The field of neuroscience is booming, and the future of schizophrenia treatments is bright. In addition to all the research resources being devoted to understanding the disease itself, many scientists are exploring how to treat the debilitating symptoms while minimizing side effects. The sheer number of medications in development right now is a tribute to their efforts, and to their early success.

This article contains some general information about how new drugs get approved by the FDA, and a list of possible future medications for schizophrenia, in various stages of clinical testing and development. Each medication has a specific mechanism of action, and many are meant to target a certain symptom or group of symptoms. Current knowledge and research about these medications, as well as links to currently recruiting clinical studies, are all included below. We have compiled as comprehensive a list as possible, but excluded drugs for which no published research information (or at least an explanation of mechanism and current investigations) was available. If you know of a medication in trials that we have missed, please email us at szwebmaster@yahoo.com

The information below, describing clinical trial and drug approval procedures, is provided by the FDA government website

(to skip intro information about clinical trials, go directly to list of schizophrenia drugs in development)

Explanation of Clinical Trial Phases:

Phase I: conducted in a small group of people (20-80) to assess safety, dosage range, and possible side effects. The primary goal of these trials is to look at the overall safety of a given medication. Phase I studies may last several months.

Phase II: further assessment of efficacy and safety in a larger group of people (100-300). Although safety is still a serious consideration, the primary goal of Phase II trials is to determine effectiveness. Phase II studies will last from several months to up to two years.

Phase III: testing with approximately 1000-3000 subjects to confirm efficacy, compare with other treatments, monitor safety and side effects. Phase III trials can last from 1-4 years, and are a final consideration of safety, effectiveness, and dosage of a given medication.

How many medications will progress through all three phases?

According to information provided by the FDA, 70% of candidate medications will pass through phase I, 33% will pass through phase II, and 25-30% will continue through phase III. About 20% (or 20 out of every 100) will eventually be approved for marketing.

How does a medication go from clinical trials to the consumer market?

There are numerous checks and balances that a developing institution must go through as a new investigational medication advances through the three clinical trial phases (chief among these is IRB committees, which are in place to protect the interest and welfare of human subjects). After data from all three phases has been collected, the developer will submit a New Drug Application (NDA) to the FDA. The NDA does not have to provide all study information obtained in the preclinical and clinical trial periods, but it does have to provide convincing evidence to allow the FDA review committee (made up of medical doctors, chemists, statisticians, microbiologists, pharmacologists and other experts), to make several key decisions:

1) Is the drug safe and effective? (Note: under current requirements, developers only have to show that a new drug is effective over a placebo in clinical trials, not necessarily over an already-available treatment. Therefore, the newest drug is not necessarily always the most advanced or the most effective one available.)

2) Do the benefits of the drug outweigh the risks?

3) Is the proposed labeling appropriate?

4) Are there adequate manufacturing methods in place to ensure purity and integrity of the drug?

Each team member prepares a separate evaluation concerning the NDA and the conclusions of the submitted data. These evaluations are reviewed by directors and team leaders. At the end of this process, the NDA will either be approved - meaning it can be legally released into the market immediately - or denied. Depending on the specific reasons for the denial, a developing company may be able to revise the NDA and resubmit the medication for later approval.

Once clinical trials are complete and an NDA is submitted for approval, it is generally assigned a status by the review committee within 10-12 months.

Schizophrenia Medications Currently in Phase III trials:

• Asenapine (for positive/negative symptoms)
• Bifeprunox (positive, negative, cognitive symptoms; may also relieve side effects)
• Iloperidone/Zomaril (positive, negative, cognitive symptoms)
• Lamictal (adjunct therapy; may improve positive symptoms)
• Osanetant (for movement side-effects caused by traditional neuroleptics)
• Paliperidone (for treatment-refractory patients)
• RG1068 (for autistic-type symptoms in schizophrenia patients)
• Seromycin/d-cycloserine (adjunct treatment, for negative symptoms)

Schizophrenia Medications Currently in Phase II trials:

• AMPAkines/CX-516 (to enhance the therapeutic effects of current medications)
• Galantamine (for cognitive/negative symptoms and learning deficits)
• Memantine (for cognitive symptoms)
• Modafinil (for cognitive symptoms and working memory)
• Ocaperidone (for positive symptoms, with few side effects)
• Talnetant (for movement side-effects, cognitive symptoms)
• Tolcapone (for cognitive symptoms)

