Addressing multiple symptoms through multiple drug targets could be the route to genuinely innovative treatments for mental illness, suggests a panel of US academic, government and industry representatives convened by the American College of Neuropsychopharmacology (ACNP).

Following a review of factors impeding the development of novel psychotropics, the ACNP panel of leading brain and behavioural researchers called for a change of direction to generate treatments that were more effective and less prone to side-effects than those currently available.

Their conclusions will add fuel to the debate over whether second-generation antipsychotics offer any real advance over treatments that have been on the market for decades. They also come at a time when mental disorders cause more disability in Americans aged 15-44 years than any other class of illness, with a suicide rate higher than the annual mortality from homicide, AIDS and most cancers, the ACNP noted.

Issuing their call to action at the association’s annual meeting in Florida, the ACNP panel said over-reliance on a ‘silver bullet’ approach was one of several reasons for the slow progress in developing new drugs for schizophrenia and other affective disorders. Others included failure to understand the full complexity of these illnesses, industry preference for ‘me-too’ drugs and the difficulty of extrapolating from animal models for mood disorders.

Single disease model prevalance

The review of more than 10 years’ clinical research in the field highlighted the prevalence of a ‘single disease model’ for mental illnesses. “Increasingly, clinicians and researchers have begun to understand that a combination of several key symptom modalities may need to be addressed separately,” the ACNP commented.

This was particularly true of schizophrenia, where psychosis has long been targeted as the dominant symptom. More attention is now being paid to other symptoms, such as cognitive impairment and depression, that could have a greater impact on long-term functionality.

In terms of drug development, that meant moving beyond a strategy of hitting one molecular target at a time and either designing therapies with a more complex mode of action, or looking at combination treatments, suggested panel member Dr Bryan Roth, director of the US National Institute of Mental Health’s Psychoactive Drug Screening Program.

Marketers of second-generation antipsychotics have been thrown onto the defensive by two damning studies in recent months. The latest analysis of the comprehensive CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study funded by the US NIMH indicated that the first-generation perphenazine was just as effective as – and a good deal cheaper than – AstraZeneca’s Seroquel (quetiapine), Eli Lilly’s Zyprexa (olanzapine), Pfizer’s Geodon (ziprasidone) and Johnson & Johnson’s Risperidal (risperidone) in treating schizophrenia. In October, results from the CUtLASS prospective study carried out at 14 community psychiatric hospitals in the UK found that Seroquel, Zyprexa, Risperidal and other atypical antipsychotics were no better than first-generation drugs in terms of efficacy or tolerability.