Schizophrenia is a brain disorder that affects thinking and behaviour. It is found in up to 1 in 100 people and first appears between the ages of 18 and 30. Existing medicines can have distressing side effects. However, recent research has led to highly effective medicines with fewer side effects. Such developments offer hope of improved therapies to help sufferers lead more fruitful lives.

What is schizophrenia? Top

Schizophrenia is a brain disorder that affects thinking, perception and behaviour. It is the commonest of a number of diseases called psychoses. About 25 per cent of people with schizophrenia experience just one episode, experiencing what are called positive symptoms, and then make a good recovery. ‘Positive’ symptoms of schizophrenia include:

• confused, illogical thinking, poor concentration and speech

• delusions - belief that one is famous, or being persecuted or controlled by others

• hallucinations - hearing voices, seeing visions, smelling or feeling things that are not there

• inappropriate emotional responses, e.g. laughing at bad news.

Another 50 per cent continue to experience symptoms, with often prolonged intervals of being well. A remaining 25 per cent develop a chronic form of the disease, often accompanied by withdrawal, social isolation and depression (negative symptoms). The hopelessness felt by many of those with schizophrenia leads to a suicide rate of around ten per cent.

Who does schizophrenia affect? Top

Schizophrenia affects one in 100 people at some point in their lives, with about 1.9 million diagnosed cases in Europe at any one time. It is most often diagnosed between the ages of 18 and 30. Research has shown that schizophrenia affects men and women equally and occurs at similar rates in all ethnic groups around the world.

The chances of developing the illness are higher if a close relative is affected. It is 12 times the average for a parent, 40 to 50 times for an identical twin, suggesting a genetic predisposition. However, up to 60 per cent of people with schizophrenia have no family history of the illness, so that genetic predisposition is likely to be only one factor in the disease. Brain scans during a hallucination show activity in both the visual and auditory areas of the brain. The person experiencing the hallucination is thus not imagining the sights and voices - to them they are real.




FIGURE 1: Risk of schizophrenia when a relative is affected

Present treatments Top

Traditional medicines for treating schizophrenia, called neuroleptic medicines, have been mainly derivatives of phenothiazine, thioxanthene and butyrophenone. They are still in use, but have serious side-effects. Some can be given as injections every two to four weeks, which may aid compliance. The worst of secondary effects affect a part of the brain called the extrapyramidal motor tracts. They range from rigidity and trembling to painful spasms, eye rolling and an inner restlessness called akathisia.

The development, sometimes months or even years after starting a particular medicine, of uncontrollable facial and bodily movement called tardive dyskinesia is especially serious and is often irreversible even when the medication is stopped. Anti-Parkinson´s disease medications may be given to control these extrapyramidal symptoms.

The other principal medications for schizophrenia are the atypical neuroleptics. They interact with receptors for a variety of neurotransmitters in the brain, including dopamine and serotonin (5HT), and have much improved side-effect profiles, as well as providing good control of positive and negative symptoms. A selective dopamine D2A receptor antagonist which shows efficacy on both positive and negative symptoms is also available.

Patients respond individually to antipsychotic medications, although agitation and hallucinations usually improve within days and delusions usually improve within a few weeks. Many people see substantial improvement by the sixth week of treatment. Sometimes several medications must be tried before the right one is found.

While medical treatment is important in schizophrenia, psychological therapies can also be of benefit and can be used at the same time. Those most likely to be used include cognitive behavioural therapy, psychotherapy and family interventions. However, a need for improved medications remains.

What’s in the pipeline? Top

There are more atypical compounds to treat schizophrenia and schizo-effective disorder under investigation. Clinical trials are undertaken to study once-daily dosing and the safety of switching from other compounds. As atypicals are mostly taken as twice-daily doses, so these once-a-day formulations should be a useful addition to existing options.

There is ongoing work on further neuroleptics to test an intramuscular depot injection form. Also under investigation is a compound which acts preferentially on dopamine D4 and serotonin 5HT₂ receptors. In addition, an existing medicine for epilepsy is also in Phase 3 trial in schizophrenia. Several further compounds that act on neurotransmitter receptors in the brain are being studied in clinical trials. These include antagonists to dopamine D₃, neurokinin-3 and 5HT₂ receptors and various other compounds whose exact ways of working may not yet have been fully determined.

Scientists are also investigating the effects of mGlu2/3 receptor agonists that influence glutamate levels, a brain chemical necessary for learning and memory that is also known to be involved in schizophrenia. Such treatment may avoid certain adverse events that occur with currently approved schizophrenia medications, including involuntary movements and muscle stiffness, or weight gain. Additional and longer-term studies are needed to confirm initial findings. However, it is a hopeful sign that progress is being made in the search for better treatments for schizophrenia.

In addition, several research groups are exploring a dopamine D₂ receptor partial agonist, a mixed 5HT agonist/dopamine D₂ antagonist and a mixed dopamine and 5HT antagonist. All are attempts to find an optimal balance between maximal control of both positive and negative symptoms and the lowest possible incidence of unwanted effects.

Another important issue is the research into preventive treatment for schizophrenia. The notion of early pharmacological intervention during the starting phase of the disorder has the aims to treat early active symptoms and to prevent further deterioration and progression toward chronicity. This type of intervention has not been systematically assessed in the past.

Recently, the development of improved criteria for detecting individuals at risk of developing schizophrenia, has led to clinical trials that have assessed the role of preventive therapy with atypical antipsychotics for these subjects. Among others, research projects are underway to assess N-methyl-D-aspartate (NMDA) glutamate receptor modulators. The dysfunction of the NMDA receptor plays a central role in schizophrenia pathophysiology and the establishment of neuro-developmental deficits.

Furthermore, preliminary findings suggest that glycine treatment may also be beneficial for patients at high risk of developing schizophrenia. To find out whether increasing glycine synaptic levels may generate improved therapeutic effects in high risk individuals, synthetic compounds conceptually similar to the natural amino acid sarcosine are presently in various stages of development by major research groups.

The longer-term future: Top

This bewildering array of candidate medicines in Phase 2 trials is mirrored at earlier stages too, reflecting the great complexity of brain chemistry and the many possible pathways by which it might be influenced to affect positive and negative symptoms. All of these compounds are being developed in an attempt to find an optimal balance between maximal control of symptoms and the lowest possible incidence of unwanted effects.

Recent research has shown that people with schizophrenia have an unusually high level of dopamine D1 receptors in the frontal cortex of the brain, and that this is related to short-term memory dysfunction. A specific dopamine D₁ receptor antagonist is in pre-clinical development and it may be that exploration of this new pathway may open the way to new classes of improved medications for schizophrenia in the future.