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Schizophrenia is a brain disorder of unknown origin which severely deteriorates numerous complex functions of the central nervous system (CNS) including thought, emotion, perception, cognition, and behavior. Schizophrenia is one of the most debilitating psychiatric disorders. Due to the high lifetime prevalence (about 1.5 percent), the typical onset in early adulthood, and the strong tendency towards a chronic course, the disorder requires a very high degree of health care provisions. About one-quarter of hospital beds are occupied by schizophrenic patients, and the total costs of treatment are enormous (e.g., US$50 billion per year in the United States). Although there is no cure for schizophrenia, the combined administration of pharmacological and psychosocial interventions considerably improves outcome, enhances quality of life in the patients aﬀected, and enables social integration to a large extent.
1. Causes And Pathophysiology Of Schizophrenia
The causes of schizophrenia are unknown so far. Therefore, the term ‘schizophrenia’ refers to an empirically deﬁned syndrome characterized by a combination of certain symptoms which occur in a particular temporal pattern. The idea that schizophrenia is a distinct brain disorder is rooted in Emil Kraepelin’s concept of dementia praecox (Kraepelin 1893). This concept emphasized one particular aspect of the disorder: the onset of persistent cognitive disturbances early in life. The term ‘schizophrenia’ was coined by Eugen Bleuler (1916), who wanted to emphasize the loss of coherence between thought, emotion, and behavior which represents another important feature of the disorder. Bleuler actually spoke about ‘schizophrenias,’ implying a group of diseases rather than one distinct disease entity. The present diagnostic systems compiled by the World Health Organization (ICD-10 1992) and the American Psychiatric Association (DSM-IV 1994) distinguish various subtypes of schizophrenia (see Table 1) which are classiﬁed according to particular symptom combinations, and according to certain aspects of the course and prognosis of the disease. However, these subtypes are deﬁned in a phenomenological manner which neither implies distinct causes for any of the subtypes nor any particular treatment.
Although we do not know individual causes of schizophrenia, we know that the basis for the disorder is an interaction between genetic susceptibility factors and environmental components. According to numerous genetic studies the estimates of hereditability converge to about 80 percent (Owen and Cardno 1999). However, although linkage studies have yielded evidence for a number of susceptibility loci on various chromosomes, neither a single gene nor a combination of genes have been discovered so far which are deﬁnitively involved. Similarly, a number of environmental factors (e.g., birth and pregnancy complications, viral infections) are likely to play a role, but details of this role remain to be established.
Although the symptoms of schizophrenia clearly demonstrate a severe disturbance of brain functions, only subtle alterations of brain morphology have been detected. The most stable ﬁnding is a slight enlargement of brain ventricles. Recent sophisticated studies combining morphological and functional brain imaging have been suggested to indicate that subtle structural or functional lesions particularly in prefrontal and limbic neural circuits impair the integrity of these circuits (Andreasen et al. 1998). Although it is still a matter of debate whether these lesions are due to a neurodevelopmental or a neurodegenerative process (Lieberman 1999), it is clear that disturbed functioning of neuronal circuits goes along with altered neurotransmission. Dopamine, serotonin, and glutamate are the neurotransmitters most frequently implicated in the pathophysiology of schizophrenia. However, it is still not clear whether disturbed neurotransmission is the cause or the consequence of the major disease process.
Due to this scantiness of etiological and pathophysiological knowledge, the treatment of patients suﬀering from schizophrenia is based exclusively on empirical clinical knowledge. As outlined in detail below, the treatment approach is multimodal and based on the symptom patterns present in any individual patient.
2. Symptoms Of Schizophrenia—The Targets For Treatment
Schizophrenia aﬀects almost all areas of complex brain functions, and thought, perception, emotion, cognition, and behavior in particular. There have been numerous approaches to systematize the plethora of symptoms according to a variety of theoretical concepts. One widely accepted concept is the distinction between positive and negative symptoms (Andreasen et al. 1995, Table 2). This approach groups symptoms according to whether they represent a loss of or a deﬁciency in a normal brain function (negative symptoms) or the appearance of abnormal phenomena (positive symptoms). From the perspective of treatment the positive–negative dichotomy is of importance because these two domains react somewhat diﬀerently to treatment. In general, positive symptoms respond fairly well to treatment with antipsychotic drugs, whereas negative symptoms are rather diﬃcult to inﬂuence. The latter is particularly problematic, because negative symptoms are usually the limiting factor for personal and social rehabilitation. In addition to the typical symptoms, patients suﬀering from schizophrenia often present numerous other psychiatric problems. Among these, anxiety, sleep disturbances, obsessions and compulsions, depression and drug or substance abuse are particularly frequent. Although these additional symptoms and problems may in many cases be the consequence of the typical symptoms rather than signs of independent additional psychiatric disorders, they complicate the course of the disease and often necessitate speciﬁc treatment approaches.
