SCHIZOPHRENIA is a devastating illness that afflicts over 2 million people in the U.S. and over 50 million people worldwide. In many ways, this is the most serious of all psychiatric illnesses: more hospital beds (psychiatric and medical combined) are filled by schizophrenics than due to any other medical condition. Despite the occasional reference to this condition in the media, schizophrenia may be the most misunderstood psychiatric illness to the general public. Many people confuse the quite dramatic (but much rarer) multiple personality disorder with schizophrenia. In fact, schizophrenia is not associated with many different personalities, but rather with the fragmentation of a single, often dysfunctional, personality.

I. Background: Schizophrenia
Schizophrenia is an illness characterized by a constellation of features that are divided into “positive” and “negative” psychotic symptoms. The striking positive symptoms include dramatic hallucinations, which are most often auditory. Patients report that they hear voices that are clearly located outside of their heads, most often engaged in a running commentary on their thoughts and behaviors. The “voices” occasionally command the patient to action. Less commonly, patients report visual hallucinations, stating that they can clearly see images that are not real. Other common positive symptoms are delusions, which are false but fixed beliefs that the patient cannot be convinced are not accurate. Delusions most often are paranoid or grandiose, occasionally having an element of both. Other positive symptoms include paranoia and disorders in the organization of thought processes. Much more insidious and debilitating are the negative symptoms, which are associated with the diminution of normal social behaviors, and include withdrawal, decreased spontaneous communication, decreased eye contact, the decrease or absence of facial expression and vocal inflection, and decreased spontaneous movement. Few individuals suffering from schizophrenia have all of these symptoms, but several symptoms, like auditory hallucinations, must be present in order for someone to be diagnosed with schizophrenia.

Even though we refer to schizophrenia as one illness, there is actually great heterogeneity in this disease. In one scheme, schizophrenia is subdivided into five categories, each associated with specific symptoms. The paranoid subtype is probably the most familiar, and paranoid schizophrenics have populated movies as either villains or objects of ridicule. While these people hear voices that sometimes command them to do things, and often do have a belief that someone is out to get them, these caricatures are demeaning and demonstrate a fundamental misunderstanding of the disease. In fact, few schizophrenics are violent, and many are actually afraid of their own thoughts. Fortunately, these patients have the best response to antipsychotic medication, compared to other schizophrenic subtypes, though this improvement is usually suboptimal. Patients with another subtype, catatonic schizophrenia, respond poorly to antipsychotic medications. These patients have very severe negative psychotic symptoms, to the point of immobility, and some cannot feed themselves. Schizophrenics with the disorganized subtype also have trouble taking care of themselves because their disease causes their thinking to be illogical and disorganized. It is sometimes difficult to understand what these patients are trying to communicate because their sentences don’t fit together. The undifferentiated subtype defines patients who don’t quite meet the criteria for the other three subtypes, but clearly have psychotic symptoms. The final subtype is called residual schizophrenia, and patients with this subtype had more severe positive symptoms when they were younger, but now display more negative symptomatology. Some patients with paranoid schizophrenia develop the residual subtype when they are in their 40s and 50s. Although we subdivide schizophrenics into five groups, there is great diversity within each group, to the point where it is felt that schizophrenia represents a spectrum of disorders rather than a discrete illness. The debate about defining the illness has understandably hindered research efforts examining its underlying pathophysiology.

The onset of schizophrenia is postpubertal, frequently occurring when the patient is in high school or just beginning college. The so-called “psychotic break” can sometimes have an identifiable trigger, but not always. A death in the family, the stress that comes with changing schools or going to college, experimenting with illicit drugs, or the breakup with a significant other can precipitate a psychotic break. Triggers should not be construed to imply blame on family, friends, or the patient, however, nor is there something inherent in the trigger that causes the illness. Rather, people with a susceptibility to the illness usually require some stressor to cause the final biochemical changes in the brain that produce the onset of psychotic symptoms. This critical event may occur rather early in life, but has far-reaching implications for the patients’ future.

