Needs Assessment: Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. It causes a deterioration in patients afflicted. The current agents, though helpful, only diminish the frequency and severity of positive psychotic symptoms by 20% to 30% and have less of an effect on the negative symptoms and the cognitive deterioration. There is a tremendous need to develop novel agents with unique mechanisms of action for the treatment of psychotic disorders.  

Learning Objectives:
• Identify drugs in the pipeline for the treatment of schizophrenia
• Understand the need for new medication treatment of psychotic disorders
• Understand the mechanisms involved in the development of new antipsychotics

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 20, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by December 1, 2010 to be eligible for credit. Release date: December 1, 2008. Termination date: December 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours. 

Primary Psychiatry. 2008;15(12):57-64

 

Dr. Glick is professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in California. Dr. Peselow is research professor at New York University School of Medicine in New York City.

Disclosures: Dr. Glick is a consultant to Bristol-Myers Squibb, Janssen, Lundbeck, Organon, Pfizer, Shire, Solvay, and Vanda; on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb/Otsuka, Janssen, Pfizer, and Shire; receives research support from AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, the National Institute of Mental Health, Shire, and Solvay; and owns stock in Forest and Johnson and Johnson. Dr. Peselow is on the speaker’s bureaus of Forest and Pfizer.

Off-label disclosure: This article includes discussion of investigational treatments for schizophrenia or psychotic illness.

Please direct all correspondence to: Ira D. Glick, MD, Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University Medical Center, 401 Quarry Rd, Rm 2122, Stanford, CA 94305-5543; Tel: 650-723-3519; Fax: 650-723-2507; E-mail: iraglick@stanford.edu.


Abstract

Due to the severity caused by schizophrenia, it is important to develop effective treatments. The current antipsychotics, including both typical and atypical, are at best effective only partially effective. Response is usually defined as a 20% to 30% reduction in the positive symptoms (delusions, hallucinations) with a lesser affect on the negative and cognitive symptoms. There has been a tremendous effort to develop newer antipsychotics to improve outcome. This article describes the current antipsychotics in the pipeline being clinically tested. The article also describes preclinical and clinical studies on a variety of agents that affect multiple receptors that are thought to be related to etioilogy.

Introduction

Schizophrenia and other forms of psychotic illness have plagued mankind for centuries. The conceptualization of psychosis as a “mental illness,” however, has only occurred recently. The development of effective pharmacotherapy began with the development of chlorpromazine in 1952,1 which revolutionized the treatment of schizophrenia. Older agents such as haloperidol and chlorpromazine (first-generation antipsychotics [FGAs]) are very effective for managing the positive symptoms of schizophrenia but display relatively poor long-term efficacy for negative symptoms, mood disturbances, and cognitive deficits. They are also associated with debilitating extrapyramidal symptoms (EPS) and tardive dyskinesia, thus often nullifying their therapeutic effect. There were no new agents approved by the Food and Drug Administration from 1977–1988. However, the introduction of clozapine from Europe in 19892 dispelled the notion that EPS and tardive dyskinesia were inevitable conclusions of antipsychotic therapy.

The FDA approval of clozapine led to a new generation of antipsychotics which seemed to provide a broader range of efficacy (both positive and negative symptoms and less cognitive decline) with a lower risk of EPS and tardive dyskinesia versus the older agents.3 Recent work4 has suggested that the newer agents cause a great risk for the metabolic syndrome—including diabetes, weight gain, and hyperlipidemia—which might be (in the long-run) more problematic than EPS or tardive dyskinesia. Thus, the continuing need for newer, safer, more efficacious antipsychotics continues.

Second-Generation Antipsychotics

The original agents, FGAs or typical antipsychotics, were thought to act by blocking striatal dopamine (D)2 receptors; indeed, the antipsychotic potency was positively correlated with in vitro potency of the D2 receptor.5,6 The evidence for this was that positron emission tomography positively demonstrated that N-methylspiperone (a radiolabeled ligand of the D2 receptor) blocked striatal dopamine receptors.

The second-generation antipsychotics (SGAs) which included risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole were characterized by strong or stronger antagonism for the serotonin (5-HT)2 receptor than for the D2 receptor.6 These newer agents (which also include clozapine) only partially block striatal dopamine receptors and more potently block serotonin receptors in the frontal cortex.

