Indications for Antipsychotics
The indication for antipsychotics is the presence of psychosis in such disparate disorders as
Schizophrenia
Schizophreniform disorder
Schizoaffective disorder
Delusional disorder
Brief psychotic disorder
Psychosis secondary to a nonpsychiatric medical condition
Depression or mania with mood-congruent or mood-incongruent psychotic symptoms
Because the most common condition studied is schizophrenia, this is the primary disorder discussed. We also consider the “schizophrenic spectrum” (e.g., schizophreniform, schizoaffective, and delusional disorders); mood disorders with psychotic features; and various nonpsychotic conditions (e.g., in the developmentally disabled) for which antipsychotics are used. The role of these agents for bipolar disorder is discussed in Chapter 10 and for delirium and dementia in Chapter 15.
Schizophrenia
HISTORY OF THE CONCEPT
The identification of this illness in modern psychiatry began with Kahlbaum (1), who described catatonia; Hecker (2), who described hebephrenia; and Kraepelin (3), who described dementia praecox.
The syndrome identified by Kraepelin is similar to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) (4) diagnosis of schizophrenia and to the Research Diagnostic Criteria (RDC) definition of chronic schizophrenia. It usually begins in adolescence or young adulthood and often follows a progressively deteriorating course, with few patients ever achieving complete recovery
In contrast to Kraepelin, who emphasized the progressive course and poor outcome, the Swiss psychiatrist Eugen Bleuler (5) used a much broader concept of schizophrenia. Focusing on the thought disorder and the inconsistent, inappropriate, and disorganized affect, he identified four fundamental symptoms:
Autism
Ambivalence
Association disturbance
Abnormal affect
He also emphasized the incongruent relationships among thought, emotions, and behavior. Unlike his predecessors, he did not believe hallucinations and delusions were fundamental to the schizophrenic process, considering them accessory symptoms.
Historically, the diagnosis of schizophrenia in the United States was based on Bleulerian and psychoanalytic theory, partly due to the greater influence of the latter group in the 1950s and 1960s. In contrast, European psychiatry used a narrower set of diagnostic criteria similar to Kraepelin’s approach.
Psychoanalytic theoryconceptualized schizophrenia as the use of primitive defenses (e.g., denial) against anxiety in the presence of a weakened ego. Because these patients are unable to use more mature defenses against id-derived impulses, they regress to a more primitive level
of functioning, with the intrusion of primary process thinking into consciousness. Because this condition was seen as a severe regression, almost any significantly ill patient could be diagnosed as suffering from schizophrenia. If this hypothesis were true, anxiolytics should have an antipsychotic effect, but that is typically not the case. Further, antipsychotics have a different biochemical action (e.g., dopamine and serotonin receptor blockade) than the antianxiety agents (e.g., modulation of γ-aminobutyric acid [GABA] receptor-chloride ion channels), constituting both a mechanistic and a clinical difference between these two drug classes. More importantly, the relative lack of efficacy with anxiolytics undermines the theory that anxiety is critical to the pathogenesis of schizophrenia.
of functioning, with the intrusion of primary process thinking into consciousness. Because this condition was seen as a severe regression, almost any significantly ill patient could be diagnosed as suffering from schizophrenia. If this hypothesis were true, anxiolytics should have an antipsychotic effect, but that is typically not the case. Further, antipsychotics have a different biochemical action (e.g., dopamine and serotonin receptor blockade) than the antianxiety agents (e.g., modulation of γ-aminobutyric acid [GABA] receptor-chloride ion channels), constituting both a mechanistic and a clinical difference between these two drug classes. More importantly, the relative lack of efficacy with anxiolytics undermines the theory that anxiety is critical to the pathogenesis of schizophrenia.
Another perspective comes from family systems theory, which characterizes the schizophrenia patient’s family as having disordered communication, with various members playing unusual or aberrant roles. According to this theory, patients experience “double binds” when faced with contradictory expectations (6). Related controversial hypotheses held that the “schizophrenogenic” mother was the critical factor and then later that the schizophrenia patient’s father also played a significant role (7,8). Intensive therapy, in the context of in-hospital separation from the family, was considered the treatment of choice. In contrast to classic psychodynamic therapy which focuses on the individual patient, this approach attempts to resolve conflicts in the family system as well as in the patient’s psyche. Typically, this involves sessions that include all or as many family members as possible. Thus, even though one member is identified as the patient, it is the disturbed communication and interactions among all family members that is the focus of therapy. Evidence from genetics and other areas has not supported the theory that parenting style can cause schizophrenia. On the other hand, therapeutic approaches that improve the family environment can improve outcomes (9). This approach and the therapeutic approaches discussed later in this chapter are most effective when medication is used concurrently
CATEGORICAL AND DIMENSIONAL APPROACHES
Kraepelin believed that schizophrenia and bipolar disorder were two separate illnesses that are diagnosed based on clinical symptoms and course. Recent findings in genetics and the neurosciences, however, have called this dichotomy into question. To this date, there is no clear disease etiology or pathologic process that defines either illness. Rather, the two disorders appear to be syndromes with some overlap of symptoms and common neural impairments (10). Also, genetic studies find that schizophrenia and bipolar disorder share a number of risk genes and that family coaggregation of these two disorders supports a continuum model in understanding their relationship (11,12). Thus, our views of these two illnesses and their relationship are likely to be refined as new information emerges from research in genetics and neurobiology.
