Laurie Barclay, MD, June 2005

Schizophrenia is a chronically disabling psychiatric disease characterized by disturbances in thinking, emotional response and behavior. Negative symptoms typically include lack of emotional range, disturbed relationships with others, and cognitive disturbances, whereas positive symptoms include hallucinations and delusions. Typically, patients require lifelong medical treatment and suffer from chronically impaired social and vocational adjustment.

Lifetime incidence of schizophrenia is 1%, prevalence in the developed world is eight million, and US prevalence is between two and three million, according to the National Institute of Mental Health.

The mainstay of therapy is currently first generation (typical), or second generation (atypical) antipsychotic agents. First generation antipsychotics, which were introduced in the late 1950s, block dopamine receptors. Although they are effective against the positive symptoms of schizophrenia, they have a wide range of adverse effects.

Most disabling are the motor disturbances, including tardive dyskinesia (uncontrollable smacking movements of the lips and tongue) and extrapyramidal rigidity (stiffness, tremor, and other Parkinsonian symptoms). Furthermore, the typical antipsychotic agents are ineffective for the negative symptoms of schizophrenia, and their use has therefore decreased in the US and Europe.

Atypical antipsychotic drugs target both dopamine and 5-HT2A receptors. Although they have fewer motor adverse effects than do the typical antipsychotics, they are only partially effective in addressing the negative symptoms. Among the atypical antipsychotics, clozapine may partially relieve cognitive symptoms, whereas typical antipsychotics often worsen cognitive function.

Adverse events associated with atypical antipsychotics include severe obesity, type II diabetes, and cardiovascular effects. Depending on the specific drug, adverse effects may also include agranulocytosis, a life-threatening loss of white blood cells; movement disorders; and lens changes in the eye which may eventually cause cataracts.

Both typical and atypical antipsychotic agents may give rise to hyperprolactinemia, often associated with increased risk of osteoporosis, and decreased libido and enlarged breasts in men. Both classes may also cause akathisia, a highly unpleasant sensation of inner restlessness and a relentless urge to move, which often contributes to noncompliance. Some evidence suggests that increasing relative activity at 5-HT2A receptors while decreasing relative activity at dopamine D2 receptors may reduce the risk of akathisia.

Because of these often disabling and sometimes serious side effects, compliance with available antipsychotic agents is typically poor. In fact, some experts estimate that nearly half of patients with schizophrenia are not receiving medical treatment because of poor tolerability.

CenterWatch has identified 14 drugs in various phases of development for schizophrenia, most of which act at one or more neurotransmitter receptors. Agonists mimic the action of the naturally found neurotransmitter, whereas antagonists counteract it.

Solvay Pharmaceuticals is in Phase III testing of bifeprunox (DU127090), a mixed dopamine D2 partial agonist and 5-HT 1a partial agonist. This full spectrum, atypical antipsychotic targets both the positive and negative symptoms of schizophrenia.

Also in Phase III development is Zomaril (iloperidone), Vanda Pharmaceuticals' novel antipsychotic agent for the treatment of schizophrenia and related psychoses. Zomaril is one of a new class of drugs known as serotonin/dopamine receptor antagonists (SDAs), which inhibit serotonin and dopamine activity by binding to these receptors in the brain. Specifically, it is a mixed 5-HT 2a /dopamine D2 antagonist.

Seven Phase III clinical trials of Zomaril to date have included more than 3,700 patients at approximately 300 sites in 27 countries. At doses ranging from 4 to 24 mg per day, Zomaril was safe and effective, except for QTc interval prolongation with 24 mg daily. This change in QTc interval was similar to that of ziprasidone, a currently approved active comparator in the study. Nonetheless, this adverse effect may potentially limit use of Zomaril as first-line therapy.

ACP-103, a potent and selective 5-HT2A inverse agonist, is in Phase II testing by ACADIA Pharmaceuticals as adjunctive therapy. The hope is that adding ACP-103 to currently available antipsychotic agents may achieve the best combination of dopamine receptor blockade and 5-HT2A inverse agonism. In theory, this should reduce adverse effects while expanding the range of efficacy.

Results from a double-blind, placebo-controlled clinical study were announced in September 2004. Of 18 healthy Swedish volunteers, 11 developed measurable akathisia after receiving a single 7.5 mg dose of haloperidol. Prolactin secretion also increased about threefold. After a single treatment with ACP-103, four of the subjects had complete disappearance of haloperidol-induced akathisia, and most subjects had reduced akathisia symptoms.

ACP-103 treatment was also associated with a highly statistically significant (33%; P < .001) reduction in haloperidol-induced increases in prolactin secretion. Coadministration of haloperidol and ACP-103 did not affect their pharmacokinetics, suggesting a lack of drug-drug interactions between these two agents.