The course of schizophrenia varies considerably between patients. Typically, the disease begins during early adulthood with the appearance of rather unspeciﬁc negative symptoms resulting in social withdrawal and impaired social and scholastic adjustment. Months to years later positive symptoms such as delusions and hallucinations appear either gradually or abruptly. Across time, positive symptoms tend to show an episodic course, whereas negative symptoms either remain quite stable or even progress. The associated psychiatric problems mentioned above do not show any systematic temporal relationship to the course of schizophrenia itself. Since the syndrome of schizophrenia has been deﬁned, data on the ﬁnal outcome have varied considerably, depending mainly on the diagnostic concepts applied. There is no doubt that full remission occurs, but probably in less than 20 percent of patients. In the majority of patients schizophrenia takes a chronic course (Schultz and Andreasen 1999). The major beneﬁt from modern treatment strategies is probably not a substantial increase in the rate of full remissions, but a signiﬁcant reduction in the number of extremely ill patients, and in the severity and number of episodes characterized by prominent positive symptoms.
3. The Principles Of Treatment
Treatment of schizophrenia is usually multimodal and comprises approaches from two major areas, which are drug treatment and psychosocial interventions. In general, appropriate drug treatment is a prerequisite for the ability of the patients to comply with and actively take part in psychosocial treatments. The more eﬀective drug treatment is, the more specialized and sophisticated psychosocial interventions can be successfully applied. Vice versa, appropriate psychosocial treatment considerably improves the compliance with drug treatment, because it enhances insight into the disease process, which initially is poor in many patients suﬀering from schizophrenia.
Antipsychotic drugs (also called neuroleptics) are the most important and most eﬀective therapeutic weapon. The major targets of these drugs are positive symptoms, although newer substances might also reduce negative symptoms to some extent (see below). Treatment with antipsychotic drugs is usually a long-term treatment, whereas drugs to control accessory symptoms (anxiolytics, hypnotics, and antidepressants) are prescribed intermittently when needed. The use of electroconvulsive therapy was widespread before antipsychotic drugs were available, but today is very limited, although this treatment is eﬀective in certain conditions (Fink and Sackeim 1996).
Among the psychosocial interventions, supportive and psychoeducative approaches are feasible for the majority of patients, whereas structured social skill training, family therapy, or complex programs including cognitive-behavioral therapies require a considerable degree of insight and compliance. Although recent psychosocial treatment approaches incorporate also psychodynamic aspects, classical psychodynamic psychotherapy, in general, is not eﬀective and sometimes even counterproductive.
Prior to the discovery of antipsychotic drugs, most schizophrenic patients had been hospitalized for decades or even for their entire life. Today, very diﬀerentiated treatment facilities are available, which to a large extent are community based. These include, besides classical hospitals and outpatient departments, short-term crisis intervention facilities, day-time clinics, and supported living facilities. This network of facilities considerably increases the chance for social integration and reduces the time spent overall in hospitals. However, recent aggressive approaches to shorten the duration of hospital stays dramatically might lead to a high frequency of rehospitalization, poor long-term outcome, and an overall increase in the costs of treatment.
An important limiting factor for all treatment approaches is the patients’ compliance. In particular in severely ill patients compliance is often poor. In schizophrenia noncompliance is particularly due to a lack of insight into the fact of being ill, reduced ability to actively take part in the treatment process due to negative symptoms, or active avoidance of treatment due to positive symptoms such as delusions or imperative voices. To enable stable treatment compliance in patients suﬀering from schizophrenia, a conﬁdential and empathetic attitude of the people involved is an important prerequisite.
4. Particular Aspects Of Treatment
The introduction of chlorpromazine into clinical practice in 1952 is the hallmark of the pharmacological treatment of schizophrenia (Delay and Deniker 1952). Chemically, chlorpromazine is a phenothiazine and other substances of this group also possess antipsychotic properties. In the 1950s and 1960s, numerous antipsychotic drugs with diﬀerent structures (in particular butyrophenones [e.g., haloperidol] and thio-xanthenes [e.g., ﬂupentixol]) were developed. Despite this diversity in chemical structure, these ﬁrst-generation drugs do not diﬀer qualitatively with respect to their proﬁle of beneﬁcial and undesired eﬀects. They target mainly the positive symptoms of schizophrenia mentioned in Table 2 without preferentially aﬀecting one or the other of these symptoms. Their eﬀectiveness does not depend on the subtype of schizophrenia (see Table 1).