Schizophrenia is not a static condition, however, and the vast majority of these patients experience a steady deterioration in their ability to function over their lifetimes. They first become ill at a time when they are learning the skills necessary to work and function in society. Frequent hospitalizations, medication side effects, and the psychotic symptoms themselves all hinder vocational and social development. Consequently, many schizophrenics never develop the skills to support themselves, and have to rely on family and governmental assistance to survive. Some schizophrenics are not able to utilize the services available to them and become homeless. This is a particular problem since the deinstitutionalization of the chronically mentally ill that started in the 1960s and persists today. An important goal of psychiatry is to find improved treatments, developed from a greater understanding of the pathophysiology of this illness, to arrest this downward spiral for millions of schizophrenics.

Because of the toll schizophrenia takes on patients and their families, there has been a great deal of research on schizophrenia. Any theory of the pathophysiology of schizophrenia has to be able to explain the postpubertal onset of the illness, which necessitates an understanding of developmental changes in brain function. Adolescence is a time when the brain normally undergoes a dramatic reorganization, with new connections made and a greater number of connections broken. Schizophrenics are thought to have a disruption in this process, leading to the abnormal brain function that may produce psychotic symptoms. This disruption may partially explain how the activation of a major physical or emotional stress might precipitate a psychotic break.

There is also a genetic component to schizophrenia. The risk for having the disease increases as the number of affected relatives increases, with the highest risks occurring in people with two schizophrenic parents or an affected identical twin. However, this risk is not 100%, suggesting that getting the disease is involves more than just having a gene. In fact, it is likely that there are multiple, interacting genes that increase an individual’s susceptibility to schizophrenia, and these genes require environmental factors (the “trigger” mentioned earlier) for expression of the illness. This complexity has made it difficult to find these genes.

The myriad approaches to the study of schizophrenia reflect both the biases of researchers and the difficulty inherent in understanding complex human behaviors and emotions. Studies on neurochemical and neuroanatomical abnormalities have been the mainstay of schizophrenia research. Certain regions in the brain mediate higher order functions, and these regions have been examined extensively. Further, these regions utilize certain chemicals, called neurotransmitters, to permit the communication of the different cells that comprise these regions as well as connecting them to other regions. This complex interplay must be regulated to ensure proper function, and disruption in one part of the brain or in one neurotransmitter can have far-reaching implications. An integrative approach will be necessary to begin to assemble the clues we have about the cause of schizophrenia.

II. Major Questions and Strategies in Schizophrenia Research
The major research strategies in schizophrenia have focused on three domains, examining disturbances of brain function, abnormalities of brain structure, and genetic aspects of this illness.

1. Studies of disturbances of brain function: neurotransmitter systems.

The vast majority of studies on disturbances of brain function in schizophrenia have examined various aspects of neurotransmission, the means by which brain cells communicate with each other using molecules termed “neurotransmitters.” These are typically small but very potent molecules that are found in every brain cell, and typically exert their effects by interacting with larger, more complex molecules termed receptors. There are specific neurotransmitter receptors for each neurotransmitter. Most drugs that are used to treat neurological and psychiatric disorders have therapeutic effects by either interfering with or enhancing the function of a specific neurotransmitter, often through a receptor for that neurotransmitter. Several key neurotransmitters are thought to be linked to both the expression and treatment of schizophrenia.

A. Dopamine. The mainstay of research in schizophrenia has been to focus on the neurotransmitter dopamine. The most consistent observation that we have about the possible underlying chemical abnormalities in schizophrenia is that all drugs with effective antipsychotic properties diminish the activity of dopamine in the brain, either by blocking the receptors for dopamine, or by altering the rate or amount of release of this chemical. The observation was made over twenty years ago that there is a direct relationship between the ability of an antipsychotic drug to block dopamine receptors and the daily dose that psychiatrists normally use to treat schizophrenics. This observation has been interpreted to suggest that dopamine receptors are overly active in schizophrenia, and the drugs that are used to treat this condition do so by decreasing the activity of dopamine at its own receptor.

