Schizophrenia is among the most serious of all unsolved diseases. This was the opinion expressed 60 years ago in Medical Research: A Mid-Century Survey, sponsored by the American Foundation. Because of a worldwide lifetime prevalence of approximately 0.85 percent and particularly because of its onset early in life, its chronicity, and the associated social, vocational, and personal disabilities, the same conclusion is justified today (see Carpenter and Buchanan).
Neurologists and psychiatrists currently accept the idea that schizophrenia comprises a group of closely related disorders characterized by a particular type of disordered thinking, affect, and behavior. The syndrome by which these disorders manifest themselves differs from those of delirium, confusional states, dementia, and depression in ways that will become clear in the following pages. Unfortunately, the diagnosis of schizophrenia depends on the recognition of characteristic psychologic disturbances largely unsupported by physical findings and laboratory data. This inevitably results in a certain degree of diagnostic imprecision. In other words, any group classified as schizophrenic will include patients with diseases that only resemble schizophrenia, whereas variant or incomplete cases of schizophrenia may not have been included. Moreover, there is not full agreement as to whether all the conditions that are called schizophrenic are the expression of a single disease process. In the United States, for example, paranoid schizophrenia is usually considered to be a subtype of the common syndrome, whereas in some parts of Europe it is thought to be a separate disease.
Present views of the disease now called schizophrenia originated with Emil Kraepelin, a Munich psychiatrist, who first clearly separated it from bipolar psychosis. He called it dementia praecox (adopting the term introduced earlier by Morel) to refer to a deterioration of mental function at an early age, from a previous level of normalcy. At first, Kraepelin believed that "catatonia" and "hebephrenia," which had previously been described by Kahlbaum and by Hecker, respectively, as well as the paranoid form of schizophrenia, were separate diseases, but later, by 1898, he had concluded that several subtypes were a single disease. He emphasized an onset in adolescence or early adult life and a chronic course, often ending in marked deterioration of personality as the defining attributes of all forms of the disease. Early in the twentieth century, the Swiss psychiatrist Eugen Bleuler substituted the term schizophrenia for dementia praecox. This was an improvement insofar as the term dementia was already being used to specify the clinical effects of another category of disease; unfortunately, however, the new name implied a "split personality" or "split mind." By the "splitting" of psychic functions, Bleuler meant the lack of correspondence between ideation and emotional display—the inappropriateness of the patient's affect in relation to his thoughts and behavior. In contrast, in bipolar disease, the patient's mood and affect accurately express his morbid thoughts. Bleuler also introduced the term autism ("thinking divorced from reality") as an aspect of the thought disorder.
Bleuler believed that all the schizophrenic syndromes were composed of primary or basic symptoms, summarized by subsequent authors as the "four A's" (loose associations, flat affect, ambivalence, and autism) and of secondary or "partial phenomena" such as delusions, hallucinations, negativism, and stupor. However interesting this formulation proved to be, the psychologic abnormalities are so difficult to define precisely that these divisions have come to be of only mnemonic value.
Meyer, who introduced the "psychobiologic approach" to psychiatry, sought the origins of schizophrenia, as well as other psychiatric syndromes, in the personal and medical history of patients, emphasizing particularly their habitual reactions to life events. Freud viewed schizophrenia as a manifestation of a "weak ego" and an inability to control anxiety and instinctual forces—the result of a fixation of libido at an early ("narcissistic") stage of psychosexual development. None of these theories has been corroborated, and none ever gained wide acceptance.
A contemporary approach to schizophrenia, summarized below, has involved the isolation of its many pervasive mental and behavioral features into three clusters: (1) negative symptoms of diminished psychomotor activity (poverty of speech and spontaneous movement, flatness of affect); (2) a "disorganization" syndrome, or thought disorder (fragmentation of ideas, loosening of associations, tangentiality, and inappropriate emotional expression); and (3) reality distortion, comprising hallucinations and delusions, or positive symptoms (see Liddle). The separation of behaviors into "positive" and "negative" symptoms was believed to be useful in distinguishing among the types of schizophrenias and perhaps to align the mental status with conventional physiologic analysis, but this view is an oversimplification, as pointed out by Andreasen. Although there is disagreement as to whether each of these features is primary or secondary, positive or negative, they have the value of lending themselves to objective study.
Schizophrenia has been found in every racial and social group so far studied. On average, 35 new cases per 100,000 population appear annually (Jablensky). As indicated earlier, studies of prevalence suggest that at any given time 0.85 percent of the world population is suffering from schizophrenia and expectancy rates are estimated to be as high as 1 chance in 100 that a person will manifest the condition during his or her lifetime. The incidence of schizophrenia has remained more or less the same over the past several decades. Males and females are affected with equal frequency. For unknown reasons, the incidence is higher in social classes showing high mobility and disorganization. It has been suggested that this is a by-product of "downward drift"—a result of deteriorating function in those with the disease that forces them into the lowest socioeconomic stratum where one finds poverty, crowding, limited education, and associated handicaps—and the same data have been used to support the idea that schizophrenia can be caused by such social factors.
Schizophrenic patients occupy about half the beds in mental hospitals—more hospital beds than are allocated to any other single disease—and they constitute 20 to 30 percent of all new admissions to psychiatric institutions (100,000 to 200,000 new cases per year in the United States). The age of admission generally is between 20 and 40 years, with a peak between 28 and 34 years. The economic burden created by this disease is enormous—the direct and indirect costs in the United States have been estimated to be over $50 billion.
Clinical Syndrome of Schizophrenia
The central abnormalities in schizophrenia are hallucinations and a special disorder in the perception of one's self in relation to the external world. It is unlike the condition that prevails in delirium and other confusional states, dementia, and depression. Some patients with chronic schizophrenia, before the onset of a flagrant psychosis or when in remission, show none of the usual symptoms and—during brief testing of mental status—might even pass for normal. But on longer observation, they are vague and preoccupied with their own thoughts. They seem unable to think in the abstract, to understand fully figurative statements, or are able to separate relevant from irrelevant data. There is what has been called a circumstantiality and tangentiality about their thinking and remarks. They fail to communicate their ideas clearly. Their thinking no longer respects the logical limits of time and space so that parts of ideas are confused with the whole or are clustered together or condensed in an illogical way. In an analysis of a problem or a situation, there is a tendency to be overinclusive rather than underinclusive (as happens in dementia). In conversation and in writing, the trend of an argument or thought sequence is often interrupted abruptly, with a resulting disorder of verbal communication. Such disorders of thinking are reflected in the patient's behavior. Over time there is a general deterioration in functioning, social withdrawal and bizarre actions, self-absorption, and aimlessness.
In more severely affected schizophrenic patients, thinking is even more disintegrated. They appear to be totally preoccupied with their inner psychic life (thus the early use of the term autism) and may do no more than utter a series of meaningless phrases or neologisms, or their speech may be reduced to a nonsensical "word salad." They are unable to attend to any task or to concentrate, and their performance is interrupted by sudden "blocking" or by insertion of some extraneous idea or inexplicable act, somewhat like that observed in a severely confused or delirious patient. At times these patients are talkative and exhibit odd behavior; at other times they are quiet and idle. In the extreme, the patients are mute or assume and maintain imposed postures or remain immobile (catalepsy). With remission, they may remember much of what has happened or may have only fragmentary memories of events that occurred.
