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20+ New Schizophrenia Medications In Development (2015)

It is estimated that over 2.5 million adults in the United States have been diagnosed with schizophrenia; this equates to approximately 1.1% of the population.  There are many different types of schizophrenia, in fact, genetic clusters suggest it is 8 distinct diseases.  Therefore not everyone diagnosed with schizophrenia has the same set of symptoms.

Certain subtypes of schizophrenia are associated with more negative symptoms such as avolition, blunted affect, and slower movement patterns – while others are associated with positive symptoms such as hallucinations and/or delusions.  Some individuals suffer from a spectrum of both positive and negative symptoms, yet for others, most debilitating are the cognitive symptoms such as: memory impairment, inattentiveness, and brain fog.

While the neurogenic correlates of schizophrenia aren’t fully understood,  researchers are making progress.  A majority of individuals with schizophrenia have a difficult time functioning in society (holding down a job, socializing, etc.) without proper treatment.  Modern day treatments for schizophrenia include medications called atypical antipsychotics, which aim to primarily normalize dopamine dysfunction within the brain.

New Schizophrenia Medications In Development (2015)

The major drawback associated with most modern day antipsychotics is their side effect profiles.  Many antipsychotics provoke extreme weight gain, metabolic changes, alter hormones, and trigger extrapyramidal effects.  To make matters worse, evidence indicates that antipsychotics cause brain volume loss over time, literally accelerating brain atrophy.

Adverse reactions to antipsychotics can include: diabetes, tardive dyskinesia, and neuroleptic malignant syndrome – all of which are serious medical conditions.  For this reason, most educated individuals are aware that antipsychotics should be regarded as dangerous psychiatric drugs – only to be taken at the minimal effective dose for approved conditions like schizophrenia.  Despite the relatively unappealing antipsychotics on the market, pharmaceutical companies are working to create better options.

Included below is a list of new antipsychotics in the pipeline for the treatment of schizophrenia.  Realize that while many of these compounds are merely slight tweaks of current-market drugs, others provide novel mechanisms of action.  Also, realize that not all of these drugs are necessarily “antipsychotics” in that some are solely being developed to target the cognitive impairments of schizophrenia.

  1. ABT-126

  • Mechanism: α7-nAChR agonist
  • Status: Phase II clinical trials
  • Company: AbbVie

ABT-126 functions as an α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist.  It is being tested primarily for the treatment of Alzheimer’s disease, but may also serve to address many cognitive deficits associated with schizophrenia.  The drug was initially created by Abbott Laboratories, which rebranded a portion of its company responsible for pharmaceutical development as “AbbVie” (based in Chicago, Illinois).

ABT-126 is currently in Phase II clinical trials for treating the cognitive symptoms of schizophrenia.  The idea behind ABT-126 is that it will enhance cognitive function without any significant side effects that often develop when stimulating other nicotinic acetylcholine receptors or muscarinic acetylcholine receptors.  What’s interesting about ABT-126 is the fact that it may decrease inflammation while enhancing cognitive function; possibly serving as a nootropic.

Preliminary evidence from animal studies suggest that ABT-126 are able to correct cognitive and sensory gating (ability to filter out unnecessary stimuli) deficits.  There is also some evidence to surmise that this drug could alleviate many negative symptoms of schizophrenia, despite targeting only cognitive symptoms.  This formulation is showing significant promise in early trials, and targeting Alpha-7 nAChRs as an agonist seems like a promising intervention.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26044974
  • Source: http://www.ecnp.eu/presentationpdfs/7/S_18_04.pdf
  • Source: https://clinicaltrials.gov/ct2/show/NCT01655680
  1. ADX-1149 (JNJ-40411813)

  • Mechanism: mGlu2 positive allosteric modulator (PAM)
  • Status: Phase II clinical trials
  • Company: Addex Therapeutics / Janssen Pharmaceuticals

ADX-71149 (or JNJ-4041183) functions as a metobotropic glutamatergic receptor 2 (mGlu2) selective positive allosteric modulator.  It is currently being researched by Addex Therapeutics (based in Geneva, Switzerland) and Janssen Pharmaceuticals.  Many speculate that properly altering glutamatergic function within the brain could significantly decrease symptoms of schizophrenia, as well as other mental disorders.

