, hallucinations may occur in any sensory modality, but auditory hallucinations (e.g., noises, voices, or music) are most common. Illusions differ from hallucinations in that a sensory stimulus is present but is misinterpreted. Disturbances of affect commonly occur in schizophrenia. Patients may exhibit inappropriate affect: an emotion not normally compatible with the individual’s expressed thoughts or situation (e.g., laughing hysterically while describing the death of a parent). Other patients may have profound blunting or flattening of affect: a marked decrease in responsiveness to other people and to the environment. Apparent blunting of affect may also be caused by overmedication with antipsychotic drugs or by an intercurrent depression. Abnormalities in the content of thought include delusions and ideas of reference. Delusions are fixed, culturally inappropriate beliefs that the patient holds despite all reasonable evidence to the contrary. It was traditionally held that bizarre delusions (e.g., the belief that an outside force is inserting thoughts into the patient’s mind) were particularly characteristic of schizophrenia, but bizarre delusions occur in other psychotic disorders as well. Moreover, many schizophrenic patients do not experience bizarre delusions.25 Nonbizarre delusions include persecutory or paranoid delusions, delusions of jealousy, and delusions of reference, which are beliefs that ordinary events have special significance for the individual (e.g., that a song being played on the radio contains a secret message intended for the patient). Delusions of reference that are somewhat less strongly held are referred to as ideas of reference. Somatic delusions occur as symptoms of schizophrenia and generally focus on disease or abnormality of some body part. Somatic delusions also occur in depression with psychotic features. When somatic delusions occur as isolated symptoms, they are diagnosed as dysmorphophobia. Grandiose delusions (e.g., a belief that one has special powers or a special mission) may occur in schizophrenia, although they are more characteristic of mania. Abnormalities in the form of thought (also called formal thought disorder) are cognitive disturbances that manifest themselves as disorganized or illogical language or reasoning–for example, vague, digressive, or overelaborate speech. The term tangentiality is applied when questions are answered obliquely in such a way that over time the answers become progressively less related to the original question. Loosening of associations is the term that describes a patient whose speech consists of ideas that have no discernible connection to one another. In extreme cases of loosening of associations, the patient’s speech may be entirely incoherent and is sometimes described as word salad. When the connections in a patient’s speech are based on similarities in the sound of words rather than on their meanings, the speech is described as having clang associations. Other manifestations of formal thought disorder include poverty of the content of speech (i.e., speech that conveys little information even when it is more or less coherent), long latency before responding to questions, and blocking, in which the flow of speech stops and the individual is unable to continue the train of thought even with cueing. Schizophrenic patients may also be mute at times. Another symptom of formal thought disorder is impairment of ability to abstract; for example, when asked to interpret a proverb, schizophrenic patients may be overly concrete. The symptoms of schizophrenia are often separated into positive symptoms and negative symptoms. Positive symptoms are thoughts, perceptions, emotions, and behaviors that are not present in the normal human population (e.g., hallucinations). Negative symptoms describe the absence of normal human responses and behaviors (e.g., social withdrawal, impaired motivation). Often, negative symptoms prove more disabling than positive symptoms. Most patients with schizophrenia experience both positive and negative symptoms. Although positive symptoms often respond better to treatment with antipsychotic drugs, negative symptoms may respond as well. Although the course of schizophrenia is variable, the onset is most common in late adolescence or early adulthood; it rarely occurs later in life. There may be a higher overall incidence in males ; females often have a somewhat later onset and a better prognosis in terms of overall functioning. The illness is characterized by periods of exacerbation of florid psychotic symptoms followed by remission. Suicide attempts and episodes of depression are common during the course of schizophrenia. Social and cognitive functioning usually deteriorate for several years and then stabilize. Approximately 80 percent of schizophrenic patients have a poor outcome as measured by frequency and severity of relapses, continuing symptoms, and overall functioning. Differential Diagnosis Psychotic symptoms, even when florid and bizarre, are not by themselves diagnostic of schizophrenia, because they may also occur during the course of mania, depression, and a variety of less well characterized psychotic disorders, such as schizoaffective disorder. Psychotic symptoms may also occur as a result of metabolic derangements, structural brain lesions, or other medical conditions [see Table 2[ or as a result of drug toxicity [see Table 3[.Whenever a physician is faced with a newly psychotic or relapsed patient, it is important to rule out drug abuse, drug reactions, or medical illness as the cause of the psychosis. A variety of psychiatric disorders may mimic schizophrenia. Psychotic symptoms are common during manic episodes. Although these are most often congruent with elevated mood (e.g., grandiose delusions), some patients, especially adolescents, may have florid psychotic symptoms such as bizarre delusions (once thought to be pathognomonic of schizophrenia).22,30 Some manic patients exhibit little or no euphoria or are euphoric only early in the manic episode; such patients may be predominantly irritable, paranoid, and dysphoric and may be misdiagnosed as schizophrenic or depressed. Because symptoms of these various disorders overlap, diagnosis must be based on the course of illness (acute onset and episodic course in mania versus insidious onset and chronic course in schizophrenia) and the presence of neurovegetative symptoms, such as decreased need for sleep in mania [see Subsection II]. Schizoaffective disorder is diagnosed when patients experience a full manic or depressed syndrome during the course of illness but have psychotic symptoms when the mood disorder is not prominent. The validity of this diagnosis has long been questioned. For clinical purposes, the diagnosis of schizoaffective disorder identifies a group of patients with a worse outcome than most bipolar depressive patients and a better outcome than most schizophrenic patients2,31; patients with schizoaffective disorder are likely to require both antipsychotic therapy and mood-stabilization therapy. When patients have psychotic symptoms of less than six months’ duration in the absence of prominent symptoms of mood disorder, they are classified as having schizophreniform disorder. These patients represent a heterogeneous group: some have atypical presentations of mood disorder, whereas others go on to manifest typical schizophrenia at follow-up. Treatment The treatment of schizophrenia is based on the use of antipsychotic drugs, the maintenance of a safe, predictable environment, and the application of supportive psychotherapies aimed at improving social and coping skills. Antipsychotic drugs are prescribed at higher dosages (equivalent to approximately 10 mg of haloperidol daily) to treat acute exacerbations of schizophrenia33,34 and at lower dosages (equivalent to approximately 2 to 5 mg of haloperidol daily) during periods of remission [see Subsection VIII]. Continued administration of antipsychotic drugs significantly decreases the relapse rate in schizophrenia.35 There is now good evidence that the atypical antipsychotic drug clozapine is superior to the typical haloperidol-like drugs for the treatment of both positive and negative symptoms of schizophrenia in many patients.36 Clozapine is considered an atypical antipsychotic drug because of its lack of extrapyramidal effects and its relatively low affinity for D2 dopamine receptors [see Subsection VIII]. The use of clozapine is complicated by the idiosyncratic occurrence of agranulocytosis, which necessitates weekly monitoring of the white blood cell count. Reduction of stress in the schizophrenic patient may also prolong the time between relapses. Patients have higher relapse rates when living with highly intrusive families who express angry or distressed responses to the patient’s symptoms, doubt about the legitimacy of the illness, or low tolerance for the patient’s behaviors. It appears that family therapies aimed at reducing these types of responses, as well as enhancing the patient’s social skills, improve the course of the individual’s illness. |