Typical of schizophrenia is the patient's expression of remarkably unusual experiences and ideas. The patient may express the thought that his body is somehow separated from his mind, that he does not feel like himself, that his body belongs to someone else, or that he is unsure of his own identity or even sex. These experiences have been called depersonalization. Thought insertion, wherein it seems to the patient that an idea has been implanted into his mind, or thought withdrawal, wherein an idea has been extracted from his mind by an outside agency, are other parts of this problem. Closely related, and characteristic of schizophrenia, are ideas of being under the control of some external agency or being made to speak or act in ways that are dictated by others, often through the medium of radar, telepathy, or the Internet (passivity feelings). Thought projection, the notion that external elements in the environment are being controlled by the patient's mind, is similar. Frequently, there are ideas of reference—that the remarks or actions of others are subtly or overtly directed to the patient. Finally, the patient may feel that the world about him is changed or unnatural, or his perception of time may be altered, not in a brief episode like the jamais vu of a temporal lobe seizure, but continuously; this is the phenomenon of derealization. However, the bizarreness of these delusions, once considered a characteristic feature, has been removed from the diagnostic criteria for schizophrenia in the latest recursion of the DSM because of its nonspecificity and the difficulty determining exactly what constitutes bizarre.
Auditory hallucinations are frequent and a core feature of the classic illness. They consist of voices that comment on the patient's character and activities and are usually accusatory, threatening, or claiming control of the patient's actions. The voices may or may not be recognized; they may belong to one person or two or more persons who converse with the patient or with one another. Seldom can the voices be localized to a point outside the patient. Instead, they seem to come from within, so that they cannot be distinguished from his own feelings and thoughts. Certain somatic hallucinations and delusions may predominate in any one individual. Visual, olfactory, and other types of hallucinations also occur but are much less frequent. The patient believes in the reality of these hallucinations and often weaves them into a delusional system.
It should be reiterated here that hallucinations are a feature of a number of neurologic processes, but in most people visual hallucinations predominate, whereas auditory hallucinations are the hallmark of schizophrenia. Of interest in this regard is "The Report on the Census of Hallucinations" by Sidgwick in 1894 who suggested (as cited by Frith) that almost 1 in 10 ostensibly normal respondents has experienced hallucinations, mostly visual. The main illnesses in which hallucinations and delusions are prominent, for example, hallucinogenic drug ingestion and the Charles Bonnet syndrome (see Chap. 13), have been reviewed by Frith.
Of interest has been the belated affirmation of the importance of negative symptoms in schizophrenia. Liddle and Barnes, looking objectively at all aspects of schizophrenic thought and behavior, divided them into four groups: (1) flat affect, diminution in expressive gestures, latency of response, reduced spontaneous movements, apathy, restricted recreational activities, inability to feel intimate or close, and motor retardation; these negative symptoms, which have resemblances to frontal lobe behavioral syndromes, correlate with reduced blood flow in the frontal lobes and a poor prognosis; (2) disorganization of thought, incoherence, inappropriate affect, illogicality, bizarre behavior, aggression, agitation, and tangentiality; these abnormalities are nonfrontal; (3) hallucinations and delusions that the patient's mind is being read and that thoughts are being extracted from his mind or being controlled or broadcasted, probably related to temporal lobe function; and (4) suspicion, hostility, and delusions of reference. These authors also found that the four syndromes can coexist in various combinations. However valid such subdivisions prove to be, they direct attention to the functional anatomy and physiology of particular neuronal systems in the brain (see further on; also Friston et al).
The behavior of the schizophrenic who experiences these ideas and feelings is correspondingly altered. Early in the course of the illness, normal activities may be slowed or interrupted. No longer does the patient function properly in school or at work. Associates and relatives are likely to find the patient's complaints and ideas disturbing. The patient may be idle for long periods—preoccupied with inner ruminations—and may withdraw socially. A panic or frenzy of excitement may lead to an emergency ward visit (a high degree of anxiety occurring for the first time in a young person should always raise the suspicion of a developing schizophrenia), or the patient may become mute and immobile, i.e., catatonic. Attacks of catatonia are infrequent, but lack of will, drive, assertiveness, and motor activity are characteristic of the disease. Ultimately, a deteriorated and dilapidated state occurs, which in the extreme results in an unkempt and malnourished state with which the public unfortunately associates schizophrenia. Individuals of this type roam the streets and live in appalling conditions on the fringes of society where they are subject to the criminal behavior of others.
That schizophrenia of all types carries a significant risk of suicide is not widely appreciated by nonpsychiatry practitioners. In a followup study of schizophrenic and bipolar patients, Winokur and Tsuang found that in each group the proportion of patients who had committed suicide was the same (approximately 10 percent). Suicide occurs most often among young schizophrenic patients living apart from their families who are frightened and overwhelmed by their symptoms and who experience the difficulties of independent existence. Sometimes suicide is a response to terrifying and commanding vocal hallucinations. The schizophrenic patient may also be homicidal, usually acting upon a delusion that he has been wronged or is threatened by the victim. Incidents of this type are unpredictable, but the presence of escalating paranoia should be a warning.
Finally, whether a genuine dementia results from chronic schizophrenia has been much debated over the years. The notion of this type of "dementia praecox" was discarded, but clinicians continue to encounter cases of progressive generalized, and sometimes severe, intellectual impairment in both acute and long-standing cases of schizophrenia; this has been true before and after the modern era of therapeutics. The problem was highlighted by de Vries and colleagues who analyzed what they considered to be a frontotemporal type of dementia in eight patients after 9 to 30 years of schizophrenia; they found minor changes on CT scans, and frontal or temporal hypoperfusion on single-photon emission computed tomography (SPECT).
Included in the early definitions of the disease, both of Kraepelin and of Bleuler, were a characteristic premorbid personality, an insidious onset of the more flagrant symptoms in adolescence or early adult life, and a chronic but fluctuating course with a tendency to progressive deterioration. Both of these early investigators regarded hallucinations and delusions as secondary symptoms that could be absent, as in their category of "simple schizophrenia." Embodied in both their definitions was the concept of disease characterized by a poor prognosis and, as stated earlier, a unique constellation of symptoms different from those of delirium, confusion, depression, mania, and dementia—the other manifestations of brain diseases. Many of their seminal ideas, including those of Schneider discussed below, have been retained but others have been discarded in various diagnostic criteria. Nonetheless, they established a lexicon for the clinical description and grading of schizophrenic disorders and all subsequent progress has been essentially to refine these ideas. For that reason, they are summarized here so that the student may appreciate the evolutionary nature of diagnostic criteria, as expressed through the DSM, currently in its fifth recursion.
