Schizophrenia
Schizophrenia is the most common major mental disorder in the UK, and directly affects one in 100 people at some point during their lives. It usually begins during adolescence or the early twenties, and often causes very disturbing experiences – resulting in a large amount of personal suffering, family disruption and heath and social care. MRC researchers are investigating the condition and what causes it, how to treat it and how to prevent it.
Scientists divide the symptoms of schizophrenia, which include delusions, abnormal thoughts and behaviour and lethargy, into ‘positive’ and ‘negative’.
The positive symptoms occur in the acute phase of the condition and include restless, noisy and irrational behaviour, sudden mood changes, inappropriate moods, hallucinations – often hearing voices – delusions and disordered thinking. The negative symptoms include tiredness, social withdrawal, physical slowness, lack of activity and interest in things and self-neglect, and usually occur in the chronic stage of schizophrenia.
Since the 1980s, cognitive impairments – difficulties in attention, concentration, memory and planning – have been regarded as a main feature of the disorder. They are present in most patients throughout the illness and even before the positive symptoms, such as delusions and hallucinations, beginadmin
Most people with schizophrenia are prescribed drug treatments, and may also be given ‘talking treatments’ such as counselling and psychotherapy. Schizophrenia is a high cost illness because of the wide range of health and social needs that people have1. Also, nearly 80 per cent of schizophrenia patients remain unemployed. The estimated total cost of schizophrenia to UK society was £6.7 billion in 2004/05.
Schizophrenia is frequently misunderstood as split personality or multiple personality – the split refers to the discrepancy between thinking and feeling, not personality. People with schizophrenia are very rarely dangerous to other people and most are vulnerable and withdrawn and more likely to hurt themselves than others.
History
Schizophrenia was first described in 1896 by a German psychiatrist, Dr Emil Kraepelin. During the 1930s, scientists thought that schizophrenia was hereditary. Then, after the Second World War, people began to wonder whether schizophrenia was a reaction to pathological relationships or patterns of communication within a patient’s family. The management of schizophrenia generally took place in large asylums, where people remained confined for much of their lives.
Doctors began using drugs with antipsychotic actions around the middle of the 20th century. A French surgeon, Henri Laborit, tested a drug called chlorpromazine (a phenothiazine) as an anaesthetic on soldiers and noticed that they became calmer. Later, researchers showed in a trial that these drugs were effective against the acute symptoms of schizophrenia and were not only acting as a sedative2.
As all antipsychotic drugs were thought to interfere with the brain chemical dopamine, researchers began to focus on neurochemistry. This has been the basis of pharmaceutical development for schizophrenia ever since. The neurochemical serotonin has also been implicated and, for a long time, scientists have considered the relevance of glutamate – this year a team found evidence linking it to the cognitive deficits caused by the condition3.
Hidden signs
A major scientific development was the introduction non-invasive imaging. This allows scientists to study the activity and structure of the brain without harming the person. Brain imaging has resulted in a large amount of progress towards understanding the nature and causes of schizophrenia and treating and even preventing it.
Professor Eve Johnstone at the University of Edinburgh is funded by the MRC and is studying teenagers with learning disabilities. She has been working on schizophrenia since 1974, trying to understand its biological basis. The main method her team uses is a brain scanner. In 1976, they were the first to demonstrate that there were actual structural faults in the brains of schizophrenic patients4.
Recently, her Edinburgh team’s experiments showed that brain scanning could predict that someone would develop schizophrenia even before they developed any symptoms. This was part of the MRC Edinburgh High Risk study, which has been tracking families with a history of schizophrenia since 1994.
Our current scientific knowledge shows that schizophrenia has both a genetic and an environmental basis and that these factors interact – scientists are investigating this by studying large groups of people, called cohorts. In 2006, Professor Johnstone’s team discovered a variation in a gene at risk of schizophrenia that strongly suggested people would develop the condition. Brain scans of young people predisposed to schizophrenia showed that those who went on to develop the symptoms had the mutated gene. The researchers followed 163 at-risk young people from their late teens for 10 years. They found that there was a clear link between one particular variation of a gene called neuregulin and the risk of developing psychotic symptoms5.
The role of genes
At the University of Oxford, MRC researcher Professor Paul Harrison is investigating the biological role of a number of genes implicated in the development of schizophrenia, and how they influence brain function. He hopes that his findings could lead to novel ways of treating the illness. His group has characterised a gene that is important in the development of the brain and is associated with an increased risk of schizophrenia6.
Other genes have been linked to the condition, such as one that affects an important enzyme involved in the way the brain functions on a molecular level – a family of enzymes called PDE4. This could lead to new treatments, using drugs that inhibit this gene, and a new way of diagnosing the condition. This work has been carried out by MRC researchers at the University of Glasgow, led by Professor Miles Houslay, who is collaborating with Professor David Porteous’s group at the University of Edinburgh and the pharmaceutical company Merck.
An AESOP tale
MRC researchers are investigating environmental risk factors and consequences associated with schizophrenia. Professor Robin Murray at the Institute of Psychiatry is leading the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (AESOP) study, which began in 1997. The team is comparing the rates of psychosis and exploring biological and social risk factors in different ethnic groups in South London, Nottingham and Bristol. The researchers have already found that African Caribbean and Black African populations in England suffer from relatively high rates of schizophrenia and manic psychosis and that other ethnic minority groups had modestly increased rates7.
Schizophrenia is also linked to increased substance misuse, such as drug addiction or alcoholism. The MRC is funding Dr Christine Barrowclough at the University of Manchester to investigate this. She is also looking into whether cognitive therapy is beneficial in this group. Around half of all patients with schizophrenia are thought to abuse drugs or alcohol8. There is evidence to suggest that cannabis may have a causal role in the development of psychopathology.
Cognitive therapy
Professor Til Wykes, an MRC scientist at King’s College London, has been investigating cognitive remediation therapy and has shown in a trial that mental exercise can improve cognition in early onset schizophrenia9. The study is being considered for future public health policy by the National Institute for Health and Clinical Excellence (NICE).
Professor Wykes’s group, with another team of MRC researchers at the University of Birmingham led by Professor Max Birchwood, has also been testing the effect of cognitive therapy on people who experience hallucinations with schizophrenia and respond to them, often in a dangerous way. The researchers demonstrated in a small randomised trial, with 20 people who hear voices, that cognitive behavioural interventions reduce the frequency of auditory hallucinations10.
References
1. Mangalore & Knapp (2007) Cost of schizophrenia in England. J Ment Health Policy Econ., 10, 23.
2. Cole et al. (1964). Phenothiazine treatment in acute schizophrenia. Archives of General Psychiatry, 10, 246.
3. Lecourtier et al. (2007). Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex. Biol Psychiatry, 62, 739.
4. Johnstone et al. (1976). Cerebral ventricular size and cognitive impairment in chronic schizophrenia, The Lancet, 2, 924
5. Hall et al. (2006). A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nature Neuroscience, 9, 1477.
6. Tan et al. (2007). Molecular cloning of a brain-specific, developmentally regulated Neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem. 282, 24343.
7. Kirkbride et al. (2006). Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AESOP study. Archives of General Psychiatry, 63, 250.
8. Gregg et al. (2007). Reasons for increased substance use in psychosis. Clin Psychol Rev., 27, 494.
9. Wykes et al. (2007). Cognitive remediation therapy in schizophrenia: randomised controlled trial. Br J Psychiatry, 190, 421.
10. McLeod et al. (2007). Cognitive behavioural therapy group work with voice hearers. Part 1. Br J Nurs., 16, 248.