DESCRIPTIVE PHENOMENOLOGICAL APPROACH
At one time, schizophrenia was broadly defined and almost all patients with moderate to severe psychotic symptoms were given this diagnosis. In contrast, bipolar disorder was defined very narrowly and only diagnosed in classic cases. Indeed, the prevalence of hospitalized patients diagnosed with schizophrenia in the United States was once almost double that in Great Britain. Conversely, mood disorders were diagnosed five times more often in Great Britain than in the United States. To explore these differences, the United States and the United Kingdom conducted a systematic, structured interview research study of patients in New York and London (13). The Present State Examination (PSE) was used to standardize the diagnostic process. As a result, many schizophrenia patients in New York were rediagnosed as having mood disorders, usually psychotic depression or mania. This project also demonstrated that many patients in the United States diagnosed with schizophrenia would have received a diagnosis of mania or depression in the United Kingdom.
American psychiatry’s approach to diagnosis began to change substantially with the development of specific diagnostic criteria (as well as the availability of effective treatments for bipolar disorder). These criteria were initially formulated by Feighner et al. (14) and later expanded by Spitzer et al. (15) into the RDC, which were the basis of the DSM-III, DSM-III-R, DSM-IV, and DSM-IV-TR (4,16). In addition to being more descriptive in orientation, this approach recognized the
importance of empirical data to develop explicit inclusion and exclusion criteria, which can then be studied for reliability and validity.
importance of empirical data to develop explicit inclusion and exclusion criteria, which can then be studied for reliability and validity.
EPIDEMIOLOGY
Throughout the world, the lifetime prevalence of schizophrenia is about 1%. Although the prevalence is slightly higher in the lower socioeconomic classes, data from a number of countries indicate that the social class distribution of the parents of schizophrenia probands is similar to that of the general population (17). This supports the “social drift hypothesis,” which postulates that the increased concentration of patients with schizophrenia in the lower socioeconomic stratum is the result of their impaired functioning.
Schizophrenia patients tend to be born during the late winter or early spring in the Northern hemisphere, an observation that suggests the possibility of a viral infectious process in the mother and the fetus, most probably during the first trimester (18). One epidemiologic report, however, indicates that viral exposure in utero may not be critical. Rather, it postulates that postpartum stressors in relationship to the number and age distribution of siblings may be more important (19). There is also evidence that the mothers of schizophrenia patients have a higher incidence of obstetric complications (20,21) and that individuals with schizophrenia have more soft neurologic signsand developmental anomaliesassociated with fetal damage (20). The relationship between obstetric complications and schizophrenia, however, is not clearly characterized (22). Although women have an onset of illness about six years later than men and the course of illness is somewhat milder, they have an increased incidence of illness onset at menopause, so the lifetime incidence is essentially identical.
SYMPTOMS
Many conceptualize schizophrenia as a heterogeneous condition. Within this general categorization, patients may present with symptoms that can vary over the life cycle. Thus, some may manifest soft neurologic signs early in life, develop florid positive symptoms in adolescence or young adulthood, and ultimately experience predominantly negative symptoms (or deficit syndrome) later in life. Others may develop positive symptoms only later in life which do not develop into the full deficit syndrome. Implicit in these observations is the possibility of varying genetic, developmental, and environmental influences, with the common underlying diathesis being psychosis (23).
Schizophrenia as presently conceptualized is characterized by symptom complexes such as positive symptoms (e.g., delusions and hallucinations) occurring in a clear sensorium. It is also associated with cognitive disturbances such as deficits in memory, attention, and executive functioning (24). Negative symptoms (e.g., alogia, asociality, anergy, avolition) may be primary to the disorder (i.e., the deficit syndrome) or secondary to such concurrent issues as dysphoria or medicationinduced neurologic adverse effects. Mood disturbances are also common. For example, depression frequently occurs, is associated with increased suicidal behavior, may worsen with first-generation antipsychotics (FGAs), and may improve with second-generation antipsychotics (SGAs) or the addition of an antidepressant (25,26). This information is important, given the increased suicidal behavior in schizophrenia patients (27). Common comorbid disorders include substance abuse and various anxiety-related symptoms (e.g., panic attacks, obsessive-compulsive features) (28,29 and 30).
Delusions are false beliefs that the patient maintains in the face of incontrovertible, contradictory evidence. The schizophrenia patient often has no insight that these beliefs are false but, rather, maintains a firm conviction in them. Schizophrenia is characterized by a variety of delusions, of which the persecutory type predominates. Other delusions often involve bizarre bodily changes. In contrast to delusional disorder, these convictions are not as well formed and occur in the context of other psychotic symptoms (e.g., hallucinations, negative symptoms).