Interestingly enough, the compound ADX-71149 was also in clinical trials for the treatment of “anxious depression” (depression with comorbid anxiety), but lacked efficacy.  The compound is currently (as of 2015) in Phase II clinical trials for the treatment of schizophrenia.  Some researchers speculate that using positive allosteric modulators to target mGluR2 transmission will become an increasingly novel target in forthcoming years to treat schizophrenia.

Preclinical evidence from animal models has documented efficacy of ADX-1149 as an antipsychotic.  Initial evidence from small-trials suggests that it is well-tolerated and effective for reduction of negative symptoms.  However, it seems as though the drug may slightly affect alertness and attention.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23421671
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25692027
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25735992
  1. ALKS 3831

  • Mechanism: D1, D2, 5-HT2 antagonist + mu-receptor antagonist
  • Status: Phase II clinical trials
  • Company: Alkermes

Alkermes seems to love combining multiple pharmacological compounds into fixed doses.  They’ve had some preliminary success with the fast-track status of their ALKS-5461 antidepressant compound, containing Buprenorphine and Samidorphan in a fixed amount.  Their new drug for schizophrenia combines Olanzapine (Zyprexa) with Samidorphan.

The olanzapine element of the drug function as a D2, D1, and 5-HT2 receptor antagonist, while the samidorphan element elicits effects as a mu-opioid receptor antagonist.  The purpose for this formulated blending of olanzapine and samidorphan is to maintain antipsychotic efficacy, while minimizing weight gain.  The drug Zyprexa causes weight gain, often to a significant extent, but is a very potent antipsychotic.

The compound ALKS 3831 has been suggested to minimize weight gain by up to 37% compared to standalone treatment with olanzapine.  Preliminary evidence from trials suggests that the inhibition of weight gain as a result of samidorphan is maintained throughout 24 weeks.  Should antipsychotic efficacy hold up, this could be an appealing option for those who gain significant weight during treatment.

  1. AQW051

  • Mechanism: α7-nAChR agonist
  • Status: Phase II clinical trials
  • Company: Novartis Pharmaceuticals

Novartis Pharmaceuticals created AQW051, a new compound in development for the treatment of cognitive impairment associated with schizophrenia.  The drug is thought to enhance cognitive function with minimal side effects by specifically targeting the alpha-7 nicotinic acetylcholine receptor as an agonist.  In the first phase of clinical trials, AQW051 was considered well-tolerated with a safe pharmacokinetic profile among a group of 180 healthy participants.

It is considered to have favorable oral bioavailability, with fast-acting effects upon ingestion.  Rodent studies indicated that AQW051 improved measures of learning and memory; this was evidenced by superior performance on social and object recognition tests.  This drug also improved water maze performance in a group of rats.  Thus far, the adverse effects stemming from AQW051 are equal to that of a placebo.

Researchers believe that AQW051 will be a favorable compound for the treatment of cognitive impairment associated with a variety of conditions, not limited to schizophrenia.  Those with neurodegenerative diseases (e.g. Alzheimer’s) may derive significant benefit from this alpha-7 nicotinic acetylcholine receptor agonist.  In trials conducted with monkeys, AQW051 extended the duration of L-Dopa’s effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25363835
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25172125
  • Source: https://clinicaltrials.gov/ct2/show/NCT01730768
  1. Aripiprazole Lauroxil (ALKS 9072)

  • Mechanism: D2 partial agonist, 5-HT1A partial agonist, 5-HT2A antagonist
  • Status: Phase III clinical trials
  • Company: Alkermes

Aripiprazole lauroxil is a once-monthly injectable formulation used for the treatment of schizophrenia.  It is considered a “linker lipid ester” of the drug aripiprazole, more commonly known as Abilify.  While the drug Abilify is manufactured in once per month injectable doses as “Abilify Maintena” the approval of Aripiprazole lauroxil would drive up competition and ultimately cut costs for patients in-need of these treatments.

