Disorders of Thought and Volition: Schizophrenia

Diagnosis of Schizophrenia Is Based on Standardized Clinical Criteria

The Symptoms of Schizophrenia Can Be Grouped into Positive, Negative, and Cognitive

Schizophrenia Is Characterized by Psychotic Episodes

Both Genetic and Nongenetic Risk Factors Contribute to Schizophrenia

Neuroanatomic Abnormalities May Be a Causative Factor in Schizophrenia

Loss of Gray Matter in the Cerebral Cortex Appears to Result from Loss of Synaptic Contacts Rather Than Loss of Cells

Abnormalities in Brain Development During Adolescence May Contribute to Schizophrenia

Antipsychotic Drugs Act on Dopaminergic Systems in the Brain

An Overall View

THE SUCCESS OF NEUROBIOLOGY in providing insights into perception, cognition, and more recently emotion has inspired increasingly sophisticated biological investigations into disorders of thought and mood. In this chapter and the next we examine the four most serious disorders of thinking and mood: schizophrenia, depression, mania, and the anxiety states. These disorders involve disturbances in thought, self-awareness, perception, affect, volition, and social interaction.

In addition to being scientifically challenging, mental illness such as schizophrenia is of great social importance. Tragically this illness results in lifelong disability. The World Health Organization counts schizophrenia as one of the most significant contributors to disease burden (defined as healthy years of life lost to illness) worldwide. Fully 5% of people with schizophrenia commit suicide. Many more are homeless. The vast majority are unable to function successfully in school or in the workplace. Before the advent of psychopharmaco-logic therapies, schizophrenia and the mood disorders accounted for more than half of all hospital admissions in the United States. Even now schizophrenia accounts for approximately 30% of all hospitalizations.

The pattern of symptoms of schizophrenia are remarkably similar in all countries and cultures. The average prevalence worldwide ranges between 0.5 and 1%; the male-female ratio is 1.4:1. Diagnosis is usually made during late adolescence or early adulthood with the emergence of full symptoms, but in retrospect the illness begins far earlier with prodromal symptoms.

Diagnosis of Schizophrenia Is Based on Standardized Clinical Criteria

In medicine the understanding of a disease, and therefore its diagnosis, is ultimately based on identification of (1) etiological factors (such as microbes, toxins, or genetic risks) and (2) pathogenesis (mechanisms by which etiologic agents produce disease). Unfortunately, the etiology and pathogenesis of most mental disorders have not been determined. As a result, psychiatric diagnoses still rely on the patient’s description of symptoms, the examiner’s observations, a detailed natural history (the course of the illness over time), and the response to treatment.

This approach to psychiatric diagnosis began at the turn of the 20th century with the work of Emil Kraepelin in Germany. Influenced by Rudolf Virchow, the German pioneer of cellular pathology, and by Thomas Sydenham, the English clinician who focused attention on the natural history of medical diseases, Kraepelin studied mental disorders as specific disease processes. Even without knowledge about the etiology and pathogenesis, of diseases affecting thought, emotion, and behavior, he argued, such diseases could still be distinguished on the basis of signs, symptoms, and natural history.

Of course, the presentation of a single sign or symptom is not in itself evidence for disease because it may occur in healthy people. But when certain signs and symptoms occur together they form a syndrome, a condition that can be distinguished from normal behavior or from other clusters of signs and symptoms. The natural history of a disease is studied by tracing the onset of signs and symptoms in patients’ lives and how they change with time. Thus a syndrome can emerge at a characteristic age or it can follow a characteristic clinical course. For example, Kraepelin recognized that most patients with schizophrenia (which he called dementia praecox) do not recover the level of functioning they had prior to the onset of the disease, whereas most patients with mood disorders experience cycles of relapse and at least partial recovery.

Since the 1980s the diagnosis of psychiatric disorders has been based on standardized criteria that have made diagnosis more reliable. Two different clinicians applying standardized criteria for schizophrenia are very likely to arrive at the same diagnosis. Nevertheless, without etiological or pathophysiological data and lacking objective tests, current diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) of the American Psychiatric Association cannot define disease states in scientifically verifiable terms. With progress in such areas as genetics and neuroimaging, it eventually should be possible to arrive at objectively verifiable and thus valid diagnostic criteria for mental disorders.

The Symptoms of Schizophrenia Can Be Grouped into Positive, Negative, and Cognitive

It is useful to subdivide the symptoms of schizophrenia into three clusters because each may reflect different aspects of the pathophysiology and because each responds differently to the medications presently used. Positive or psychotic symptoms include mental phenomena that do not occur in healthy people, such as hallucinations and delusions. Negative (or “deficit”) symptoms result from impairment of normal functions and can include blunted emotional responses, withdrawal from social interactions, impoverished content of thought and speech (Box 62–1), and a lack of motivation.

A third symptom cluster includes cognitive abnormalities—sometimes described as “disorganization symptoms.” These symptoms impair working memory and executive functions—the ability to organize one’s life. These cognitive symptoms typically persist even during otherwise successful treatment with medication and are thought to be significant contributors to long-term disability. Interestingly, cognitive symptoms can be found to some degree in persons at very high risk of developing schizophrenia but who have not yet experienced hallucinations or delusions, and in otherwise healthy relatives of patients with schizophrenia, suggesting that cognitive symptoms reflect genetic predispositions to schizophrenia.

