Schizophrenia is a neurological disorder that affects the cognitive functions of an individual. The cause of this illness is unknown, but there are several theories of how an individual may acquire schizophrenia. Because there are many symptoms of the disease and because the symptoms can vary quite dramatically among several individuals and even within the same individual over time, the diagnosis of schizophrenia can be quite difficult.

In the United States and Europe, schizophrenia occurs in about 3 to 6 of every 10,000 individuals. Schizophrenia occurs equally in males and females; however, the age of onset of the disease is different between the sexes. The primary age of onset in males occurs roughly between the ages of 15 and 25, whereas that in females occurs between the ages of 25 and 35. In almost all cases of schizophrenia, the primary age of onset occurs between the ages of 10 and 50; of those being treated for schizophrenia, 90 percent are between the ages of 15 and 54. Among those having schizophrenia, about 50 percent attempt suicide at some point during the disease, and sadly about 10 percent of schizophrenics actually succeed in committing suicide. Also, schizophrenics have a high mortality rate due to accidents (1).

Schizophrenia occurs in all socioeconomic classes. However, a larger number of schizophrenics are in the lower socioeconomic classes. Two theories have been provided to attempt to explain this disproportionate phenomenon. The social causation hypotheses states that those of lower socioeconomic classes experience different types or amounts of stress that may result in the development or exacerbation of schizophrenia. The more widely accepted downward drift hypothesis argues that the illness itself causes either the descent of the individual into a lower socioeconomic class or the inability of the individual to rise out of the lower socioeconomic class. Since the social causation hypothesis is more narrow and only accounts for the assumption that schizophrenia results from stress (one hypothesis for the development of schizophrenia), the downward drift hypothesis seems to better explain the disproportionate numbers of schizophrenics in the lower socioeconomic classes. Moreover, a number of estimations have claimed that between one-third and two-thirds of homeless individuals have schizophrenia (1).

However, the theory that social factors may produce the stressors that lead to schizophrenia does correlate with several key points. Epidemiological studies have shown that a higher proportion of schizophrenics are found in large cities, particularly in those cities with populations of over one million people, whereas smaller cities have virtually no incidence of schizophrenia. Also, the development of schizophrenia in children of a schizophrenic parent or parents appears to be twice as likely in those residing in large cities as compared to those in smaller communities. Moreover, schizophrenia occurs in a higher percentage of immigrants that move from a less industrialized area or nation to a more industrialized area or nation (1). However, other factors may be present that contribute to the disproportionate localization of schizophrenia in relation to geography which will be discussed later.

The symptoms of schizophrenia are quite variable in type and severity. There is no single symptom that is solely found in schizophrenia, which makes it difficult to diagnose. Also the symptoms within an individual can change over time, with symptoms occurring then disappearing. Before a person is diagnosed with schizophrenia, several early symptoms may be seen in the individual who may subsequently become ill. A child may appear passive, quiet, have few friends, daydream, and reject social events. Once diagnosed with schizophrenia, symptoms range from violent or agitated behavior to catatonia. The individual may experience hallucinations, of which auditory hallucinations are the most prominent type. The person may perceive himself as indestructible or conversely that he is physically deteriorating. Such patients may claim to perceive sensations that are not normally felt, such as that their brain is burning or that there is a cutting sensation in their bone marrow. Many cognitive schizophrenics have little focus or attention to one subject; they haphazardly skip from one thought to another. Delusions and paranoia are also seen (1).

Although the cause of schizophrenia remains a mystery, several theories have been proposed to explain what factor or factors may lead to schizophrenia. One of the more heavily studied theories is the dopamine hypothesis. This theory states that increased levels of dopamine in the brain may be a causative agent of schizophrenia. This hypothesis appears to have some evidence to lend credence to this theory. For instance, some experiments have shown that several schizophrenics have increased plasma concentrations of homovanillic acid (HVA), the major dopamine metabolite (1). Studies have shown that the higher the concentrations of HVA in the plasma of schizophrenics, the more severe are the symptoms of the disease and the more severe is the regimen necessary to treat the disease. It also has been pointed out that almost ail of the effective drugs for the treatment of schizophrenia are dopamine receptor antagonists which decrease the effects of dopamine (1).

