The cause of schizophrenia has not yet been determined, although research points to the interaction of genetic endowment and major environmental upheaval during development of the brain. This section first discusses genetic studies and then turns to the evidence for neurodevelopmental disruption. These lines of research are beginning to converge: neurodevelopmental disruption may be the result of genetic and/or environmental stressors early in development, leading to subtle alterations in the brain. Furthermore, environmental factors later in development can either exacerbate or ameliorate expression of genetic or neurodevelopmental defects. The overarching message is that the onset and course of schizophrenia are most likely the result of an interaction between genetic and environmental influences.
Family, twin, and adoption studies support the role of genetic influences in schizophrenia (Kendler & Diehl, 1993; McGuffin et al., 1995; Portin & Alanen, 1997). Immediate biological relatives of people with schizophrenia have about 10 times greater risk than that of the general population. Given prevalence estimates, this translates into a 5 to 10 percent lifetime risk for first-degree relatives (including children and siblings) and suggests a substantial genetic component to schizophrenia (e.g., Kety, 1987; Tsuang et al., 1991; Cannon et al., 1998). What also bolsters a genetic role are findings that the identical twin of a person with schizophrenia is at greater risk than a sibling or fraternal twin, and that adoptive relatives do not share the increased risk of biological relatives (see Figure 4-3). However, in about 40 percent of identical twins in which one is diagnosed with schizophrenia, the other never meets the diagnostic criteria. The discordance among identical twins clearly indicates that environmental factors likely also play a role (DSM-IV).
Current research proposes that schizophrenia is caused by a genetic vulnerability coupled with environmental and psychosocial stressors, the so-called diathesis-stress model (Zubin & Spring, 1977; Russo et al., 1995; Portin & Alanen, 1997). Family studies suggest that people have varying levels of inherited genetic vulnerability, from very low to very high, to schizophrenia. Whether or not the person develops schizophrenia is partly determined by this vulnerability. At the same time, the development of schizophrenia also depends on the amount and types of stresses the person experiences over time. An analogy can be drawn to diabetes by virtue of both genetic factors (e.g., family history) and behavioral factors (e.g., diet, exercise, stress) that interact to determine whether or not a given person develops diabetes. How the interaction works in schizophrenia is unknown, yet the subject of ongoing research (Murray et al., 1992; Spaulding, 1997; Jones & Cannon, 1998; van Os & Marcelis, 1998).
Despite the evidence for genetic vulnerability to schizophrenia, scientists have not yet identified the genes responsible (Kendler & Diehl, 1993; Levinson et al., 1998). The current consensus is that multiple genes are responsible (Kendler et al., 1996; Kunugi et al., 1996, 1997; Portin & Alanen, 1997; Straub et al., 1998).
Numerous brain abnormalities have been found in schizophrenia. For example, patients often have enlarged cranial ventricles (cavities in the brain that transport cerebrospinal fluid), especially the third ventricle (Weinberger, 1987; Schwarzkopf et al., 1991; Woods & Yurgelun-Todd, 1991; Dykes et al., 1992; Lieberman et al., 1993; DeQuardo et al., 1996), and decreased cerebral size (Schwarzkopf et al., 1991; Ward et al., 1996) compared with control groups. Several studies suggest this may be more common among men (Nopoulos et al., 1997) whose families do not have a history of schizophrenia (Schwarzkopf et al., 1991; Vita et al., 1994). There is also some evidence that at least some people with schizophrenia have unusual cortical laterality, with dysfunction localizing to the left hemisphere (Braun et al., 1995). To explain laterality, some have proposed a prenatal injury or insult at the time of left hemisphere development, which normally lags behind that of the right hemisphere (Bracha, 1991).