In addition, newer antipsychotics may have more unique actions. They appear to enhance glutamatergic function at the N-methyl-D-aspartate (NMDA) receptor and block the behavioral and physiologic effects of phencyclidine, a non-competitive NMDA receptor antagonist that produces a syndrome in normal individuals that closely mimics schizophrenia.7 In addition, SGAs, while alike, often show differences that may lead one to different mechanistic possibilities. For example, aripiprazole is a high affinity partial agonist of the dopamine receptor. It displays both dopamine agonist and antagonist properties.8 The partial dopamine agonist may thus reduce dopamine synthesis and release by stimulating presynaptic dopamine autoreceptors. They may also diminish the dopaminergic signal at postsynaptic sites by competing with dopamine for postsynaptic receptors.9

Newer Drugs and Strategies in Schizophrenia

A fundamental barrier to the discovery of novel treatments remains that our level of the biologic processes involved in schizophrenia is not sufficient to predict the therapeutic value of novel drug targets. Newer agents usually represent drugs that hit known and validated targets (“me too type drugs”). It is important to note that it is important to look at specific symptoms in schizophrenia. FGAs and SGAs are efficacious in treating the positive symptoms (delusions, hallucinations, thought disorganization, and loose associations), but even here the response rate is 67% to 75% with response being a 20% to 30% reduction in overall symptoms.

However, it is the negative symptoms (alogia, avolition, flat affect, and anhedonia) along with cognitive impairments that contribute disproportionately more to the long-term disability in patients with schizophrenia.10 The negative symptoms lead to particularly poor functional capacity and quality of life. Despite the fact that there was high optimism that the SGAs represented a breakthrough for the treatment of negative symptoms, a complete response has not been shown clinically.4,11 The cognitive impairments are significant in that patients with schizophrenia have been known to have documented problems with attention, working memory, and learning in addition to executive level functions such as abstract thinking and problem solving.12,13 Thus, improved efficacy with negative symptom relief and improvement in cognition remains unsolved.

Dopaminergic Approaches

Of note, all marketed drugs to date have efficacy at the D2 receptor. Many of the drugs in Phases II and III clinical trials have the same mechanism of action as the already available agents, that is, 5-HT2A and D2 antagonism.

Iloperidone

Iloperidone, which is currently in placebo-controlled, phase III trials, affects multiple receptor sites. It is an antagonist at D2 and D3 receptors, as well as an antagonist at the 5-HT2A and 5-HT1A receptor site. It has had a long developmental process after being dropped by Novartis due to concerns that the drug may cause cardiac arrhythmias (specifically, it might increase the QT interval of the heartbeat). A study14 in the November 2001 issue of Psychiatric Times noted no cardiac abnormalities in 10 patients receiving 0.5–6.0 mg of iloperidone; however, this is an extraordinarily small sample size, and the study was sponsored by Novartis. In other words, these safety concerns have yet to be resolved in the public domain. However, iloperidone is still in development (currently in phase III FDA clinical trials). Because it acts as an antagonist on many different receptors—including several different classes of dopamine, serotonin, and norepinephrine receptors—it has the potential to alleviate a wide range of symptoms.

Bifeprunox

Bifeprunox was in phase III clinical trials until recently. It is a partial dopamine agonist/antagonist as well as a serotonin receptor agonist. It is expected that partial dopamine agonist action will have beneficial effects for positive, negative, and cognitive symptoms, while the serotonergic agonist action will help alleviate some side effects and possibly combat depression and anxiety that can accompany schizophrenia treatment. Early results report little to no weight gain, and no cardiac effects or EPS. Efficacy was uncertain, and the company investigating it has discontinued the trials.

Blonanserin

Blonanserin [AD 5423] is a combined D and 5-HT receptor antagonist currently undergoing development in Japan with Dainippon Sumitomo Pharmaceutical as a potential antipsychotic. Blonanserin is unrelated structurally to typical antipsychotics or to newer agents such as risperidone. It is hoped that the combination of receptor blockade possessed by blonanserin will be effective against both the positive and negative symptoms of schizophrenia, with a low tendency to cause EPS. Blonanserin is expected to have minimal sedative and hypotensive effects, as its adrenaline receptor-blocking function is weak.