Accordingly, the dopamine receptor has been a major focus of research for several decades. Interestingly, more than one type of dopamine receptor exists in the brain. Until recently, two dopamine receptor types had been identified, named D1 and D2. These two receptors differ in a number of ways, including where in the brain they are expressed, the types of drugs that tend to interact with each, and how the message that the receptor receives from interacting with dopamine is transduced by so-called “second messenger systems.” The relationship between antipsychotic potency of a drug and ability to block dopamine receptors is restricted to the D2-class of dopamine receptors, suggesting that schizophrenia may be associated with hyperactivity of this receptor subtype.

As molecular biological tools have become available recently, it has become apparent that there are actually more than two dopamine receptors. There are least five different genes that encode five distinct dopamine receptors, and some of these five receptors can be expressed in alternative forms. The older D1/D2 dichotomy still exists, but D1 and D2 are now know to represent families of receptors rather than individual receptors. The D2 family of receptors consists of D2, D3, and D4 receptors in the new nomenclature. It is this family of receptors that is associated with antipsychotic efficacy. Of particular interest is that the newest class of antipsychotic drugs, the “atypical antipsychotics” represented by the prototypical drug clozapine, all have high affinities for the D4 receptor.

The identification of the D2 family of receptors has guided current research on neurotransmitter abnormalities in schizophrenia. This research primarily focuses on two questions:

Are the D2-like receptors abnormal in schizophrenia? Efforts have focused on directly examining the expression and activity of the D2 like receptors in the brains of schizophrenics, using a variety of methodologies. Studies on brains from schizophrenics that were obtained at autopsy have revealed abnormalities of the expression of the D2 family of receptors both in specific regions of the brain, as well as on a cellular basis. What is interesting is that some regions of the brain make too many of these receptors (especially the D2 and D3 receptors), while other areas make too few of them (particularly the D3 and D4 receptors). Understanding the nature of faulty expression of dopamine receptors is a major area of research. In particular, the relationship between brain-region and cellular over- and underexpression of the same receptor in schizophrenia is an important issue to understand, and is an area of current investigation.

The expression of dopamine receptors in the brains of schizophrenics has also been determined in living patients using in vivo imaging techniques, particularly PET scanning. These studies have also found abnormalities of the expression of the D2 like receptors in some brain regions. A limitation of these studies is the lack of availability of safe drugs that can be appropriately tagged to be seen with the imaging equipment, the lack of drugs that are specific for each member of the D2 family of receptors (i.e., drugs that can specifically label the D3 and D4 receptors), and the lack of availability of labeled compounds that can be seen in those brain regions where dopamine receptors are expressed at only modest levels. The development of new compounds for in vivo imaging studies that avoid these limitations is an area of intense research interest, in order to be able to study how the dopamine receptors are disturbed in schizophrenics while they are still alive, and in particular be able to monitor how they may change over time and during treatment.

How do antipsychotic drugs work? In the end, it may be found that the primary defect in schizophrenia is only peripherally related to dopamine receptors, but we are still left with the observation that for drugs to have antipsychotic properties they typically need to be able to block the D2-like receptors. Accordingly, understanding fundamental aspects of dopamine receptor function is important to be able to inform the development of new and improved treatments for this illness. Particularly relevant research questions that are being explored today include elucidating the structural features of both drugs and individual receptors that determine why certain drugs are particularly active at some receptors but not others. This is especially important as new drugs are developed. One of the best drugs that is available today is clozapine, a so-called “atypical” antipsychotic: if we can determine the unique structural features of this drug, and with which receptors it most strongly interacts, then newer drugs can be targeted to contain similar structural motifs in order to develop the next generation of treatments for schizophrenics. Other research questions focus on how the dopamine receptors can be regulated in the brain by antipsychotic drugs, and in turn how the message that these receptors, when activated by dopamine, is communicated into the cell by second messenger systems. These types of studies in which the basic pharmacology of these receptors is elucidated will be important to our determination of which features of a drug make it a good treatment for schizophrenia, as well as determining the substrates for untoward side effects that can be designed out of the next generation of treatments.

