SCHIZOPHRENIA Part 2 ETIOLOGY AND PATHOGENESIS
ETIOLOGY AND PATHOGENESIS
Part 2 of my series on Schizophrenia.
The exact cause (etiology) and disease-forming mechanism (pathogenesis) of schizophrenia are not known. The experts in the field state that the etiology and pathogenesis of schizophrenia is incredibly complex, multifactorial, and variable from person to person. There is no one schizophrenia; there are multiple schizophrenias with different ranges, severity, and variability of symptoms. This must mean that there are many subtypes of schizophrenia.
Schizophrenia, which means split mind, tends to run in families in 80 percent of cases. However, a single specific schizophrenic gene has not been identified. It is believed that hundreds of genes may be involved in the pathogenesis of the disease.
Some other scientists think that schizophrenia is more a neurodevelopmental vulnerability than a genetic disorder. Vulnerability may be caused by the following factors:
- Genetic predisposition,
- Maternal drug abuse,
- Maternal exposure to a viral infection,
- Viral CNS infection in early childhood.
- Environmental stressors in early childhood, such as neglect, violence, sexual abuse, and mistreatment,
Therefore, detection of vulnerability factors and the early prodromal signs and symptoms of schizophrenia is of utmost importance, so that preventive measures can be taken.
Another rare cause of schizophrenia was found to be due to “autoimmune encephalitis”. Studies of these patients revealed numerous autoimmune antibodies in their cerebrospinal fluid (CSF) samples. Spinal tap and CSF examinations are not routinely done in the USA, but in Europe, they are a part of the diagnostic workup for schizophrenia.
The immune system plays an important role in disease formation. Scientific studies on the immune system of schizophrenic patients have shown overactivity, especially in the brain’s own immune cells called microglia. That is why in some medical centers, the use of immunotherapy is advocated in the
Drug research for the treatment of schizophrenia has contributed significantly to understanding the complex pathogenesis of the disease. In the 1950s, a group of psychiatrists noted that a sedative drug called chlorpromazine also had antipsychotic effects on some schizophrenic patients. Further studies on the drug's mechanism of action revealed that it blocks dopamine receptors, thereby preventing excess dopamine from entering the brain nerve cells. It is assumed that excess dopamine activity in the nerve cells is causing schizophrenia. This idea is the essence of the excess dopamine theory. To prove their point, some researchers gave normal people a drug called amphetamine, which is known to stimulate excess dopamine production in the brain. These normal people developed transitory psychotic symptoms of hallucinations, paranoia, and delirium of schizophrenia for very short periods of time.
The excess dopamine theory accelerated drug research; many new and more effective antipsychotic anti-dopamine) drugs were discovered.
However, the excess dopamine theory was not accepted by everyone. It is found to be very simplistic to explain one of the most complex diseases, such as schizophrenia. Dopamine is not the only neurotransmitter molecule produced by the brain cells. Other neurotransmitters must also play a role in the pathogenesis of schizophrenia. In addition, research studies on schizophrenic patients have shown no excess dopamine activity in their brains. Moreover, other important neurotransmitters and signaling molecules include serotonin, glutamate, and acetylcholine. They may also be involved in the pathogenesis of schizophrenia. Studies have shown that even minute changes in neurochemical levels in the brain can have a marked impact on a person's psychological expression and behavior.
Some psychopharmacological studies have shown that psychotic symptoms of schizophrenia are triggered by the overactivity of three neurotransmitters: dopamine, serotonin, and glutamate in the corpus striatum part of the brain.
There are other researchers who believe that the information processing mechanism is defective in schizophrenia. As we know, information received by receptive neurons is encoded in electrical signals and travels along the axon of the nerve cell to reach the synaptic cleft of the target neurons, where these signals are converted into one or more chemical messengers that cross the cleft to reach the target neurons for the required action. The remaining excess neurotransmitters in the synaptic cleft are immediately neutralized by special enzymes to terminate the stimulus. Dysfunction in this very complex and delicate process may be the main culprit in schizophrenia.
Emerging awareness about the role of neurotransmitters in the pathogenesis of the disease led drug researchers to investigate the role of other neurotransmitters in the pathogenesis of schizophrenia. Many glutamate-targeting drugs are in clinical trials. Along these lines, a new drug called KarXT (cobenfy) targets acetylcholine, which acts on muscarinic receptors in brain cells. In clinical trials, it’s been found to be effective not only controlling psychotic symptoms of schizophrenia but also in partly improving cognitive deficiencies related to schizophrenia without causing dangerous weight gains from antipsychotic drugs.
Cobenfy is a combination medication; it has mild to moderate side effects due to anticholinergic effects, such as urinary retention, decreased gastrointestinal motility, increased pulse rates, and increased blood pressure. It is approved by the FDA for the treatment of schizophrenia in otherwise healthy adult patients.