This drug is injected into the deltoid or gluteal muscle, whereas other formulations are injected solely into the gluteal muscle.  Preliminary evidence indicates that this formulation is well-tolerated and effective for the treatment of schizophrenia and/or schizoaffective disorder.  It really shouldn’t be much different than traditional Abilify Maintena, except some may prefer injections in the deltoid and may be able to save money.

Like all injectable formulations, some patients will report pain in the area of the injection.  The side effect profile associated with aripiprazole lauroxil shouldn’t be considered significantly different than Abilify – it’s the same active ingredients.  Injections within the delts seem to result in a greater number of adverse effects, but is still effective and may be preferred by patients.  It’s just a matter of time before this repackaged Abilify Maintena is approved.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25266547
  1. AVL-3288

  • Mechanism: (Type 1) α7 nAChR positive allosteric modulator (PAM)
  • Status: Phase I clinical trials
  • Company: Anvyl Pharmaceuticals

AVL-3288 is considered a one-of-a-kind “type 1” positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor.  It is in trials for the treatment of cognitive impairment associated with schizophrenia.  It is thought to elicit slightly different effects than other drugs targeting the alpha-7 nicotinic receptor in that it is classified specifically as a “type 1” positive allosteric modulator (PAM).

Treatment with this drug should significantly enhance cognitive function.  That said, as a “type 1” positive allosteric modulator (PAM) it will have different effects on the upregulation of alpha-7 nicotinic acetylcholine receptors than “type 2” PAMs.  Preliminary research comparing type 1 and type 2 PAMs suggests that: type 2 PAMs inhibit upregulation of α7 nAChRs – whereas type 1 PAMs have no effect.

The inhibited upregulation of α7 nAChRs results in receptor desensitization, whereas no such effect is associated with type 1 PAMs like AVL-3288.  As a PAM, this drug will differ from α7 nAChR agonists in that it won’t immediately enhance short-term memory or cognitive function.  However, when consistently administered, the drug significantly boosts cognitive performance, and thus may be promising for those with schizophrenia (and Alzheimer’s).

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22804734
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22096516
  • Source: https://clinicaltrials.gov/ct2/show/NCT01851603
  1. AVN-211

  • Mechanism: 5-HT6 receptor antagonist
  • Status: Phase II clinical trials
  • Company: AllaChem / Avineuro Pharmaceuticals

AVN-211 targets the serotonergic system by functioning primarily as a 5-HT6 receptor antagonist.  In other words, it binds to the 5-HT6 receptor and inhibits neurotransmission at this receptor site.  When the 5-HT6 receptor is blocked, glutamatergic and cholinergic neurotransmission increases throughout various regions of the brain, with dopamine and norepinephrine levels increasing in the prefrontal cortex.

The simultaneous increase in glutamatergic and cholinergic (and to a lesser extent dopaminergic and noradrenergic) activity is thought to improve aspects of cognitive function, particularly attention.  For this reason, the drug is being tested as an adjunct (to antipsychotics) with the aim of improving attention and cognition.  This will allow those with schizophrenia to take an already available antipsychotic for management of positive and/or negative symptoms, yet add AVN-211 as an adjunct for improvements in attention and focus.

A trial involving 47 individuals diagnosed with schizophrenia tested the effects of AVN-211 for one month as an adjunct.  The treatment improved symptoms of schizophrenia as evidenced by the PANSS and CGI-S post-treatment scores compared to baseline.  It appears as though this drug is promising for improvement of cognitive (and possibly positive symptoms) of schizophrenia.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23768250
  1. Cariprazine

  • Mechanism: D2 & D3 receptor partial agonist
  • Status: FDA approval pending
  • Company: Forest Laboratories

Cariprazine (RGH-188) is an antipsychotic that was developed by Gedeon Richter and is pending FDA approval for the treatment of schizophrenia (and Type 1 bipolar disorder).  It functions as a D2 and D3 receptor partial agonist, with a high affinity for the D3 receptor.  The drug performed well throughout Phase III clinical trials and was submitted for FDA approval in March 2015.

It is believed that the FDA will likely approve the drug by the end of 2015.  The drug is thought to effectively ameliorate both the positive and negative symptoms associated with schizophrenia.  Most current-market antipsychotics do not elicit significant effects on the D3 receptor, and many act as full-antagonists of the D2 receptor (as opposed to partial agonists).