B. Other neurotransmitters. Although dopamine and its D2 family of receptors appear to be a critical step in the pathophysiology and treatment of schizophrenia, it has become increasingly apparent that the pathophysiology underlying schizophrenia is not quite so simple. For example, although the drugs that we use to treat this disorder interfere with dopamine neurotransmission, it often takes weeks to months for these drugs to have their effects, and therapeutic effects are often suboptimal, with patients still reporting psychotic symptoms albeit at reduced levels. One possible interpretation of this is that there are other neurotransmitter systems involved in schizophrenia, either directly or through their interactions with dopamine. Candidate neurotransmitters that are currently being studied for their possible involvement in schizophrenia are serotonin and glutamate. Like dopamine, these two neurotransmitters have their own respective set of specific receptors, and current efforts are underway to determine (a) if these neurotransmitters or receptors are dysfunctional in schizophrenia, and (b) how these transmitter systems are regulated. Particularly interesting is that both of these neurotransmitters are regulated by, and in turn themselves regulate, dopamine receptor systems. Teasing apart the nature of these neurotransmitter interactions in the brain will likely advance our knowledge of both normal brain function as well as how it becomes dysfunctional in psychotic illnesses.

2. Studies on structural abnormalities in schizophrenic brain

A parallel set of questions have been addressed in schizophrenia focused more on the structure than the function of brain regions, both at levels of gross, large-scale abnormalities as well as more subtle abnormalities of cell to cell communication. To use a computer as a metaphor for the brain, the studies on neurotransmitter abnormalities in schizophrenia have been examining “software” problems, while the studies on structural defects have emphasized that there may also be an underlying “hardware” defect in schizophrenia.

Early studies utilized various structural imaging techniques as they were developed, especially CT and MRI scans. A large body of work has revealed that there are large-scale defects in schizophrenic brain, most typically manifested by enlarged ventricles, the large fluid-filled cavities that normally occur in the brain. The enlargement of these ventricles in schizophrenia is felt to be at the expense of reduced brain tissue volume, although the location of this is still hotly debated. While some investigators have argued that this finding is non-specific and associated with less brain volume everywhere in the brain, others have suggested that specific regions are abnormally small. This question remains unresolved.

Another class of structural studies have focused on the microscopic arrangement of brain cells in autopsy samples, finding abnormal patterns of cell distribution and connectivity in several brain regions that likely are responsible for the generation of the “positive symptoms” discussed earlier. These abnormalities appear best explained by a defect in the normal development of the brain, with a malposition of brain cells occurring during the second trimester of pregnancy in some schizophrenic individuals. Understanding these structural problems in schizophrenia, and then relating them to the functional abnormalities discussed above, remains one of the critical problems for understanding this illness.

3. Genetic aspects of schizophrenia

Although schizophrenia has a fairly strong genetic component, research in this area has been less fruitful than others. Two strategies have been employed to search for genetic components to schizophrenia. The first has been to look for genetic linkage in large families containing members with schizophrenia. A more recent strategy has been identifying genes that seem likely to be involved in the illness on theoretical grounds (so-called “candidate genes”…a dopamine receptor gene would be a good example of this) and screening schizophrenics for abnormalities in these genes. Unfortunately, neither approach has resulted in the unambiguous identification of genes associated with the illness. The current view is that it is likely that for an individual to develop this illness, they must have inherited multiple genes, all of which are affected. This makes the search for the genetic roots of schizophrenia considerably more difficult, but the determination of these genetic features remains a significant research focus in this illness.