Attempts to apply the early criteria initially met with difficulty, especially when hallucinations and delusions were absent. To overcome this, Schneider proposed that the distinction between primary and accessory manifestations be abandoned. He attached more importance and reliability to the occurrence of auditory hallucinations, perceptual delusions (misinterpretation of what the patient hears and feels), and disturbances of thinking (experiences of alienation and influence). This constellation of symptoms, which was more precise and easy to recognize, came to be known as Schneider's first-rank symptoms of active schizophrenia. The Schneider's diagnostic criteria, when applied to a group of patients admitted to the hospital with a diagnosis of schizophrenia, served to distinguish those with and those without first-rank symptoms (Taylor). Those without hallucinations, delusions, and thought control or projection responded more poorly to treatment and required a more prolonged period in the hospital and higher doses of neuroleptic drugs than did those with these features. The two groups correspond closely to two categories of schizophrenic disorders later separated by Robins and Guze on the basis of prognosis. The Schneider-positive, poor-prognosis schizophrenia (also referred to in older literature as nuclear or process schizophrenia) corresponded closely to kraepelinian schizophrenia, while many of the Schneider-negative patients with good prognosis were probably suffering from some other nonschizophrenic illness or schizophreniform illness or from bipolar disease (see Chap. 52). Having made these comments, it must be acknowledged that the newer classifications of schizophrenia gives these distinctions less credibility and points to marginal differences in outcome and responses to treatment.
Feighner and colleagues, who drew up a set of diagnostic criteria for research in the major psychiatric syndromes (which were subsequently incorporated, until recently, into successive editions of the Diagnostic and Statistical Manual of Mental Disorders [DSM]), stated that the diagnosis of schizophrenia is tenable only in the presence of (1) a chronic illness of at least 6 months' duration and a failure (after an acute episode) to return to the premorbid level of psychosocial adjustment, (2) delusions or hallucinations without significant confusion or disorientation (i.e., without clouding of consciousness), (3) verbal productions that are so illogical and confusing as to make communication difficult (if the patient is mute, diagnosis should be deferred), and (4) at least three of the following manifestations: (a) among adults, the lack of a partner or spouse; (b) poor premorbid social adjustment or work history; (c) family history of schizophrenia; or (d) onset of illness prior to age of 40 years. Important exclusions from certainty in the diagnosis of schizophrenia include the absence of a family history of bipolar disease, absence of an earlier illness with depressive or manic symptoms, and absence of alcoholism, drug abuse, or other organic disease.
While the Feighner criteria are so strict as to exclude certain patients with a schizophrenic illness, those patients who are included will be found to constitute a fairly homogeneous group. Morrison and colleagues, who used these criteria, noted that after a 10-year period there was practically no need to change the diagnosis to another category of mental disease; in other words, they had reliably separated schizophrenia from schizophreniform psychosis (in which only the acute delusional-hallucinatory syndrome was present), and from bipolar psychosis.
The newer diagnostic criteria are no less refined but achieve clarity by stating that a patient must have at least one of the symptoms of delusions, hallucinations, and disorganized speech (not thinking). Also updated in DSM-5 is the removal of the necessity for delusions to be "bizarre" and for there to be what were in the past termed Schneiderian first-rank symptoms, namely an auditory experience of two or more voices conversing.
Subtypes of Schizophrenia
Psychiatrists had traditionally distinguished a number of subtypes of schizophrenia, although the usefulness of these distinctions has been questioned in recent years and the newest edition of DSM-5 eliminates them entirely because they have proved to have limited clinical and therapeutic importance. Indeed, the various types may overlap or change during the course of the illness. And there are many cases that do not conform entirely to the conventional subtypes or display characteristics of more than one type (referred to as undifferentiated or mixed types). They are briefly reviewed here for their historical interest and because their elimination in modern work signals a willingness of the field to move ahead with classification of mental disease on the basis of demonstrated biologic and therapeutic distinctions. However, they do allow an explication the more interesting symptoms and signs of schizophrenia that while entirely descriptive, are instructive and retain clinical interest.
In simple schizophrenia, the least florid form, the patient exhibits thought disorder, bland affect, social withdrawal, and reduction in speech and movement, all of which impair work performance. Poverty of psychomotor activity is the dominant feature and hallucinations and delusions are absent. These patients may attract notice in middle and high school because they behave in an odd manner, tending to remain by themselves ("loners"), making no effort to adjust to a social group at school or to find work, have dates, or later, to establish a family.
Catatonic schizophrenia is still the most readily identifiable type because of the striking syndrome of catatonia, and while still distinctive when seen, it is now, for unclear reasons found to be quite infrequent. In most cases the onset is relatively acute. In others, after a long prodrome of slackening interest, apathy, and dreamy preoccupation, a state of dull stupor supervenes, with mutism, inactivity, refusal of food, and a tendency to maintain one position "like a mummy" (catalepsy). Like other forms of catatonia, this type of schizophrenia was the one most characterized by the retention of a posture: if a limb is lifted by the examiner, it will be held in that position for hours (flexibilitas cerea). The patient may require tube-feeding (or will eat mechanically) and has to be dressed and undressed. Pinprick or pinch induces no reaction. Extreme "negativism," every command being resisted, characterizes some cases. Yet these patients may be fully aware of what is said to them or happening around them and will reproduce much of this information during a later spontaneous remission or one induced by intravenous sodium amytal or midazolam. Even if untreated, the patient, after weeks or months in this state, begins to talk and act more normally and there is then rapid recovery. In certain phases of catatonia there may be a period of excitement and impulsivity, during which the patient may be suicidal or homicidal. Catatonia is currently recognized to be a feature of other mental illnesses and is more frequent in severe involutional depression than in schizophrenia (see Chap. 17)
Disorganized, or hebephrenic, schizophrenia was believed by Kraepelin to be a particularly malignant form of the disease. It tended to occur at an earlier age than the other varieties, hence the prefix hebe ("youth"). The thought disorder is pronounced—there is a striking incoherence of ideas and a grossly inappropriate affect; the frequent occurrence of hallucinations and delusions leaves little doubt that the patient is psychotic. Kraepelin remarked on the changeable, fantastic, and bizarre character of the delusions. Motor symptoms, in the form of grimacing, stereotyped mannerisms, and other oddities of behavior, are prominent. In hebephrenic patients, since early life, there is likely to have been a history of tantrums and of being overly pious, shy, fearful, solitary, conscientious, and idealistic—traits that may have marked these individuals as odd. This latter state corresponds to what was referred to earlier on as a schizoid personality but could just as well represent the early phase of the disease itself (see Chap. 51).
Paranoid schizophrenia is still one of the most frequent and well-circumscribed types, even if now unattached from schizophrenia in the DSM-5 diagnostic criteria. The mean age of onset is in the early forties, much later than that of the preceding types (Winokur). The central feature is the preoccupation with one or more delusions related to a single or to a limited ensemble of themes, accompanied by auditory hallucinations. More often than not, the delusional hallucinatory content is persecutory, but it may also be religious, depressive, grandiose, or bizarrely hypochondriacal in nature. Delusional jealousy may be added. Many such patients settle into a chronic hallucinatory psychosis with disorders of thinking featuring mistrust and suspiciousness. They appear cold, aloof, and indifferent. Some European psychiatrists, impressed with the lack of schizoid traits in the premorbid period and late onset, insisted that paranoid schizophrenia is a separate disease. The studies of Rosenthal and colleagues and the clinical and family studies of Winokur tend to bear them out in that simple, catatonic, and hebephrenic types have different characteristics from paranoid schizophrenia. Therefore, modern classifications consider it to not be aligned with schizophrenia and instead to characterize an isolated paranoid-delusional disorder described in a later section. There is, in addition, a special form of delusional disorder in which the individual is consumed by a single persecutory, grandiose, or amorous delusional system without any other disorder of thinking. An exotic form is known as folie à deux, in which two closely related persons share a delusional system. These types of delusions are discussed further on in this chapter.
