Since the first edition of this book was published in 1974, there has been little change in our ability to diagnose schizophrenia. We now have greater consensus on the diagnostic criteria (DSM-III, DSM-IIIR, and DSM-IV) we have standardized interviews to reliably apply these criteria. Even with this increased precision, however, the diagnosis is still solely based on history and observation; we do not yet have a laboratory test that can confirm the diagnosis of schizophrenia.
In the early 1970s schizophrenia was the common label for any psychosis. In the U.S., DSM-II (1968) embodied diagnostic criteria that were much broader than European criteria (Hordern et al., 1968; Kendell, 1975). Consequently, schizophrenia was the most common diagnosis for acutely psychotic patients being treated on the newly emerging general hospital psychiatric units. It later became apparent that many of these psychotic patients were not schizophrenic. Many other causes of psychosis emerged: affective disorder, drug reactions, head trauma, seizure disorders, encephalitis, and metabolic disturbances can all mimic schizophrenia. The recent DSM editions have narrowed the definition of schizophrenia and currently we apply the schizophrenic label to a much smaller group of patients, but there is still great variability in probable etiology within this group.
Quite dissimilar patients can meet the current diagnostic criteria for schizophrenia.
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Is it valid to compare a patient whose onset of symptoms occurred at the age of 15 with one whose onset was at age 35; one who has always had positive symptoms with one who has always had negative symptoms; a patient who shows great disorganization and confusion to a patient with a fixed delusion who is otherwise well organized; someone who has never needed or been given any psychopharmacologic agent with someone who has been treated with many different antipsychotic drugs; a patient with birth complications with who had no birth complications; a patient whose cerebral ventricles are enlarged with a patient whose cerebral ventricles are normal? When one considers the variability of the clinical features patients who can fit under the rubric of “schizophrenia,” it is no wonder that the research findings vary. This leaves many studies to conclude that “these findings are valid for a subgroup of schizophrenic patients.” American psychiatry's recent attempts at diagnostic rigor are a vast improvement and have brought us into closer agreement with our colleagues in other countries. Our diagnostic criteria are still basically descriptive, however, and real diagnostic vigor will come only with either biologic or etiologic criteria.
Despite these diagnostic problems, there was an enormous amount of research on schizophrenia during the 1990s, often with conflicting results. There was renewed interest in the gross and microscopic anatomy of brains schizophrenic patients. Although no definitive anatomic area of dysfunction has been identified, abnormalities in the frontal lobes and the hippocampus have been described (Bogerts and Falki, 1995). Molecular neurobiologists have made major advances in defining the neurotransmitter systems of the brain but no specific neurotransmitter defect has been definitively linked to the disease, though the roles of dopamine and glutamate in the disease are becoming clearer (Olney Farber, 1995, Carlsson, 1988). Similarly, there have been many sophisticated genetic studies of schizophrenic families, but no specific gene for schizophrenia has yet been isolated.
In published work over the past decade, there has been less emphasis on psychopathological description. Now the clinician only needs to look for the symptoms required by DSM-IV to make a diagnosis of schizophrenia. There has also been less emphasis on the classical subtypes of schizophrenia (hebephrenic, paranoid, etc.), in favor of dividing schizophrenics into those with positive and negative symptoms (Table 3-1). Although several new antipsychotic drugs have been developed, treatment remains symptom oriented rather than curative.
Schizophrenia is a very complex illness and the answers will not be simple. We do have a better understanding of how the antipsychotic medications work. We also have an intriguing emerging glutamatergic hypothesis that possibly explains some of the clinical phenomenology schizophrenia. And at last we seem to have research methods that match the complexity of the illness.
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Table 3-1 Symptomatic Diagnostic Criteria |
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Clinical Features
Schizophrenia occurs in approximately 1 percent of the population worldwide. The first symptoms usually develop in late adolescence. The primary symptoms are disorganized thinking, delusions, hallucinations, and deteriorating social function. These symptoms usually persist leading to a chronic course (Table 3-2).
In most classifications of schizophrenia, thought disturbance is considered a fundamental symptom. Though all patients may not manifest a specific type of thought disorder to warrant the diagnosis, some defect in cognition must be present during the course of the illness. Certainly one could consider hallucinations and delusions as disturbances of thinking; however, to classify them such fails to make the distinction between a disturbance of the formal aspects of language structure and a perception or thought that is not consensually validated. A patient with paranoid delusions can appear both coherent and logical but yet be quite delusional. Hallucinations and delusions refer more to perceptions or thoughts that lack consensual validation. It is not usually difficult to recognize delusions and hallucinations, but other types of conceptual disorganization in schizophrenics are often more difficult to grasp (Andreasen, 1979; Taylor and Abrams, 1984).
Bleuler (1950) defined the thought disorder of schizophrenia as loose associations. Loose associations were essential for establishing a diagnosis of schizophrenia. Loosening of associations means an absence normal connections between expressed thoughts. Bleuler gave an extreme example of this symptom. “My last teacher in that subject was Professor A. He was a man with black eyes. I also like black eyes. There are blue and gray eyes other sorts too. I have heard it said that snakes green eyes. All people eyes” (Bleuler, 1950). In a milder form, the patient's thought pattern may not immediately appear to be abnormal, but after 10 or 15 minutes of conversation, one may not be quite sure what the patient is talking about or how he arrived at a particular point. If the examiner then pays attention to associative pattern, he or she will find that the patient is constantly switching from one topic to another, often introducing new ideas that are unrelated to what has gone before.
In DSM-IV derailment means the same thing as loose associations. Incoherence, another manifestation of thought disorder, means that the person's speech is incomprehensible, almost a word salad, with little meaning. At times the speech of schizophrenics is so disorganized that it has an almost aphasic quality, with many word finding difficulties, and neologisms (Critchley, 1964). Faber et al. (1983) explored this by comparing the verbal behavior of schizophrenics with that of aphasics. Although observers were able to distinguish the two groups, there was some overlap. Paraphasic (word finding) errors were equally present in both groups, but the schizophrenics showed more illogicality, loose
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associations, and complex word usage. By giving tests for aphasia to chronic schizophrenics, Goren et al. (1996) were also able to show some similarities between the two disorders.
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Table 3-2 Follow-up Studies of Schizophrenic Patients |
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Another abnormal pattern of thought that has been characterized as fundamental to schizophrenia is overinclusion. This refers the patient's apparent failure to exclude from his consciousness competing, contradictory, or merely irrelevant thoughts so that his thinking is encumbered with ideas that are insufficiently connected to his main train of thought (Cameron, 1963). Overinclusion, in our view, can be placed under the rubric of loose association.
Another defect in the thought patterns of schizophrenics lies what has been called the abstract-concrete dimension. The Russian psychologist Vygotsky felt that schizophrenic thought disorder essentially represented a loss of the ability to think abstractly and a tendency toward concreteness (Vygotsky, 1962). Concreteness has been defined as an attitude that is determined by and cannot proceed beyond some immediate experience, object, or stimulus (Mayer-Gross et al., 1969). From his work on patients with brain injuries, Kurt Goldstein developed a similar concept of the “concrete attitude,” which be applied to problem of schizophrenic thinking. Goldstein believed that many of the peculiarities in the behavior of schizophrenics became understandable when they were considered an expression of abnormal concreteness (Goldstein, 1944). He was quick to point out, however, that the level and type of concreteness is not identical with that seen in neurological cases, primarily because of the intrusion idiosyncratic and personalized ideas in schizophrenic thinking (Goldstein, 1958). Not all schizophrenics seem to be concrete or literal, and some patients, especially those with markedly paranoid features, have even been described as overly abstract.
Among the most striking of the abnormalities thought and speech in schizophrenics is the idiosyncratic, personalized, and often bizarre character of their verbal expressions (Harrow et al., 1972; Tucker and Rosenberg, 1975). When it is bizarre, this quality is easy to notice, but it may be subtle and become apparent only during a formal mental status examination. The part of the examination that is especially useful for this purpose proverb interpretation and discernment of similarities and differences. For example, when asked the meaning “People in glass houses should not throw stones,” one of our patients replied, “Because people would see me in my house and throw stones at me.” Another, when asked the similarity between an apple and an orange, said, “An is round and symbolizes perfection but none of us can be perfect.” In these responses one can see aspects of many the disturbances thinking mentioned above. During the mental status examination, one may be able to determine not only personalized, bizarre, and idiosyncratic concept formation in schizophrenics but also abnormal concreteness, loose associations, and overinclusive thought. Obviously, there is much overlap in these descriptions of schizophrenic thought
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patterns. When examining for schizophrenia it is important to use several proverbs and similarities, since abnormal responses may occur only after several adequate answers. Disjointedness, idiosyncrasy, and bizarreness seem to be more characteristic of schizophrenia than any other psychiatric or neurological condition. If this type of thinking is present, one must suspect schizophrenia.
The other “fundamental” symptoms described by Bleuler are not only still observed, but also pertinent to understanding the clinical phenomenology. He felt that disturbances of affect, ambivalence, and autism were also characteristic of schizophrenic patients, but we now realize are also common to many psychotic and brain damaged patients. Affect in schizophrenics is classically described as flattened:emotional expression is absent or its range limited. This is found to be true more frequently in chronic patients; acute schizophrenic breaks, it is uncommon. The affect may also be inappropriate in that a patient can tell a happy story and appear sad or vice versa.
Ambivalence is the capacity of schizophrenic patients to feel intense contradictory emotions at the same time, for instance, to express both hate and love for a person in almost the same breath: “I hate that Dr. X and want to strangle him, that wonderful man who saved my life.” Neither ambivalence nor flattened affect is consistently present in schizophrenia; therefore, we do not feel that either is necessary for diagnosis.