The anatomical abnormalities found in different parts of the brain tend to correlate with schizophrenias positive symptoms (Barta et al., 1990; Shenton et al., 1992; Bogerts et al., 1993; Wible et al., 1995) and negative symptoms (Buchanan et al., 1993). Positive symptoms are often linked to temporal lobe dysfunction, as shown by imaging studies that utilize blood flow and glucose metabolism. Such dysfunction possibly is related to abnormal phospholipid metabolism (Fukuzako et al., 1996). Disorganized speech (taken to reflect disorganized thinking) has been associated with abnormalities in brain regions associated with speech regulation (McGuire et al., 1998). Negative and cognitive symptoms, especially those related to volition and planning, are commonly associated with prefrontal lobe dysfunction (Capleton, 1996; Abbruzzese et al., 1997; Mattson et al., 1997). This is perhaps related to unusual neuronal density (Selemon et al., 1998) and may be more prevalent among patients whose families have a history of schizophrenia than those whose do not (Sautter et al., 1995). However, mapping patients symptoms with brain regions is complex and variable. Researchers believe that the dysfunctions are present in brain circuitry rather than in one or two localized areas of the brain (Andreasen et al., 1997, 1998; Wiser et al., 1998).
Excessive levels of the neurotransmitter dopamine have long been implicated in schizophrenia, although it is unclear whether the excess is a primary cause of schizophrenia or a result of a more fundamental dysfunction. More recent evidence implicates much greater complexity in the dysregulation of dopamine and other neurotransmitter systems (Grace, 1991, 1992; Olie & Bayle, 1997). Some of this research ties schizophrenia to certain variations in dopamine receptors (Nakamura et al., 1995; Serretti et al., 1998), while other research focuses on the serotonin system (Inayama et al., 1996). However, it must be emphasized that in many cases it is possible that perturbations in neurotransmitter systems may result from complications of schizophrenia, or its treatment, rather than from its causes (Csernansky & Grace, 1998).
The stressors investigated in schizophrenia research include a wide range of biological, environmental, psychological, and social factors. There is consistent evidence that prenatal stressors are associated with increased risk of the child developing schizophrenia in adulthood, although the mechanisms for these associations are unexplained. Some interesting preliminary research suggests risk factors include maternal prenatal poverty (Cohen, 1993), poor nutrition (Susser & Lin, 1992; Susser et al., 1996, 1998), and depression (Jones et al., 1998). Other stressors are exposure to influenza outbreaks (Mednick et al., 1988; Adams et al., 1993; Rantakallio et al., 1997), war zone exposure (van Os & Selten, 1998), and Rh-factor incompatibility (Hollister, 1996). Their variety suggests other stressors might also be risk factors, under the general rubric of maternal stress.
As a result of such stresses, newborns of low birth weight and short gestation have been linked to increased risk of later developing schizophrenia (Jones et al., 1998), as have delivery complications (Hultman et al., 1997; Jones & Cannon, 1998) and other early developmental problems (Brixey et al., 1993; Ellenbroek & Cools, 1998; Portin & Alanen, 1998; Preti et al., 1998). Among children, especially infants, viral central nervous system infections may be associated with greater risk (Rantakallio et al., 1997; Iwahashi et al., 1998), thereby explaining links between schizophrenia and being born or raised in crowded conditions (Torrey & Yolken, 1998) or during the flu-prone winter and spring months (Castrogiovanni et al., 1998). However, support for these hypotheses is inconsistent and incomplete (Yolken & Torrey, 1995). In fact, it is possible that prenatal and obstetric complications associated with schizophrenia could reflect already disrupted fetal development, rather than being causal themselves (Lipska & Weinberger, 1997). More generally, across the life span, the chronic stresses of poverty (Cohen, 1993; Saraceno & Barbui, 1997) and some facets of minority social status appear to alter the course of schizophrenia.
Presently, it is unclear whether and how these risks contribute to the diathesis-stress interaction for any one person because specific causes may differ (Onstad et al., 1991; Cardno & Farmer, 1995; Tsuang & Faraone, 1995; Miller, 1996). Although genetic vulnerability is difficult to control, certain other important factors can be addressed with current knowledge. An awareness of stressors that increase the likelihood of genetic vulnerability being actualized supports preventive strategies, such as good prenatal health care and nutrition. Furthermore, since life stresses can exacerbate the course of the illness, access to good quality services and social supports, as well as attention to relapse prevention interventions, can have beneficial effects on longer term outcome (Wiersma et al., 1998).