Some schizophrenic patients are subject to periodic exacerbations of their illness, sometimes at regular intervals, as if the process was a metabolic disorder. Remissions that allow some degree of functioning in society are more frequent and lasting when medication is given and prolonged institutionalization is avoided. A small proportion of patients (approximately 10 percent), after an acute schizophrenic episode, have a long-lasting and fairly complete remission before lapsing into a chronic form of the illness. Unfortunately, these latter patients, at the time of their acute psychosis, cannot be distinguished from those few who will have a permanent remission.
Modern therapeutic programs have vastly reduced the number of patients in mental hospitals. However, readmission rates have also risen (revolving-door phenomenon) and the total number of very young and very old patients in hospitals has even increased slightly. The life expectancy of schizophrenic patients is somewhat reduced, possibly because of the malnutrition, neglect, and exposure to infections that occur in some public institutions and from living on the streets or in marginal circumstances. Most of these aspects of the disease were elucidated many decades ago by Langfeldt (1937 and 1969).
Neurologic and Neuropsychologic Abnormalities in Schizophrenia
The early findings of Kraepelin and of Bleuler, that many schizophrenic patients will, on detailed examination, show some neurologic abnormalities, have been substantiated by Stevens, Kennard, Hertzig and Birch, Tucker and colleagues, and Woods. They all found a much higher frequency of "soft neurologic signs" in schizophrenic patients than they did in a healthy population. The signs to which they refer include impersistence in assigned motor and mental tasks, astereognosis and graphesthesia, sensory extinction, hyperreflexia and hyporeflexia, slight tendency to grasping, mild impairment of coordination and disturbances of balance, abnormal (choreiform) movements, abnormalities of motor activity, adventitious and overflow movements, anisocoria, slight esotropia, and faults in visual auditory integration. Signs of this type were noted in 50 percent of patients and correlated with the degree of cognitive disorder. Also evident in about half of schizophrenic patients are subtle defects in ocular tracking movements (Levin et al). These take the form mainly of slowed smooth pursuit and intrusions of saccades during pursuit; some relatives of schizophrenic patients also show these eye signs when carefully tested. In contrast, "hard neurologic signs" (such as unilateral motor or sensory defects) are not seen unless they are the result of an engrafted neurologic disease. Electroencephalographic (EEG) abnormalities have been detected in about one-third of patients, but are generally minor; their meaning is uncertain, especially if they have occurred after long-standing treatment. When these were the focus of research in the past, they were more frequent in the group of schizophrenic patients who had a positive family history and in those with enlarged ventricles (Murray et al).
Sophisticated psychometric testing has disclosed abnormalities not so much in intelligence and memory (which are slightly reduced in 20 to 30 percent of cases) as in other psychologic functions. Alertness is not impaired, but the ability to maintain attention, as measured by continuous performance tasks, is reduced (Seidman). In tests of verbal and visual pattern learning, problem solving, and memorizing, Cutting found a surprising degree of impairment in both acute and chronic schizophrenic patients that was not attributable to previous treatment. In the acute schizophrenic patient, verbal memory was more affected than visual pattern memory, in agreement with the findings of Flor-Henry that left-hemispheric functions are more reduced than right-hemispheric ones. Yet, in the chronic schizophrenic, there is usually evidence of bihemispheric impairment.
Theories of Causation and Mechanism
Although there is no agreement as to the cause of the disease, an increasing weight of evidence favors an interaction between a genetic predisposition and one or more early developmental events. One widely held hypothesis is that this disease reflects an underlying developmental disorder, determined either genetically or because of an environmental insult, leading to abnormalities of synaptic connectivity, prominently affecting the hippocampus and prefrontal cortex. The evidence supporting this view is summarized briefly later. More detailed analysis of potential causes that can be given here are found in reviews of Waddington, Carpenter and Buchanan, Harrison, Pearlson, and Freedman.
Several authors have estimated that genetic factors can account for upward of 80 percent of the risk of developing schizophrenia, more than for any other mental illness. The early studies of Kallmann showed that the frequency of disease in 5,000 siblings of schizophrenic patients was 11 percent, in contrast to slightly less than 1 percent in the general population. In 90 sets of fraternal twins of whom one had schizophrenia, the incidence of disease in the other twin was also 11 percent, the same as in nontwin siblings; however, in 62 sets of monozygotic twins, the incidence in the second twin was 68 percent. The risk that a child of a schizophrenic parent will develop schizophrenia is the same as that for the sibling of a schizophrenic patient (i.e., 11 percent); if one sibling and one parent have schizophrenia, the risk is 17 percent. If both parents are schizophrenic the chances are 46 percent that the child will have the disease. Subsequent family and twin studies have repeatedly confirmed these findings (see Goodwin and Guze for a more complete tabulation). It is noteworthy, however, that the penetrance of this trait appears to be less than it is for bipolar disease and that genetic factors seem to play a larger role in patients whose illness manifests itself in teenage years.
Although the importance of genetic factors in the etiology of schizophrenia is undeniable, a mendelian pattern of inheritance has not been determined. Within the last several years, polymorphisms in several genes have been implicated as risk factors for schizophrenia. Such genes include those expressing neuregulin, dysbindin, COMT (catechol O-methyltransferase), proline dehydrogenase, and DISC1 ("disrupted in schizophrenia 1"). The most provocative sites, however, have rare alleles been in genes that also are overrepresented in autism—NRXN1, SHANK3, CNTNAP2, and PRODH, as summarized by McLellan and King. No single mutation accounts for more than perhaps 1 percent of cases but collectively, they seem to be associated with a fair proportion of cases of schizophrenia. There are also a copy number variations at particular genetic "hotspots" that occur in schizophrenia, autism, and other developmental disorders. What has merged from large population studies using genome-wide array screening, is that there are not likely to be common risk variants for schizophrenia (or any other psychiatric disease). Instead, the cumulative contribution of many small variants, each with a minor effect, could best account for the inherited aspects of these disorders. It should be pointed out that many of the polymorphisms mentioned seem to be of recent evolutionary origin or have a substantial rate of arising de novo.
The studies implicating these genes must further be interpreted cautiously because the functional significance, if any, of the allelic variants are not defined. Nonetheless, considered together, they point to disorders both of neuronal development and neurotransmission. Further supporting this view is the provocative finding that allelic variants associated with specific neurotransmitter systems or in developmental guidance are overrepresented in schizophrenia; these findings are more compelling than the aforementioned ones because the genetic variants have well-defined functional consequences.