The partial agonist effect at the D2 and D3 receptors allows the drug to modulate dopamine dysfunction, rather than an extreme dopaminergic blockade.  It is unique in that it is able to antagonize receptors when a person has high dopamine, yet agonize receptors when a person has low dopamine.  It also affects several serotonergic receptors such as 5-HT2B (inverse agonist) and 5-HT1A (partial agonist), instantly making it a highly-appealing new treatment.

  1. CEP-26401 (Irdabisant)

  • Mechanism: H3 receptor antagonist / inverse agonist
  • Status: Phase I clinical trials (complete)
  • Company: Teva Pharmaceutical

CEP-26401 (Irdabisant) is a novel antipsychotic being developed by Teva Pharmaceutical Industries.  It differs from most antipsychotics in that it functions as a highly-potent H3 receptor antagonist and inverse agonist.  In other words, it binds to the H3 histamine receptor and inhibits histaminergic effects, while simultaneously increases alertness (the opposite of histamine).

Although it is only in Phase 1 clinical trials, evidence from rodent studies discovered that it improves short-term memory performance tasks involving social recognition. Additionally, the drug was found to promote wakefulness and is believed to ameliorate cognitive impairment associated with schizophrenia.  While significantly more research needs to be conducted with CEP-26401 to verify its safety, it will likely be co-administered with antipsychotics.

Co-administration will allow the antipsychotics to target the dopaminergic dysfunction that triggers positive and negative symptoms, while CEP-26401 theoretically should improve cognitive function among those with schizophrenia.  Due to its cognitive enhancing effect and ability to promote wakefulness, should the drug advance through clinical trials, it may be approved for a variety of other medical conditions.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22001260
  • Source: https://clinicaltrials.gov/ct2/show/NCT01903824
  1. Encenicline

  • Mechanism: α7 nAChR selective partial agonist
  • Status: Phase III clinical trials
  • Company: Forum Pharmaceuticals

Encenicline (EVP-6124 or MT-4666) is a drug developed by Forum Pharmaceuticals for the treatment of cognitive impairment associated with schizophrenia (and Alzheimer’s disease).  It functions as a selective partial agonist of the alpha-7 nicotinic acetylcholine receptor.  The drug is meant to be added as an adjunct to an antipsychotic medication and is currently in Phase III clinical trials.

In Phase II clinical trials, individuals diagnosed with schizophrenia had received either encenicline or a placebo as an adjunct to their existing atypical antipsychotics for 12 weeks.  Prior to the addition of encenicline to existing treatments, cognitive performance assessments were administered with a computerized test called “CogState.”  The scores from the “CogState” test were reported in the form of an OCI (Overall Cognition Index) score.

Addition of encenicline significantly improved OCI scores compared to a placebo.  More promising is the fact that over 15% of individuals experienced more adverse effects with a placebo.  The drug is considered well-tolerated and has potential to significantly improve cognitive function among those with impairments stemming from schizophrenia.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26089183
  1. ITI-007

  • Mechanism: 5-HT2A receptor antagonist
  • Status: Phase III clinical trials
  • Company: Intra-Cellular Therapies

ITI-007 is an atypical antipsychotic developed by Intra-Cellular Therapies for the treatment of schizophrenia.  It has shown promise in early research, advancing to Phase III clinical trials as of May 2015 for the treatment of schizophrenia.  ITI-007 differs from most current-market and pipeline antipsychotics in that it functions primarily as a 5-HT2A receptor antagonist.

To nearly a 60-fold lesser extent (than its antagonist effect at the 5-HT2A receptor), it functions as a presynaptic partial agonist and postsynaptic antagonist of D2 receptors.  If approved, it will be the only antipsychotic to exhibit nearly 60 times the affinity for 5-HT2A receptors compared to D2 receptors.  As a comparison, Zyprexa and Risperdal affect 5-HT2A approximately 12 times the extent of D2 receptors; ITI-007 affects them approximately 60 times the extent.