Dainippon is conducting phase III clinical trials with oral formulations (tablet and powder) of the compound in psychotic disorders in the United States.

Ocaperidone

Ocaperidone is a D2 and 5-HT antagonist. Due to the dual-action mechanism of the drug, early research reports it to have “haloperidol-like effects” on the positive symptoms of schizophrenia, but with a lower incidence of EPS (more like the side-effect profile of risperidone). Neuro3d, the France-based developers of the medication, report that they are nearing the end of phase II clinical trials.

Nemonapride

Nemonapride (international nonproprietary name [INN]; tradename Emilace) is a dopamine receptor antagonist approved in Japan for the treatment of schizophrenia. Its mechanism of action is proposed to involve both D2 and D3 antagonism Nemonapride is a substituted benzamide antipsychotic with general antipsychotic properties–with effects on positive and negative symptoms of schizophrenia. The average daily dose of nemonapride was 18 mg/day. Plasma prolactin concentrations are significantly (P<·01) increased.

Perospirone

Perospirone (INN; trade name Lullan) is a neuroleptic in Japan. It is a D and 5-HT2A receptor antagonist. Clinical trials show that EPS tend to occur less often and were generally milder than with haloperidol.

Zuclopenthixol

Zuclopenthixol (marketed as Cisordinol, Clopixol, or Acuphase) is a typical antipsychotic neuroleptic of the thioxanthene group. It mainly acts by antagonism of D1 and D2 receptors, though it also has some antihistamine activity. It is produced and marketed by Lundbeck pharmaceutical company. It is available in three forms, namely, zuclopenthixol decanoate (clopixol), a long-acting intramuscular injection; zuclopenthixol acetate (clopixol acuphase), a shorter-acting intramuscular injection; and zuclopenthixol dihydrochloride (clopixol tablets), a tablet taken orally. Side effects, such as EPS and elevated prolactin levels, are similar to many other typical antipsychotics. In addition, the taking the drug may occasionally result in amenorrhoea or galactorrhoea in severe cases. Neuroleptic malignant syndrome is a rare but potentially fatal side effect. Zuclopenthixol is available wordwide. None of the findings suggest any clear difference between zuclopenthixol and other typical antipsycotics across a wide range of adverse effects. When compared with the newer generation of drugs, those taking zuclopenthixol were associated with no greater risk of being unchanged or worse compared with those taking risperidone.

Lurasidone

Lurasidone is an atypical antipsychotic in Japan. As of 2008, it is undergoing a Phase III clinical trial. Lurasidone blocks D1, D2 and 5-HT2A receptors. It seems to cause fewer EPS than current antipsychotics.

ACP-104

ACP-104, or N-desmethylclozapine, is the major metabolite of clozapine and is being developed by ACADIA as a novel, stand-alone therapy for schizophrenia. It combines an atypical antipsychotic efficacy profile with the added potential benefit of enhanced cognition, thereby addressing one of the major challenges in treating schizophrenia today. ACP-104 combines muscarinic (M)1 agonism, 5-HT2A inverse agonism, and D2 and D3 partial agonism in a single compound and, therefore, uniquely addresses what ACADIA believes are the three most promising target mechanisms for treating schizophrenia. As of this writing it is in phase II clinical trials. Two clinical studies15,16 showed the drug was safe with the major side effects being sleepiness, increased salivation, constipation, and tachycardia. No significant changes were observed in safety parameters such as electrocardiograph measures (including QT/QTc interval) and clinical chemistries. No EPS were observed in the patients. The Phase IIb study of ACP-104 for the treatment of schizophrenia did not meet its primary endpoint of antipsychotic efficacy (improvement in Positive and Negative Syndrome Scale (PANSS) or any of the secondary endpoints). Neither dose of ACP-104 600 mg or 800 mg demonstrated improved efficacy compared to a placebo. The drug’s future is uncertain.