In a drug receptor occupancy study using PET (positron emission tomography) scanning conducted at the Karolinska Institute, ACP-103 administered at single, low acute doses targeted 5-HT2A receptors without affecting motor control in healthy volunteers. In 2003, ACADIA completed two Phase I clinical trials evaluating safety, tolerability and blood drug levels of ACP-103. Tolerability was good in all trials thus far, with no serious adverse effects.

ACADIA plans to conduct multiple Phase II clinical trials of ACP-103 as adjunctive therapy in schizophrenia, testing its ability to ameliorate motor disturbances and improve efficacy of currently available antipsychotic drugs. One trial will study the effect of ACP-103 on haloperidol-induced adverse effects in patients with schizophrenia, and another trial will determine the effect of six weeks of adjunctive ACP-103 treatment in combination with low doses of haloperidol or risperidone.

Blonanserin (AD-5423) is a D2/5-HT2 antagonist in Phase II testing by Dainippon Pharmaceutical. This novel antipsychotic agent differs in chemical structure from currently available antipsychotic agents. Because it has dopamine 2 and 5-HT2 receptor antagonistic properties, it is expected to be effective for both positive and negative symptoms.

Compared with other agents with a similar mechanism of action, blonanserin appears to be associated with fewer adverse drug reactions, including extrapyramidal symptoms, hypotension, and weight gain. Another 5-HT2a/dopamine D2 antagonist is ocaperidone (ND-1087), in Phase II testing by Neuro3d.

Abbott Laboratories is in Phase II development of ABT-089 (2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride), a selective neuronal cholinergic channel modulator. Like nicotine, ABT-089 binds to nicotinic acetylcholine receptors, but with reduced adverse effects and improved oral bioavailability.

In surgically brain-injured rats, ABT-089 given short-term was associated with marginal improvement in performance on a water maze test of spatial discrimination. However, there was greater improvement, with 45% error reduction on the last training day, when ABT-089 was given continuously by subcutaneous osmotic pumps at a minimum effective dose of 1.3 µmol/kg/day. In monkeys, short-term administration of ABT-089 modestly improved a delayed memory task in young adult monkeys, with greater improvements in aged monkeys.

Another nicotinic agonist is MEM 3454, in Phase I testing by Memory Pharma. In several preclinical models, this novel nicotinic alpha-7 receptor partial agonist showed robust activity and beneficial pharmacokinetics. The alpha-7 receptor, located primarily in the brain, appears to play important roles in nerve cell function, protection and plasticity.

Ampalex, an ampakine (AMPA) receptor enhancer, is in Phase II development by Cortex Pharmaceuticals as a potential treatment for schizophrenia. Results in Phase I trials were encouraging, with improvements in memory in healthy young and elderly, and in measures of attention, memory and cognition in schizophrenic patients. Another AMPA-receptor modulator is ORG-24448 (CX-619), in Phase II testing by Organon.

DarPharma is in Phase II testing of DAR-0100, a D1 dopamine receptor agonist targeting deficits in working memory and cognition associated with schizophrenia. An ongoing trial at the Medical University of South Carolina has enrolled patients with schizophrenia that is stabilized on available medications. Using functional magnetic resonance imaging (fMRI), the investigators will evaluate the effect of DAR-0100 on brain activation.

GlaxoSmithKline is in Phase II testing of talnetant (SB 223412), a tachykinin (neurokinin 3; NK3) receptor antagonist. Because neurokinin receptors are involved in movement, this drug may in theory relieve some of the movement adverse effects associated with other antipsychotics.

In early trials, a small subset of patients on a high dose of talnetant had a positive response with good tolerability and minimal adverse effects such as weight gain. Talnetant may also help improve cognitive deficits associated with schizophrenia. Another NK3 antagonist is osanetant (SR 142801), in Phase II development by Sanofi-Aventis.

On March 29 of this year, Saegis Pharmaceuticals, Inc. announced the completion of a Phase I clinical study of SGS518, a 5HT-6 antagonist targeting cognitive impairment associated with schizophrenia (CIAS). Two cohorts of healthy volunteers were enrolled in a placebo-controlled, blinded study to evaluate safety, tolerability, and pharmacokinetics. This was followed by a multi-dose study.

The therapeutic challenge in schizophrenia appears to be not only efficacy in reducing both positive and negative symptoms, but tolerability, which thus far has greatly limited compliance. Novel agents in development may achieve these goals by targeting a range of different neurotransmitter receptors, with the added benefit of relieving memory impairment associated with schizophrenia.