At the same time, researchers and clinicians are striving to integrate findings concerning both diathesis and stress into models of how schizophrenia develops (Andreasen, 1997b). Not only does brain biology influence behavior and experience, but behavior and experience mold brain biology as well. One promising integrative model is the neurodevelopmental theory of schizophrenia developed by Weinberger and others (Murray & Lewis, 1987; Weinberger, 1987, 1995; Bloom, 1993; Weinberger & Lipska, 1995; Lipska & Weinberger, 1997). It posits that schizophrenia develops from a subtle defect in cerebral development that disrupts late-maturing, highly evolved neocortical functions, and fully manifests itself years later in adult life (Lipska & Weinberger, 1997; see also Susser et al., 1998).
The nature of the defect, which has not been identified, may be a product of a pre- or neonatal insult to the brain. Further support for the neurodevelopmental theory comes from abnormalities in brain structure that have long been found in people with schizophrenia. Such findings have been interpreted to reflect abnormal neuronal migration in early development (Jakob & Beckmann, 1986; Arnold et al., 1991; Akbarian et al., 1993; Falkai et al., 1995). Researchers have developed animal models of early neurodevelopmental dysfunctions that manifest in later behavioral and functional deficits (Geyer et al., 1993; Lipska & Weinberger, 1993; Wilkinson et al., 1994; Lipska et al., 1995) and are influenced by genetics (de Kloet et al., 1996; Zaharia et al., 1996). As promising as these theories are, the causes and mechanisms of schizophrenia remain unknown. Nonetheless, research has uncovered several of treatments for schizophrenia that are effective in reducing symptoms and functional impairments.
The treatment of schizophrenia has advanced considerably in recent years. A battery of treatments has become available to ameliorate symptoms, to improve quality of life, and to restore productive lives. Treatment and other service interventions often are linked to the clinical phases of schizophrenia: acute phase, stabilizing phase, stable (or maintenance) phase, and recovery phase. Where possible, this report ties available data to these treatment phases.
Optimal treatment across all phases of treatment includes some form of pharmacotherapy with antipsychotic medication, usually combined with a variety of psychosocial interventions. Psychosocial interventions include supportive psychotherapy, and family psychoeducational interventions, as well as psychosocial and vocational rehabilitation. The treatment of individuals with schizophrenia who are high service users should be orchestrated by an interdisciplinary treatment team to ensure continuity of services (i.e., assertive community treatment, which is discussed below). Others may benefit from less intensive forms of case management and various self-help and consumer-operated services, described later. It is also important to assist individuals with schizophrenia in meeting their many related needs, such as for supported housing, transportation, and general medical care. These are among the 30 pivotal treatment recommendations of the Agency for Healthcare Research and Quality (AHRQ)- and NIMH-sponsored Schizophrenia Patient Outcomes Research Team (PORT), which developed its recommendations on the basis of a comprehensive review of the treatment outcomes literature (Lehman & Steinwachs, 1998a). Table 4-8 contains a distillation of key recommendations.
Although the Schizophrenia PORT study recommendations are grounded in research such as that reviewed in the following paragraphs, it is noteworthy that treatment practices fail to adhere to these recommendations, with conformance generally falling below 50 percent (Lehman & Steinwachs, 1998b). The disturbing gap between knowledge and practice is discussed later in this chapter. Many barriers exist in the transfer of information about treatment and evidence-based practice to clinicians, family members, and service users.
Conventional antipsychotics have been shown to be highly effective both in treating acute symptom episodes and in long-term maintenance and prevention of relapse (Cole & Davis, 1969; Davis et al., 1989; Kane, 1992). Across many studies, positive symptoms improved in about 70 percent of patients, compared with only 25 percent improvement in placebo groups (Kane, 1989; Kane & Marder, 1993). Their common mechanism of action is by blocking dopamine D2 receptors, and their therapeutic effects are presumably due to D2 blockade in the mesolimbic system (Dixon et al., 1995).
