with chronic physical conditions.

References

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Genetics and Schizophrenia Anisha Tripathi

What is schizophrenia?

The term schizophrenia, means split mind, and describes a detachment between the different functions of the mind so that thoughts become disconnected and coordination between emotional, cognitive, and volitional (acting based on your own will) processes become weaker. It affects approximately 24 million people or 1 in 300 people (0.32%) worldwide. It is most apparent during late adolescence and tends to occur earlier in men than in women.

Symptoms

• Hallucinations

• Delusions

• Losing interest in everyday activities

• Wanting to avoid people

• Disorganised thinking (speech)

• Abnormal motor behaviour

Is schizophrenia genetic?

By pooling data from many studies carried out between 1920 and 1987, the American psychologist Irving Gottesman, was able to show that the risk of schizophrenia increases from approximately 1% in the general population to nearly 50% in the offspring of two schizophrenic patients and in identical twins of schizophrenics. The concordance of schizophrenia between monozygotic (identical) twins is 31% greater than that of dizygotic (fraternal) twins, strongly suggesting that there is a hereditary factor in schizophrenia. If the condition was purely genetic, however, then the concordance between monozygotic twins would be 100%. Furthermore, in Gottesman’s review he noted that 89% of patients have parents who are not schizophrenic, 81% have no affected first-degree relatives, and 63% show no family history of the disorder whatsoever. However, the reliability of these statistics is limited since family members may be unaware of or unwilling to disclose this information due to the stigma around mental illness. One reason for this 50% concordance between monozygotic twins may be due to epigenetic influences. These alter gene expression through DNA methylation and histone modification. Evidence supporting the role of epigenetic effects is presented in a study that found increased methylation for the dopamine D2 (a receptor linked to schizophrenia ) in a male without schizophrenia in comparison to his monozygotic twin brother and another sibling with schizophrenia.

Why is it so difficult to identify the genes causing schizophrenia?

RFLP (restriction fragment length polymorphisms) analysis has been used to find where a specific gene for a disease lies on a chromosome. It has helped to identify the faulty gene in several hereditary disorders such as Huntington’s disease, muscular dystrophy, and cystic fibrosis. Schizophrenia, however, has a complex pattern of inheritance. Evidence from genetic studies, suggests that there may be several genes responsible, each with a small effect. These genes interact with each other and with environmental factors to influence the susceptibility of a person to schizophrenia. However, none of these genes are either necessary or sufficient to cause schizophrenia. The great difficulty for genetic studies of schizophrenia is that there is no clear pattern of inheritance. A recent study undertaken by the University of Cardiff analysed DNA from 76,755 people with schizophrenia and 243,2649 people without the condition. They then identified 120 genes which were likely to contribute to the disorder. Although there are large numbers of genetic variants involved in schizophrenia, the study showed they are concentrated in genes expressed in neurons, pointing to these cells as the most important site of pathology. The findings also suggest abnormal neuron function in schizophrenia affects many brain areas, which could explain its diverse symptoms, which can include hallucinations, delusions, and problems with thinking clearly.

Schizophrenia and the Brain

Inside the brain, there are two lateral ventricles and a third and fourth ventricle which are filled with fluid (cerebrospinal fluid). Enlarged cerebral ventricles are found in 80% of individuals with schizophrenia. The mechanisms that lead to this ventricular enlargement are unknown although it is believed to be linked to the deletion of a region on chromosome 22 which increases the risk of developing schizophrenia approximately 30-fold in humans.

Brain scans undertaken by the UK Medical Research Council discovered higher levels of activity in part of the brain’s immune system in schizophrenia patients in comparison to healthy volunteers. Microglia cells are the immune cells of the brain and regulate brain development, maintenance of neuronal networks and injury repair. A chemical dye which sticks to microglia was injected into 56 people to record their microglia activity. The scans showed that levels of microglia were highest in those which schizophrenia and high in those at high risk of developing the condition.

It is thought that the microglia may sever the wrong connections in the brain, leaving it wired incorrectly which links to the symptoms of the illness as patients often make unusual connections of what is happening around them as well as mistaking thoughts as voices outside their head.

Environmental factors Stress

When under stress, the brain releases the hormone cortisol. Cortisol has been shown to damage nerve cells in the hippocampus. Excessive cortisol production, damage to the hippocampus and impairment in memory are all common occurrences in patients with schizophrenia. Research has shown that these patients have smaller hippocampal volumes than those without the disease. These stresses can be brought about by events such as bereavement, losing your job or home, divorce or physical, sexual and emotional abuse.