BL-1020

BL-1020 is an orally available gamma-aminobutyric acid-enhanced antipsychotic clinical candidate for the treatment of schizophrenia. It is a dopamine receptor antagonist. Data from preclinical and Phase I studies demonstrated that the compound may retain the efficacy of currently available typical and atypical antipsychotics while achieving a much higher safety profile as evidenced by a lack of metabolic or EPS. In an open-label, multi-center, 6-week trial17 conducted in hospitalized patients with treatment-resistant schizophrenia, BL-1020 showed statistically significant efficacy with minimal side effects. Overall, BL-1020 treatment reduces the PANSS total score by 26.1 points from the baseline (P<.001; baseline=85.6, day 42=58.2). There was a significant (P<.001) improvement in PANSS negative score by 7.1 points when compared to baseline values (baseline=20.5, day 42=13.4). Furthermore, computer-generated imagery results showed that 92.35% of patients improved by at least one category by the end of this part of the study.

RGH-188

RGH-188 (INN; generic cariprazine), discovered by researchers at Gedeon Richter, is a novel antipsychotic which preferentially binds to D3 receptors and acts as a dopamine system stabilizer. It is also a D2 antagonist. A phase II study18 involving 389 schizophrenia patients. evaluating a primary endpoint change from baseline to Week 6 on the PANSS and RGH-188 demonstrated a nominally statistically significant (ie, not adjusted for multiple comparisons) therapeutic effect compared to placebo in the treatment of schizophrenia in the low-dose arm and a numerical improvement compared to placebo in the high dose arm that did not reach nominal statistical significance. RGH-188 was generally well tolerated and overall premature discontinuation rates (all causes including adverse event related) were 47% for patients receiving low dose of RGH-188 up to 4.5mg/day, 46% for patients receiving high dose RGH-188 up to 12 mg/day, and 47% for patients receiving placebo.

ACR-325

ACR-325 is a dopaminergic stabilizer (primarily a dopamine agonist), a new class of compounds with a unique ability to either enhance or inhibit dopamine-controlled functions depending on the initial level of dopaminergic activity. ACR-325 has also demonstrated an ability to strengthen the glutamatergic and noradrenalinergic (agonistic) functions, which is an important aspect in novel treatments of psychosis and motor dysfunctions.

In June 2008 NeuroSearch has completed Phase I evaluation ACR-325 with a highly positive outcome. The results of single- and multiple-dose studies19 in healthy volunteers show that ACR-325 has a linear and predictable pharmacokinetic profile after oral administration. Further, the compound proved very well tolerated at doses and plasma levels exceeding by far the predicted therapeutic levels.

SLV-313

SLV-313 is a combined D2 receptor antagonist and 5-HT1A receptor agonist that may improve efficacy and alleviate some side effects associated with classical antipsychotics. As a full 5-HT1A receptor agonist and full D2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, it represents a potential novel treatment for schizophrenia. A phase I study randomizing patients to fixed doses of 2 mg, 5 mg, and 10 mg is currently underway.

YKP-1358

YKP-1358 is a novel 5-HT2A and D2 antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. It is currently undergoing phase I trials.

Asenapine

Asenapine is a 5-HT and D2 antagonist, part of a class of atypical antipsychotics that have typically been more effective than medications that act only at D2 receptors. For example, clozapine, risperidone, and olanzapine all have serotonin-dopamine antagonist properties, and these drugs are popular for their low incidence of side effects (particularly EPS) and their efficacy against both positive and negative symptoms. Early data from previous trials shows good tolerability and superior efficacy when tested against placebo. Schering-Plough Corp. acquired Organon in 2007—now asenapine is currently pending FDA approval for both mania and schizophrenia.

The problem with the above drugs is that they have the same mechanism of action as the already available agents.

Attempts to Look at Various Neurotransmitter Systems to Develop New Antipsychotics

Other Dopamine Strategies: D1, D3, and D4 Receptors

The D1 receptor plays an important role in schizophrenic illness as it is thought to have a role in cognitive dysfunction.20 Chronic blockade of D2 receptors leads to down regulation of D1 receptors in the prefrontal cortex, and this produces severe working memory impairment in non-human primates. Thus, novel compounds targeted at stimulating the D1 receptor may be of great value in treating the cognitive symptoms of schizophrenia. Many drugs have been proposed, such as ZD-3638, a 5-HT2A/D2, D1 agent developed by AstraZeneca in phase II development; BSF-78438 (Abbott); and LE-300 (sanofi-aventis), the latter two in preclinical development.21