For acute symptom episodes, treatment recommendations call for dosages of antipsychotic medication in the range of 300 to 1,000 chlorpromazine equivalents14 per day (Lehman & Steinwachs, 1998b). Among patients discharged from inpatient units whose dosage fell outside of this range, minority patients often are much more likely than Caucasian patients to be on a higher dose (> 1,000 chlorpromazine equivalents) (Lehman & Steinwachs, 1998b). Such dosing patterns run counter to evidence that a higher proportion of minority patients, because of lower rates of drug metabolism, may require lower doses of antipsychotics.
Dosage studies have found that moderate levels (300 to 750 chlorpromazine equivalents daily for acute episodes, 300 to 600 for maintenance, although many people require less than 300) are more effective for positive symptom reduction over the long run than very high (loading), intermittent, or very low doses (Donlon et al., 1978, 1980; Neborsky et al., 1981; Baldessarini et al., 1990; Levinson et al., 1990; Van Putten et al., 1990, 1992; Rifkin et al., 1991). Very low and intermittent dosing substantially increases the risk of relapse, while rapid loading and very high doses greatly increase adverse effects (Davis et al., 1989), although medication programs must be tailored to individual needs. On conventional neuroleptics, patients experience symptom reduction over the first 5 to 10 weeks of treatment, with more gradual improvement sometimes continuing for more than double that time (Baldessarini et al., 1990). The older medications are occasionally found to reduce some negative symptoms as well, although it is impossible to tell from existing research if this is a primary or secondary effect of reduced positive symptoms (Davis et al., 1989; Cassens et al., 1990).
Apart from their minimal effects on negative symptoms, the greatest problem with conventional neuroleptic medications is their pervasive, uncomfortable, and sometimes disabling and dangerous side effects. The spectrum of side effects is broad (Davis et al., 1989; Casey, 1997), yet the most common and troubling are extrapyramidal effects such as acute dystonia, parkinsonism, and tardive dyskinesia (Chakos et al., 1996; Yuen et al., 1996; Trugman, 1998) and akathisia (Kane, 1985).15 Side effects are evident in an estimated 40 percent of patients, but pinpointing their prevalence is complicated by the vagaries of diagnosis, length of prescription and observation, and variability across individuals and medications. Rare side effects (seizures, paradoxical exacerbation of psychotic symptoms, neuroleptic malignant syndrome) also can be devastating.
Acute dystonia, parkinsonism, dyskinesias, and akathisia are usually treated by lowering the doses of neuroleptics and/or using adjunctive anticholinergic, antiparkinsonian medications (e.g., benztropine). Because these side effects can be mistaken for core psychotic symptoms, the neuroleptic dose is often increased, rather than decreased, exacerbating the side effects. Many other side effects such as attention and vigilance problems, sleepiness, blurry vision, dry mouth, and constipation are worse in the initial weeks of treatment and usually taper off as a person adjusts to the medication. However, the discomfort and disability of the initial weeks are intolerably disruptive to some individuals. Dosages can be individualized to minimize side effects while maximizing benefit.
Efficacy data on the newer antipsychotics indicate that they are as efficacious as the older agents at reducing positive symptoms and carry fewer side effects. They also offer important additional advantages for some who have had treatment-resistant schizophrenia (Kane, 1996, 1997; Vanelle, 1997; van Os et al., 1997; Andersson et al., 1998).