Substance abuse

Dopamine is a neurotransmitter which the brain releases in response to pleasurable activities such as when we eat food. It boosts mood, motivation and attention and helps to regulate movement, learning and emotional responses. Most drugs work by interfering with neurotransmission in the brain. This interference can happen in many ways. Drugs that cause receptors to be over-stimulated are called agonists. Amphetamine in large doses can cause hallucinations and delusions as it is a dopamine agonist. This means that it stimulates the axons of neurons containing dopamine, causing the synapse to be flooded with this neurotransmitter. This over-stimulation of the dopamine receptors results in hallucinations and delusions.

The use of cannabis among schizophrenic patients is associated with greater severity of psychotic symptoms as well as earlier and more frequent relapses. The Edinburgh High Risk study conducted between 1994 and 2004 was carried out to determine the features that distinguish highrisk individuals who go on to develop schizophrenia from those who do not. The study found that in genetically predisposed individuals, high cannabis use is associated with the development of psychotic symptoms. This conveys that schizophrenia is a result of an interaction between genetic and environmental factors.

Ketamine, Phencyclidine (PCP) and ecstasy have also been reported to induce hallucinations, delusions, and paranoia.

Obstetric complications

A 2018 study published in the journal ‘Nature Medicine’ shows that serious obstetric complications such as pre-eclampsia (high blood pressure during pregnancy), asphyxia (lack of oxygen during birth) and premature labour can increase the risk of the developing schizophrenia by 5 times in a child who is genetically predisposed to the condition. This is because these complications appear to ‘turn on’ genes in the placenta that have been associated with schizophrenia. The placenta is composed of foetal and maternal tissue and is a vital organ for the well-being of the foetus.

Nutritional factors

A lack of certain micronutrients and general nutritional deprivation are factors which increase the risk of schizophrenia. The Dutch Famine study of 1998 found that the rates of schizophrenia doubled amongst individuals who were conceived under circumstances of nutritional deprivation throughout premature foetal development. Further studies in 2001 found evidence that low birth weight can be associated with schizophrenia.

Treatments for schizophrenia

Prior to the discovery of antipsychotic drugs in the early 1930s, a common treatment for schizophrenia was insulin coma therapy. This consists of giving the patient increasingly large doses of the hormone insulin, which reduces the sugar content of the blood to produce a state of coma. The patient is then kept in a comatose condition for an hour, after which time they were brought back to consciousness by administrating a warm sugar solution or by an intravenous injection of glucose. This would result in a remission in symptoms for a period (which varied from several months to a couple of years. Insulin-coma therapy is rarely used today is due to the very high risk of a prolonged coma where it is impossible to bring the patient out of this state using usual methods. Electroconvulsive therapy (ECT) was initially used for the treatment of schizophrenia, but over the years its use in schizophrenia has become limited. Before an ECT treatment, general anaesthetic and a muscle relaxant is given to the patient to restrict movement during the procedure. The treatment consists of electrodes being placed at precise locations on the patient’s head. Breathing, heart rate and blood pressure is monitored throughout. For roughly a minute, a small electric current pass from electrodes into the brain and triggers a seizure. ECT causes changes in the patient’s brain chemistry and thus results in a change to a patient’s catatonic symptoms.

Antipsychotic drugs

As mentioned earlier, it is the drugs that stimulate the dopamine system that produce psychotic states most like schizophrenia. Thus, drugs that block dopamine receptors in the brain can successfully treat schizophrenic symptoms. Antipsychotic drugs bind to dopamine receptors without stimulating them, thus preventing the receptors from being stimulated by dopamine. This reduced stimulation of the dopamine system reduces the severity of hallucinations and delusions in those with schizophrenia. Despite this, there is still no evidence that schizophrenic symptoms are due to an excess of brain dopamine. Although post-mortem brain studies have revealed increases in the densities of dopamine D2 receptors (the main receptor for most antipsychotic drugs).

Other treatments for schizophrenia consist of admissions to a psychiatric ward in a hospital. Under the 2007 Mental Health Act, people who are at risk of harming themselves or others can be compulsorily detained in a hospital. Therapies such as cognitive behaviour therapy, family therapy and arts therapy are also prescribed.

To conclude, it is undeniable that genetic factors play a significant role in the onset for schizophrenia. However, it can be deduced that it is a combination of both environmental and genetic factors, with the environmental effects having a larger effect when the individual is genetically predisposed to the condition. Overall, research into the genes which are responsible for schizophrenia and explanations for the mechanisms causing the neurological impacts seen is largely inconclusive and thus there is still a long way to go before finding a potential cure for this illness.

References

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