The D3 receptor is structurally similar to the D2 receptor and is, thus, a target for drug development. Interestingly, a study evaluating drug-free schizophrenics found elevated levels of D3 receptors with normal D2 receptors. A few agents are being evaluated. A-437203 is undergoing Phase II trials as is SB-773812. BP 4.879a (Bioproject), SB-277011 (GlaxoSmithKline), PD 157533 (Pfizer), U 99194A (Pfizer), and PNU 177864 are in preclinical development. The potential antipsychotic efficacy of D3 receptor antagonists remains unknown at this time but there is some suggestion that D3 receptor antagonists have a role in improving negative symptoms22 and working memory.23

The D4 receptor was initially cloned. It was noted that clozapine had a higher affinity for this receptor than for the D2 receptor, leading to speculation that the D4 receptor might be the receptor responsible for clozapine’s unique enhanced efficacy.24 However, clinical trials have not yet demonstrated any appreciable evidence of efficacy of D4 receptor antagonists in the treatment of schizophrenia.25,26 These clinical failures suggest that selective D4 antagonism alone is not responsible for the unique antipsychotic efficacy of clozapine but it is possible that D4 antagonism along with the action of other neurotransmitter receptors may be important in treating psychosis. There is some suggestion that D4 antagonism may play an important role in impulsivity and working memory.24 Pfizer has three D4 agents in clinical development, namely, PD 165167, PD 172760, and U99363E.

Serotonergic Issues

Since the atypical antipsychotics bind with higher affinity to the 5-HT2A receptors versus dopamine receptors, selective 5-HT2A receptor antagonists have been evaluated as possible antipsychotics.

Eplivanserin: A 5-HT2A/2C Receptor Antagonist

Adults with schizophrenia or schizoaffective disorder (N=481) were randomly assigned in a 3:1:1 ratio to receive fixed doses of investigational drug, placebo, or haloperidol for 6 weeks. Reductions in the PANSS total and negative scores in the group receiving the 5-HT2A/2C antagonist were equal to haloperidol and were significantly larger than those in the group receiving placebo.27

Another 5-HT2A selective antagonist, M100907, though more effective than placebo in two cumulative studies, was not as effective as haloperidol.28

The above studies suggest that although 5-HT2A receptor antagonists have antipsychotic properties, they are not superior to D2 antagonists. It does appear that 5-HT2A receptor antagonists may help with negative symptoms by elevating dopamine in the mesocortical region.29

5-HT1A agonists like clozapine have been suggested to boost dopamine levels in the prefrontal cortex. This may be responsible for clozapine’s efficacy with respect to negative symptoms and cognitive dysfunction in schizophrenics. So far, attemts to develop 5-HT1A agonists have not replicated the clinical efficacy profile of clozapine.30

The 5-HT2C, 5-HT4, and 5-HT6 receptors have also been targets of antipsychotic drug development. Selectively of the 5-HT2C receptor by decreasing dopamine in the mesolimbic and mesocortical region but not the nigrostriatal region suggests it might have antipsychotic efficacy without EPS.29 Since the 5-HT2C receptor antagonism has been shown to cause weight gain, a 5-HT2C receptor agonist may be useful in reducing food intake and weight in patients.31

The 5-HT4 receptor is prominent in the hippocampus, frontal cortex, and amygdala. This receptor is decreased in Alzheimer’s disease and, thus, 5-HT4 receptor agonists may be helpful in schizophrenia with the mechanism of increasing cholinergic transmission in the hippocampus. Thus, there is the possibility that these agents may be helpful in the cognitive dysfunction in schizophrenics.32 The affinity of clozapine and olanzapine on the 5-HT6 receptor, which preclinically improves cholinergic neurotransmission, may help with the neurocognitive deficits in schizophrenia.33

To date, human clinical studies involving the 5-HT1A, 5-HT2C, 5-HT4, and 5-HT6 agents have not been published.

Other Receptors

Alpha-adrenergic receptors may play a role in improving the cognitive functioning for schizophrenics. Indeed, alpha-adrenergic-2 receptor agonists such as clonidine and guanfacine have shown some efficacy in improving cognitive function in schizophrenics when added to standard antipsychotics.34,35 The problem with this is many alpha-adrenergic-2 receptor antagonists are traditional antipsychotics and thus a choice between alpha-adrenergic-2 receptor agonism and antagonism will be challenging.