The common mode of action of the ﬁrst-generation antipsychotics is believed to be blockade of the D2 subtype of dopamine receptors (Pickar 1995). Blockade of these receptors in the mesolimbic dopamine system is thought to cause a reduction in positive symptoms, and blockade in the nigrostriatal dopamine system is believed to be responsible for the typical side eﬀects of these drugs. These are severe disturbances of motor behavior caused by a drug-induced dysfunction of the dopaminergic extrapyramidal system, which plays a pivotal role in the control of movements. Table 3 summarizes these extrapyramidal syndromes. Those which occur acutely are often very disturbing, but respond fairly well to treatment (e.g., acute dystonia to anticholinergic drugs), or at least cease upon drug discontinuation or dose reduction. Tardive extrapyramidal syndromes, however, are frequent (5–10 percent on long-term treatment with ﬁrst-generation antipsychotics), often resistant to treatment approaches, and they usually persist if the antipsychotic drug is stopped. Another severe side eﬀect of unknown cause, which might be related to the extrapyramidal system, is the neuroleptic malignant syndrome (Pelonero et al. 1998; see also Sect. 4.3). Extrapyramidal side eﬀects are common to all ﬁrst-generation drugs, whereas other, less speciﬁc side eﬀects (e.g., sedation, weight gain, postural hypotension) occur with some but not all substances.
Due to the central role attributed to D2 dopamine receptor blockade, it has been thought for a long time that antipsychotic eﬀectiveness and extrapyramidal syndromes are inevitably linked to each other. However, in the late 1960s it turned out that the dibenzodiazepine clozapine is a potent antipsychotic drug that almost never induces extrapyramidal symptoms and is eﬀective in a proportion of otherwise treatmentresistant patients (Angst et al. 1971). Moreover, it was shown that clozapine not only improves positive but to some extent also negative symptoms. Therefore, the introduction of clozapine into clinical practice was the ﬁrst qualitative advance after the discovery of chlorpromazine, and it is justiﬁed to call this substance a second-generation antipsychotic drug. Unfortunately it turned out quickly that clozapine has a very particular and important drawback: it induces lifethreatening agranulocytosis in about one percent of patients treated (Baldessarini and Frankenburg 1991). Therefore, the use of this drug is only possible when white blood cell counts are monitored in short intervals.
It is still not known why clozapine is a potent antipsychotic drug, but lacks extrapyramidal side eﬀects. Among the possible reasons are that clozapine aﬀects mainly the mesolimbic dopamine system, that it blocks D1 receptors to the same extent as D2 receptors, that it has a high aﬃnity to D4 receptors, and that it also has high aﬃnity to serotonin receptors. This theoretical framework was the basis for the development of various second-generation antipsychotics (see Table 4). Most of them have high aﬃnities for serotonin receptors, although only one substance (olanzapine) is similar to clozapine in the equivalent binding to D1 and D2 receptors. So far there is no indication that any of these newer drugs carries a substantial risk of agranulocytosis, the most dangerous side eﬀect of clozapine. Moreover, these substances have shown to be eﬀective when compared to ﬁrst-generation antipsychotic drugs and indeed to induce fewer extrapyramidal side eﬀects. For two of them (olanzapine and risperidone) there are data suggesting that they also might ameliorate negative symptoms. However, it still remains to be seen how the eﬀectiveness of these newer drugs compares to clozapine.
Treatment with antipsychotic drugs in schizophrenic patients is usually a long-term treatment continuing for many years. Intermittently, patients may need additional other psychotropic medications. Most frequently anxiolytics, hypnotics, and antidepressants are administered. The recognition and treatment of intervening depressive episodes is particularly important because depressive and negative symptoms are sometimes diﬃcult to diﬀerentiate, but need diﬀerent treatment. When administering antidepressant drugs to schizophrenic patients, one should be aware that during treatment with antidepressants positive symptoms sometimes exacerbate.
4.2 Psychosocial Treatment
It is now generally accepted that psychosocial treatment of patients with schizophrenia is not an alternative to pharmacological treatment, but rather an important complementary approach (Bustillo et al. 2000). Psychosocial measures yield little beneﬁt for positive symptoms; in contrast, intensive psycho- dynamic psychotherapy might induce exacerbations. The most important and successful interventions are psychoeducative teaching and training in social skills and problem solving. Although it is still debated whether these treatments are directly eﬀective against negative symptoms, there is no doubt that they considerably improve coping with these symptoms.
