Schizophrenia therapy: beyond atypical antipsychotics

From Nature Reviews Drug Discovery 7, 471-472 (June 2008) | doi:10.1038/nrd2571:

By Eric M. Snyder & Melanie R. Murphy

Antipsychotics remain the current standard of care for mental disorders including schizophrenia (1% prevalence) and bipolar mania (3% prevalence), and generate over US$16 billion worldwide in annual sales (Fig. 1; Table 1). However, a large trial known as CATIE, sponsored by the US National Institutes of Health, found that 74% of patients discontinue use within 18 months of therapy due to either poor tolerability or incomplete efficacy (1), indicating a need for novel therapies.


Figure 1. The schizophrenia drug market has grown from less than $1 billion annually in 1993 to more than $10 billion. This rapid growth has followed the introduction of Risperdal in 1993, followed by Zyprexa, Seroquel, Geodon [Zeldox in Canada] (ziprasidone; Pfizer) and Abilify (aripiprazole; Bristol–Myers Squibb). Annual prescriptions have increased from approximately 20 million to more than 40 million in this time. Source: IMS. (Click on the figure to magnify it.)


Table 1. Currently marketed antipsychotics. (Click on the table to magnify it.)


The first generation of antipsychotics — termed conventional or 'typical' antipsychotics — such as haloperidol, inhibit dopamine D2 receptors and are moderately effective in treating positive symptoms of schizophrenia (for example, hallucinations), but may cause extrapyramidal movement disorders. Second-generation 'atypical' antipsychotics — such as Lilly's Zyprexa (olanzapine), Johnson & Johnson's Risperdal (risperidone) and AstraZeneca's Seroquel (quetiapine) — inhibit D2 receptors in conjunction with other receptors (notably 5-hydroxytryptamine 2A (5-HT2A) receptors) (Table 1). Atypical antipsychotics have proved less likely to cause movement disorders, but are associated with weight gain, prolactin and glucose elevation, and sedation.

Zyprexa is widely regarded as being the most effective atypical antipsychotic on the market, but in the past 3 years, issues related to side effects have led to the drug losing nearly half its market share, as well as over 28,000 lawsuits, again indicating the need for drugs with better side-effect profiles. Furthermore, with all of the currently marketed atypicals facing generic competition within 5 years, there is a considerable market opportunity for new branded antipsychotics.

A new approach: mGluRs

In September 2007, Eli Lilly announced results of a 4-week Phase II trial of their metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY2140023 for schizophrenia. Although LY2140023 exhibited slightly less efficacy than Zyprexa in reducing positive symptoms, it nonetheless delivered significant improvement (2). Importantly, while treatment with Zyprexa was associated with weight gain, patients who received LY2140023 actually lost an average of 0.5 kg. These data indicate that mGluR agonists could represent a breakthrough in the search for a better-tolerated antipsychotic.

Indeed, this mechanism appears so promising that Eli Lilly, Merck, Johnson & Johnson and Pfizer (as well as partners Addex and Taisho) are all racing to develop mGluR-targeted drugs for schizophrenia. For example, early this year, Merck expanded their commitment to develop a new antipsychotic by entering into an exclusive worldwide license agreement with Addex for their preclinical, positive allosteric mGluR5 modulator ADX63365. This is Merck's second deal for an mGluR modulator for schizophrenia, having previously partnered with Taisho for another preclinical compound.

Eli Lilly clearly holds the lead in the mGluR race, with proof-of-concept data in hand and Phase III trials anticipated to begin later this year, whereas other competitors are not yet in the clinic. However, it remains to be seen whether Eli Lilly's LY2140023 will prove superior in the long run. This compound is a traditional, orthosteric agonist that provides continual activity as long as it is bound to the receptor. Conversely, allosteric modulators such as those being developed by Addex provide activity only when the endogenous agonist is present. This might provide a more normal pattern of signalling and be more attractive for long-term use.

The precise mechanism by which LY2140023 and other mGluR-targeted agents have efficacy in schizophrenia is not understood, although there may be some overlap with previously established mechanisms. Glutamate and dopamine axons converge on the medium spiny neurons of the striatum (3), 4 (Fig. 2). In addition, mGluR2/3 agonists have been shown to inhibit dopamine release, demonstrating functional interconnectivity of these two neurotransmitter pathways. It remains possible that mGluR2/3 agonists may in fact target the conventional pathway of dopamine D2 antagonism. Alternatively, mGluR2/3 may form a complex with 5-HT2A receptors, suggesting that mGluR activation can regulate 5-HT signalling5.


Figure 2. Metabotropic glutamate receptors (mGluRs) in the synapse. (Click on the figure to magnify it.)


Addex and Merck's ADX63365 targets mGluR5, which has no known effect on dopamine signalling, but which can modulate the signalling of the ionotropic NMDA (N-methyl-D-aspartate) glutamate receptor, another receptor that has long been thought to be associated with schizophrenia. This pathway may have additional benefits: while Merck and Addex still await human clinical data for ADX63365, animal studies suggest that this compound can improve cognition as well as positive symptoms. Thus, in addition to being safer than atypicals, mGluR agonists might offer improved efficacy in the cognitive domains of schizophrenia.