Asenapine is a serotonin and dopamine (5HT/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, risperadone, and olanzapine all have serotonin-dopamine antagonist properties, and these drugs are popular for their low incidence of side effects (particularly EPS side effects) and their efficacy against both positive and negative symptoms. Asenapine is being jointly developed by Pfizer and Organon, and is in phase III clinical trials. Early data from previous trials (according to a press release from Pfizer) shows good tolerability and superior efficacy when tested against a placebo. No information was available about the nature or the methods of the study.

The evolution of the serotonin-dopamine antagonist concept. J Clin Psychopharmacol. 1995 Feb;15(1 Suppl 1):4S-10S.

The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics. J Clin Psychopharmacol. 1995 Feb;15(1 Suppl 1):2S-3S

 

Bifeprunox is in phase III clinical trials, set to launch in the U.S. market sometime in 2007. 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 or EPS effects.

Psychiatric News - Med Checks (May 2004). This is the only public source available that details anything about the results of early trials. There were no links to the actual trials themselves, nor any further data on research on this compound.

 

Iloperidone (Zomaril) is currently being developed by Titan Pharmaceuticals, 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 study in the Nov 2001 issue of psychiatric times noted no cardiac abnormalities in 10 patients receiving 0.5mg-6mg 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.

Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist for the management of psychotic disorders. Neuropsychopharmacology. 2001 Dec;25(6):904-14.

An Assessment of Iloperidone for the Treatment of Schizophrenia. Expert Opin Investig Drugs. 2000 Dec;9(12):2935-43.

 

Lamictal is an FDA approved mood-stabilizer for bipolar disorder, and is now in phase III clinical trials as an adjunct treatment for schizophrenia. Research shows that a combination therapy of clozapine and lamictal in treatment-resistant schizophrenia patients results in reduced positive symptoms and improved general pathophysiology.

Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol Psychiatry. 2004 Sep 15;56(6):441-6.

Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry. 2003 Dec 1;54(11):1241-8.

Currently Recruiting NIMH Study: Study of an FDA-Approved Drug as Additional Therapy in Patients with Schizophrenia (sponsored by GlaxoSmithKline)

 

Talnetant and Osanetant are both NK3 (neurokinin 3, a neurotransmitter receptor in the brain) antagonists, being independently developed by GlaxoSmithKline and Sanofi-Synthélabo, respectively. Talnetant is in phase II FDA clinical trials, and Osanetant is in phase III. Neurokinin receptors play a role in movement; therefore, both medications may potentially alleviate some of the movement side effects caused by other neuroleptics. Early data for Talnetant, according to a GlaxoSmithKline press release, showed that a small subset of patients on a high dose of the drug had a positive response with good tolerability, and a minimum of side effects such as weight gain. Talnetant may also have a beneficial impact on cognitive deficits. Journal articles on the effects of NK3 antagonists (but not on Talnetant or Osanetant specifically) report some positive improvements in subjects with schizophrenia.

Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry. 2004 Jun;161(6):975-84.

 

Paliperidone ER is the active metabolite of antipsychotic medication Risperdal (risperidone). It fully blocks serotonin receptors, and partially blocks D2 dopamine receptors. It is being developed by Johnson and Johnson. The metabolite may end up being clinically beneficial for patients who don't respond to conventional treatment with risperidone. No research information was found on this specific compound.

Currently Recruiting Johnson and Johnson studies - to test the efficacy and safety of paliperidone vs. other atypical antipsychotics (i.e. olanzapine) in various schizophrenia populations.

 

RG1068 is a synthetic human secretin compound, developed by Repligen. It has already proven helpful for autistic patients (the same drug is in phase III trials for treating autism), and Repligen is conducting phase II trials to determine whether it might be useful for treating some of the autistic-type symptoms in schizophrenia patients. Early research indicates preliminary promise for the compound as an adjunct treatment; patients given the drug in placebo-controlled trials show modest, although transient, symptom improvement.

Secretin for refractory schizophrenia. Schizophr Res. 2004 Feb 1;66(2-3):177-81.