Environmental and Developmental Factors
There continues to be debate concerning the relative importance of genetic versus environmental factors in the causation of the disease. The lack of complete concordance between monozygotic twins and the fact that approximately 80 percent of schizophrenic patients have no other family members with the disease, indicate that factors other than genetic ones probably play a role. Some of these appear to be early events that occur in utero or infancy and alter normal developmental programs of brain structure.
The neuropsychiatric literature contains tentative and only circumstantial evidence that schizophrenia is associated with overt brain injury during the intrauterine or neonatal period, but there is reportedly an increased incidence of obstetric complications during the gestational period and birth of schizophrenic patients. Also consistent with an early adverse environmental factor is the observation by several groups that in the northern latitudes, more schizophrenic persons are born in the winter months and to women who were exposed to influenza during midpregnancy—inviting speculation that a viral infection may have damaged the fetal brain. Mortensen and colleagues found that being born in an urban region, particularly in February or March, carried with it a higher risk for developing the disease than having an affected parent or sibling. They suggested that these inexplicable demographic features accounted for more cases than did inheritance. Among 5,362 infants who were followed prospectively since their birth in 1946 by Jones and colleagues, the 30 individuals who later developed schizophrenia had been delayed in the attainment of motor milestones and speech and exhibited greater social withdrawal and schoolroom anxiety as well as lower scholastic achievement. Thus it appears that schizophrenic patients are not entirely normal in early childhood, but whether their abnormalities are already early manifestations of schizophrenia or risk factors for the disease has not been determined.
Neuropathologic, Brain Imaging, and Neurophysiologic Findings
Notably lacking in all the previously described reports of developmental changes are neuropathologic data. Dunlap, in 1928, in a critical analysis, repudiated all earlier interpretations of cellular alterations that had been reported in the brains of schizophrenic patients. He pointed out that many of them, such as dark "sclerotic" nerve cells, were artifacts and that the presence of lipofuscin was a nonspecific age change. He also asserted that the neuronal loss described by Alzheimer was based on impression and could not be corroborated by quantitative methods. Similarly, the claim of Oscar Vogt of neuronal loss in the cortex was rejected by his contemporaries, Spielmeyer and Scholz, who were unable to find any consistent cellular abnormality in schizophrenia. Spielmeyer, in a critical study of the problem in 1930, concluded that such changes as had been described up to that time could not be clearly distinguished from the normal, and that the more marked changes in some cases were due to coincidental causes. Corsellis, on the basis of yet another thorough review of the neuropathologic data in 1976, found no reason to deviate from Spielmeyer's view. The uncertain neuropathologic findings were responsible for the enigmatic categorization of schizophrenia as a "functional" disorder, i.e., a disorder with no structural basis.
Nonetheless, there has been a general sense that while the number of neurons in the gray matter is normal, the pyramidal cells are smaller and more densely packed, resulting in a thinning of laminae II and III. These cytoarchitectonic changes have been the most difficult to interpret and to confirm. Capricious methods such as the rapid Golgi stain indicate that density of dendritic spines is decreased in the frontal and temporal cortex of chronic schizophrenic patients.
A number of more contemporary reports using special cell-labeling studies have found cytoarchitectonic abnormalities in the brains of schizophrenic patients. For example, Akbarian and colleagues, following previous similar findings, have described an aberrant distribution of interstitial neurons in the frontal lobe white matter. These cells have their origin in the embryologic subplate that guides neuronal migration, and the inference is that the abnormally migrating cells have formed aberrant neuronal connections. Benes and colleagues observed that the number of small neurons was reduced in at least one layer (usually layer II) of the anterior cingulate cortex. These are gamma-aminobutyric acid (GABA)–releasing (inhibitory) neurons. Benes also noted that the arrays of macrocolumns of cortical neurons were smaller in the occipital lobes (vertical axons increased in number). Newer studies also describe a paucity of gabanergic, inhibitory interneurons (so-called chandelier cells) in the prefrontal cortex (Woo et al). These observations suggest a developmental rather than an acquired lesion. The absence of gliosis supports but does not prove that the developmental disorder occurs prenatally.
The advent of CT and subsequently of MRI of the brain provided a new stimulus to the anatomic study of schizophrenia. Johnstone and coworkers were the first to describe ventricular enlargement and sulcal widening in 18 patients and correlate these findings with dulling of intellect and affect. In a study of 58 chronic schizophrenics younger than age 50 years, Weinberger and colleagues (1979) found enlargement of the lateral ventricles in 40 percent. In 9 of 11 CT studies, the third ventricle was found to be enlarged, and in 14 of 17 the sulci were widened. In 15 pairs of monozygotic twins, one of whom had schizophrenia, the anterior hippocampi were found to be smaller and the lateral and third ventricles larger in the affected twin (Suddath et al). Shenton and colleagues demonstrated a reduction in the volume of gray matter in the posterior part of the left superior temporal gyrus, which includes Heschl gyri and the planum temporale. The degree of volumetric reduction correlated roughly with the severity of the thought disorder. A reduction in volume of the superior temporal gyrus has also been associated with the occurrence of auditory hallucinations (Barta et al). Other MRI studies have shown a volumetric change in the gray matter of the left hippocampus, parahippocampal gyrus, and amygdala (in right-handed patients). Equally compelling is the finding that young individuals having two or more relatives with the disease, and therefore being at risk for developing schizophrenia, have certain volumetric brain changes detected by imaging studies (Lawrie et al). In unaffected relatives, the left hippocampal–amygdaloid region was smaller than in healthy people, but slightly larger than in affected relatives.
In an attempt to organize the neuroradiologic findings, Murray and coworkers raised the possibility that there are two types of this disease: one with ventricular enlargement and a negative family history and the other with normal ventricles and a positive family history. In the first group of sporadic, "acquired" schizophrenia, environmental factors, such as birth injury and EEG abnormalities (see later), were considered to be more frequent. In summarizing the many cerebral changes observed in schizophrenic patients, Harrison concluded that several are quite consistent. These include mild enlargement of the lateral and third ventricles; decreased cortical volume, perhaps disproportionate in the temporal lobe; microscopically, diminution in size of cortical and hippocampal neurons; a diminished number of neurons in the dorsal thalamus; and a notable absence of gliosis.
EEG data, for the most part not useful, were alluded to earlier. Detailed neuropsychologic testing has disclosed deficits in attention and abnormalities of the P300 waves (cortical "event-related" potentials). These deficits correlate with reduced cognitive activation activity in functional MRI. It is unclear, however, if these changes represent primary defects or are secondary to an inherent lack of motivation.