The prototype of the newer medications, clozapine, has been found effective for about 30 to 50 percent of treatment-resistant patients (Kane & Marder, 1993; Lieberman et al., 1994; Buchanan, 1995; Kane & McGlashan, 1995; Kane, 1996), as well as for patients who have responded to previous medications. Clozapine also seems to help secondary depression and anxiety, and perhaps the negative symptoms of schizophrenia (Buchanan, 1995). Clozapine not only has a very low incidence of tardive dyskinesia (Barnes & McPhillips, 1998) but may also show some promise as its treatment (Walters et al., 1997). However, the use of clozapine was constrained for many years in the United States because of findings that in about 1 percent of patients it causes a potentially fatal blood condition: agranulocytosis, a loss of white blood cells that fight infection. Because agranulocytosis is reversible if detected early, frequent (weekly) blood monitoring is critical (Lamarque, 1996; Meltzer, 1997). Although effective safeguards exist, use of clozapine tends to be limited to those who are unresponsive to, or cannot tolerate, other antipsychotics. The Veterans Administration sponsored the largest cost-effectiveness study to date of clozapine, comparing it to haloperidol. Studies by Rosenheck and his collaborators (1997, 1998b, 1999) replicated previous findings that clozapine was more effective than haloperidol in treating positive and negative symptoms and had fewer extrapyramidal side effects. In addition to its direct pharmacologic effect, the investigators found that clozapine enhances participation in psychosocial treatments, which augments its overall clinical effectiveness (Rosenheck et al., 1998b). Savings associated with use of clozapine were particularly significant among study participants who had averaged 215 inpatient hospital days in the year prior to the study (Rosenheck et al., 1998b).
Increasing numbers of patients with schizophrenia receive newer agents like risperidone (Smith et al., 1996a; Foster & Goa, 1998), olanzapine (Bymaster et al., 1997), and quetiapine (Wetzel et al., 1995; Gunasekara & Spencer, 1998). They have replaced the older antipsychotics in many cases because they cause fewer side effects at therapeutic levels (Umbricht & Kane, 1995) and do not require clozapines close monitoring. Their effects on negative schizophrenia symptoms are currently being evaluated and hold some promise, as do their effects on some cognitive dysfunctions (Gallhofer et al., 1996; Green et al., 1997; Kern et al., 1998). Furthermore, current cost analyses find these newer medications at least cost-neutral and sometimes more cost-effective in the long run than older agents, despite being more expensive per pill (Loebel et al., 1998).
Thus, as a whole, there is evidence that the newer antipsychotics are more clinically advantageous than the older ones due to the combination of their effective treatment of positive (and perhaps negative) symptoms, their treatment of ancillary symptoms such as anxiety and depression, and their more favorable side effect profile (Lieberman, 1993, 1996; Fleischhacker & Hummer, 1997; Shore, 1998). Having fewer side effects generally results in better compliance with the medication, although atypical side effects can include sedation, weight gain, sexual dysfunction, and other dose-related discomforts (Casey, 1997; Hasan & Buckley, 1998). Although the newer agents have less adverse impact on fecundity, so that more women with schizophrenia can conceive, there are very little data to address the impact of treatment on pregnancy and lactation. While it is not clear whether the newer medications directly lessen the functional disabilities that usually accompany schizophrenia, they may improve a persons quality of life (Lehman, 1996) and responsiveness to psychosocial, rehabilitation, and therapeutic interventions (Buckley, 1997). Effectiveness in real-world settings may be substantially lower than efficacy in clinical trials, possibly due to patient heterogeneity, prescribing practices, and noncompliance (Dixon et al., 1995).
At the same time, it is possible that the documented medication differences are the result of underlying biological mechanisms of mental illness related to ethnicity, culture, and gender variations. Additionally, the effects of psychotropic medications may be interpreted differently by culture (Lewis et al., 1980). Although knowledge in these areas is incomplete, it is important to consider cultural patterns in dosing decisions and medication management, as well as risks of side effects and tardive dyskinesia. Furthermore, studies suggest that medication differences among African American people diagnosed with schizophrenia may reflect clinician biases in diagnosis and prescription practices more than differences in medication metabolism or health behaviors alone (Frackiewicz et al., 1997).