Cholinergic Agents

Acetylcholine is important in various domains of cognition, including attention, learning, and memory. Cholinergic dysfunction is central to the treatment of Alzheimer’s disease as cholinesterase inhibitors have been shown to slow down the cognitive decline of Alzheimer’s disease and other neurodegenerative disease.36 These agents have been hypothesized to help with respect to cognitive dysfunction in schizophrenia, but the results have been disappointing.37

Muscarinic Acetylcholine Receptors

There are five types of muscarinic receptors (M1–M5), with M1 the most closely linked to schizophrenia. Clozapine and its metabolite N-desmethylclozapine bind to the M1 receptor with N-desmethylclozapine acting as a potent agonist.38

Xanomeline, an agonist at the M1 and M4 receptor with activity at 5-HT1A and 5-HT2A receptors, has shown improvement with active psychotic symptoms in a double-blind, placebo-controlled study39 assessing 10 patients receiving xanomeline versus 10 patients receiving placebo. Patients on xanomeline showed greater improvement on Brief Psychiatric Rating Scale (BPRS) and PANSS scores as well as verbal learning and short-term memory function compared with placebo.

Nicotinic-acetylcholine receptors have shown interest as schizophrenics have been shown to have significantly higher smoking rates than normal control40 and smoking has been shown to improve various measures of cognition while easing the side effects of antipsychotics.40 Considerable efforts are being made to explore the potential use of nicotinic agents in the treatment of schizophrenia.

Glutamate in Schizophrenia

The role of glutamate in schizophrenia is complex. Since phencyclidine and ketamine—both NMDA antagonists—may cause psychotic symptoms as well as worsen cognition and negative symptoms, it has been hypothesized that schizophrenia may be related to NMDA hypofunction.41 However, it is also thought that hyperactivity of the NMDA receptor may alleviate psychosis.

The NMDA receptors are ligand-gated ion channels with both a primary glutamate-binding site and an allosteric glycine-binding site. In view of the fact that a direct agonist to the glutamate-binding site may cause excessive excitation possibly giving rise to seizures, the glycine-binding site on the NMDA receptor has been the focus of much attention in the development of new antipsychotics.

NMDA receptor agonists attaching to the glycine site have been evaluated. These include the amino acids such as glycine, D-cycloserine, D-serine, and D-alanine. These agents have been added to either typical or atypical antipsychotics and show some significant benefits in reducing negative symptoms and cognitive impairment in schizophrenia.42

Other attempts to increase glycine is by inhibiting the glycine transporter. A low-potency glycine transport inhibitor, sarcosine, has been investigated in relation to schizophrenia. Early evidence suggests that intake of sarcosine 2 g/day as add-on therapy to certain antipsychotics43 in schizophrenia gives significant additional reductions in both positive and negative symptomatology as well as the neurocognitive and general psychopathologic symptoms that are common to the illness. This was not found to be the case when sarcosine was added on to clozapine.44 Sarcosine has been tolerated well. It is also under investigation for the possible prevention of schizophrenic illness during the prodromal stage of the disease. It acts as a type 1 glycine transporter inhibitor. It increases glycine concentrations in the brain, thus causing increased NMDA receptor activation and a reduction in symptoms. As such, sarcosine and other glycine transporters might be interesting treatment options and a possible new direction in the treatment of schizophrenia in the future.

Glutamate Receptor

The glutamate receptor family is subdivided into ionotropic receptors and metatropic receptors which activate G-protein coupled intracellular metabolic processes.45 NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate are ionotropic receptors. The NMDA receptor is mainly coupled to the calcium channel while AMPA and kainate are coupled to sodium channels. Allosteric potentiation of the AMPA receptor by a group of compounds known as ampakines may help in alleviating some symptoms of schizophrenia. Indeed, the ampakine CX-516, when added to clozapine, yielded significant improvement in memory and attention,46 although when given as monotherapy it had no benefit.47

Currently, there are eight metabotropic receptors divided into three classes. Group 1, classified as mGLU R 1 and mGLU R 5, uses inositol 3P as its second messenger; Group 2, classified as mGLU R 2 and mGLU R 3, uses cyclic adenosine monophosphate (cAMP) as its second messenger; Group 3, which includes mGLU R 4, mGLU R 6 (mainly confined to the retina), mGLU R 7, and mGLU R 8, also uses cAMP as its second messenger. Selective allosteric modulators of these mGLU R receptors are being examined in schizophrenia.