Attention has also been drawn to the regional alterations of cerebral blood flow in chronic stable schizophrenic patients, as revealed by positron emission tomography (PET) and functional MRI. Weinberger and colleagues (1986) and Liddle and Barnes have reported a decrease in blood flow in the prefrontal areas during cognitive performances. Friston and associates found consistent abnormalities in the left parahippocampal region in all forms of chronic schizophrenia. Studies of regional glucose metabolism and postmortem norepinephrine measurements have yielded equivocal data, although most patients show a reduction in glucose metabolism in the thalamus and frontal cortex. Several lines of investigation point to the medial part of the left temporal lobe and related limbic and frontal systems as being the focus of a developmental abnormality (see Tsuang et al and Friston et al for pertinent references). According to Sabri and colleagues, the inconsistent findings on functional imaging may be accounted for by correlations between certain blood flow patterns and specific symptoms. For example, the formal thought disorder corresponded to increased flow in the frontal and temporal regions, whereas delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. Our colleague Silbersweig and his coworkers have performed PET studies in schizophrenic patients while they were experiencing auditory hallucinations and found increased blood flow mainly in both thalami, left hippocampus, and right striatum, but also in the parahippocampal, orbitofrontal, and cingulate areas. One of their drug-naive patients with visual and auditory hallucinations showed activation in these regions.
Alterations in Neurotransmitters
When certain hallucinogens, such as mescaline and lysergic acid diethylamide (LSD), were first observed to induce hallucinations and abnormalities of thinking, it was hoped that they might provide experimental models of schizophrenia. This hope was never realized but there are instances, difficult to interpret, in which these drugs have induced a prolonged relapse in a schizophrenic patient. Similarly, when methionine, a potent source of methyl groups, was observed to exacerbate the symptoms of some schizophrenic patients, it was thought that a primary metabolic fault had been discovered; increased serum concentrations of dimethoxyphenylethylamine and N-methylated indoleamines lent support to this idea. Again, none of these observations has been unequivocally corroborated.
The formerly leading biochemical hypothesis is based on the response of psychotic symptoms to phenothiazine and related medications, which implicates the dopaminergic system of the temporal lobe (see review by Carlsson). The evidence for this is circumstantial but is supported by observations that antipsychotic drugs reduce the electrical activity of mesolimbic dopaminergic neurons in experimental models. Furthermore, there have been several demonstrations of increased concentrations of dopamine or its metabolite, homovanillic acid, in schizophrenic brains obtained at autopsy. The finding that dopamine receptors are organized in two systems, one limbic and the other cortical, has led to an expanded but speculative hypothesis that an excess of dopaminergic activity in the mesolimbic system gives rise to the positive symptoms of schizophrenia—i.e., psychosis—whereas a diminished activity in the mesocortical system accounts for the negative symptoms. The involvement of the mesolimbic system, which plays a role in attention, has prompted further speculation that the thought disorder of schizophrenia is attributable to a breakdown of the normal "filtering" of stimuli reaching cognition. As mentioned earlier, it has been found that a variant in the gene for COMT that enhances metabolism of dopamine is overrepresented in schizophrenia, further incriminating a disorder of dopaminergic neurotransmission in the pathophysiology of this disease (Egan et al).
As pointed out in the review by Freedman, however, the dopamine hypothesis has many weaknesses, the most prominent of which is the relative ineffectiveness of dopamine-blocking drugs in alleviating many aspects of the disease. The complexity of dopamine systems and their interaction with other neurotransmitter circuits make a simplistic mechanism unlikely.
More recently, a hypothesis based on changes in the serotoninergic system was proposed. As with the dopaminergic model, attention was drawn to mechanisms relating to a new class of antipsychotics (clozapine, risperidone), which have major effects on the serotonin system and were found to ameliorate the psychosis. Several groups have reported alterations in serotonin receptors in the brains of schizophrenic patients (see later). A further connection is based on the finding by Williams and colleagues of an allelic variation in the gene on chromosome 13 encoding for a serotonin receptor (5-HT2A) that confers a susceptibility to schizophrenia. The variation in this gene is insufficient to explain the presence of the disease in any one individual, if for no other reason than that many patients who are homozygous for the suspect allele do not develop schizophrenia. Perhaps a nearby region relating to the receptor may be at fault through linkage disequilibrium (see commentary by Harrison and Geddes). A third currently favored biochemical hypothesis derives from the psychosis syndrome produced by chronic ingestion of phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) antagonist. This implicates the glutaminergic system, but it must be pointed out that the dopaminergic and glutaminergic systems converge on certain cortical neurons and that glutaminergic release is modulated in several places in the brain by dopamine.
A great variety of physiologic and endocrine differences between schizophrenic and healthy subjects have been claimed. None has proved to be significant. Because psychoses may complicate corticosteroid administration and certain endocrine disorders (Cushing syndrome, thyrotoxicosis, see later), there have been many attempts to uncover such abnormalities in the schizophrenic patient. All have failed.
The notion that psychosocial factors play an important role in the genesis of schizophrenia was a recurrent theme in older psychiatric writings, but is now given little credence. Prominent in these early writings was Freud's view that the schizophrenic process represents a fixation at an early autoerotic stage of sexual development. There is no way of affirming or refuting this proposition. The same can be said for the many suggestions that disturbed intrafamily relationships engender schizophrenic traits or possibly provoke psychosis in persons who are genetically vulnerable. Behind all these suggestions was the notion that disturbed interpersonal relations in the family in some way interfered with the normal maturation of personality. The extent to which these aberrations of family relationships are primary or secondary cannot be ascertained.
The often-cited observations of Harlow on the deleterious effects of maternal and peer deprivation in primates opened the possibility that similar deprivations in humans may be responsible for the development of schizophrenia. However, such severe degrees of familial deprivation have rarely been documented in humans and when they were, as in some orphans, the effects were only transitory.
From a neurologic standpoint, the main initial distinction to be made is between an acute schizophrenia-like psychosis and the chronic disease, schizophrenia. The acute schizophreniform illness takes the form of a delusional-hallucinatory syndrome in which there is little if any disturbance of consciousness. Although such a syndrome is characteristic of schizophrenia, it may occur in the manic phase of bipolar disease, encephalitis, temporal lobe epilepsy, chronic amphetamine intoxication, withdrawal from alcohol after a sustained period of intoxication, and most often in the emergency department, from PCP, angel dust, LSD, and other drug intoxications. On rare occasions it is seen with postpartum psychosis (see further on) and with certain endocrine and metabolic disorders in which consciousness is not impaired. Thus whenever this syndrome is recognized, these several causes need to be differentiated. On our services, less than one of five of the acute schizophreniform psychoses has proved to be a result of the disease schizophrenia. This distinction is made by the premorbid history and the course of the illness. If the patient had been reclusive, withdrawn, and socially maladapted and does not seem to recover fully from the acute psychosis, then the diagnosis of schizophrenia is more likely. Lacking these features, and in particular with a full remission, one assumes the occurrence of hypomania or of a toxic-metabolic psychosis, which can be detected by laboratory screening for drugs and endocrine diseases. Only 10 percent of patients with classic schizophrenia will have such an acute episode. Adherence to the criteria enumerated earlier, particularly to those devised by Feighner and colleagues will avoid most errors in diagnosis.
It is the present authors' opinion that the status of acute schizophrenia and of the so-called schizothymic and schizoaffective states brings to light a crucial nosologic problem. Is the traditional separation of depressive disease, bipolar disease, and schizophrenia biologically sound? The suggestion is that they are linked in some way by these transitional forms. Neurologists should keep an open mind about these and other theoretical problems that lack a firm genetic and neuropathologic basis.