Psychosocial Rehabilitation and Skills Development
The evolution of psychosocial skills training is important yet incomplete. A review in the mid-1990s concluded that its overall impact on social, cognitive, or vocational functioning is modest, and it remains unclear whether these gains are maintained after the training is over and can be used in real-life situations (Scott & Dixon, 1995a). However, a more recent study found greater independent living skills among clients who had received skills training during a 2-year followup of everyday community functioning (Liberman et al., 1998). Several others agree that skills training is effective for specific behavioral outcomes (Marder et al., 1996; Penn & Mueser, 1996). Specific symptom profiles may also influence how effective skills training is for a given person (Kopelowicz et al., 1997). Furthermore, Medalia and coworkers (1998) report recent success adapting cognitive rehabilitation techniques, originally developed for survivors of serious head injuries, for people with schizophrenia, but long-term effects and generalizability have not been determined. This exemplifies both the progress and the need for further refinement of this intervention (Smith et al., 1996b).
In a recent review article, a team of researchers concluded that the most potent rehabilitation programs (1) establish direct, behavioral goals; (2) are oriented to specific effects on related outcomes; (3) focus on long-term interventions; (4) occur within or close to clients naturally preferred settings; and (5) combine skills training with an array of social and environmental supports. They also note that most programs do not contain all of these elements, but most are much improved over previous eras (Mueser et al., 1997b).
There are a host of multi-component psychosocial rehabilitation services that combine pharmacologic treatment, independent living and social skills training, psychological support to clients and their families, housing, vocational rehabilitation, social support and network enhancement, and access to leisure activities (World Health Organization [WHO], 1997). These are discussed in the later section on service delivery.
Coping and Self-Monitoring
For example, some people find it very useful to pay attention to their own warning signs of relapse or symptom exacerbation, so that additional coping practices, supports, or interventions can be put into place. Norman and Malla (1995) conclude that there is not a standardized set of signs that predict relapse, but that some individuals have and get to know their own reasonably consistent patterns. Herz and Lamberti (1995) agree that many people experience predictable signs, although whether a relapse occurs depends on many factors besides the signs themselves. Therefore, the risk and magnitude of relapse can be reduced by monitoring early symptoms and intervening when they emerge (Herz & Lamberti, 1995). Watching for such signs is recommended for consumers, family members, and clinicians (Jorgensen, 1998). Specific training programs for teaching individuals with schizophrenia to identify the warning signs of relapse and to develop relapse prevention plans have been shown to be effective (Liberman et al., 1998).
Controlled studies of vocational rehabilitation interventions have shown mixed results (Lehman, 1995, 1998; Cook & Jonikas, 1996). Although such programs do seem to increase work-related activities while people are engaged in them, the gains do not seem to be translated into more independent employment once services cease. This has led to the conclusion that ongoing support is needed for many individuals with schizophrenia who wish to work in competitive employment (Wehman, 1988). Recent controlled studies have shown the effectiveness of this newer type of so-called supported employment models, which emphasize rapid placement in a real job setting and strong support from a job coach to learn, adapt, and maintain the position (Drake et al., 1994, 1996; Bond et al., 1997). These models, which are growing in use, strike a dynamic balance between being supportive yet challenging in order to avoid clients dependency and maximize their growth (Mowbray et al., 1997).
As vocational rehabilitation has moved away from sheltered workshops and toward supported employment models, the Americans With Disabilities Act of 1990 has helped to open jobs and educate employers about reasonable accommodations for people with psychiatric disabilities (Mechanic, 1998; Scheid, 1998). Additionally, innovations like client-run and client-owned vocational programs and independent businesses have begun to be developed on a larger scale (Rowland et al., 1993; Miller & Miller, 1997). These innovations are part of a larger movement of consumer involvement in the provision of services for people with mental illness (see Chapter 2).
14 A chlorpromazine equivalent is a measure in milligrams of antipsychotic medication doses indexed to the potency of a standard dosage of chlorpromazine, one of the earliest, most widely used antipsychotic medications.
15 Acute dystonia is involuntary muscle spasms resulting in abnormal and usually painful body positions. Parkinsonism is defined by tremors, muscle rigidity, and stuporous appearance. Dyskinesias are involuntary repetitive movements, often of the mouth, face, or hands, and akathisia is painful muscular restlessness requiring the person to move constantly.