Bleuler defined autism as a break with external reality, in which the patient becomes preoccupied with his inner life. External events may become so blended with subjective feelings or fantasy that the patient sees them as relating specifically to him; at this point such symptoms could be called delusional or hallucinatory, an example is the patient thinks that the people in television show, that all the patients in the day room are watching, commenting on his behavior and specifically telling him what to do. Autism in schizophrenics appears to be a behavioral result of thought disorder.
Age at Onset and Gender
Schizophrenia is primarily a disease of young people. Kraeplin noted that most patients were under the age of 35 at the time of diagnosis, a finding that has been confirmed in many studies. The first clear-cut symptoms appear before the age of 25 in 50 percent of the cases; onset after the age of 40 is unusual (Kraeplin, 1925). Although Jeste and colleagues (Jeste et al., 1995, 1998) have described a group of patients (most frequently women), with history good social functioning, who had their first episode of schizophrenia after the age of 45. This late-onset schizophrenia seems unrelated to any dementing process or cerebral insult. These patients meet all the diagnostic criteria for schizophrenia.
Symptoms of schizophrenia rarely begin in the first decade, but when they
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do, they virtually always occur in the latter half, seldom before the age of 5. Childhood schizophrenia has often been confused with infantile autism; a condition that usually begins in the first year of life and that always appears before age 5 (see p. 162).
Recent studies of schizophrenia have also delineated interesting gender differences. Szymanski et al. (1995) reported that the onset of schizophrenic symptoms tends to occur between the ages of 15 and 25 in men and between ages of 25 and 35 in women. They also presented evidence that the course the illness is milder in women. Men seem to have poorer outcomes, higher relapse rates, and more hospitalizations. These gender differences are interesting findings in light of recent studies that have shown consistent neural differences by gender. Shaywitz et al. (1995) have shown that women have more diffuse neural networks for language. Harasty et al., (1997)demonstrated that women's temporal lobes have larger volumes than men's do. There is also a whole range of well-known neuroendocrine differences.
Changing Diagnostic Criteria and Symptomatic Classifications
In 1980, the publication of the American Psychiatric Association's Diagnostic and Statistical Manual III (DSM-III) made the diagnostic criteria very specific, but the symptoms used were not new. From Table 3-1 it is clear that symptoms used to establish the DSM-III diagnostic criteria were a mixture of the diagnostic symptoms used by Krapelin, Bleuler, and Schneider. In 1987, DSM-IIIR changed the diagnostic criteria again, reducing requirement that acute schizophrenic symptoms be present from 1 month to a single week. DSM-IIIR also did away with the criterion that onset of illness had to occur before age of 45 years. In 1994, DSM-IV returned to the 1-month acute phase criterion and added negative symptoms to the positive ones. These rapid changes in diagnostic criteria not only highlight the descriptive and arbitrary nature of the diagnostic process but also make it hard to compare research using diagnostic criteria developed at different times.
The historical diagnostic subtypes of schizophrenia (hebephrenic, catatonic, undifferentiated, etc.) have proven to be of little clinical utility. A symptomatic distinction that does seem to have some clinical value has been the categorization by positive and negative symptoms (Table 3-1). Negative symptoms are characterized by an absence of affect and few verbal productions. Patients with positive symptoms have hallucinations, delusions, and the more vivid florid symptoms (Andreasen, 1982; Andreasen and Olsen, 1982; Andreasen et al., 1995;Buchanan and Carpenter, 1997). This distinction is similar to the older and well-studied concept of process and reactive schizophrenia, with the process
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schizophrenic having a preponderance of negative symptoms and a poor prognosis and the reactive having the more florid positive symptoms with a better prognosis (Phillips, 1953; Kantor and Herron, 1966). Both of these symptomatic distinctions recognize the difficulty in treating patient's negative symptoms. The positive symptoms have always seemed more amenable to antipsychotic treatment than the negative symptoms. Recently, however, investigators have observed that the new atypical antipsychotic medications are wholly or partially effective for the treatment of negative symptoms (Buchanan et al., 1996; Rosenheck et al., 1997). (The term atypical is used for the recently developed antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, sertindole, and ziprasidone, whose mechanisms of action seem somewhat different from the older neuroleptics. These new atypical drugs have fewer extrapyramidal side effects, and are weak D2 antagonists.) However the positive negative distinction may be artificial. It is not clear if positive (reactive) or negative (process) symptoms represent something about schizophrenia, psychosis in general, or brain damage. At some point in their illness, the same schizophrenic patient can manifest either predominantly positive or negative symptoms; and many schizophrenic patients will have both types of symptoms during the same episode illness (Carpenter, 1992). Negative symptoms have also been observed in patients with Alzheimer's disease who are not psychotic (Reichman et al., 1996). A recent study by Ratakonda et al. (1998) of a large sample schizophrenic and nonschizophrenic psychotic patients (n = 412) has shown great overlap in both positive and negative symptoms in both groups. Consequently the effectiveness of the new atypicals for negative symptoms may simply represent another nonspecific effect of these drugs in the treatment psychosis.
Schizoaffective Disorder
The term schizoaffective is used to indicate the presence of both schizophrenic and affective symptoms that meet the DSM-IV criteria for schizophrenia and affective disorder (DSM-IV 1994). How this disorder relates to either schizophrenia or bipolar affective disorder is still in question. There are indications that it is primarily an affective disorder (Pope et al., 1980; Winokur, 1989). From a study of 39 schizoaffective patients, their family histories, and first-degree relatives, Clayton et al. (1968) found more affective disease in the families and concluded that schizoaffective disorder is a genetic variant of affective illness. This conclusion was supported by data from a review of 420 twin pairs selected from military veterans in which one or both twins were psychotic (Cohen et al., 1972). The concordance rate for schizoaffective disorder in this group was the same as that for manic-depressive illness (50%) and more than twice as high as that for schizophrenia.
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Clayton (1982) noted that the manic schizoaffective cases seemed more of a variant of bipolar disorder (perhaps a more severe form). The depressed cases seemed more heterogeneous, consisting of both depressed schizophrenics and patients with primary affective disorders. Schizoaffective patients are less successfully treated than typical bipolar patients (Strakowski et al., 1999) and the psychosis in a group of schizoaffective patients persists despite treatment compared to the psychosis of typical bipolar patients. The difficulty in successfully treating schizoaffective symptoms places the condition closer to schizophrenia.
Personality Disorders and Schizophrenia
Paranoid, borderline, avoidant (social inhibition), schizoid (a pattern of poor social contacts and little emotional expression), schizotypal (poor social contacts plus cognitive or perceptual distortions and eccentricities) personality disorders have been associated with schizophrenia. In a case-controlled study of 534 schizophrenics and 2043 of their relatives, Kendler et al. (1993) clarified this relationship. Schizotypal personality disorders have a strong familial link to schizophrenia. Paranoid, schizoid, and avoidant personality disorders are modestly but significantly associated with schizophrenia. Borderline personality disorder is not related to schizophrenia.
Some have classified these personality disorders (schizoid, schizotypal, paranoid disorders) as schizophrenia spectrum disorders. Thaker et al. (1993) found a much higher rate of schizophrenia and spectrum personality disorders in the relatives of schizophrenia spectrum personality disorders than in controls. These findings indicate that the schizophrenia spectrum disorders are probably genetic variants of schizophrenia and, like schizophrenia, are genetically transmitted.
Course and Natural History
Kraepelin's original clinical delineation of schizophrenia as a disease entity was made primarily on the basis of its poor prognosis; he postulated that schizophrenic patients manifested a consistently progressive deteriorating course over time without full recovery. Psychotic patients who recovered were not schizophrenic by definition. In recent years, this has been questioned. Manfred Bleuler, for instance, described several patterns of evolution the disease. One pattern, which varies in severity, is characterized by gradual deterioration over time, and another pattern is episodic. In the episodic course, complete or partial remissions are punctuated by acute exacerbation (Bleuler, 1968). Bleuler also noted that the milder chronic conditions have increased in frequency and that the severe
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chronic conditions have diminished. This trend has been observed by others, who also noted shorter psychotic episodes and less bizarre, generally more moderate symptoms (Grinker, 1972; Remar and Hagopian, 1972; Harding et al., 1987). Some of the investigators believe this change in phenomenology may be related to the increased use of psychopharmacological agents. Others feel that it represents less repression and greater tolerance of deviance in our contemporary society and take this as evidence that schizophrenia is a culturally determined disorder.
However, the actual symptoms seem to have changed very little. In a study of the charts of schizophrenic patients hospitalized in 1850 and 1950, only minor differences were noted in the symptoms and course (Klaf Hamilton, 1961). The most marked differences between the two groups were in the kind of delusions the patients had. Patients in 1850 tended to be preoccupied with religion, whereas patients in 1950 were more preoccupied with sex. The average age, the proportion of married to single patients, and the incidence mental illness in the patients' families were the same. Though hospital stays were twice as long in the nineteenth as in the twentieth century, percentages of cure in both centuries were the same. The remarkable similarity of the symptoms, family history, age of patients, and clinical course lends credence to the concept that schizophrenia is a disease of the brain rather than an individual response to environmental stimuli.
It is notable that Kraepelin studied his patients over a long period of time. Though many of these patients made short-term recoveries, they all ultimately deteriorated. Current data suggest that his prognostic view was unnecessarily gloomy (Huber et al., 1975; Ciompi, 1980;Harding et al., 1987). Harding et al. (1987) in a 30-year follow-up of schizophrenic patients, using DSM-III criteria for diagnosis and standardized rating scales, found that one-half to two-thirds had achieved improvement or had recovered. An interesting and unexplained empirical finding in the natural history of schizophrenia is an inordinately high death rate. Ciompi (1980) noted that the average mortality in his study group of schizophrenics was almost twice as high is expected in a normal population of the same age. This high rate of death in schizophrenics has been noted by others (Niswander et al., 1963; Tsuang et al., 1979; Schwab et al., 1988; Winokur and Tsuang, 1996).