It could be suspected that the goal of targeting the 5-HT2A receptors to a significantly greater extent than D2 receptors is to minimize certain side effects.  In addition, ITI-007 doesn’t affect dopaminergic signaling due to its partial agonist at the presynapses of D2 receptors.  This medication could provide major benefit to certain patients in that it is thought to improve social abilities, reduce negative symptoms, and ameliorate depression – with minimal side effects (e.g. weight gain).

  • Source: http://www.intracellulartherapies.com/products-technology/iti-007.html
  • Source: https://clinicaltrials.gov/ct2/show/NCT01499563
  1. MIN-101

  • Mechanism: 5-HT2A/Sigma-2 receptor antagonist
  • Status: Phase II clinical trials
  • Company: Minerva Neurosciences

MIN-101 is an antipsychotic under development by Minerva Neurosciences for the treatment of schizophrenia.  This drug functions primarily by targeting the 5-HT2A receptor and Sigma-2 receptor as an antagonist.  The blockade of 5-HT2A is thought to improve negative symptoms of schizophrenia by improving mood without carrying significant side effects.

In addition, the antagonist effect at the Sigma-2 receptor may improve motor control, learning, and memory functions – thus ameliorating many cognitive deficits associated with the disease.  Sigma-2 receptor blockage may modulate a variety of neuronal signaling processes such as dopamine and calcium ions.  While many current-market medications target 5-HT2A, not many specifically target the Sigma-2 receptor.

Results from early stage research suggests that the drug is likely tolerable, safe, and possesses a good pharmacokinetic profile. However, the drug is only in Phase II(b) clinical trials and the safety and tolerability will warrant confirmation before advancing to Phase III.  Minerva Neurosciences believes that MIN-101 will improve negative symptoms, cognitive symptoms, and correct (slow-wave) sleep abnormalities among those with schizophrenia.

  • Source: https://clinicaltrials.gov/ct2/show/NCT02232529
  1. NW-3509

  • Mechanism: Voltage-gated sodium channel (VGSC) modulator
  • Status: Phase I clinical trials
  • Company: Newron Pharmaceuticals

NW-3509 is a novel drug under development by Newron Pharmaceuticals as an adjunct treatment for schizophrenia.  The drug functions as a sodium channel modulator, which regulates hyperexcitability of neurons.  In other words, when certain neurons are firing too rapidly or at an abnormal rate, NW-3509 serves to normalize their activity.

This modulation is necessary due to the fact that many individuals with schizophrenia exhibit abnormal exitability of neurons in certain regions of the brain.  This abnormal excitability translates into high levels of glutamate, which may be responsible for many symptoms of schizophrenia.  Modulation of hyperexcitability could ameliorate psychotic symptoms such as hallucinations and delusions, especially when used as an adjunct to antipsychotics.

Further, researchers believe that addition of NW-3509 as an adjunct to antipsychotics may reduce antipsychotic-induced side effects and allow the patient to take a lower dose.  In addition, it is speculated that NW-3509 may treat a variety of comorbidities such as anxiety disorders, cognitive impairment, and depressive symptoms.  It should be noted that this novel drug is currently in Phase I clinical trials, meaning it is a long ways (years) away from FDA approval.

  • Source: http://www.newron.com/eng/Default.aspx?SEZ=3&PAG=44
  1. OMS-824

  • Mechanism: PDE10 inhibitor
  • Status: Phase II clinical trials
  • Company: Omeros

OMS-824 is a drug under development by Omeros Corporation for the treatment of cognitive impairment associated with schizophrenia.  The drug functions by inhibiting PDE10, a phosphodiesterase enzyme associated with a variety of diseases including: schizophrenia and Huntington’s disease.  Inhibition of PDE 10 has proven effective in animals for improving both behavior and cognitive function.

Phosphodiesterase remains an underexplored therapeutic target for the treatment of cognitive deficits associated with diseases, but has garnered increased attention from drug developers.  This is due to the fact that inhibition of PDE (phosphodiesterase) often results in improved cognitive function.  For example, PDE4B inhibition in mice results in super-intelligence and significantly less anxiety.