Hallucinations are false perceptions in the absence of a real sensory stimulus. They are typically auditory, consisting of voices that arise from both within and outside the body. They may be threatening, can ridicule, or may urge patients to objectionable acts (i.e., command hallucinations). Visual hallucinations are also relatively frequent, but olfactory (e.g., unpleasant smells arising from the patient’s own body) or tactile hallucinations (e.g., animals crawling inside one’s body or insects crawling over the skin) are less common.
Catatonia (withdrawn type) is characterized by prolonged immobility, waxy flexibility, posturing, and grimacing. Because catatonic symptoms
can also occur in other types of psychosis, they are not specific to schizophrenia.
can also occur in other types of psychosis, they are not specific to schizophrenia.
Schneiderian, first-rank symptoms describe hallucinations and delusions thought to be typical in schizophrenia (31). Examples include
Audible thoughts (i.e., voices speak the patient’s thoughts out loud)
Voices arguing (e.g., two or more voices argue or discuss issues, sometimes referring to the patient in the third person)
Voices commenting on the patient’s behavior
Somatic passivity believed to be imposed by outside forces
Thought withdrawal by outside forces, leaving the patient feeling as if his or her mind is empty
Thought insertions by outside forces
Thought broadcasting (i.e., thoughts escape from the patient’s mind and are overheard by others)
Impulses, volitional acts, or feelings that are not one’s own but are imposed by outside forces
Delusional perceptions (i.e., the patient attributes delusional meaning to normal perceptions)
Although positive symptoms are usually the focus of acute intervention and are at least partially responsive to antipsychotics, cognitive, mood, and negative symptoms are generally more debilitating and are less responsive to these agents.
COURSE OF ILLNESS
Several studies investigated outcome in schizophrenia patients before antipsychotics were available (32,33). They generally found that an early onset of insidious symptoms, most characterized by negativity and a gradual deterioration into psychosis without clear precipitating events, was predictive of a poor outcome. These patients often demonstrated asocial and bizarre behavior during childhood and typically never married (34).
Longitudinal follow-up of carefully defined schizophrenia shows that approximately 95% of patients have a lifetime illness and are rarely rediagnosed later as having a mood disorder (35,36). They also often have the following characteristics:
Poor performance in school (37)
Slightly lower IQ (38)
Abnormalities in cognitive and motor development
Visual-motor incoordination
Proprioceptive and vestibular difficulties
In contrast, patients with good premorbid personalities and more typical functioning during childhood who later developed schizophrenia, especially in the face of massive precipitating events, had better outcomes. They also tended to have family histories of mood disorders as well as affective features as part of their own illness, which led to the concept of process versus reactive schizophrenia (i.e., poor prognosis vs. good prognosis) (39,40).
Increasingly, studies are also considering issues of recovery, functionality, and quality of life. For example, a post hoc analysis of data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study indicated that both psychotic symptoms and neurocognitive deficits independently decreased quality of life (41). Further, data from a crossnational study (i.e., New York City and rural Sweden) indicate that cultural and support systems can lead to very different real-world outcomes (i.e., living independently) despite the same levels of disability (42).
BIOLOGIC CORRELATES
Neuroimaging
In 1976, Johnstone et al. (43) applied the then newly developed computed tomography (CT) imaging technology to study schizophrenia patients and reported slightly larger ventricles as compared with matched control subjects. Indeed, these abnormalities were first noted in 1927, when Jacoby and Winkley (44) reported enlarged ventricles using pneumoencephalography, with a number of open studies subsequently confirming this result in the 1930s. Furthermore, patients with larger ventricles were usually more cognitively impaired and had fewer positive and more negative symptoms. The suggestion of enlarged ventricles in association with negative symptoms spurred even more interest in this distinction. Subsequent studies with CT imaging and later with magnetic resonance imaging (MRI) verified that many people with schizophrenia have enlarged ventricles and associated cortical atrophy, especially in the temporal lobe and the hippocampal nuclei (45,46 and 47). This may even be evident in first-episode psychosis (48). Although schizophrenia patients do not show a specific
abnormality such as hydrocephalus, blind measurements over many studies have replicated these changes with several different radiographic techniques. It is important to note, however, that the observed ventricular enlargement and the cortical atrophy are statistical phenomena. Thus, although these abnormalities are present in many patients with schizophrenia, there is significant overlap with normal control subjects, as well as with other psychiatric conditions.
abnormality such as hydrocephalus, blind measurements over many studies have replicated these changes with several different radiographic techniques. It is important to note, however, that the observed ventricular enlargement and the cortical atrophy are statistical phenomena. Thus, although these abnormalities are present in many patients with schizophrenia, there is significant overlap with normal control subjects, as well as with other psychiatric conditions.
To date, the literature indicates that enlarged ventricles and reduced cortical volume or activity are positively correlated with
Positive and negative symptoms
Poor performance on neuropsychological tests
The presence of soft neurologic signs
Poorer response to treatment
A worse prognosis
Increasingly, MRI is used to assess structural volumetric changes in schizophrenia; changes in functional activity (i.e., functional MRI [fMRI]); and the biochemistry of various central nervous system (CNS) regions (i.e., magnetic resonance spectroscopy [MRS]).
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