One of the main obstacles to long-term prospective studies in this country is the strong tradition of divorcing hospital treatment from outpatient treatment. The hospital psychiatrist seldom follows his patient through into outpatient treatment. After discharge, the patients return to their homes, group homes or other community facilities, or to the streets in the metropolitan areas where attempts to establish outpatient treatment are made. Often all contacts with the patient are lost. This not only complicates patient care but makes good follow-up studies
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much more difficult. Table 3-2 is a summary of some the follow-up studies done over the years.
Various forms of psychoeducational treatment (a form patient and family education about the illness rather than a strict psychotherapeutic approach) have been reported to yield better outcomes for schizophrenic patients, preventing relapse and improving quality of life (Davis et al., 1993; Penn and Mueser, 1996). When 151 schizophrenics, who had been ill 6–10 years, were treated with a form of individual psychoeducational therapy and medication, only 29 percent had recurrent psychotic episodes resulting in hospitalization during the 3-year study period (Hogarty et al., 1997).
Differential Diagnosis
Differentiating from Other Psychiatric Disorders
It is often difficult on the basis of the clinical presentation alone, to accurately diagnose a patient during an acute psychotic state, particularly if this is the patient's first psychotic episode. If one took a 5-minute video tape of a patient with schizophrenia, mania, psychotic depression, or an other patient who has delusions and hallucinations it would be almost impossible to make the diagnosis from the video tape alone. The phenomenology of all acutely psychotic patients is very similar. The key factors in differentiating schizophrenia from other psychiatric disorders are the history of the illness, the demographics each condition, and the family history. For example with the manic patient there is usually a history of mood swings and alternating depressive manic episodes, with periods of normality between; the psychotic depressive is usually older and shows clear symptoms of affective disorder with mood congruent delusions. The young patient who is experiencing his first psychotic break poses the most difficult diagnostic problem. Often we must treat the psychosis symptomatically and follow the patient over a period of time before making definitive diagnosis. In a young patient with acute psychosis bipolar disorder, intoxication, drug with-drawal, metabolic encephalopathy, infection, seizures, thyroid disease, organ failure, and hypoglycemia are important considerations.
Brief psychotic disorders (DSM-IV) have the symptoms of schizophrenia for at least a day but for no longer than month. Many Europeans call such episodes hysterical or psychogenic psychosis. Hirsch and Hollender (1969) described hysterical psychosis as a “state marked by sudden and dramatic onset, temporarily related to a profoundly upsetting event.” Patients may have hallucinations and delusions, they may engage in unusual behavior; thought disorder is transient and circumscribed, affect is volatile rather than flat. The acute
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episode typically lasts 1 to 3 weeks and leaves no residual symptoms. Most clinicians have seen dramatic cases of this type, which are more common in some subcultures than in others, but the question arises as to the relation of these episodes to the psychotic disorders they resemble, especially schizophrenia. European psychiatrists make a clear distinction between schizophrenia and psychogenic psychosis.Stromgren (1974) describes psychogenic psychosis as follows: (1) the psychosis would not have arisen without some distinct mental trauma, which often makes it easy to understand the etiology. (2) There tends to be a psychological predisposition, of neurotic or psychopathic nature, to the reactions that represent hysterical psychosis, but no genetic relationship with schizophrenia exists. (3) There must be a close temporal relation between the onset of trauma and of psychosis, and the psychosis often ends shortly after the trauma does. There are no residual symptoms. Hysterical psychosis takes three common forms: (1) emotional reactions that are usually depressive, (2) alterations of consciousness or clouded states (see Chapter 6, pp. 97–98), and (3) paranoid states and delusions. These conditions can be distinguished from schizophrenia by applying the diagnostic criteria for the latter.
Neurological Diseases
Any disease of the central nervous system or disruption its function (e.g., by drugs, sleep deprivation, etc.) may cause behavioral manifestations that mimic schizophrenia. The differential diagnosis rests heavily on the type of symptoms present, the mode of onset, family history mental illness, medical history, and the clinical course (Yudofsky and Hales, 1997; Tucker, 1997, 1998).
Schizophrenia is not the only condition that can cause disturbances of thinking, though schizophrenia, affective disorder, and drug-induced psychoses are by far the most common causes of such symptoms in young adults. Because its high incidence, there is a strong temptation to make the diagnosis of schizophrenia whenever a young person develops serious cognitive disturbance. Schizophrenia-like episodes, however, have been described in association with other psychiatric disorders and with other neurological conditions such as cerebral trauma, tumor, encephalitis, presenile degeneration and other degenerative diseases of the gray and white matter, narcolepsy, vascular disorders, and a host of metabolic or toxic disorders, such as endocrinopathies, cerebral anoxia, and hypercapnia (Davison and Bagley, 1969). Though psychoses are commonly seen in these conditions, they rarely mimic the symptoms of schizophrenia exactly; the disorientation, memory deficit, confusion, and fluctuating states of consciousness that are characteristic of some neurological diseases seldom encountered in schizophrenia. The difficulty differentiating schizophrenia from neurological conditions arises mainly in the initial onset of neurological disease.
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Most neurological diseases will either progress to overt symptoms or else clear up completely. So our comments deal mostly with diagnostic problems of acute onset. The mistake often made by inexperienced clinicians is to label as schizophrenic any bizarre, delusional, or mute behavior that cannot be easily explained by a familiar medical condition. Clinicians faced with delusions and hallucinations, often overlook such overt signs of disorientation, dysmnesia, tremor, myoclonic jerks, Babinski reflexes, and asterixis or other clear evidence that the disorder is neurological.
In addition to disorientation and dysmnesia, there are a few simple guidelines for the differentiation of acute neurological disease from classical schizophrenia. In the former there are usually: (1) A good premorbid social history. The patient does not have problems at work and his family is generally warm supportive rather than disturbed, as is so often the case in schizophrenia (Wynne, 1968). Sociability is characteristically preserved in most neurological disorders until a very late stage of deterioration, long after disorientation and dysmnesia have appeared. In schizophrenia, early loss of sociabiliy is common. (2) An abrupt change in personality, mood, and ability to function at work at home of less than 6 months' duration. The abruptness of the onset such symptoms supports a neurological cause. (3) Rapid fluctuations in mental status. The patient has a clouded sensorium and is disoriented one day, then completely oriented the next. Though fluctuations can also be seen in some schizophrenics, they are generally not so rapid. Even when the schizophrenic's mental status seems to clear suddenly, he will still show some signs of bizarre behavior or delusional thinking. Marked fluctuations in mental status are, in general, more characteristic of acute neurological disease than schizophrenia, but this is not necessarily true of chronic neurological disease. The fluctuations in mental status of neurological patients may also be accompanied by fluctuating motor behavior. The patient may display aggressive impulses and engage in assaultive behavior at one moment but at the next apologize profusely and try to befriend the people be has just abused. The mode of behavior during this period frequently has a driven quality to it, as has been described in brain-injured patients by Goldstein and Scheerer (1941) and Kahn (1934). (4) A patient with an acute neurological problem is usually unresponsive to psychiatric intervention, whether psychotherapeutic or pharmacological. Rather than controlling behavior, psychophar-macological agents may precipitate a stuporous or comatose state depending on the underlying condition.
Many patients who present with bizarre behavior and mute states are shunted immediately to the psychiatrist. Even major neurological signs can be over-looked or interpreted as part of the patient's “functional” disturbance. It goes without saying that marked behavioral aberrations should not blind clinicians to neurological symptoms.
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Drug Reactions
Symptoms suggesting schizophrenia are commonly seen in patients who have taken amphetamines, cocaine, LSD, mescaline, ketamine, and belladonna alkaloids. Hallucinations and psychosis may also accompany alcohol barbiturate withdrawal. These states of intoxication and withdrawal may cause a psychosis without major disorientation (though this is rare) as well any of the physical changes seen in the neurological impaired. The presence of visual hallucinations, however, should always suggest the possibility of a drug reaction or toxic metabolic encephalopathy. Formed visual hallucinations are unusual in schizophrenia and in diseases that affect the macroscopic structure of the brain (e.g., brain tumors). Auditory hallucinations, however, are common in schizophrenia and unusual in drug reactions.
Sleep Disorders
Prolonged inability to sleep may produce disorganized thought patterns and even such major distortions of reality as illusions, delusions, and hallucinations. It is possible that this happens only in individuals with a schizophrenic predisposition. Resumption of a normal sleep pattern in such individuals will resolve their symptoms quickly. Residual thought disorder persists in most schizophrenics even after normal sleep has been restored (Berger and Oswald, 1962).
Biologic Basis of Schizophrenia
Early editions of this book properly emphasized the genetic and neurological findings in schizophrenic patients to make the case that schizophrenia was a disorder of the brain. At that time the identification of schizophrenia with brain was controversial; many conceptualized schizophrenia as primarily a “psychological” reaction to an abnormal environment, a view that is no longer respectable. We now look at the genetic and neurological findings in schizophrenia as clues to the etiology of this disorder and no longer argue about whether such findings exist.
Genetics
The incidence of schizophrenia in the general population is approximately 1 percent. The data obtained in epidemiological surveys of schizophrenia different countries and cultures are similar, all investigators agree that the incidence is increased in families of schizophrenics and is highest their first-degree relatives. The rate is roughly 10 to 15 percent in the parents, siblings,
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and children of schizophrenics. This consistency is remarkable considering the differences and imprecision of the various diagnostic criteria applied.