The application of OMS-824 in humans would be to ameliorate cognitive deficits associated with schizophrenia, Huntington’s disease, and other neurological conditions.  Thus far it is considered safe and well-tolerated in 4-week human trials, but warrants further research to confirm preliminary safety.  Assuming the drug remains safe, the drug has potential to improve cognitive symptoms of schizophrenia and may increase IQ among those without cognitive impairment.

  • Source: http://www.omeros.com/pipeline/pde10.htm
  1. Pimavanserin (Nuplazid)

  • Mechanism: SSIA (Selective Serotonin Inverse Agonist)
  • Status: Phase II clinical trials
  • Company: ACADIA Pharmaceuticals

Pimavanserin (Nuplazid) is a drug that has already advanced through Phase III clinical trials for the treatment of Parkinson’s disease psychosis, and is awaiting FDA approval.  It is currently in Phase II clinical trials for the treatment of schizophrenia (as an adjunct) as well as Alzheimer’s disease psychosis.  It has a novel mechanism of action as a selective serotonin inverse agonist, primarily at the 5-HT2A receptor.

It also affects the 5-HT2C receptor to a significantly lesser (40x) extent than 5-HT2A and is not thought to significantly affect dopaminergic neurotransmission.  This drug would be administered along with an antipsychotic, ultimately providing superior potency of effect at the 5-HT2A receptor site.  Certain trials have documented the fact that Pimavanserin as an adjunct provides enhanced symptomatic relief and minimizes side effects – compared to standalone antipsychotic treatment.

What’s more is the fact that Pimavanserin potentiates the efficacy of antipsychotics, even when administered at low doses.  In theory, this would possibly allow patients to reduce the dosage of their antipsychotic medication, thereby reducing a significant number of unwanted side effects.  Assuming the FDA approves this drug for Parkinson’s psychosis, it is highly likely that approval for schizophrenia will follow suit.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22954754
  • Source: http://www.acadia-pharm.com/pipeline/pimavanserin-schizophrenia/
  1. RBP-7000

  • Mechanism: D2 & 5-HT2A antagonist
  • Status: Phase III clinical trials
  • Company: Reckitt Benckiser Pharmaceutical

RBP-7000 is nothing more than a reengineered version of Risperdal Consta designed for once-monthly subcutaneous injections.  Many patients with schizophrenia like the idea of receiving an injection that delivers a full-month’s worth of the drug rather than popping a pill every day.  Popping pills on a daily basis often results in poorer compliance for the fact that people can lose pills, forget to take them, and/or simply decide to stop taking them.

This injectable formulation is thought to be faster-acting than oral Risperdal due to the fact that it reaches optimal plasma concentrations immediately after injection.  Many believe that RBP-7000 will provide superior efficacy over competitors due to its instantaneous to achieve optimal plasma concentrations.  Assuming the drug advances through Phase III clinical trials and is approved by the FDA, many Risperdal users may consider switching to RBP-7000.

RBP-7000 comes in dosages of 60 mg, 90 mg, and 120 mg – equivalent to taking 2 mg, 3 mg, or 4 mg daily of oral Risperdal.  Not all injectable forms of antipsychotics are able to instantly provide plasma concentrations akin to steady-state values.  Due to the fact that D2 receptor occupancy doesn’t fluctuate as much with RBP-7000 compared to oral Risperidone, many believe that it will be a safer option with reduced extrapyramidal side effects.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25043337
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24464285
  • Source: https://clinicaltrials.gov/ct2/show/NCT02203838
  1. RP5063

  • Mechanism: Dopamine-serotonin system stabilizer
  • Status: Phase III clinical trials
  • Company: Reviva Pharmaceuticals

RP5063 (also RP5000) is an atypical antipsychotic developed by Reviva Pharmaceuticals for the treatment of schizophrenia.  This drug has a relatively complex mechanism of action, encompassing a variety of serotonergic and dopaminergic receptors.  It functions primarily as a dopamine-serotonin system stabilizer by targeting the D2, D3, and D4 receptors and 5-HT1A and 5-HT2A receptors as a partial agonist.

