Schizophrenia is a chronic, devastating brain disorder that is characterized by psychotic symptoms, such as hallucinations and delusions, and by deficits in normal cognitive, emotional, and social functioning. Schizophrenia affects approximately one percent of the world's population, and onset is most often between 15 and 30 years of age-when society has a maximal investment in a person's development. Therefore, schizophrenia represents a serious problem not only in terms of direct costs and lost productivity but also in terms of lost human potential. Further, patients with schizophrenia utilize a disproportionate share of medical resources. Patients with schizophrenia may constitute as much as 10 percent of the totally and permanently disabled and a large fraction of the homeless population. 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 and often have difficulty complying with medical treatment for such reasons as homelessness and lack of financial support. Because of suicide and poor access to medical treatment, the mortality of schizophrenic patients is double that of the general population.

Schizophrenia: Epidemiology and genetics

In three well-studied sites in the United States, the lifetime prevalence of schizophrenia ranged from 0.6 to 1.9 percent of the population. Worldwide, despite some pockets of increased prevalence, there is remarkable cross-cultural consistency in the prevalence of schizophrenia, with a mean prevalence of approximately one percent.

On the basis of twin studies and adoption studies, a genetic component to the risk of development of schizophrenia has long been established. In adoption studies, increased risk of schizophrenia is conferred by biologic rather than adoptive parents; twin studies reveal a far higher concordance rate in monozygotic twins (40 to 50 percent) than in dizygotic twins (six to 12 percent). Nonetheless, molecular genetic analyses of schizophrenia over the past decade have failed to produce replicable linkages to known genetic markers. This situation is similar to that for essentially all common complex genetic disorders but stands in marked contrast to diseases in which a single major gene defect causes the disease (i.e., diseases with a mendelian pattern of transmission). Disease-causing alleles have been identified in several brain diseases transmitted in mendelian fashion, including Huntington's disease, several forms of familial Alzheimer's disease, and, most recently, one form of familial Parkinson's disease. The findings in Alzheimer's disease reflect a degree of genetic complexity in that different mutations occurring within three separate genes produce early-onset forms of the disease. However, for schizophrenia, the best available models of transmission suggest a higher degree of complexity in that the disorder is a result of both genetic and nongenetic factors, and multiple genes are likely to be involved, even within a single family. It is possible that genetic vulnerability to schizo phrenia results from multiple genes, each of which make only a small contribution. The smaller the contribution of any allele, the more difficult it is to detect it. Moreover, if many genes act together to produce vulnerability to schizophrenia, no single allele may be required, and thus, different pedigrees may have both shared and unshared genes contributing to vulnerability.

As illustrated by the maximal concordance rate of 50 percent for monozygotic twins, nongenetic factors play an important role in converting genetic vulnerability into illness. Nongenetic factors that predispose to schizophrenia may include stochastic developmental factors and environmental factors. Possible environmental risk factors that have been identified by epidemiological means include in utero difficulties, such as starvation, influenza, and Rh blood group incompatibilities, and perinatal complications.

Finally, genetic analyses of schizophrenia are hampered by the lack of pathognomonic features and by the decreased fertility of persons with schizophrenia. For example, in one study, persons with schizophrenia reproduced at a rate of about one quarter that of control subjects.

Findings of family studies of schizophrenia are consistent with the possibility that a subset of genes that predispose to schizophrenia may also predispose to related forms of psychopathology. Thus, having a first-degree relative with schizophrenia increases the risk not only of schizophrenia but also of schizotypal personality disorder, schizoaffective disorder, and perhaps mood disorders with psychotic features.

Schizophrenia: Pathophysiology

Schizophrenia is characterized both by gross anatomic pathology and by microscopic neuropathology of the prefrontal cerebral cortex, the hippocampus, and related limbic structures. In vivo neuroradiological studies and postmortem brain analyses demonstrate enlargement of the ventricular system. Neuroimaging studies are consistent with loss of cortical volume in the prefrontal cortex and in the region of the hippocampus.In addition, magnetic resonance spectroscopy reveals a reduction in concentration of multiple neuronal markers limited to the dorsolateral prefrontal cortex and the hippocampal region. There are, however, neuroimaging studies that have found abnormalities in the thalamus, a structure that interacts with essentially all regions of the cerebral cortex and with the striatum. As methods of data normalization for the normal variance in head size and brain architecture are developed, brain abnormalities associated with schizophrenia should come into sharper focus.

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. In 14 of the pairs, the schizophrenic twin had a smaller anterior hippocampus on the left; in 13 of the pairs, the schizophrenic 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 demonstrated 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 ventricular enlargement can be detected even with new onset of active schizophrenic symptoms, because it suggests that the anatomic abnormalities antedate the onset of symptoms of schizophrenia. Moreover, neither gliosis nor inflammatory cells have been found in neuropathological studies, 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) in 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, they perform poorly. This impaired performance correlates with the failure of frontal lobe neurons to activate normally in response to the task.