The medications used to treat schizophrenia are called antipsychotic drugs and are most effective at diminishing the positive symptoms as well as psychotic symptoms that occur in mood disorders. None of the medications reliably benefits the cognitive symptoms.

Schizophrenia Is Characterized by Psychotic Episodes

The most dramatic manifestations of schizophrenia are psychotic symptoms, including hallucinations and delusions. Hallucinations are percepts that occur in the absence of appropriate sensory stimuli and can occur in any sensory modality. In schizophrenia the most common hallucinations are auditory. Typically, a patient hears voices, but noises or music are also common. Sometimes the voices will carry on a dialog and frequently are experienced as bullying and derogatory. Occasionally, voices will issue commands to the patient that can create a high risk of harm, including suicide. Neuroimaging studies of subjects experiencing auditory hallucinations suggest that areas normally involved in the processing of language are recruited during hallucinations. These include Broca’s area in the frontal lobe and Wernicke’s area in the superior temporal lobe of the cerebral cortex (see Chapter 60).

Delusions are firm beliefs that are not realistic and not explained by the patient’s culture. They can be so powerful that sufferers cannot (or refuse to) compare their beliefs to what is actually happening in the world. Delusions can be quite varied in form. For some patients reality is distorted: The world is full of hidden signs meant only for them (delusions of reference), or they are being closely watched or persecuted (paranoid delusions). Others experience bizarre delusions, for example that some entity is inserting or extracting thoughts from their brain or that their dental fillings are radio transmitters broadcasting what they say to nefarious groups. Psychotic symptoms can also occur in mood disorders and drug-induced delirium, but the other symptoms and clinical course of those states are not consistent with schizophrenia.

The full emergence of schizophrenia is often preceded by a period of early symptoms. In this prodromal period the patient can behave eccentrically, become socially isolated, exhibit blunted affect, poverty of speech, a poor attention span, and lack of motivation. Once the disease is fully manifest, periods of florid psychosis typically occur, accompanied by markedly disordered thinking and abnormalities in the regulation of emotion. These periods of overt psychosis are interspersed with periods of residual symptoms. After the first few episodes the patient rarely returns to full normal functioning.

Both Genetic and Nongenetic Risk Factors Contribute to Schizophrenia

Schizophrenia, like many other mental illnesses, runs in families. As early as 1930 Franz Kalman in Germany studied familial patterns of transmission and concluded that genes contribute significantly to schizophrenia. Three major strategies have been used to quantify the contribution of heredity to the risk of schizophrenia and to understand how genetic risk is transmitted.

In one strategy the rate of concordance for schizophrenia in monozygotic twin pairs, whose DNA sequences are 100% identical, is compared with that in dizygotic twin pairs, whose DNA sequences are on average 50% identical. Assuming that the familial environment is roughly identical for both types of twin pairs, then if genes play a significant role the concordance rates should be higher among monozygotic pairs than among dizygotic pairs. In fact, monozygotic twins have a concordance rate of nearly 50% for schizophrenia, whereas dizygotic twins have a concordance rate of approximately 15% (slightly higher than that for ordinary siblings, which also have on average 50% genetic identity).

Although these rates suggest an important role for genes in schizophrenia, they also demonstrate that genes are not completely determinative. If they were, the concordance rate for monozygotic twins would be 100% as it is in Huntington disease for example. Thus factors other than inherited DNA sequence, such as new mutations, epigenetic modification of DNA, environmental factors, and stochastic factors occurring during brain development, play a role in converting inherited genetic vulnerability into the disease.

To separate genetic factors and environmental influences more clearly, Seymour Kety, David Rosenthal, and Paul Wender examined children who were adopted at or shortly after birth in Denmark, a country where very accurate family and health records are kept. They found that the rate of schizophrenia in the biological family of an adoptee was much more strongly predictive of schizophrenia than the rate in the adoptive family. Kety and his colleagues also observed that some of the blood relatives of schizophrenic adoptees exhibited some symptoms of schizophrenia, such as social isolation, suspiciousness, eccentric beliefs, and magical thinking, even though they did not have full-blown schizophrenia. These symptoms are part of what is now called schizotypal personality disorder. Kety and his colleagues did not possess modern understandings of working memory, but it would have been interesting to know whether their sample also exhibited the cognitive abnormalities now documented in some relatives of people with schizophrenia. Overall the schizotypal symptoms are thought to be a mild, nonpsychotic form of the disease.

More recently, unaffected monozygotic twins and even siblings of patients with schizophrenia have been found to exhibit some neuroanatomic abnormalities similar to those with the disease. In one magnetic resonance imaging (MRI) study monozygotic twins discordant for schizophrenia had similar deficits in the dorsolateral prefrontal cortex and superior temporal gyrus.

Studies by Irving Gottesman of extended pedigrees of Danish patients with schizophrenia also support the importance of genes. Gottesman noted the correlations between the risk of schizophrenia in relatives and the percentage of the total genetic material each relative shared with the patient. He found a greater lifetime risk of schizophrenia among first-degree relatives (parents, siblings, and children, who share 50% of the relatives’ DNA sequences) than among second-degree relatives (aunts, uncles, nieces, nephews, and grandchildren), who share 25% of their DNA sequences with the patient. Even third-degree relatives (who share only 12.5% of the patient’s DNA sequences) were at higher risk for schizophrenia than the 1% of the population at risk for this disease (Figure 62–1).

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