There have been many twin studies of schizophrenia in the U.S., the U.K., Japan, Germany, and Scandinavia. In all but one (Tienari, 1963), the incidence of schizophrenia is much higher in monozygote than dizygotic twins of schizophrenics (Gottesman and Sheilds, 1982; McGuffin et al., 1995). The overall incidence of schizophrenia in the monozygotic twins schizophrenics is 61 percent. In the dizygotic twins studied, there was a 12 percent concordance rate. These figures do not change in twin studies that use more modern diagnostic criteria (DSM-III and IIIR) for schizophrenia (Farmer et al., 1987; Onstad al., 1991).
Another approach to testing the environmental hypothesis was taken in a study of the psychosocial adjustment of 47 adults born to schizophrenic mothers and permanently separated from their mothers in the first few days of life (Heston, 1966). They were compared to 50 control adults with nonschizophrenic mothers who had also been permanently separated from their natural mothers in the first few days of life. The comparison was based on a review school, police, army, and hospital records, plus a personal interview and personality testing using the Minnesota Multiphasic Personality Inventory (MMPI). Social-class determinations and IQ testing were also done, three psychiatrists independently rated the subjects. In this study, schizophrenia was significantly more prevalent in the individuals born to schizophrenic mothers. Of 47 persons with schizophrenic mothers, 5 were schizophrenic. No cases of schizophrenia were found in the 50 control subjects. The age-corrected rate for schizophrenia in the experimental group was 16.6 percent, a finding consistent with that of all the family studies that had been done on children raised by schizophrenic biological parents. In addition, serious psychosocial disability, that is, psychiatric diagnosis other than schizophrenia was found in approximately half of the persons born to schizophrenic mothers. An increased incidence of schizophrenia-related personality disorders has also been noted in the families of schizophrenic patients (Kendler et al., 1985). Many had been discharged from the armed forces for behavioral reasons; others had police records or a history of alcoholism. The diagnosis sociopathic personality was more than 4 times as common in the experimental group, in which 5 times as many persons spent more than 1 year a penal or psychiatric institution.
These findings were substantiated by an independent study (Kety, 1976). In this study, 364 first-degree relatives of 33 schizophrenic adoptees and controls (nonschizophrenic adoptees) living in Copenhagen, Denmark, were interviewed by a man who did not know the relationship of the person he was interviewing to the adoptee. In almost all cases, the relative being interviewed did not know of the relationship or the adoptee's diagnosis. From summaries of these interviews, three independent raters made a psychiatric diagnosis. After consensus
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was reached among these three psychiatrists, the subjects were divided into four groups: biological or adoptive relatives of schizophrenic index adoptees (two groups) and biological or adoptive relatives of control adoptees (two groups). The prevalence of schizophrenic illness (chronic schizophrenia, latent schizophrenia, and uncertain schizophrenia) in subjects genetically related to the schizophrenic index cases was 13.9 percent. The prevalence of schizophrenic illness among the adoptive relatives of schizophrenics was 2.7 percent, and it was 3.8 percent in all subjects not genetically related to a schizophrenic index case. The difference between the group genetically related to the schizophrenic index cases and the group not so related is highly significant. These relatives did not differ from the rest, however, with regard to mental illness other than schizophrenia. This study was replicated in the entire population of Denmark 1994 with similar results (Kety et al., 1994; Ingraham and Kety, 2000) in Finland (Tienari et al., 2000).
Although molecular genetic techniques hold much promise for unraveling the genetic basis of schizophrenia, the results to date molecular approaches have not been conclusive. Neither association studies nor linkage studies have identified a specific genetic locus for schizophrenia. Suggestive sites that have been implicated but only variably replicated include the short arms of chromosomes 6 and 8, the long arm of chromosomes 2, 11, 22 as well as the X and Y chromosomes; and the HLA region of 6p. Attempts to locate specific defects in the chromosomal areas of genes that control neurotransmitter systems such as dopamine have also been inconclusive (Kendler, 1999).
Molecular genetics demands a precise identification of the disorder to be studied. Perhaps we do not yet have this precision in the study of complex behavioral disorders. In Huntington's disease, an autosomal dominant disorder for which the exact genetic defect has been identified, several different psychiatric syndromes can occur during the illness, ranging from affective to schizophrenialike symptoms. Jason et al. (1997) have shown that although the severity of the cognitive decline and early onset of Huntington's disease is related to the number of trinucleotide repeats (CAG) on the Huntington's gene, the number of repeats was not associated with the varied psychiatric manifestations seen in Huntington's that is, the patients with more repeats were not more or less likely to be psychotic as their dementia progressed (Zappacosta et al., 1996). Similarly, the newly described Velo-cardio-facial syndrome has been associated with schizophrenia, bipolar disorder, and attention-deficit hyperactivity dsiorder (ADHD) and is clearly related to a deletion on chromosome 22q11 (Lachman et al., 1996). The deletion of this chromosome leads to a lack catechol-omethyltransferase, one of the enzymes that catabolizes dopamine. Varied psychiatric manifestations have also been noted in the fragile X syndrome (Levitas, 1996). It is possible that what is genetically transmitted a general predisposition to psychosis or behavioral disorder that could be modified by the individual's
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environment (Kendler et al., 1985, 1997; Cloninger, 1994; Crow, 1994) or other genes that modify behavior. Erlenmeyer-Kimling et al. (1995, 1997) studied the offspring of patients with schizophrenia and found many unspecified psychotic conditions and affective psychoses in them.
A recent postmortem study examined the brains of 15 patients with schizophrenia, 15 with bipolar disorder (11 psychotic), nonpsychotic unipolar depression, and 15 controls. Compared to the controls the nonpsychotic bipolar and unipolar depressed patients, the psychotic patients, both those with schizophrenia and bipolar disorders, had 50 percent reduction in the messenger RNA for reelin and glutamate decarboxylase in the prefrontal cortex. Reelin is a large intracellular lipoprotein that is involved in the develoment of architectonic patterns in hippocampus and in cortex seems to be involved learning and the early growth and development of neuronal architecture (Guidotti et al., 2000). Reduction in reelin and glutamate decarboxylase may represent genetically transmitted nonspecific factors that lead to a vulnerability psychosis; this vulnerability, interacting with other genetic disorders, may produce a variety of diseases, such as schizophrenia, bipolar disorder, Huntington's disease, etc.
In summary, there is a clear genetic component in schizophrenia. The risk increases with the number of relatives already affected. McGuffin et al. (1995) noted that the risk of becoming schizophrenic increases from 9 percent to 16 percent when both a parent and sibling have the disorder. The risk is slightly higher than 10 percent if the mother alone is schizophrenic and developed the condition early in her adolescence. The risk is even higher (46%) when both parents have the disorder. Still, 60 percent of schizophrenics do not have first- or second-degree relatives with the disease. (Bleuler, 1978). The most credible contemporary hypothesis at this stage is that what transmitted a predisposition or vulnerability to develop schizophrenia; also required are the presence of other genes and environmental factors to produce the illness (Kendell, 1991; Maier et al., 1993; McGuffin 1995).
Biochemical Findings
Molecular biology has greatly expanded our capacity to identify and to localize neurotransmitter receptors in the brain specific anatomic areas, and it has considerably amplified our view of the complexity the central nervous system. Instead of one dopamine receptor, for example, at least five have been identified, conveniently titled D1–D5; as many 15 serotonin receptor subtypes have also been identified (Cooper et. al., 1996). The fact that most of the agents that are effective in treating schizophrenia block dopamine has led to the hypothesis that schizophrenia is related to an excess of dopamine (Breier, 1996).
The anatomic localization of the dopamine receptors is consistent with the functional imaging and neuropathologic abnormalities described in schizophrenia.
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The five postsynaptic dopamine receptors are distributed differently in the brain. In the brain the D1 receptors are found chiefly in cortex; D2 receptors are prominent in the striatum (presumably the source of drug induced Parkinsonism and other extrapyramidal symptoms caused by dopamine receptor blocking drugs); the D3 and D4 receptors are found mainly in the limbic system; and D5 receptors are mainly in the hippocampus and to some extent thalamus. Actually, all five dopamine receptors have some representation in the thalamus and hippocampus. There are three major pathways taken by the dopaminergic axons whose terminals lead to dopaminergic receptors. All three dopamine pathways originate from cell bodies in the substantia nigra the midbrain's ventral tegmentum. The first set projects to the caudate and putamen (nigrostriatal); second set to the medial prefrontal, cingulate, and entorhinal cortex (mesocortical); and the third projects to the septum, nucleus accumbens, amygdala, olfactory tubercle, and piriform cortex (mesolimbic). There are also localized sites of dopaminergic neurons in the olfactory bulbs, the pituitary, and the hypothalamus.
Evidence that schizophrenia derives from excessive sensitivity to dopamine is inferential. Most antipsychotic drugs block D2 receptors. Direct evidence for dopamine hyperactivity in schizophrenia has been minimal. An increased quantity of D2 receptors has been reported in the postmortem brains schizophrenic patients. This has been presumed to be the basis for excessive dopaminergic function in schizophrenia (Cooper et al., 1996). The increase, however, D2 receptor density may well be the result of neuroleptic use in the patients rather than the primary cause of the illness. The fact that clozapine, an effective antipsychotic drug, has its primary action on the D4 receptors and almost none on the D2 receptors raises a question about the role of the D2 in mediating psychosis.
Actually, clozapine has at least some blocking action at all five of the dopamine receptors, as well four of the serotonin receptors. Serotonin excess has been proposed as an alternative cause of schizophrenia. The major serotonin receptors fall into three classes: those that use protein G transduction as a second messenger, those that use phosphoinositol transduction, and those that iongated channel transduction. Serotonergic neurons send their axons over two major pathways in the brain originating from the raphe nuclei, where their cell bodies are located. One projects from the dorsal raphe to the cortex and striatal regions, and the other from the median raphe to the limbic regions (Kapur et al., 1996). Serotonin neurons tend to inhibit dopamine neurons. Blocking serotonin might improve a postulated dopamine hypofunction in the prefrontal areas by disinhibiting the dopamine neurons. The beneficial effect of the atypical antipsychotic drugs on the negative symptoms of schizophrenia has been thought to result from the frontal lobe stimulation that serotonin blockade produces. This concept questions the hypothesis of schizophrenia being related to a hyperdopaminergic state. The fact that clozapine is also a potent antagonist of adrenergic,
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muscarinic, and histaminic systems also potentially implicates these neurotrans-mitters in the drug's therapeutic actions and in systems that may be altered schizophrenia.