There are several dopamine receptors within the central nervous system. However, the particular subtype that has received the most attention in studying schizophrenia is the D2 receptor. The D2 receptor is the particular subtype of dopamine receptors that does not stimulate adenylate cyclase. The D2 receptor is a seven transmembrane protein containing a cytoplasmic loop on the third segment; this large loop is believed to directly interact with a G-protein. There appears to be two types of the D2 receptor: a long form composed of 444 amino acids and a short form composed of 415 amino acids. The long form of the D2 receptor is believed to be the major form in the majority of the brain (1).

Neuropathological studies have shown that many schizophrenics have increased levels of the D2 receptors in the basal ganglia and the limbic system (specifically in the amygdala, hippocampus, and accumbens) of postmortem brain samples. However, these studies have been unable to determine if this increase in D2 receptors is due to schizophrenia or to the use of anti-psychotic drugs as a means of treating schizophrenia (1). Also, studies have revealed that areas of degeneration of the brain have been found in many schizophrenic individuals. In particular, this degeneration appears to occur in the limbic system (primarily the medial temporal lobe, cingulate gyrus, nucleus accumbens, amygdala, and hippocampus) and the basal ganglia (primarily the medial pallidus) of postmortem schizophrenic brain samples. This degeneration seems to result in decreased neuronal number, decreased volume, and increased gliosis (1).

There is further evidence that dopamine hyperactivity may be a direct cause of a particular form of schizophrenia: paranoid schizophrenia. Paranoid schizophrenia is a delusional form of schizophrenia whose symptoms include euphoria, agitation, and excitement. Those individuals suffering from this illness usually have unreasonable beliefs and are constantly preoccupied with those beliefs. Recent studies have indicated that the hippocampus is directly involved with paranoid schizophrenia. Pyramidal cells in the CA 1 layer of the hippocampus are plentiful in D2, dopaminergic receptors. Those neurons in the CA 1 layer of the hippocampus have input into the parietal-temporal-occipital association cortices (PTO) via the inferior involved in the temporal cortex (ITC). The PTO appears to be fixation of declarative belief or, to reinforce thoughts and ideas. It seems that any increase in stimulation of the CA 1 (i.e. increased dopamine levels) would cause an increase stimulation of the PTO. The result of this increased stimulation would cause an increase in belief reinforcement. Thus, those ideas that would normally receive little attention by the individual would receive great attention (and thus lead to delusions and even paranoia). In many paranoid schizophrenics, the hippocampi are considerably smaller due to neuronal degeneration. The pyramidal cells of the CA 1 layer are thought to degenerate as a result of the disease, due to overactivity of the CA 1 D2 synapses. Therefore, increased dopamine activity of the CA 1 pyramidal cells appears to increase their excitability with subsequent neuronal loss. This increased excitability would cause increased activity in the PTO. The increased PTO activity would then cause the increased fixation of beliefs characteristic of paranoid schizophrenia (2).

However, there are factors that seem to pose problems with the dopamine hypothesis as being the cause of schizophrenia. First, although dopamine receptor antagonists relieve the symptoms of schizophrenia, they also relieve the symptoms of almost all psychotic diseases. Therefore, dopamine might not be the cause of schizophrenia but may play a role in the majority of psychotic diseases. Also, some data appear to indicate that anti-psychotic drugs may actually cause an increase in the firing of dopaminergic neurons. These data imply that schizophrenia may be a result of lower amounts of dopamine in the CNS (1). Most of the focus in the dopaminergic theory has been on the mesocortical and mesolimbic tracts which are dopaminergic tracts. However, the neurons of these tracts contain many more D1 receptors than D2 receptors. These examples seem to contradict the dopaminergic theory in schizophrenia (1).

Other neurotransmitters have been implicated as possible causative agents of schizophrenia. There is a belief that an increase in norepinephrine activity in the brain can result in schizophrenia. This belief is backed by the fact that some schizophrenics have increased levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid. Also, amphetamine, a dopaminergic and noradrenergic agonist, when given to individuals can produce paranoid schizophrenia like symptoms (1). Others believe that gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, may play a role in schizophrenia. It is hypothesized that decreased levels of GABA could cause an increased firing rate of dopaminergic neurons. Support of this theory comes from the fact that some schizophrenic patients recover with treatment with benzodiazepine (1).