Secretin in a patient with treatment-resistant schizophrenia and prominent autistic features. (single case-study). Schizophr Res. 2004 Feb 1;66(2-3):183-6

 

Seromycin (d-cycloserine) is a partial NMDA receptor agonist, or a glutamatergic agent. It acts to enhance glutamate receptor responses in certain areas of the brain. Because research has suggested that glutamate dysfunction may be a cause of negative symptoms, seromycin and other glutamatergic agents are being tested for their therapeutic effects. Early studies with such agents have shown mixed results - some studies show no effects (although small sample size and high drop-out rates are noted as possible confounding factors), while others indicate that d-cycloserine may be modestly effective in conjunction with other schizophrenia medications. It is in phase III clinical trials.

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2005 Jan 1 (publication pending). 72(2-3):225-34.

A six-month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients.
Psychopharmacology (Berl). 2004 Oct 21; [Epub ahead of print]

D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophr Res. 2002 Jul 1;56(1-2):19-23.

 

AMPAkines are a series of related compounds designed to improve memory and cognition. Some compounds (notably CX-516 for schizophrenia) are currently in phase II clinical trials. Research indicates that ampakines may help to enhance the effects of typical and atypical antipsychotics, although they may not be therapeutically effective on their own.

A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001 Oct;21(5):484-7.

Synergistic interactions between ampakines and antipsychotic drugs. J Pharmacol Exp Ther. 1999 Apr;289(1):392-7.

Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002 Oct 1;57(2-3):221-6.

 

Galantamine is a compound that enhances cholinergic function (the activity of acetylcholine) in the hippocampal and cortex regions of the brain. Preliminary research shows that it may improve negative and cognitive symptoms of schizophrenia. It is currently in phase II clinical trials to establish effects on cognitive and learning deficits.

Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl). 2004 Jun;174(1):45-53. Epub 2004 Feb 19.

Adjunct galantamine administration improves negative symptoms in a patient with treatment-refractory schizophrenia. Clin Neuropharmacol. 2002 Sep-Oct;25(5):272-5

Currently Recruiting Johnson and Johnson Study: A Study of Galantamine as an Adjunctive Treatment to Atypical Antipsychotics in Schizophrenia Patients with Cognitive Deficits

Memantine is an NMDA receptor antagonist, designed to address the cognitive symptoms of schizophrenia. Research shows that NMDA hyperactivity in some areas of the brain may cause some of the cognitive dysfunction seen in schizophrenia patients. It is currently in Phase II clinical trialss. No further research information was found regarding the compound.

Currently recruiting NIMH study: Evaluation of the Safety and Efficacy of Memantine as Adjunctive Treatment in Schizophrenia Patients

Modafinil, a drug currently used to treat narcolepsy, is now being examined for its potential to improve cognitive symptoms and working memory in schizophrenia patients with certain genotypes. The mechanism of action is still not entirely clear, although it appears that the medication induces wakefulness through activation of sleep/wake centers in the hypothalamus, and increases dopamine levels in the pre-frontal cortex. Modafinil is currently in Phase II clinical trials, to test whether it improves working memory in schizophrenia patients with particular gene variations.

Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol. 2004 Jan-Feb;27(1):38-43.

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology. 2004 Jul;29(7):1363-73.

Currently Recruiting NIMH Study: Effects of Modafinil on Brain Function in Patients with Schizophrenia

 

Ocaperidone is a D2 dopamine antagonist, as well as a serotonin 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 extrapyramidal side effects (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. They expect further results to be released in March or April of this year.

Pharmacological profile of the new potent neuroleptic ocaperidone. Pharmacology and Experimental Therapeutics. 1992 Volume 260, Issue 1, pp. 146-159

 

Tolcapone is a COMT gene inhibitor that acts in the medial prefrontal cortex of the brain. Its measurable effects in rat brains include an increase in dopamine neurotransmitter levels in the prefrontal cortex. This medication augments some of the actions of clozapine, and may be helpful for relieving some of the cognitive deficits associated with antipsychotic treatment (esp. working memory deficits). It is currently in Phase II clinical trials.

Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5.

Currently Recruiting NIMH Study: Clinical Trial of Tolcapone for Cognition in Schizophrenia