Although some studies have shown increased norepinephrine levels in schizophrenic patients, it has been difficult to separate these levels from the possibility of a secondary stress-induced reaction (Litman and Pickar, 1996). There is some evidence that an experimental alpha-2 adrenergic blocking agent may improve treatment response (Litman and Pickar, 1996). Some have also postulated that the muscarinic cholinergic system may be important in establishing a balance with dopamine to ameliorate the positive symptoms of schizophrenia and that increased muscarinic activity in itself may intensify the negative symptoms of schizophrenia (Tandon and Greden, 1991). To complicate the picture even further, Sharma et al. (1997) presented rather convincing data indicating that low neurotensin levels in schizophrenia become elevated with antipsychotic drug treatment. It is clear that there are many systems that interact with dopamine; and it also clear that blocking dopamine receptors ameliorates many of the symptoms but does not cure schizophrenia. It is also likely that dopamine plays some role in the complex and dynamic biochemical processes that underlie schizophrenia.
Using similarities in the biochemical and clinical effects of pharmacologic agents, some have postulated a role for glutamate in schizophrenia. Glutamate neurons are located in the pyramidal cells of cerebral cortex, the granule cells of the hippocampus, and the pathways from the thalamus to cortex. All are areas in which abnormalities have been found the neuroimaging and neuropathologic studies of schizophrenic brains. Drugs that inhibit the activity glutamate neurons can reproduce many of the clinical symptoms schizophrenia and one of the most interesting of these is phencyclidine (PCP), a major antagonist of the glutamate NMDA receptor. Clinically, this produces a psychosis that is similar to schizophrenia, manifested by delusions and hallucinations and disorganization of thoughts and speech. When injected repeatedly into rat brains for 3 to 4 days, PCP and other NMDA antagonists, cause subtle, permanent neurodegenerative changes in the corticolimbic region. These changes and their distribution are very similar to those that have been described in postmortem studies of schizophrenic brains (Benes et al., 1991). The changes are age-dependent in that rats do not become susceptible to them until they are approximately 10 months of age. This has a human parallel, as children seem not to be as susceptible the psychotogenic effects of PCP as are adults.
On the basis of these observations, it has been proposed that schizophrenia could result from a genetic deficit of NMDA receptors. The clinical, behavioral, and cognitive disorganization and gating defects noted in schizophrenic patients are also evident in PCP-induced psychosis. Hypofunction of the excitatory glutamate NMDA receptors on inhibitory gamma-aminobutyric acid (GABA) neurons
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would have a net excitatory effect. When GABA neurons are not stimulated, there is less inhibition and hence more excitation. This might cause the cortical areas in which these neurons are located to lose their ability filter incoming information. This might be the cellular explanation for the clinical experience of the schizophrenic patient who describes being flooded with unmodulated information. Dopamine inhibits glutamate release and could also lead to disinhibition. Dopamine blocking drugs, by correcting this, could reverse psychosis (Olney and Farber, 1995; Coyle, 1996). The consideration of glutamate's role in schizophrenia has added another dimension to the complex biochemical state that schizophrenia seems to represent.
Neurological Abnormalities in Schizophrenic Patients
Minor physical and neurological abnormalities are commonly found in schizophrenia (Heinrichs and Buchanan, 1988). Although the effects of medication, malnutrition, and multiple electrical shock treatment may have something to do with these abnormalities they have been most often related to environmental influences such as perinatal trauma, prenatal infection, autoimmune disorders, and prenatal malnutrition (Susser, 1999). Abnormalities include minor motor and sensory (soft) neurological signs on physical examination, electroencepha-lographic abnormalities, changes in information processing, and organic patterns on psychological tests. All of these minor neurological findings no longer seem inexplicable or incidental in light of the recent histological and structural changes observed in the brains of schizophrenics. The question has now turned to the implications of these findings, e.g., do findings imply that schizophrenia is a neurodegenerative process, such as Alzheimer's, or is it more related to a prenatal maldevelopment process (Woods, 1998).
Minor, nonlocalizing neurological abnormalities
Soft signs have been noted in many studies of acute schizophrenic adult patients (Kennard, 1960; Larsen, 1964; Pollin and Stabenau, 1968;Rochford et al., 1970, Heinrichs Buchanan, 1988; Flashman et al., 1996; Arango et al., 1999; Karp et al., 2001) and adolescent schizophrenics (Hertzig and Birch, 1966, 1968). Rochford colleagues (1970) examined 65 hospitalized, untreated psychiatric patients for the presence of the following minor signs: (1) motor impersistence; (2) astereognosis; (3) agraphesthesia; (4) extinction during bilateral simultaneous stimulation; (5) excessive bilateral hyperreflexia; (6) coordination defects; (7) disturbance of balance and gait; (8) cortical sensory abnormalities; (9) mild movement disorders; (10) speech defects; (11) abnormal motor activity; (12) defective auditory-visual integration; (13) choreiform movements and adventitious motor overflow (tremor); (14) cranial nerve abnormalities, such as slight anisocoria, esotropia, auditory deficit, and visual field and retinal defects; (15) un-equivocally
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abnormal EEGs. He found neurological abnormalities in 36.8 percent of the psychiatric patients (all diagnostic groups). This was significantly different from an age-matched normal control population (5%). Neurological soft signs were found in 65.5 percent of the schizophrenic patients. By way of comparison, there were no soft signs in patients with primary affective disorders.
In 72.5 percent of schizophrenics, Pollin and Stabenau (1968) found at least one neurological sign. The most common neurological abnormalities in Pollin's schizophrenic patients were defects in stereognosis; graphesthesia; difficulty coordination, balance, and gait; tremor. There was also some difficulty in the integration of auditory-visual stimuli.
In several studies, not only has an increased incidence of soft signs in schizophrenic patients been observed, but also a high correlation between these signs and thought disorder, especially overinclusive thinking. The relation of neurological impairment to thought disorder is stronger than its relations the diagnostic category of schizophrenia (Tucker et al., 1974; Tucker and Silberfarb, 1975). The main tests for these neurological impairments were specific sensorimotor portions of the Halstead-Reitan battery (e.g., finger agnosia, fingertip writing, tactile form recognition, and the tactile performance test). Davies et al. (1975) found a high correlation of neurological soft signs and behavioral symptoms in schizophrenics, especially those with paroxysmally abnormal EEGs. Quitkin et al. (1976) found more neurological soft signs in schizophrenics with premorbid asocial behavior as well in individuals with emotionally unstable character disorders—two conditions that are generally chronic. Rosenbaum (1971) noted defects in schizophrenic patients with regard to weight discrimination and proprioception. He postulated that these defects are related to “insufficiently articulated proprioceptive signals… in schizophrenic persons.” The abnormalities he found can be considered soft signs, similar to those observed in the studies cited above.
Abnormalities in the frontal lobes and prefrontal cortex of schizophrenic patients and their nonschizophrenic relatives have been increasingly identified neuropsychological studies (Weinberger et al., 1986; Liddle and Morris, 1991; Goldman-Rakic, 1995; Park et al., 1995). An extensive review of motor and sensory abnormalities in schizophrenic patients by Heinrichs and Buchanan (1988) confirms their prevalence in 50%-65% of schizophrenic patients. They noted that the majority of these minor neurologic abnormalities are in the areas of integrative sensory function, motor coordination, and the sequencing of complex motor acts, i.e., executive functions usually associated with frontal lobe dysfunction. Flashman et al. (1996) observed a similar array of impairments in schizophrenic disorders unrelated to the cognitive disorders that characterize posterior brain functions (parietal, occipital, temporal). Hoff et al. (1999) has shown that these neuropsychological impairments are stable over the first 4–5 years of illness.
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Chatterjee et al. (1995) reported a 17 percent incidence of extrapyramidal signs in first-episode schizophrenic patients prior to any treatment with neuroleptics. The signs included akinesia, rigidity, cogwheeling, and even a case of dyskinesia; the patients with these signs were more likely to develop parkinsonian side effects with antipsychotics medications and seemed to have a poorer short-term prognosis with relation to the control of their psychosis. Choreoathetoid movements, indistinguishable from tardive dyskinesia, occur in 20 percent of schizophrenic patients before treatment (Buckley et al., 1996, 1998; Fenn et al., 1996).
Fish (1975) has described neurointegrative defects in infancy that she considers signs of dysregulation maturation in neurological systems that represent a biological continuum with schizophrenic disorders in later life. The prospective study of persons at high risk for schizophrenia, particularly the offspring schizophrenic parents, is an important area of research, not only for the evaluation of the role central nervous system but also for an understanding of the spectrum concept of schizophrenia (Campion and Tucker, 1973). Rieder et al. (1975) compared the offspring of schizophrenics with a matched control group to find a surprising increase in the incidence of fetal and neonatal deaths among the children of schizophrenics. This was confirmed by Walker and Emory (1983) but found not to be true in a British perinatal mortality survey for schizophrenic offspring; but they did note a higher mortality in the offspring from mothers with affective psychosis (Done et al., 1991).
