SCHIZOPHRENIA

What is schizophrenia?

Schizophrenia is a mental illness that affects thinking, perception and behaviour. It is the commonest of a number of diseases called psychoses. About a quarter of people with schizophrenia have just one episode, experiencing what are called positive symptoms, and then make a good recovery. About two-thirds continue to experience symptoms, with often prolonged intervals of being well. About 10 per cent develop a chronic form of the disease, experiencing severe long-term incapacity, perhaps accompanied by withdrawal, social isolation, flattened mood and poor self-care (negative symptoms), but some will eventually recover fully. Approximately 30-40 per cent of people with schizophrenia attempt suicide at some time in their lives.

Brain scans during a hallucination show activity in both the visual and auditory areas of the brain (Figure 1). The person experiencing the hallucination is thus not imagining the sights and voices - to them they are real.

Who does schizophrenia affect and what does it cost?

Schizophrenia affects 1 in 100 people at some point in their lives, with about 250,000 diagnosed cases in Britain at any one time. It is most often diagnosed between the ages of 18 and 30. The chances of developing the illness are higher if a near relative is affected, suggesting a genetic predisposition, but up to 60 per cent of people with schizophrenia have no family history of the illness, so that genetic risks are likely to be only one factor in the disease.

Mental illness places a huge burden on the NHS. In 2003/04, in-patient treatment of mental illness cost £1.3 billion (nearly 10 per cent of all inpatient costs). Schizophrenia and related disorders accounted for over 34,000 in-patient admissions and over 2.24 million hospital bed-days of treatment in that year. It has been estimated that the total cost to society of treating schizophrenia amounted to more than £3.7 billion in 2000.

Present treatments and shortcomings

Early medicines for treating schizophrenia (such as haloperidol and chlorpromazine) are still in use, but have serious side-effects. The worst of these 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 medications may be given to control these extrapyramidal symptoms.

Established medicines for schizophrenia include several classes of compounds, such as phenothiazines (e.g. chlorpromazine, fluphenazine and trifluoroperazine), butyrophenones (haloperidol and benperidol) and thioxanthenes (flupentixol, zuclopenthixol).

These vary in the pattern and intensity of side-effects they produce (sedation, extrapyramidal symptoms, dry mouth, blurred vision etc) and tolerability varies from patient to patient. Some can be given as injections every two to four weeks, which may aid compliance.

The other principal medications for schizophrenia are the so-called 'atypical' antipsychotic medicines. Clozapine (Clozaril, Novartis) was the first to be introduced, but is now used less often because of the need for continuing blood monitoring. Atypical antipsychotics interact with receptors for neurotransmitters in the brain, including dopamine (DA) and serotonin (5HT), and have improved side-effect profiles, as well as providing good control of positive and negative symptoms. They are, however, more expensive than the older medicines. Other atypicals are risperidone (Risperdal, Janssen-Cilag), olanzapine (Zyprexa, Lilly), quetiapine (Seroquel, AstraZeneca), and amisulpride (Solian, sanofi-aventis). Weight gain is the most common side-effect associated with atypical antipsychotics. It has also been suggested that their use may be associated with a higher incidence of diabetes, although the evidence for this is controversial. However, a need for improved medications remains.

Aripiprazole (Abilify, Bristol-Myers Squibb/Otsuka) works somewhat differently from other atypicals. It is thought to act as a dopamine system stabiliser, through partial agonism, unlike other agents, which mainly act to suppress dopamine.

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 in schizophrenia include cognitive behavioural therapy, psychotherapy and family interventions. Unfortunately, access to such therapies under the NHS is currently limited.

What's in the development pipeline?

Two modified-release forms of existing atypical antipsychotics are in advanced development. These are Janssen-Cilag's extendedrelease form of paliperidone, a derivative of risperidone, and AstraZeneca's sustained-release form of quetiapine (Seroquel SR). Other atypicals are mostly taken as twice-daily doses, so these once-a-day formulations should be a useful addition to existing options.

Completely new atypical agents in Phase 3 trial include asenapine (Organon) and bifeprunox, which is being studied by Solvay, Lundbeck and Wyeth, both of which have reached an advanced stage of development. In addition, an existing medicine for epilepsy is also in Phase 3 trial in schizophrenia. Topiramate (Topamax, Janssen-Cilag) is being studied for control of positive symptoms in patients who are resistant to atypicals such as clozapine.

At Phase 2, there are many compounds in clinical trial that act on neurotransmitter receptors in the brain. These include blonanserin (Dainippon-Sumitomo), SB-773812 and SB-223412 (talnetant; both GSK), Org 24448 (farampator; Organon/Cortex), ABT-089 (Abbott), AVE 1625 (sanofi-aventis), idazoxan (Pierre Fabre/Potomac) and SGS518 (Lilly). Also, there are ACP-103 (Acadia Pharma), sabcomeline (Minster Pharma) and ACP-104 (Acadia), SLV313 from Solvay and Wyeth and various other compounds whose exact ways of working may not yet have been fully determined, including lurasidone (Merck Sharp & Dohme /Dainippon-Sumitomo), ocaperidone (Neuro3d), vabicaserin (Wyeth) and others.

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. Companies with a particular engagement in this research include GlaxoSmithKline, Wyeth, Pfizer, Solvay, Lundbeck, sanofi-aventis and others and it must be hoped that their efforts soon result in better treatment options for schizophrenia.

FOR FURTHER INFORMATION CONTACT:

RETHINK, severe mental illness
5th floor, Royal London House
22-25 Finsbury Square
London, EC2A 1DX
Phone: 020 8974 6814 (Helpline)
Website: www.rethink.org