The prefrontal cortex and the limbic structures implicated by these anatomic and function 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 alleviate the symptoms of schizophrenia remains unknown.

There are currently five known types of dopamine receptors, designated D₁ to D₅. Abnormalities in receptor number or function have been postulated to be associated with symptoms of schizophrenia, but studies to confirm this belief have been made difficult by the dearth of well-characterized patients who have never received antipsychotic drugs, which may cause alterations in dopamine receptors. Most recently, it has been reported that D₁ dopamine receptors are decreased in the prefrontal cortex of drug-naive and drug-free persons with schizophrenia. If replicated, this finding is of interest because D₁ dopamine receptors have been shown to play a role in working memory, a form of short-term memory that is impaired in persons with schizophrenia.

Schizophrenia: Clinical features

As defined by the diagnostic criteria in the American Psychiatric Association's fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the essential features of schizophrenia are the presence of psychotic symptoms during some phase of the illness, a long-term course, and deterioration in functioning. No combination of symptoms or signs by itself is pathognomonic of schizophrenia; the course of illness must be taken into account as well [see Differential Diagnosis, below]. For a diagnosis of schizophrenia, DSM-IV requires a duration of illness of at least six months and significant functional impairment. However, the long-held belief that cognitive abilities deteriorate over the course of illness has recently been called into question. For example, in 34 schizophrenic patients whose IQs were measured as children and again 19.4 years later, no significant decline in IQ had occurred over the course of nearly two decades, but both the child and the adult IQ in these patients were lower than those of the general population. Although the six-month criterion is arbitrary, the requirement of chronicity markedly improves the validity of the diagnosis, which is determined by the stability of the diagnosis at long-term follow-up. Few investigators believe that the DSM-IV criteria characterize 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 time and do not remain consistent within familial groups.

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-that is, an emotion not normally compatible with the person'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-that is, 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. Although characteristic of schizophrenia, biza rre delusions (e.g., the belief that an outside force is inserting thoughts into one's mind) neither are required for the diagnosis³¹ nor exclude other diagnoses, such as atypical mania. 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. Somatic delusions, in the absence of other mental symptoms, are diagnosed as body dysmorphic disorders and may respond better to serotonin reuptake inhibitors than to antipsychotic drugs. 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 used to describe 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 sounds 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 person 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 or impaired motivation). Most patients with schizophrenia experience both positive and negative symptoms, but often, negative symptoms prove more disabling than positive symptoms. Positive symptoms are generally more responsive to antipsychotic medications than are negative symptoms, although atypical antipsychotic drugs, such as clozapine and possibly olanzapine, may relieve negative symptoms in a subset of patients.

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 or as a result of drug toxicity. Whenever a physician is faced with a newly psychotic patient or a patient in relapse, it is important to rule out drug abuse, drug reactions, and medical illness as the cause of the psychosis.

A variety of psychiatric disorders may mimic schizophrenia. For example, psychotic symptoms are common during manic episodes. Although these symptoms 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). 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.

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 patients; patients with schizo affective 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 pre sentations of mood disorder, whereas others go on to manifest typical schizophrenia at follow-up.

Schizophrenia: 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. In addition, intercurrent medical illnesses, comorbid mental disorders such as depression, and substance abuse-a common complication of schizophrenia-must be identified and treated.

The availability of new antipsychotic drugs with reduced liability for causing extrapyramidal side effects has revolutionized the treatment of schizophrenia. Conventional or so-called typical antipsychotic drugs, such as haloperidol, continue to have an important place in the treatment of schizophrenia because of their long track record of safety and efficacy, but they carry a side-effect burden that limits their use. Of the atypical antipsychotic drugs, only clozapine appears nearly free of the liability of causing extrapyramidal side effects and tardive dyskinesia. Clozapine is also clearly superior to typical antipsychotic drugs in the treatment of both positive and negative symptoms of schizophrenia; its use is limited, however, by the idiosyncratic occurrence of agranulocytosis, which requires weekly blood mon itoring, and by other side effects, such as sedation and increased risk of seizures. Newer antipsychotic drugs that are easier to administer than clozapine include risperidone, olanzapine, and two drugs not yet approved by the Food and Drug Administration, sertindole and quetiapine. Risperidone (4 to 6 mg/ day), olanzapine (10 to 20 mg/day), and sertindole (12 to 24 mg/ day) cause extrapyramidal side effects but at a significantly lower rate than typical antipsychotic drugs. Whether they have enhanced efficacy for negative symptoms of schizophrenia is not yet clear, although one study of olanzapine suggested that it might. None of these drugs has been shown to be as effective as clozapine for treatment-refractory patients with schizophrenia.

Reduction of stress in patients with schizophrenia may increase the interval between relapses. Patients have higher relapse rates when living with persons who respond angrily to the patient's symptoms, express doubt about the legitimacy of the illness, or show low tolerance for the patient's behaviors. Therapies that improve the family's understanding of patient needs and enhance the patient's social skills improve the course of the patient's illness. These therapies, however, are not a replacement for medication but an adjunct to medication.