The growing awareness of neurological abnormalities and reproductive problems in schizophrenia logically has led to consideration of the role of obstetrical complications in the abnormal neurodevelopment observed schizophrenia. With few exceptions (Sacker et al., 1995), studies bearing on this issue show a high prevalence of obstetrical complications in schizophrenics ranging from 21 to 40 percent (Dalman et al., 1999). Schizophrenic patients also have a high prevalence of general physical anomalies that imply congenital maldevelopement of the brain such as low set ears, and a high arched palate (Buckley et al., 1998). There is a clear relationship between maternal influenza, obstetrical complications, and the development of schizophrenia in the offspring, at an early age (Wright et al., 1995; Verdoux 1997).
The increased frequency of events known to produce brain injury, like obstetric complications, and the high prevalence of neurological abnormalities among schizophrenics suggests that brain damage can play a role in the etiology of schizophrenia. Some investigators argue that the birth complications and neurological abnormalities are caused by an already compromised fetus (Weinberger, 1995). Brain damage may also contribute to the severity of schizophrenia and may determine which carrier of the genotype becomes symptomatic. There is considerable data that the early onset group of schizophrenics has smaller cerebral volumes and lower IQs (Alaghband-Rad et al., 1997;Russell et al., 1997).
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Emphasizing the role of brain damage in the expression genetic psychosis, Kinney et al. (1998) and Zornberg (2000) have also noted that the birth histories of bipolar patients reveal many obstetrical complications.
The upshot of these studies is that we need to reexamine the idea that there are no localizing neurological findings in schizophrenia. When schizophrenic patients are tested, it is not uncommon to find deficits in motor and sensory function, in visual and auditory perception, verbal nonverbal memory, or in executive functions. All of these deficits indicate that there is some dysfunction of the frontal lobes in schizophrenia (Blanchard and Neele, 1994). Another indication of brain dysfunction, particularly in frontal lobe are the reports by Holzman et al. (1973) that abnormal smooth pursuit eye movements during pendulum tracking characterize schizophrenic patients and their families.Shagass et al. (1974) observed the same characteristic jerky eye movements but found they related more to psychosis in general than schizophrenia specifically. More recent studies found saccadic (jerky) eye movements during what should have been smooth pursuit in schizophrenics and their relatives (Thaker et al., 1996; Keefe et al., 1997; Lencer 2000). Visual tracking defects have become one of the most widely investigated phenomena in schizophrenic patients. These smooth pursuit defects may serve as an important biologic marker for schizophrenics as they occur in 50%–80% of schizophrenic patients and in 40 percent of their relatives. But they may not be as specific as once was thought given that similar defects have been also reported in affective disorders, obsessive-compulsive disorder (OCD), and in Parkinson's Alzheimer's diseases. In each of these disorders there is abundant independent evidence frontal lobe dysfunction (Hutton et al., 1998; Hutton and Kennard, 1998).
Aberrant vestibular function has been widely observed in schizophrenic patients. The vestibular system integrates sensation with motor functions and behavior. Studies made by 11 different groups over the past 50 years have all shown reduced nystagmus in schizophrenic patients response to caloric and rotational stimulation of the vestibular system (Ornitz, 1970; Myers et al., 1973). Whereas the reduced nystagmus response is directly related to duration of illness in many studies, the relation of vestibular alterations to schizophrenia remains unclear. In some studies auditory and visual hallucinations have followed pharmacological suppression of vestibular sensibility, but the possibility direct toxic effects of the drugs occurring elsewhere in brain was not ruled out (Tice, 1968). Prolonged use of psychotropic drugs may induce vestibular changes in chronic patients, which may obscure the association between vestibular defects and schizophrenia in recent studies. In the older studies, however, these psychotropic drugs were not used because they were yet available. The existence of these minor neurological abnormalities has led to theories that the behavior of schizophrenics reflects a disturbance the sensory integrative functions of the brain (Andreasen, 1999).
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Two experimental approaches have lent more credence to the idea of sensory dysfunction in schizophrenia. Braff et al. (1992, 1995) have used the startle reflex as a way of exploring sensory gating. In an experimental setting they gave schizophrenic patients a prestimulus acoustic noise followed by a loud acoustic or forceful tactile stimulus to create a startle response. This response is measured by eye blinks and changes in skin conductance. The prestimulus reduces or gates the amplitude of the startle response in normal individuals but not in schizophrenics, thus implying that the schizophrenics have deficits in adjusting, modulating, or controlling stimuli from the environment. This inability to modulate external stimuli could lead to cognitive disorganization and withdrawal under the bombardment of unfiltered stimuli from the environment. There is increasing evidence that schizophrenics have trouble in habituating to the effects of the startle, indicating that this is a persistent problem of sensory integration. The inability to integrate sensory stimuli (e.g., prioritizing and sorting external stimuli) is the type of defect that again implicates a disturbance in frontal lobe functions. Using evoked auditory potentials in a similar stimulus/prestimulus paradigm, Freedman et al. (1994, 1996) have shown that schizophrenics do not suppress the response to the second stimuli over time, indicating a defect in sensory gating or inhibition. Freedman has found similar gating defects in nonschizophrenic family members of schizophrenics, which means that this impairment may serve as a marker for genetic studies of schizophrenic patients (Young et al., 1996; Freedman et al., 1997). Interestingly, this particular gating phenomenon is partially mediated by cholinergic nicotinic receptors in the hippocampus, an anatomic area that has been identified as abnormal in histologic, neuropathologic, and imaging studies of schizophrenics (Bogerts Falkai, 1995; Leonard et al., 1996; Bunney and Bunney, 1999).
Braff et al. (1992, 1995) developed a rat model that shows great similarity to the sensory gating defect and the effects of doapamine seen in schizophrenic patients. With lesions in the premotor cortex and the hippocampus, the rats responded normally to startle stimuli, but when treated with a dopaminergic agonist, the lesioned animals manifested a gating defect. If the rats were lesioned in the neonatal period, gating defect was not evident until rat reached the postpubertal period (Lipska et al., 1995; Swerdlow et al., 1995). This be relevant to schizophrenia as the vulnerability it is genetic and presumably present from birth but the disease only becomes symptomatic in late adolescence.
The relation of the individual to environment is obviously very important to cognitive function. Gross disruptions of perceptual and sensory integrative functions produced by drugs and sensory deprivation regularly lead to psychoticlike states the symptoms of which can resemble those schizophrenia. It has long been known that people in such isolated situations as Arctic camps and solitary prison confinement, patients in iron lungs, and survivors at sea experience
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a variety of disturbing subjective alterations. In fact, any environment that is unvarying and that offers only a limited range of sensory stimuli can give rise to (1) difficulty in focusing and organizing thoughts, (2) illusions delusions, (3) a sharp sense of the need for variation in extrinsic stimuli, (4) distortion of the sense time passing, and (5) the hallucinatory experiences that occur during prolonged deprivation. These alterations are not limited to the period of deprivation but persist briefly after it has ended. Objects continue to appear to swirl, and shapes lines seem distorted (Solomon et al., 1957).
Electroencephalographic data
Most of the available data relating electroen-cephalographic (EEG) abnormalities to abnormal mental states are discussed in chapter 1. The EEG changes described in schizophrenia do not have a specific diagnostic or therapeutic significance. Reports of electroencephalographic abnormality in schizophrenic patients referred at random range from 5 to 80 percent, with an average of approximately 25 percent (Abenson, 1970); but the vagaries of EEG interpretation and the variability in diagnosing schizophrenia obscure the meaning of these data. Patients diagnosed as catatonic schizophrenics seem to show consistently higher rates of EEG abnormality, usually manifested as nonspecific slowing. Given that catatonic states are often acute and have a relatively good prognosis, one wonders if all cases so labeled are really catatonic schizophrenia. We have seen patients with seizures, toxic/metabolic encephalopathy, encephalitis, occult hydrocephalus, and left middle cerebral artery occlusion presenting with speechlessness, waxy flexibility, and other psychotic behavioral abnormalities; they were mistakenly thought to have catatonic schizophrenia. The result, a higher rate of EEG abnormality in catatonic schizophrenics, raises some question about the diagnosis (Liberson et al., 1958; Tucker et al., 1965). Still the increased prevalence of EEG abnormalities among schizophrenics in general seems well documented (Small et al., 1964; Treffert, 1964; Tucker et al., 1965). Studies using quantitative EEG's (QEEG) have been surprisingly few, however, a recent study demonstrated QEEG differences between schizophrenics with positive and negative symptoms (Harris et al., 1999). Older studies using QEEG have shown decreased variability and high mean energy content (Goldstein et al., 1963). In several studies, this stability or hyperregulation in the EEGs of schizophrenics correlated with a poor prognosis, whereas dysrhythmic records correlated with a better prognosis (Yamada, 1960; Igert and Lairy, 1962).
Many of the EEG studies schizophrenics are complicated by treatment given the patients. Fukuda and Matsuda (1969) found high voltage slow-wave changes after five electroconvulsant treatments (ECTs) in 40 to 70 percent of patients, and in 80 to 87 percent after 10 ECTs. Though they reported that almost all EEGs returned to normal in 3 days, Muscovitch and Katzelenbogen (1948) claimed that such abnormalities could last for up to 10 months. Phenothiazines
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and other psychotropic drugs complicate EEG studies even more; they typically cause slowing of alpha rhythms and an increase in amplitude, with superimposed sharp fast activity (Steiner and Pollack, 1965). These changes may persist for up to 3 months after medications are stopped (Fink and Kahn, 1956; Swain and Litteral, 1960). To make interpretation more difficult, predrug EEGs have not usually been recorded. In a study of schizophrenic patients on phenothiazines, Steiner found patterns characteristic of sleep activity in 65 percent and significant amounts of diffuse delta and theta activity in 43 percent. Since all the atypical antipsychotics, particularly clozapine, have been associated with seizures in nonepileptic patients they would also be likely to produce EEG changes (Alldredge, 1999).