In addition to the acute schizophreniform psychosis described earlier, the authors have encountered the greatest difficulties in the diagnosis of schizophrenia in the following clinical situations:
A patient with a healthy family and premorbid history with an acute illness having many of the typical features of schizophrenia but associated with confusion, forgetfulness, and/or clouding of consciousness. Mood change may be prominent. Thus the illness combines the features of an affective disorder, schizophrenia, and a confusional state. This syndrome is characteristic of chronic hallucinogenic drug use, particularly phencyclidine intoxication, corticosteroid psychosis (drug-induced or Cushing disease), thyrotoxic psychosis, and puerperal psychosis. Usually recovery is complete, and schizophrenia is excluded by the fact that the patient remains well. This may be a form of "schizoaffective" disorder.
Adolescents and young adults whose social relationships are disorganized and who are unusually sensitive, resentful, rebellious, fearful, discouraged, in trouble with school authorities and the law, and using drugs. The latter may have caused seizures, hallucinations, and withdrawal symptoms or may have resulted in addiction. Such patients are usually classified as having a borderline personality or "sociopathy" that appears to go back several years. These types of personality disorders and social maladjustments turn out not to be schizophrenia.
There is another related type of diagnostic problem, arising in an individual who has been only marginally competent because of personality problems and many vague neurotic and hypochondriacal symptoms, often requiring prolonged psychotherapy. Many such individuals will indeed be found to have simple schizophrenia (so-called pseudoneurotic form). Here errors in diagnosis usually result from a failure to assess mental status carefully and to ascertain the life profile of the disorder.
In a chronic delusional-hallucinatory state in a chronic alcoholic patient (chronic alcoholic hallucinosis) it will usually be disclosed that the illness began when alcohol was withdrawn, after a period of sustained drinking, and at first took the form of an acute auditory hallucinosis characterized by threatening, exteriorized auditory hallucinations to which the patient's emotional reaction was appropriate. Only later do a few of these patients drift into a quiet hallucinatory, mildly paranoid state, with rather bland affect. Evidence of the prepsychotic schizoid personality cannot be detected and there is usually no family history of schizophrenia. Cases of this type with which we are familiar had their onset between 45 and 50 years of age, i.e., much later than the usual age of onset of schizophrenia.
A patient who is confused or stuporous and seemingly catatonic-negativistic, refusing or unable to speak, to execute commands, or to be activated in any way. If signs of focal cerebral or brainstem disease are absent, one is tempted to make a diagnosis of catatonic schizophrenia, not appreciating that catatonia as a phenomenon may be indistinguishable from akinetic mutism (see Chap. 17). It may also appear with widespread disease of the associational cortices and as mentioned earlier, with severe depression, certain confusional states, and hysteria. The authors have seen cases of hypoxic and other metabolic encephalopathies, Schilder disease, certain storage diseases, and Creutzfeldt-Jakob disease mistaken for schizophrenia because of failure to adhere to this principle.
A patient with temporal lobe epilepsy who, apart from intermittent psychomotor seizures, has long periods (weeks or months) of hallucinations, delusions, bizarre behavior, and disorganization of thinking. Such a mental disturbance reflects the presence of a persistent state of temporal lobe seizures (temporal lobe status epilepticus), which in some cases has been demonstrated by depth electrodes to originate in the amygdaloid or other medial temporal areas. The nature of the disturbances of emotionality and mentation in such patients, a somewhat controversial subject, is discussed in Chaps. 16 and 25.
Schizophrenic patients with prominent depressive symptoms who have made repeated suicide attempts pose an exceptionally difficult problem. They were referred to in the past as schizothymic and to this day it is not certain whether they have schizophrenia, a chronic depressive illness (dysthymia), or both ("schizoaffective"). When in remission, patients with affective disorders are usually normal, whereas those with schizophrenia are not.
One should always be hesitant to make the diagnosis of schizophrenia during childhood, although such a diagnosis has been entertained in children who have a variety of developmental and adjustment problems and who at some time become psychotic, i.e., they become excited, depressed, or hallucinatory and express bizarre ideas. There is no evidence that such children go on to have schizophrenia later in life. And although what are thought to be "schizoid" traits may be recognized in childhood, a frank psychosis is hardly ever recorded at this age. Of particular importance in such children is to exclude the presence of metabolic errors, mental retardation, or an early-onset depressive illness. Similarly, childhood autism and particularly its milder forms, such as Asperger syndrome discussed in Chap. 38, should not be confused with schizophrenia. That the incidence of schizophrenia is not increased in the families of autistic children supports the idea that the two are separate diseases.
The special problem of mania that manifests for the first time as a confusional-encephalopathic state was discussed in Chap. 52.
The aims of treatment are to suppress psychotic symptoms, ameliorate the disorder of thinking and the apathetic state, prevent relapse, and optimize social adjustment. It is often possible, once the diagnosis of schizophrenia is established and the optimal regimen of medication decided upon, for a general physician to share the responsibility for following the patient with a psychiatric social worker or nurse. The physician soon becomes accustomed to the particular pattern of the patient's psychotic behavior and can help support the patient and his family during difficult periods. Relapse with psychotic decompensation demands drug therapy, and if there is a hazard of injury or suicide or difficulty in management at home, hospitalization becomes necessary. Many general hospitals and specialized psychiatric institutions have facilities for the management of such patients; state hospitals and other institutions are able to provide long-term treatment. The aim of hospitalization is to protect the patient, relieve the family of the need for constant vigilance and supervision, and ensure the administration of drugs until the exacerbation spends itself. Later, instead of mere custodial care, the patient needs a supervised program of planned activities, vocational and milieu therapy, often in a "halfway house," which involves the patient as a contributing member during the more chronic phases of the disease. If medication is successful in preventing progressive decompensation, the patient can many times return to the family and community. It is invaluable to have a competent social worker or nurse maintain frequent contact with the patient and his family and ensure continuity of medication.
The modern era of treatment of schizophrenia began in 1952, with the incidental demonstration by the French surgeon Henri Laborit of the antipsychosis properties of chlorpromazine. Subsequently, a large number of other phenothiazines have been used to treat chronic and acute psychosis. Treatment consists essentially of the administration of one of several similar antipsychotic medications. The various classes of antipsychotic drugs, their mode of action, and neurologic ("neuroleptic") side effects are discussed in Chap. 43.
The newer, second generation of "atypical" nonphenothiazine antipsychosis drugs that have complex effects on the dopamine and serotonin systems are now used in preference to the standard dopamine antagonists, the phenothiazines and the butyrophenones. They are "atypical" in that their extrapyramidal side effects are far less than that for the phenothiazines. They all serve to calm the patient, blunt emotional responses, and reduce hallucinosis and aggressive and impulsive behavior, leaving cognitive functions relatively intact. The main side effects, pertaining mostly to the phenothiazine group, are summarized in Table 53-1 and in Chap. 43 (see also the review by Freedman and the chapter by Baldessarini). The antipsychotic action of these drugs is more impressive in the short and intermediate term than over the long term, although some data suggest that they are also of value in preventing relapses. Negative symptoms (apathy and withdrawal) respond less well than positive ones, and it is generally acknowledged that 10 to 20 percent of patients respond little or not at all to medication.