Neurokinin Receptors

First identified in the 1930s, neurokinins are neurotransmitters found in the substantia nigra and striatum areas of the brain. Unlike most of the neurotransmitters identified to date, they are made from peptides rather than amino acids. They are believed to be involved in the control of movement. Their potential as therapeutic targets for drug development has only recently been suggested, but these receptors are seen as an area of rich research. The neurokinins NK1 and NK3 have been identified as suitable targets for drug development. Several antagonists to these neurokinins are now in development. Talnetant and osanetant are the two NK3 antagonists in development for schizophrenia.

NK1 has been studied with respect to depression but NK3 receptor antagonists have been evaluated in the treatment of schizophrenia. In one study,27 the group receiving the NK3 antagonist osanetant showed significantly greater improvement over baseline than the group receiving placebo as measured by PANSS total score, Clinical Global Impressions (CGI) severity of illness score, and BPRS psychosis cluster score. Talnetant has not been evaluated in clinical studies with respect to schizophrenia.

Cannabinoid Receptors

In view of the fact that there appears to be significant correlation between prior cannabis use and the development of schizophrenia, the study of the endogenous cannabinoid system has been of interest.48,49 There are two cannabinoid receptors, namely, CB1 and CB2. A selective CB1 antagonist SR 141716, while showing some preclinical antipsychotic efficacy, did not show antipsychotic efficacy versus placebo.27

Neurotensin Receptors

Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. There is evidence that since neurotensin agonists may reverse amphetamine-induced effects on hyperactivity, neurotensin may have a potential for use in schizophrenia. Clinical trials on neurotensin agonists need to be evaluated. Since there is neurotensin tone in schizophrenia, a neurotensin antagonist may be useful in schizophrenia. A recent study,27 however, showed that the neurotensin antagonist compared with haloperidol and placebo did not equal the group receiving haloperidol or differ from the group receiving placebo on any outcome measure (PANSS total score, CGI severity of illness score, and BPRS psychosis cluster score).

Conclusion

Generally, with clozapine being the ideal drug, it seems we need to develop drugs that mirror clozapine without its side-effect profile. Clozapine as the “ideal drug” has affinities for numerous receptors, including 5-HT1A, 5-HT2A, 5-HT2C, D1, D2, D3, D4, alpha-1, alpha-2, M1, M2, and H1 receptors. It would seem that this might require the use of polypharmacy and augmentation strategies, but the hope is for the development of non-selective single compounds that can target multiple domains, while decreasing side effects. Pursuing diverse molecular targets and validating these targets as effective in the treatment of schizophrenia appears to be the future for developing antipsychotics in the treatment of schizophrenia. PP

