A spotlight of hope

How far is it possible to trust the conclusions of clinical suicide prevention trials? Helen Johnson reports

The results of the recent InterSePT trial give new hope to thousands of schizophrenia sufferers around the world at high risk of suicidality who have tried other treatments without success.Suicide is a major contributor to the morbidity and mortality of schizophrenics. Approximately 50 per cent of patients with schizophrenia or schizoaffective disorder attempt suicide, and some 10 per cent die of suicide. Evidence is mounting that clozapine is extremely effective in helping to reduce suicidal behaviour in people with schizophrenia.

The International Suicide Prevention Trial (InterSePT) evaluated the risk for suicidal behaviour in 980 high-risk patients with schizophrenia or schizoaffective disorder, comparing clozapine with olanzapine. Over the course of the two-year study, clozapine therapy was found to be superior across a number of parameters. Fewer clozapine-treated patients attempted suicide or required hospitalisation or intervention to prevent suicide. Overall, only five clozapine-treated patients died of suicide during the study. The trial authors concluded, therefore, that clozapine therapy significantly reduces suicidal behaviour in patients deemed to be at high risk of attempting suicide and should be considered as the treatment of choice for all such patients.Clozapine (brand name Clozaril®) is an atypical anti-psychotic, which is used to treat schizophrenia patients who have failed to respond to other anti-psychotic treatments or who cannot tolerate the neurological side effects of anti-psychotics. It works by decreasing abnormal excitement in the brain. First licensed in the UK in 1990, clozapine was widely hailed as the first major advance in the treatment of schizophrenia since the arrival of anti-psychotic agents in the 1950s.

In June 2002, the National Institute for Clinical Excellence endorsed the use of atypical anti-psychotics on the NHS. Unfortunately Primary Care Trusts and NHS bodies have been slow to implement that guidance. A recent survey by the charity Rethink showed that 20 per cent of Primary Care Trusts had yet to implement the decision six months on.

The efficacy of clozapine in severely ill patients has never been in doubt, but treatment response rates can vary widely - anything from 30 per cent to 100 per cent for patients on short-term therapy. During long-term treatment, approximately 60 per cent of patients who are unresponsive or intolerant to other treatments respond to clozapine. Over the last 15 years, clozapine efficacy has been examined in a large number of clinical studies and been shown to be effective in improving psychotic symptoms, severe mood disorders, quality of life, social functioning and suicidality in a significant proportion of patients. It is important to take account of the social and economic benefits as well; clozapine treatment has been associated with a reduction in violent behaviour, improved compliance with medication regimes and less need for hospitalisation and inpatient care.

However, despite its proven efficacy across a range of indicators, particularly in cases of treatment-resistant schizophrenia, clozapine use is not without its risks. There are potentially dangerous side effects that require careful medical supervision. In the past, concerns about these risks have tended to ensure that the drug is only prescribed to patients as a treatment of last resort.

Clozapine use carries with it a significant risk of agranulocytosis (a potentially fatal condition characterised by a marked reduction in the number of white cells in the blood, which impairs the body's ability to fight infection), which has been observed in 1-2 per cent of patients. Other, potentially serious, side effects include seizures and convulsions (reported in up to five per cent of patients), hyperglycaemia (high blood sugar) and tachycardia. However researchers have observed that the risks must be balanced against the potential benefits, noting that the suicide mortality rate in schizophrenia patients not treated with clozapine is much higher that the mortality rate from agranulocytosis in patients who are treated. The InterSePT results, therefore, represent an important addition to this risk-benefit debate.

In any event in the UK, as in other countries, the actual risk of agranulocytosis is minimised by the obligation to register every clozapine patient with the Clozaril Patient Monitoring Service and regular monitoring of the white blood cell count.

Moreover the InterSePT study has shone the spotlight onto clinical trial research and the considerations involved in conducting ethical research into severe mental illness. How ethical is it to conduct a trial designed to measure the number of suicide attempts as one of its primary endpoints? Clozapine is the only drug proven to work in schizophrenia patients who have exhausted all other treatment options and the InterSePT conclusions on the impact of suicide mortality appear compelling. Given those facts, is it appropriate to conduct randomised controlled trials in a group of patients who are, simply by virtue of their schizophrenic diagnosis, already vulnerable and at a high risk of attempting suicide? Should manufacturers and regulators be working together to find alternative means of evaluating the efficacy of a particular drug in certain "sensitive", high-risk indications?

The InterSePT trial was a comparative study, which evaluated one schizophrenia drug against another. Consequently every patient enrolled in the study received treatment. Do placebo-controlled trials, however, pose different considerations? Once it is known or suspected that a treatment may have a positive impact in reducing the incidence of suicidal behaviour in some patients, how can one justify withholding that treatment from one cohort of trial patients in favour of a placebo? Questions can also be asked about the reliability and veracity of the trial results. How far is it possible to trust the conclusions of these trials?

Up to now, negative perception around the risk of agranulocytosis, coupled with a limited licence indication to treatment-resistant or intolerant patients, has tended to result in restricted clozapine use in the UK. Now, with the benefit of endorsement from NICE and the conclusions from the InterSePT trial, thousands of severely ill patients will be hoping that they can have access to what many consider to be the most important pharmaceutical development in the treatment of schizophrenia patients since the 1950s.