There are several other theories that have been argued to be causes of schizophrenia. One theory claims that schizophrenia may be caused by a virus. Evidence for this theory is shown by the geographical incidence of the disease, higher incidence of physical abnormalities at birth, the seasonally of birth (most schizophrenics are born during the winter months at which time in utero viral infections are the most common), and immunological abnormalities (abnormal lymphocyte count, etc.). This viral theory claims that the agent may directly cause the illness, or it may set up an autoimmune disease which destroys specific brain structures (1). An endocrine theory has also been postulated; some data show decreased luteinizing hormone and follicle stimulating hormone as causing schizophrenia (possibly associated with length of the illness and age of onset) (1).

Some investigators believe that schizophrenia may quite possibly have a genetic component. However, it is believed that the genes may not be sufficient for the development of the illness and that environmental factors may play a role in the expression of the genes (a proponent that certain stresses may result in schizophrenia). Current genetic tests (including restriction fragment length polymorphism tests) are attempting to isolate the gene or genes. In fact, two studies have reported that in several families, schizophrenia may be related to a gene or genes located on chromosome 5 (1). Unfortunately, these results have not been replicated by other researchers. The high proportion of schizophrenia in various groups of individuals lends credence to a genetic component. The fact that monozygotic twins raised in different families and different environments, both having schizophrenia was fairly high (about 47 percent), illustrates that genetic factors may outweigh environmental factors (1).

Several schizophrenic patients have undergone brain imaging, and several interesting features have been discovered. Several computed tomographic (CT) scans have indicated that some (10 to 50 percent) patients have had a relative enlargement of the lateral and third ventricles, and about 10 to 35 percent of schizophrenic patients had cortical atrophy (1). This data is corroborated with data illustrating that these factors are not a result of drug treatment but of the disease itself. Also, studies using siblings (including monozygotic twins) have shown that practically all of the schizophrenic individuals had larger ventricles that their siblings. Therefore, schizophrenia may result from a degeneration of the brain. Furthermore, magnetic resonance imaging (MRI) has found that neuronal degeneration appears to occur primarily in the temporal lobes of several schizophrenics. As to whether this degeneration is innate or progressive is unknown (1).

Some investigators believe that schizophrenia may be a result or cortical degeneration. One study illustrated that those individuals suffering from schizophrenia had decreased neuronal densities in the prefrontal and cingulate cortices, especially in layer II of the cortex. The lower cell density was due to the reduction of small interneurons in this layer of the cortex. In particular, it appears that these cells might be basket cells and chandelier cells because of their location in the cortex. These cells are inhibitory cells that use gamma-aminobutyric acid (GABA). Thus. a reduction in these cells could cause a decreased inhibition of pyramidal cells in the cortex. In these schizophrenic individuals, there appeared to be no loss of pyramidal cells in these areas of the cortex, and no significant interneuronal loss in other layers of these regions of the cortex. There also appeared to be no loss of glial cells in the cortex. These findings appear not to be influenced by the age of the individuals or by anti-psychotic drugs, since many controls and subjects were used (3).

Treatment for schizophrenia consists of the use of anti-psychotic medication with possible hospitalization. The traditional anti-psychotic drugs consist mostly of the dopamine receptor antagonists such as Thorazine or Haldol. Also, reserpine can also be given, even though it is not a dopamine receptor antagonist. Anti-psychotic medications are never used in combinations, and once a particular anti-psychotic drug works on a patient, that drug is to be continued with that patient. Although some people respond to some anti-psychotic medications and other people respond to other anti-psychotic medications, virtually all patients respond to one anti-psychotic drug or another (1).

Schizophrenia is a very complex illness, having multiple and varying symptoms and unknown causes. As research continues, more information is gained about the mechanisms and causes of schizophrenia. With the help of the many anti-psychotic medications, fortunately many schizophrenic patients have been helped to lead more happy and fruitful lives. Hopefully a cure will be discovered in the future and the mechanisms of schizophrenia known, so that one day schizophrenia will able to be prevented from occurring in other individuals.

BIBLIOGRAPHY:

1. Kaplan, H. I., and B. J. Sadock. Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 6th Ed. 1991. Williams and Wilkins Publishing Co., 320-342.

2. Krieckhaus, E. E., Donahoe, J. W., and M. A. Morgan.Paranoid Schizophrenia may be caused by Dopamine Hyperactivity of CA 1 Hippocampus. 1992. Biological Psychiatry, 31: 560-570.

3. Benes, F.M., McSparren, J., Bird, E. D., SanGiovanni, J. P., and S. L. Vincent. Deficits in Small Interneurons in Prefrontal and Cingulate Cortices of Schizophrenic and Schizoaffective Patients. 1991. Arch. of General Psychiatry, 48: 996--1001.