References

1.    Delay J, Deniker P, Harl JM. Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP). Ann Med Psychol (Paris). 1952; 110(2:1):112-117.
2.    Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988;24(1):62-67.
3.    Tandon R, Jibson MD. Efficacy of newer generation antipsychotics in the treatment of schizophrenia.Psychoneuroendocrinology. 2003;28:(suppl 1):9-26.
4.    Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.
5.    Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975;188(4194):1217-1219.
6.    Creese I, Burt DR, Snyder SH. Dopamine receptors and average clinical doses. Science. 1976;194(4264):546.
7.    Bakshi VP, Geyer MA. Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology (Berl). 1995;122(2):198-201.
8.    Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302(1):381-389.
9.    Tamminga CA. The science of antipsychotics: mechanistic insights. CNS Spectr. 2003;11(9 suppl 2):5-9.
10.    Agid Y, Buzsáki G, Diamond DM, et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 2007;6(3):189-201.
11.    Swartz MS, Perkins DO, Stroup TS, et al. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428-436.
12.    Keefe RS, Bilder RM, Harvey PD, et al. Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006;31(9):2033-2046.
13. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005;28(3):613-633,
14.    Bender KJ. Investigational agents and methodologies at NCDEU. Psychiatric Times. 2001;18(11):40.
15.    Mauri M, Volonteri LS, Fiorentini A, et al.  Clinical outcome and plasma levels of clozapine and norclozapine in drug-resistant schizophrenic patients. Schizophr Res. 2004;66(2-3):197-198.
16.    Natesan S, Reckless GE, Barlow KB, Nobrega JN, Kapur S Evaluation of N-desmethylclozapine as a potential antipsychotic–preclinical studies. Neuropsychopharmacology. 2007;32(7):1540-1549.
17.    Geffen Y, Nudelman A, Gil-Ad I, et al. BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia. Eur Neuropsychopharmacol. 2008 Aug 29 [Epub ahead of print].
18.    ClinicalTrials.gov. Safety and Efficacy of RGH-188 in the Acute Exacerbation of Schizophrenia. Available at: http://clinicaltrials.gov/ct2/show/NCT00694707?spons=%22Forest+Laboratories%22&spons_ex=Y&rank=4. Accessed November 18, 2008.
19.    NeuroSearch. ACR325. Available at: www.neurosearch.com/Default.aspx?ID=753. Accessed November 18, 2008.
20. Goldman-Rakic PS, Castner SA, Svensson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl). 2004;174(1):3-16.
21.    Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007;12(10):904-922.
22. Reavill C, Taylor SG, Wood MD, et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J Pharmacol Exp Ther. 2000;294(3):1154-1165.
23.    Laszy J, Laszlovszky I, Gyertyán I. Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005;179(3):567-575.
24.    Tarazi FI, Zhang K, Baldessarini RJ. Dopamine D4 receptors: beyond schizophrenia. J Recept Signal Transduct Res. 2004;24(3):131-147.
25.    Kramer MS, Last B, Getson A, Reines SA. The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry. 1997;54(6):567-572. Erratum in: Arch Gen Psychiatry. 1997;54(12):1080.
26. Corrigan MH, Gallen CC, Bonura ML, Merchant KM; Sonepiprazole Study Group. Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry. 2004;55(5):445-451.
27. Meltzer HY, Arvanitis L, Bauer D, Rein W; Meta-Trial Study Group. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry. 2004;161(6):975-984.
28.    de Paulis T. M-100907 (Aventis). Curr Opin Investig Drugs. 2001;2(1):123-132
29. Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113(2):296-320.
30. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3(4):353-359.
31. Zieba R. Obesity: a review of currently used antiobesity drugs and new compounds in clinical development]. Postepy Hig Med Dosw (Online). 2007;61:612-626.
32. Roth BL, Hanizavareh SM, Blum AE. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl). 2004;174(1):17-24.
33. Reavill C, Rogers DC. The therapeutic potential of 5-HT6 receptor antagonists. Curr Opin Investig Drugs. 2001;2(1):104-109.
34.    Fields RB, Van Kammen DP, Peters JL, et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;1(6):417-423.
35.    Friedman JI, Adler DN, Howanitz E, Harvey PD, Brenner G, Temporini H, White L, Parrella M, Davis KL. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry. 2002;51(5):349-357.
36.    Sarter M, Bruno JP. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev. 1997;23(1-2):28-46.
37.    Ferreri F, Agbokou C, Gauthier S. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci. 2006;31(6):369-376.
38.    Sur C, Mallorga PJ, Wittmann M, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci U S A. 2003;100(23):13674-13679.
39.    Shekhar A, Potter WZ, Lightfoot J, et al Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033-1039.
40.    Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29(6):1021-1034.
41.    Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984-997.
42.    Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19(2):151-157.
43.    Tsai G, Lane H, Yang P, Chong M, Lange N. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia”. Biol Psychiatry. 2004;55(5):452-456.
44.    Lane H, Huang C, Wu P, et al. “Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia”. Biol Psychiatry. 2006;60(6):645-649.
45.    Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl). 2005;179(1):4-29.
46.    Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001;21(5):484-487.
47.    Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, Weinberger DR. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002;57(2-3):221-226.
48.    Henquet C, Murray R, Linszen D, van Os J. The environment and schizophrenia: the role of cannabis use. Schizophr Bull. 2005;31(3):608-612.
49.    Vinod KY, Hungund BL. Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders. Expert Opin Ther Targets. 2006;10(2):203-210.