In summary, electroencephalographic abnormalities are seen in schizophrenics, especially catatonic schizophrenics, more often than in the general population. This statement seems valid even when allowances are made for an occasional misdiagnosis of schizophrenia or an EEG abnormality caused by drugs or shock therapy. It is not known whether the schizophrenic process or an underlying biochemical defect causes these electroencephalographic abnormalities. It seems likely that neurologic features that cause brain damage, so often associated with schizophrenia, may be variably reflected in the EEG.
Neuroimaging
Over the past 25 years examinations of schizophrenics using static types of imaging e.g., computerized tomography (CT) and magnetic resonance imaging (MRI) have found structural changes in sub groups of patients. There have been inconsistent reports of ventricular enlargement, decreased size of the frontal lobes, and cerebellar atrophy in schizophrenic patients with CT scans (Johnstone et al., 1976;Golden et al., 1980; Weinberger et al., 1980; Andreasen, 1999). These investigators have correlated these changes with neuropsychological impairment, poor response to treatment, and poor premorbid adjustment. The ventricular enlargements that these authors have demonstrated would often not be called abnormal by radiologists but rather are subtle variations within the normal range. The authors also clearly stated that these changes were not present in all the schizophrenics they studied. Other investigations have not confirmed their findings of ventricular enlargement (Andreasen et al., 1982; Jerinigan et al., 1982).
There has been some question about temporal lobe abnormalities revealed by MR I. Kulynych et al. (1996) found no significant difference in the volume of the superior temporal gyrus of schizophrenics. Petty et al. (1995) and Barta et al. (1997) showed that the gray matter was smaller bilaterally in the planum temporale in right-handed schizophrenics. Usually, lateralized abnormalities schizophrenics implicate the left hemisphere. Marsh et al. (1997) also showed that a group of early onset schizophrenic patients had smaller gray matter volumes in the temporal lobes but not the hippocampus. However, Jacobsen et al. (1996, 1997a, b)
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were not able to show any temporal lobe volume changes in childhood schizophrenics. Almost all the studies in this area, whatever their results, suffer from serious methodologic problems, such as: (1) The study populations have been disparate, ranging from old to young, chronic to acute, rigidly diagnosed to less rigidly diagnosed. (2) The techniques of measuring ventricular size in each study were not standardized and vary from actual manual measurements to computerized measurements; consequently, there is great variation from study to study in the incidence of abnormal findings, as well in their comparability. (3) The control populations have varied from none to reported norms in the literature, to normal populations, neurologic patients who are referred for evaluation for headaches, and so on. Very few of these studies have compared other chronic psychiatric patients to the schizophrenic patients, and none have utilized a “blind” technique for reading CAT scans. When this comparison has been made, significant differences often disappear in the schizophrenic group (Weinberger et al., 1980).
The functional imaging studies using positron emission tomography (PET), functional magnetic resonance (FMR) tomography, magnetic resonance spectroscopy (MRS), and single photon emission tomography (SPECT) make possible the study of cerebral function in the living patient. These studies have done much to expand our knowledge, particularly in terms of complimenting some of the recent neuroanatomical findings in schizophrenia. Positron emission tomography, SPECT, and FMR are dynamic techniques that access the metabolic activity of the brain. These techniques depend on blood flow. In general, the more metabolically active the region, greater its blood flow. Dramatic changes in PET and FMR can be produced by moving a limb, reading, solving mathematical problems, etc. These tests are used to best advantage when there is a reliable way to activate specific part of the cortex. For example, Shaywitz et al. (1998) compared normal and dyslexic children at rest while reading. At rest, the FMRs in both groups were comparable, as were MRIs. When attempting to read, the left parietal lobe was activated in normal children; dyslexics activated their frontal lobes. Apparently the lobes do not carry out reading functions as well the left parietal lobe but the brain recruits the frontal lobe if the left parietal is not functioning.
These functional imaging techniques have begun to show consistent abnormalities in the temporal lobes, the basal ganglia, and the frontal lobes in schizophrenic patients. In 1990, Buchsbaum reviewed 20 PET studies of schizophrenia that showed lowered activity in all or one of these three areas (Buchsbaum, 1990). More recent studies have added the thalamus to this group (Flaum et al., 1995; Vita et al., 1995;Buchsbaum et al., 1996). Single photon emission computed tomography and FMR, as well PET have demonstrated lower activity in the frontal lobes, temporal lobes, basal ganglia, and thalamus of drug naïve patients and first episode schizophrenic patients (Nopoulos et al., 1995; Vita et al., 1995; Buchsbaum et al., 1996; Bertolino et al., 1998).
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Some studies have shown a diminished size of the cerebellum but others have not confirmed this finding (Jacobson et al., 1997a,b). Some studies have shown greater differences in men but many other studies have found the changes to be unrelated gender (Flaum et al., 1995;Lauriello 1997).
The dynamic imaging techniques have also been useful in illuminating neurotransmitter pathways. Using PET, Nordstrom et al. (1995)showed that clozapine in vivo occupied Dl and 5-HT receptors and had low D2 occupancy. Holcomb et al. (1996) used PET to study glucose metabolism and found that it was the same 5 days after withdrawal of haloperidol as when patient was receiving haloperidol. But when the same patients were studied 30 days after haloperidol cessation, there was a decrease in glucose metabolism in the caudate, putamen, and anterior thalamus, whereas glucose metabolism increased in the frontal cortex and anterior cingulate gyrus. Because haloperidol blocks D2 receptors, these findings implied that the D2 pathways in the brain control parts of the basal ganglia and thalamus that these regions are involved in schizophrenia. As improved radioligands are developed such studies should become even more precise in mapping neurotransmitter sites and their actions (Ito et al., 1998).
Using nuclear magnetic resonance (NMR), Stanley and associates (1995) demonstrated a breakdown of membrane phospholipid products in the prefrontal areas in drug naive and chronic schizophrenic patients as compared to controls, which confirmed an earlier study byPettegrew et al. (1991). This again implicates a defect in the frontal lobes that occurs early schizophrenic process and persists in chronicity. Single photon emission computed tomography studies have also begun to show some potential for clinical use in predicting drug response.Klemm and collegues (1996) used a raclopride derivative with high affinity for D2 receptors to quantitate D2 receptor blockade in patients taking neuroleptics. He suggested this may be a way of monitoring neuroleptic treatment. In a SPECT study, Rodriguez (1996) showed that patients who had lower prefrontal perfusion responded more poorly to clozapine than those who had high rates of perfusion.
Dynamic imaging has also been useful in exploring specific aspects of psychopathology. Woodruff et al. (1997) used FMR to investigate auditory hallucinations in schizophrenic patients and found that when the patient was having auditory hallucinations, there was reduced blood flow in the temporal cortical regions associated with registering external speech. They postulated that this might represent competition for a common neurophysiological resource language. Carter et al. (1997) hypothesized that schizophrenic patients taking the Stroop test (used to evaluate selective attention when there are competing stimuli) would not activate the anterior cingulate gyrus as normals do when they take this test; he confirmed this hypothesis in a PET study. This study demonstrates
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that it is now possible to use functional imaging in humans test hypotheses derived from studies on animals, and to study regions of a living patient's brain that have been identified as abnormal in other studies, including postmortem studies, of the brains schizophrenics.
These dynamic imaging techniques also have the potential to play a role in the diagnosis and clinical management of schizophrenia. But some caution is in order. Schizophrenic patients who have been treated with antipsychotic drugs cannot be compared with normal individuals if the purpose is to discover a deficit that is unique to schizophrenia. In several studies, schizophrenic patients have been compared to other nonschizophrenic psychiatric patients, particularly those with mood disorders. Many changes noted in schizophrenic patients compared to normal controls are also present in the nonschizophrenic, psychiatric controls (Elkis et al., 1995; Pearlson et al., 1995; Cannon et al., 1997). Thus, the changes noted may not be specific to schizophrenia. This has been the historical fate of many findings in schizophrenic patients. When the is compared to normal patients there are differences, but when the schizophrenic is compared to other psychiatric patients, particularly patients with nonschizophrenic psychoses, the differences disappear. The findings then seem to be a common property of psychoses or of some factor-like treatment that has no etiological relationship to schizophrenia.
Neuropathological findings
Reports of neuropathologic findings whether gross or microscopic in the brains of schizophrenic patients have been scarce. Older studies observed nonspecific abnormalities. As more precise neuropathological techniques have become available, more consistent findings are emerging. This effort has been facilitated by the development of brain banks that have collected tissue from carefully diagnosed schizophrenics. Even some of the older findings that were considered random and inconclusive now correlate with many of the functional imaging studies (Bogerts and Falkai, 1995). In the limbic region, reduced cell volumes have been reported in the hippocampus as well disturbed cellular architecture that often extends to the cingulate gyrus and the entorhinal cortex.
Neuropathological studies of schizophrenics indicate that the total number neurons in the frontal area appears intact but there is an increase cell density in the premotor cortex; in addition there are decreases the density of dendritic spines of pyramidal neurons in cortical layer III and decreased signs synaptic activity (Lewis and Anderson, 1995). Neurophysiological studies of the frontal premotor area, in nonhuman primates, implicate this area working memory (Goldman-Rakic, 1987) and control in the temporal integration of information (Fuster, 1993). Because portions of the frontal lobes (cortical and subcortical) appear to be dysfunctional in schizophrenics, the animal studies may help explain the difficulties in sensory integration that have been observed schizophrenics.
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The frontal lobes permit subjects to keep events in their working memory and to sequence temporal events. The dysfunctions of the frontal areas that have been described in schizophrenics could explain both their conceptual and language disturbances.
Increases in basal ganglia volumes have also been observed schizophrenics, but most researchers attribute these changes to the use of antipsychotic medications. Kung et al. (1998), however, found an increase in the density of synapses in the caudate nucleus and striatum but not the putamen schizophrenic patients. These changes were not evident in normal controls or in other psychiatric patients. Neuroleptics act on the caudate and the putamen, the location of many dopamine receptors. The fact that the changes were found in the caudate but not in the putamen would suggest that perhaps the increases in the caudate are not caused by neuroleptic use alone but reflect some abnormality specific to schizophrenia.
