Schizophrenia is a difficult condition for patients and their families to manage. Relapse is a frequent occurrence, particularly if patients decide to discontinue antipsychotic drug treatment because of unwanted side effects. Psychiatrists say over half of patients relapse within two years and over 80 per cent within five years. Relapse is five times more likely to occur among patients who stop their treatment.
Now a phase III study investigating safety and efficacy of a new drug, soon to be available in the US, has shown the risk of relapse in patients getting the treatment over a period of one year compared to those receiving no treatment was reduced by around 75 per cent. Preventing relapse is important because it enables people with schizophrenia to carry on with their lives normally, without disruption to work, education or relationships, and helps avoid the need for hospital admission. Hopes are high that newer treatments will improve on those already available in keeping patients stable.
The drug featured in the study is a new atypical antipsychotic called asenapine, in development by Schering-Plough. It is taken by mouth, and is the first psychotropic medicine to be administered sublingually. The drug is placed under the tongue twice daily and releases slowly from a small reservoir. “The formulation gives a steady distribution of the drug. It also ensures patients under observation are actually taking their medicine and not pretending to swallow a tablet which they later surreptitiously remove,” explained psychiatrist Professor Steven Potkin, of University of California, who has experience of asenapine. “In addition, it makes it difficult for patients to overdose themselves. If they put too much in the mouth the excess is swallowed and rendered inactive in the gut.”
The drug was approved by the FDA in August for treatment of acute schizophrenia in adults and also for acute episodes of mania in bipolar 1 disorder. The first time a psychotropic medicine has been approved for two indications simultaneously. It will shortly be marketed as Saphris in the US. In Europe it is still under review by the European Medicines Evaluation Agency (EMEA). If approved it will be marketed in European countries as Sycrest.
Results presented at ECNP
Results of the phase III relapse-prevention study in schizophrenia were presented this week to psychiatrists at the 22nd annual congress of the European College of Neuropsychopharmacology (ECNP) in Istanbul. They showed that only 12 per cent of patients who received asenapine relapsed over the course of one year compared with 47 per cent of patients who received placebo. The study consisted of a six-month open label phase and a six-month randomised double blind phase where asenapine was compared against placebo in 386 patients, most of whom suffered from paranoid schizophrenia. Only patients whose disease had stabilised on asenapine were included in the randomised phase. Most of those receiving asenapine took 10mg twice daily
Patients were deemed to have relapsed on a number of assessments including if their score on the standard schizophrenia assessment tool PANSS (Positive and Negative Syndrome Scale) had increased by more than 20 per cent from the time they entered the double-blind part of the study or if they scored more than 5 on specific items such as hostility or hallucinatory behaviour. Adverse events were monitored throughout the study by formal assessments including ECGs, laboratory tests, and standard rating scales.
Lead author of the study Mary Mackle, a clinical research scientist at Schering Plough in New Jersey, USA, said: “The results we saw for asenapine were very good.” The number of patients staying with active treatment was high and the number experiencing a further episode was exceptionally low. Patients were thought to have stayed on treatment because it was effective in controlling symptoms but also because they were not deterred by side effects. “This is a well-tolerated drug, obviously, with a good side effect profile. It doesn’t cause a lot of weight gain or sedation compared to some other antipsychotics.” In fact, treatment-emergent and treatment-related side effects occurred more frequently in the placebo group, she noted.
Another Schering Plough clinical research scientist, Dr John Panagides also commented on how well patients appeared to tolerate treatment: “Given the known risk/benefit profiles of current antipsychotic drugs, asenapine is pretty favourable.” It is associated to a much lesser extent with side effects of antipsychotic drug therapy such as raised prolactin, weight gain, metabolic effects, sedation and extrapyramidal system effects (involuntary movements), he explained.
“Asenapine’s effects on these were very modest,” . The most frequently reported adverse events for both the asenapine and placebo groups were anxiety (8.2 per cent with asenapine vs 10,9 per cent with placebo), increased weight (6.7 per cent for asenapine vs 3.6 per cent for placebo) and insomnia (6.2 per cent with asenapine and 13.5 per cent with placebo.) Clinically significant weight gain (more than 7 per cent of baseline weight – amounting to around 4kg – affected only 3.7 per cent of asenapine-treated patients.) Four times as many placebo-treated patients experienced worsening of schizophrenia as did patients receiving asenapine (4.6 per cent vs 16.1 per cent).
Negative symptom improvement
One of the emerging benefits of the new treatment is itseffects on the negative symptoms of schizophrenia, remarked Professor Potkin. Negative symptoms include apathy, loss of drive and lack of motivation or interest, and poor social functioning. “In short-term studies it showed clear efficacy for negative symptoms and in longer term studies, the effect also seems to be maintained. This is a very important finding because negative symptoms are extremely difficult to treat,” he stressed.
A Schering-Plough press release in July this year reported on a study investigating asenapine’s effects on negative symptoms. In the study, asenapine was significantly more effective than olanzapine in the reduction of negative symptoms as assessed using the 16-item Negative Symptom Assessment scale (NSA-16).”Full results of the trial, including efficacy, safety and tolerability data, will be submitted for presentation at a medical meeting at a later date,” according to the company statement.
All antipsychotic drugs are different, points out Professor Potkin. “There is no ‘one size fits all ‘ drug that suits all patients with schizophrenia. Some people wont respond to one but will respond to another. Different side-effect profiles allow psychiatrists to tailor treatment to suit particular patients, for example, overweight patients would need a drug that avoids excessive weight gain or metabolic syndrome” he suggested. “All antipsychotics are effective at tackling the positive symptoms of schizophrenia but some agents also target different domains that others don’t.”
A poster at ECNP led by University of California and Yale University scientists using a primate model suggests asenapine may have potential to treat cognitive impairment in schizophrenia. The researchers concluded from asenapine’s effects on serotonergic receptors in monkeys that the drug might also improve cognitive impairment in schizophrenia although they stress large scale clinical studies would be needed for confirmation of these effects in patients.
Regarding its other indication, bipolar 1 mania, or mixed symptoms, a poster at ECNP showed asenapine rapidly reduced symptoms within 2 days and improved scores on all 11 items of the YMRS (Young Mania Rating Scale) – the standard measure for mania assessment within two weeks.
Although clinical experience with the drug is limited, some professional guidelines, notably those produced by expert bodies concerned with bipolar disease, are already recommending it to psychiatrists on the strength of evidence produced from numerous clinical trials. As further trials are completed and its performance in clinical practice is studied once it becomes widely available, more will be learned about asenapine’s strengths.
“There is great optimism that other new drugs will be developed in the future that will also help address the current unmet needs in managing patients with schizophrenia and bipolar disorder,” remarked Professor Potkin
Written by Olwen Glynn Owen