Outstanding issues

Long-term studies of mGluR-targeted agents have yet to be conducted and it remains to be seen whether the efficacy seen in Eli Lilly's 4-week study can be maintained. Further-more, although mGluRs appear to offer good tolerability, longer-term trials are needed to gauge safety. If mGluR-targeted drugs can mimic the profile seen so far with Eli Lilly's LY2140023, it will be interesting to see how physicians would use mGluR agonists. Would they be prescribed independently, even though they may not have the efficacy of their atypical predecessors? Would they be used as adjunctive therapies, in combination with lower doses of atypicals? This cocktail therapy model is being pursued by Acadia with their 5-HT2 inverse agonist primavanserin, which improves the efficacy of low doses of risperidone without causing weight gain. A third possibility is that mGluR-targeted agents could be used in conjunction with primavanserin, creating a selective, targeted therapy with few side effects.

Overall, the development of mGluR-targeted drugs for schizophrenia represents an opportunity for a new class of drugs that might represent a superior treatment option to that of currently available antipsychotics, as well as an advance in the understanding of the molecular basis for therapies for psychiatric disorders.

Beyond atypicals

The market for drugs for schizophrenia has grown tenfold in the past decade (Fig. 1, Table 1). In 2007, Risperdal and Zyprexa led the worldwide market with $4.7 billion in sales each. Zyprexa sales have grown, despite continuing concerns with side effects. In addition to the need for novel antipsychotics with improved safety and efficacy profiles, the approaching patent expirations of leading products is creating a challenge for the pharmaceutical industry. Recent data indicate that agents that target mGluRs could represent a promising new class of antipsychotics, and such agents are now being developed by several companies (Table 2).

Table 2. Next-generation antipsychotics. (Click on the table to magnify it.)


References

1. Lieberman, J. A. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209–1223 (2005).

2. Patil, S. et al. Activation of mGluR2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102–1107 (2007).

3. Sesasck, S. et al. Anatomical substrates for glutamate–dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann. NY Acad. Sci. 1003, 36–52 (2003).

4. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

5. Gonzalez-Maeso, J. et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008).

Author affiliations

Eric M. Snyder and Melanie R. Murphy are at Mehta Partners Global BioPharmaceutical Investments, 276 Fifth Avenue Suite 1100, New York 10001, USA. Email: snyder@mpglobal.com

Competing interests statement

The authors declare competing financial interests.

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Eli Lilly drug lessens schizophrenia symptoms in trial

An article published in the September 2nd edition of the International Herald Tribune:

By Alex Berenson

In a clinical trial of about 200 patients, an experimental drug from Eli Lilly lessened schizophrenia symptoms without the serious side effects of current treatments, according to a paper published Sunday in the journal Nature.

The drug must still be tested on many more patients and is at least three to four years from completing regulatory review. But schizophrenia researchers said the trial's results were surprising and impressive, especially since the drug works in a different way from existing antipsychotic medicines, all of which have serious side effects including weight gain and tremors.

Lilly will begin a new and larger clinical trial for the drug this month. If that trial confirms the results seen so far, the new drug could mark a breakthrough in the treatment of schizophrenia - and open the way to a broad new class of treatments for the disease. Schizophrenia, a devastating mental illness that affects 1 percent of adults and usually begins in the late teens or 20s, is marked by psychotic delusions as well as social withdrawal and cognitive impairment.

"This is potentially one giant step forward for patients," said Dr. Jeffrey Lieberman, chairman of the psychiatry department at Columbia and the lead investigator on a federally sponsored clinical trial of schizophrenia medicines.

Lieberman has not been involved with the development of the Lilly medicine and does not receive any payments or consulting fees from Lilly.

The new drug also has the potential to be a blockbuster for Lilly. Medicines for schizophrenia and bipolar disorder had sales of $12 billion in the United States and $18 billion worldwide last year.

The troubled history of Zyprexa, another antipsychotic medicine from Lilly, will lead regulators and psychiatrists to scrutinize the new medicine closely for hidden dangers, Lieberman said. When it introduced Zyprexa in 1996, Lilly hailed it as a breakthrough with fewer side effects than older drugs. But Zyprexa causes severe weight gain, and the American Diabetes Association has linked it to diabetes. Internal Lilly documents show that the company played down Zyprexa's side effects, worrying that they would hurt sales.

Despite that history, psychiatrists will be eager to see whether the new Lilly medicine works, since the existing drugs are of limited help for many patients. Existing schizophrenia medicines, whether older drugs such as Thorazine or newer medicines like Zyprexa, all work the same way, by blocking the brain's dopamine receptors.

But the new Lilly drug does not directly affect dopamine. Instead, it modulates brain activity through a different set of receptors. As a result, it has the potential to be the first truly novel treatment for schizophrenia since Thorazine was introduced 1954, Lieberman and other researchers said.

Lilly's new drug - which does not have a name yet and is referred to only as LY2140023 - emerged from almost two decades of research into the similarities between symptoms of users of PCP, a street drug sometimes called angel dust, and schizophrenia. By the 1980s, scientists had discovered that PCP blocked brain receptors that are triggered by an amino acid called glutamate.

The Lilly clinical trial validated the theory that modulating glutamate receptors may control the symptoms of schizophrenia, said Dr. Joseph Coyle, a professor of psychiatry and neuroscience at Harvard Medical School.

Click here for a related story from BBC News.

Click here for more information from the Schizophrenia Research Forum.

Click here for a Psychiatric News article entitled Drug Bypassing Dopamine Could Broaden Antipsychotic Arsenal.