Table 53-1 Extrapyramidal Syndromes Associated with Typical Neuroleptic-Antipsychotic Agents ||Download (.pdf)
Table 53-1 Extrapyramidal Syndromes Associated with Typical Neuroleptic-Antipsychotic Agents
Muscle spasms; tongue, face, neck, back; terrifying; rarely fatal from asphyxia
1–5 d or with each injection of decanoates
Injected antiparkinsonism agents, then oral
Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait
Evolves slowly in 1–4 wk, often persists
Oral anticholinergics, amantadine; dopaminergics are too risky
Catatonia, stupor, fever, unstable pulse, blood pressure and respirations, elevated serum creatine kinase and myoglobin; can be fatal
Days to weeks
Hypothalamic and extra-pyramidal dysfunction likely; not muscle calcium influx problem as in hyperthermia of anesthesia
Stop neuroleptic; expert intensive care; dantrolene or bromocriptine may help
Rare perioral tremor; usually reversible
Months to years
Motor restlessness with anxiety and agitation
Can start immediately and usually persists
Unknown; adrenergic component?
Reduce dose or change drug propranolol; antiparkinson agents and benzodiazepines
Oral-facial dyskinesia choreoathetosis, variable dystonia; often slowly reversible; rarely progressive
6–120 mo; worse when drug stopped
Dopaminergic excess likely
Prevention best; treatment unsatisfactory; vitamin E (400–1200 U/d) may help; slow spontaneous remission
Clozapine, olanzapine, risperidone, quetiapine, and others listed in Table 53-2 are the more recently introduced atypical drugs with incompletely defined pharmacologic properties but with narrower affinities for certain receptors. In addition to their reduced motor side effects, they produce clinical improvement in about half of patients who have proved to be unresponsive to other antipsychotic medications. These drugs bind to and inhibit serotonin receptors and, to some extent, to dopamine receptors (Meltzer and Nash), but have a much lower affinity for striatal dopamine receptors, thus providing a major advantage—the absence of immediate or tardive extrapyramidal side effects. This has led most psychiatrists to use one of the newer drugs, rather than the phenothiazines, as a first choice. The addition of a second drug, specifically combining clozapine with risperidone was not found to be useful in the trial conducted by Honer and colleagues. Moreover, in another one of the effectiveness trials sponsored by the National Institutes of Mental Health, Lieberman and colleagues ("CATIE" Investigators) found that the majority of chronic schizophrenics discontinued their antipsychosis drugs within 18 months. Among the medications they compared, olanzapine was slightly more effective than quetiapine, risperidone, and ziprasidone; of equal interest, the phenothiazine perphenazine was equivalent in efficacy and tolerability to the last three second-generation (atypical) drugs. Approximately 1 percent of patients treated with one of the most effective drugs, clozapine, develop leukopenia, which may prove fatal; there is less risk with the related agent, olanzapine, but leukopenia and agranulocytosis have been reported in rare instances with it as well. Orthostatic hypotension, tachycardia, fever, and hypersalivation may be troublesome in the first days and weeks of therapy with any agent in this class. Risperidone is a potent serotonin and dopamine receptor antagonist. Low doses reportedly attenuate the negative symptoms of schizophrenia (apathy, emotional withdrawal, lack of social interaction) and the incidence of extrapyramidal side effects is low provided that the dosage is kept below 6 mg daily.
Table 53-2 Newer Antipsychotic Drugs with Limited Extrapyramidal Side Effects ||Download (.pdf)
Table 53-2 Newer Antipsychotic Drugs with Limited Extrapyramidal Side Effects
TARGET OR MAXIMAL DOSE
POTENTIAL SIDE EFFECTSa
Orthostatic hypotension, transaminase elevation, hyperprolactinemia
25 mg bid
Orthostatic hypotension, cataracts, transaminase elevation
12.5 mg bid
Agranulocytosis, transient fever, anticholinergic activity, hyperglycemia
1 mg bid
3 mg bid
Less weight gain than others in this class. Prolongation of QT interval
Less weight gain than others in this class. Prolongation of QT interval
Table 53-2 indicates typical dosages of these antipsychotic drugs. In the higher dose ranges, parkinsonian features may nonetheless appear. Tardive dyskinesias, however, are infrequent. Common to all the drugs in the class, however, is variable weight gain and aspects of the "metabolic syndrome" including hyperlipidemia and hyperglycemia. With long-term treatment this may accumulate to 20 percent of the patient's original weight. In a few cases, the newer generation antipsychotics have induced some obsessive-compulsive symptoms. According to Leucht and colleagues who performed a meta-analysis of extrapyramidal symptoms and various drugs, low-potency first-generation antipsychotics (excluding haloperidol) may have comparable complications to the new generation of drugs when dose-equivalent amounts are given. Most clinicians seem not to agree with this perspective. Several series have also suggested that the atypical antipsychosis drugs have a risk of ventricular arrhythmias and sudden death compared to conventional medications. However, the series collected by Ray and colleagues indicates that the frequency of these complications, while increased approximately twofold compared to nonusers, are the same for older and newer drugs when adjusted for medication dose.
The optimal daily dose for treatment of an acute psychotic episode is in the range of 10 to 20 mg daily of haloperidol or the equivalent amount (400 to 800 mg) of a phenothiazine such as chlorpromazine or escalating doses of the newer agents, as listed in Table 53-2. The administration of much higher doses of phenothiazines or haloperidol is popular with some psychiatrists, but this practice entails serious risks and the advantages have not been demonstrated in controlled trials (see Kane and Marder). Attempts are made to individualize and eventually lower the dosage until the patient's behavior suggests that a relapse is imminent. Antidepressants and lithium have also been used in those schizophrenic patients with prominent affective symptoms. Electroconvulsive therapy (ECT) is now seldom used except in patients who are catatonic or severely agitated or who have prominent affective symptoms.
To some extent, the extrapyramidal side effects of haloperidol and the phenothiazines can be prevented or at least minimized by the simultaneous parenteral administration of antihistaminic drugs—e.g., diphenhydramine, 25 mg tid—and the anticholinergic drugs used in the treatment of Parkinson disease—e.g., benztropine, 0.5 to 1 mg bid. However, the latter drugs must be given cautiously for they may interfere with the action of the antipsychotic drugs and, if given in large doses, themselves induce a toxic confusional state. If it becomes necessary to treat the extrapyramidal side effects, it is usually possible to eliminate the anticholinergic drugs after 2 to 3 months without a return of motor symptoms. In chronically medicated patients, 20 to 40 percent of whom develop tardive dyskinesias, an increased dose of the antipsychotic drug may suppress the dyskinesia, but only temporarily. The most dreaded complication of pharmacotherapy is the neuroleptic malignant syndrome. The nature and management of this complication and of the more common problem of tardive dyskinesias are discussed in Chap. 43.
With modern drug therapy and supportive psychiatric management, fully 60 percent of schizophrenic patients will recover sufficiently to return to their homes and become socially adjusted to a varying degree (about half of this group can engage in some occupation). Approximately 30 percent remain severely handicapped and 10 percent remain hospitalized.