The major goal of educational approaches is to increase the knowledge about and the insight into the disease process and, as a consequence, to improve treatment compliance. Educational programs are focused on knowledge about the disease process and it’s course, the mode of action and side eﬀects of medication, early signs of exacerbation such as restlessness and insomnia, and detailed information about the various community based or hospital facilities available. These programs are particularly eﬀective when important family members are educated as well. Moreover, approaches to improve the communication styles within the patient’s network of social relationships are often useful, although the concept that particular forms of communication (‘high expressed emotions’) play a causative role in schizophrenia has been seriously challenged.
Schizophrenic patients’ social skills are often poor. This is one major reason for the often dramatically reduced amount of social contacts. Training of social skills in patients suﬀering from schizophrenia is performed in a group setting. Such groups are focused on the repetitive training of behavior in various social situations of importance for everyday life. In addition, some rather basic teaching of the theoretical background of successful social interaction might be included.
Impaired problem solving in schizophrenic patients is due to a combination of disturbances in divided attention, planning, and motivation. Problem solving training includes the analysis of problems relevant to daily life and, particularly, dividing a problem into subproblems that can be successively solved. Similar to the training of social skills, the steps of the solution are practiced repeatedly.
In recent years, more complex psychotherapeutic approaches have been developed, combining cognitive, behavioral, or psychodynamic approaches, which, however, are suitable for the minority of patients only.
In particular for chronic patients who in earlier times often were hospitalized for decades, providing supervised residential living arrangements has proven to be of considerable beneﬁt because in this setting the degree of self-sustainment can be maximized in parallel with the permanent provision of professional help.
4.3 Emergency Treatment
Schizophrenia is not only a debilitating but also a life-threatening disorder. If severe positive symptoms are present, such as verbal imperative hallucinations, delusions of persecution, or severe formal thought disturbances, the patient’s life is threatened by a misinterpretation of his or her environment (e.g., of dangerous objects or situations) and by suicidal intentions. Suicidality can also emerge when negative symptoms are prominent. Acute suicidality and an acute confusional psychotic state both necessitate immediate treatment, including the administration of anxiolytics, antipsychotics, or both, preferably in a hospital setting. Although every eﬀort should be undertaken to get the informed consent of the patient, it is often necessary to initiate treatment against his or her explicit will. This has to be done in accordance with the legal regulations in the respective country.
Less frequently occurring life-threatening situations in patients suﬀering from schizophrenia are febrile catatonia and the neuroleptic malignant syndrome, a rare side eﬀect of antipsychotic drugs (Pelonero et al. 1998). Both conditions show similarities, including fever, disturbances of motor behavior, and reduced responsiveness to external stimuli. The diﬀerential diagnosis is diﬃcult, but very important because in febrile catatonia treatment with antipsychotic drugs is necessary, whereas such treatment has to be immediately stopped when a neuroleptic malignant syndrome is suspected. In both of these conditions admission to an intensive care unit is necessary.
5. Future Perspectives On The Treatment Of Schizophrenia
Despite the rapid development of the knowledge about human genetics, it is unlikely that we will see a major advance in our understanding of the genetic causes of schizophrenia in the near future. The reason is that the available epidemiological data render a major contribution of single genes quite unlikely and suggest that multiple genes contribute to the susceptibility to schizophrenia. However, it is likely that genetic investigations will improve the management of schizophrenia by enabling prediction of the treatment response to antipsychotic drugs. Very recently, for example, it has been shown that a combination of six polymorphisms in neurotransmitter-receptor-related genes enable a signiﬁcant prediction of the treatment response to clozapine (Arranz et al. 2000). Although these preliminary studies must be replicated and extended to other drugs, it is probable that this approach will signiﬁcantly enhance the success of drug treatment in schizophrenia. It is also likely that the near future will bring new drugs which are the result of a ‘ﬁne-tuning’ of the chemical structure and the binding proﬁle to dopamine and serotonin receptors of those substances which are presently available. Another approach which is currently being pursued is to target glutamate receptors, although ﬁrst clinical trials are only in part encouraging (Farber et al. 1999). Based on a theory implicating the immune system in the pathophysiology of schizophrenia, studies are being started that use immunomodulation as a treatment. This is an interesting and promising approach, which also might help to understand the mode of action of presently available antipsychotic drugs because some of them inﬂuence the production of cytokines which are important immune mediators (Pollmacher et al. in press). Another approach based on pathophysiological theories is to target phospholipids. These are an important cell-membrane component and there is some evidence suggesting that either their uptake is deﬁcient or that they are excessively broken down in schizophrenic patients (Horrobin 1999).
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