Novel drugs needed for schizophrenia

[kkmalaysia]

Current limitations in antipsychotic drugs are triggering an urgent need for new, mechanistically novel agents for the treatment of schizophrenia.

“It is clear that pharmaceutical drugs have improved outcomes for patients with schizophrenia,” said Professor Jeffrey Lieberman, a top psychiatry researcher at Columbia University and chief psychiatrist of the New York Presbyterian Hospital, US. “But one has to be objective and realistic in realizing our limitations.”

Current antipsychotic agents have indeed improved the treatment of schizophrenia, he stated. There are now comparatively fewer cases of catatonia and hebephrenia among schizophrenics, and more patients today can be maintained in the community instead of being institutionalized. Lower doses of first generation antipsychotics and preferential use of second generation drugs have led to lower rates of neurologic side effects.

Yet, all of the available treatments employ the same mechanism of action: to inhibit the dopamine D2 receptor. This has resulted in therapeutic efficacies that are “roughly consistent” among the different drugs. “Antipsychotics are more similar than different in their mechanism of action and therapeutic effects,” said Lieberman, who is also director of the New York State Psychiatric Institute. “There may be superiority, but it is shown more conclusively in the severely ill.”

While today’s antipsychotics can suppress psychosis, prevent recurrence and with early treatment, prevent progression, they still cannot alleviate residual psychosis and treat negative and cognitive symptoms. Antipsychotics are also unable to rehabilitate patients with end stage illnesses. “Our treatments have room for improvement,” he said. Efforts to identify novel agents with affinities for targets other than D2 receptors are still underway.

In this context, Lieberman commented, multiple medications are necessary to treat the different pathologic dimensions of schizophrenia. As a result, psychiatrists are now using adjunctive therapy and polypharmacy, with benzodiazepines, antidepressants, mood stabilizers and combined antipsychotics to manage the condition.

“The problem is, there is no evidential basis to support this practice,” said Lieberman. “We are looking towards the rational development of a polypharmacy drug where compounds are used as adjunctive agents” to target specific symptoms such as cognition, psychosis and negative symptoms, which may have different pathophysiological bases that cannot be addressed by a single agent.

Another approach is to go beyond treating patients for their symptoms, and to prevent their disease progression. In this strategy, results have emerged from a recent trial of AL-108, a compound that contains a fragment of Activity-Dependent Neuroprotective Protein (ADNP), which mediates neurodevelopment and neuroprotection, said Lieberman. The double-blind trial randomized 60 chronic stabilized patients with controlled positive symptoms, already receiving antipsychotic medication, to 12 weeks of treatment with placebo, 5 mg of AL-108 or 30 mg of AL-108.

While AL-108 did not demonstrate a significant difference compared with placebo in the primary outcome measure evaluating key cognitive domains of schizophrenia, it showed a significant effect in improving symptoms and functional outcomes. “This is an interesting preliminary finding which
illustrates the direction drug development can go,” he commented.

Source: mims.com