The nature of some the neuropathological findings also provides support for the theory that schizophrenia may be congenital in origin, a disorder of early preor postnatal brain development. The changes found in the brains of schizophrenics are usually of the following types: alterations cytoarchitecture; a persistence of a cavity in the septum pellucidum (which should disappear with normal development); and an absence of normal cerebral structural asymmetries (Bogerts and Falki, 1995). This type of pathology is usually associated with prenatal or perinatal developmental problems. Few of the neuropathological studies have found any gliosis, which is usually a hallmark of aquired damage and neuronal degeneration.
The onset of schizophrenia in late adolescence or early adulthood, once was thought to imply an acquired as opposed a genetic condition. Actually, in humans and primates, as postnatal development proceeds, there is a progressive reduction of excitatory synapses, particularly in the premotor frontal lobes (Bourgeois et al., 1994). This pruning continues during adolescence. The symptoms of schizophrenia develop as the cortex develops during young adulthood. Myelinization and synapse development advance during the first two decades, bringing the premotor frontal cortex and anterior temporal regions fully into functional brain circuitry. The effects of genetically abnormal frontal lobes or hippocampus may not become apparent until the frontal lobes and hippocampus are fully attached to the brain's electrical grid. In schizophrenic, in other words, development may permit the symptoms of schizophrenia to develop as the brain matures (Arnold, 1999;Keshavan and Hogarty, 1999).
Psychological Testing for Schizophrenia
The early psychological testing of schizophrenia using projective techniques and personality inventories was aimed at validating various theories about the psychodynamic
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etiology of schizophrenia. Currently, the major use for psychological tests in schizophrenia is to assess cognitive function. The major tools have been standardized tests such as the Halstead Neuropsychological Test Battery and the Continuous Performance Test (Hoff, 1995;Calev, 1999). Personality inventories usually deal with long-standing personality traits. Though helpful in raising a suspicion of chronic schizophrenia or schizoid personality, they also fail to discriminate acute schizophrenia from acute neurological syndromes.
The tests developed to assess brain damage also cannot distinguish the chronic schizophrenic from the brain-damaged patient. This has been demonstrated quite clearly by two detailed studies in which the Halstead Neuropsychological Test Battery was used (Watson et al., 1968); in these studies, the organics could not be distinguished from the chronic schizophrenics. Vega and Parsons (1967) Lacks et al. (1970) repeated these findings.
For the past three decades, the thrust of neuropsychological research into schizophrenia shifted to testing specific cognitive functions such as memory, frontal lobe function, attention, and psychomotor performance. In most cases there is little to differentiate schizophrenic patients from patients with neurological lesions that affect these performance parameters (Calev, 1999). Abnormalities identified on neuropsychological tests in schizophrenia may not be specific as tests results can be affected by medication, age, education, gender, and even handedness (Conuit et al., 1994). In a carefully done study of schizophrenics and matched controls, schizophrenics displayed impairments of motor, sensory, and perceptual functioning, verbal and nonverbal memory, frontal lobe functioning. This study did not identify any lateralized cognitive impairments in schizophrenics (Blanchard and Neale, 1994).
The extent of the cognitive impairment in schizophrenia was further highlighted by studies that compared the disorder with Alzheimer's disease. Davidson and colleagues (1996) using the Mini-Mental Status Examination found that schizophrenic patients performed worse on the tests of naming and constructional praxis than Alzheimer's disease patients, whereas the Alzheimer's disease patients were more impaired on global recall. Grouping the patients by the severity of illness the scores showed no differences; both were impaired. Hutton et al. (1998) shed some light on executive function in schizophrenic patients. They studied first-episode schizophrenics and found in addition to performing poorly on memory tasks, the schizophrenics had significant deficits in executive functions, particularly in planning and strategy tasks, whereas more chronic patients also had trouble in tasks that required shifting attention. By studying acute and chronic patients and showing that the cognitive deficits become more severe with chronicity, the authors suggest that schizophrenia is a progressive disease that affects the frontal lobes and its connections.
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Arousal
Many studies have identified the schizophrenic as hyperaroused, a term that refers to an abnormally heightened state of neurophysiological activity (Grossberg, 2000; Pryor, 2000). Some feel that this state may actually cause thought disorders. The term arousal is not clearly defined, but, in general, it refers to a state of alertness with increased physiological measurements the kind often associated with high levels of anxiety. These include increased galvanic skin resistance, increased muscle tension as measured by electromyography, desynchronization of the EEG with alpha suppression, and increased pulse rate. This evidence of hyperarousal has been speculatively linked with statements by acute schizophrenics indicating that they are “flooded” with stimuli, that is, “When I try to read something, each bit I starts me thinking in ten different directions at once.” It has been suggested that the hyperarousal leads to a “low threshold for disorganization under increasing stress” (Epstein and Coleman, 1970). It may also refelect the defects in sensory gating noted earlier (p. 110, Braff et al. 1992, 1995) The psychophysiological disorganization caused by stimulus overload is hypothesized as the primary causal factor in the thought disturbance typical of schizophrenic patients. When the physiological parameters of arousal are studied in samples of schizophrenic and nonschizophrenic patients, the symptoms related to feeling flooded by stimuli correlate highly with measures of anxiety (Tucker et al., 1969). Consequently, hyperarousal, though frequently present in schizophrenics, may simply be a manifestation of heightened anxiety, rather than some-thing specific to schizophrenia.
Treatment
The use of antipsychotic drugs is essential to the treatment of schizophrenia (Tucker et al., 1984; Brier, 1996). Not only are these drugs more effective than placebos for schizophrenics (Brier, 1996), but they are also more effective than any type of psychotherapy alone (Grinspoon et al., 1968; May et al., 1981). Psychological forms of therapy can be useful adjuncts to drugs, but no one can claim that they offer an alternative to drugs.
The antipsychotics have now been in use for close to 50 years, and although they have brought major changes in the places where the schizophrenic is treated (now the majority of schizophrenic patients are treated in the community rather than large remote state hospitals), it is not clear that they have altered the long-term outcome. They are neither curative of schizophrenia nor do they always control the symptoms in all cases (Davis, 1993). It is still true that approximately one-third of the schizophrenics get better, approximately one-third have major residual symptoms, and approximately one-third deteriorate (see Table 3-2). Approximately 15 percent of schizophrenic patients show no effect from antipsychotic
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medications, another 15 percent will experience almost complete symptom control, and the remainder will have a mixture of residual symptoms of varying severity.
The new atypical antipsychotics have been very welcome. Clozapine provides clinical improvement for 40%–60% of the chronic patients who have failed to respond to other antipsychotics, while it and the other atypicals seem to have fewer extrapyramidal side effects (Brier and Buchanan, 1996). Clozapine, introduced in 1989, was the first radically different drug introduced since the early 1950s. Recently a whole new generation of clozapine-like drugs have been released: risperidone, olanzapine, quetiapine, sertindole, and ziprasidone. All of these drugs differ from the older antipsychotics with regard to their neuronal receptor sites of action. The traditional or typical antipsychotics primarily interact with the D2 receptor. The atypical drugs affect a whole range of receptor sites: low D1, D2 binding, high affinity for 5HT2, alpha-adrenergic 1 and 2, histaminic 1, and muscarinic receptors in varying degrees. Each of the atypical drugs has minor variations in this pattern but most are similar to each other. These new drugs seem to create less extrapyramidal effects because they occupy the D2 receptor site only transiently or at a lower occupancy rate than the traditional neuroleptics (Kapur et al., 2000). However, all the atypicals make Parkinson's symptoms worse in patients with Parkinson's disease. Only clozapine and quetiapine can be used without risk of worsening Parkinson's symptoms (Goetz et al., 2000). Risperidone produces dose-related extrapyramidal symptoms; but causes only transient rises in serum prolactin levels (the D2 receptor blockers all cause variable increases in serum prolactin related to their D2 receptor occupancy). Other major side effects of the atypicals are sedation, weight gain, hypotension, and salivation. Even though clozapine has caused seizures, the epileptogenic potential of the other drugs seems to be less. Since the atypical antipsychotics produce fewer extrapyramidal symptoms and less tardive dyskinesia (TD) they may lead to better patient compliance. With the older antipsychotics, patients often experienced uncomfortable bodily sensations, probably related to subtle extrapyramidal effects. These feelings often led them to discontinue the antipsychotic medication. Among patients taking typical antipsychotic medication, approximately 4%–5%/year will develop tardive dyskinesia. Fortunately 60 percent of the cases TD ultimately remit spontaneously (see Chapter 5). But for those that do not remit, it is a socially disabling side effect of antipsychotic therapy. The lower rate TD with the new antipsychotics is a major step forward.
Conclusion
It is obvious that schizophrenia a complex disorder. But it is a disorder has been clearly described for over a hundred years. Although the etiology and
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curative treatments are not yet known, we have made significant progress in delineating many of the central nervous system abnormalities associated with schizophrenia. For the first time investigators using different methodologies are identifying the same anatomical sites in the brain as being dysfunctional in schizophrenia. There are consistent reports from neuroanatomists, molecular biologists, neuropsychologists, and those doing functional imaging that there seem to be dysfunctions in the frontal lobes, the hippocampus, and the entorhinal cortex of schizophrenics. And although no specific gene has yet been identified, the course of the illness with onset in late adolescence and the common clinical and laboratory neurological findings indicate that schizophrenia is a disease of neurodevelopment. As these biologic findings accumulate, we may soon have biologic markers with which to diagnose and define schizophrenia. Once we can define the disorder biologically, we will be better able to determine the etiology and treatment.
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