The drug also has a high affinity for the 5-HT7 and H1 receptors.  In addition, it is thought to elicit an effect on the D1, D5, 5-HT6, 5-HT3, Alpha-1B adrenergic receptor sites, and serotonin transporter (SERT). Unlike some other antipsychotics, it doesn’t significantly affect neurotransmission at the 5-HT1B, 5-HT2C, Alpha-2 adrenergic, and muscarinic acetylcholine receptors.

As of 2015, the drug advanced to Phase III clinical trials for the treatment of schizophrenia.  Its effects are being investigated for the treatment of psychosis associated with neurodegenerative diseases (e.g. Alzheimer’s) and autism.  It’s firestorm of effects on dopaminergic and serotonergic neurotransmission means that side effects are likely, but it should serve as another much-needed treatment option between 2016 and 2017.

  • Source: http://link.springer.com/article/10.1007%2Fs40290-014-0070-6
  • Source: http://www.schres-journal.com/article/S0920-9964(14)70070-2/abstract
  • Source: http://www.businesswire.com/news/home/20131104006767/en/Reviva-Pharmaceuticals-Announces-Successful-End-of-Phase-2-Meeting#.VfCpYhFViko
  1. Syntocinon (Nasal Spray)

  • Mechanism: Synthetic oxytocin
  • Status: Phase II clinical trials
  • Company: Retrophin

Syntocinon is a nasal spray that delivers a synthetic version of the hormone oxytocin.  Individuals with schizophrenia are thought to exhibit oxytocin dysfunction, specifically in regards to receptors.  Administration of oxytocin is able to improve mood and emotions among individuals with “flat affect” (lack of emotion) as a result of schizophrenia.

As a result, the company Retrophin is testing the adjunct administration of syntocinon nasal spray among individuals with schizophrenia.  It is currently in Phase II clinical trials to assess its safety and tolerability as an adjunct.  Results from an 8-week trial suggested that addition of syntocinon to Risperdal resulted in significant improvements in positive and negative symptoms.

Patients in the 8-week trial were administered 20 IU twice per day for one week, then 40 IU twice per day for 7 more weeks.  No additional adverse effects (compared to a placebo) were associated with the usage of syntocinon.  Preliminary evidence suggests that syntocinon nasal spray may be effective as an adjuvant to antipsychotics, but its usage warrants further testing.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23233269
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23415472
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24636461
  1. TAK-063

  • Mechanism: PDE10A inhibitor
  • Status: Phase I clinical trials
  • Company: Takeda Pharmaceuticals

TAK-063 is a drug under development by Takeda Pharmaceuticals for the treatment of cognitive impairment associated with schizophrenia, as well as other neurological disorders (e.g. Huntington’s disease).  It functions as a phosphodiesterase (PDE) inhibitor, specifically displaying high selectivity (15,000-fold over other PDEs) for inhibition of PDE10A.  It is believed that by inhibiting PDE10A, the drug will increase levels of cAMP and cGMP.

Cyclic adenosine monophosphate (cAMP) plays a significant role in learning and memory.  Those with adequate levels of cAMP tend to exhibit superior performance on cognitive tasks compared to individuals with low levels.  Administration of TAK-063 may ameliorate specific schizophrenia-induced cognitive deficits.

Understand that TAK-063 is in early stage clinical trials (Phase I) and warrants considerable investigation before its safety, tolerability, and efficacy are understood.  Preclinical evidence suggests that it may have less side effects than already-approved antipsychotics such as Zyprexa and Abilify.  Assuming the drug remains safe, tolerable, and effective in initial research – it may be a promising novel treatment for schizophrenia and other pathologies.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25815469
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25525190
  • Source: https://clinicaltrials.gov/ct2/show/NCT01879722
  1. Lu AF35700

  • Mechanism: D1 receptor antagonist (?)
  • Status: Phase I clinical trials
  • Company: Lundbeck

Lu AF35700 is a drug under development by Lundbeck and is currently in Phase I clinical trials.  It is believed to be an improvement over Zicronapine (Lu 31-130), an atypical antipsychotic that had already advanced through Phase II clinical trials, but was abandoned by Lundbeck.  Lundbeck seems confident that Lu AF35700 will provide greater efficacy than Lu 31-130 via its unique mechanism of targeting the D1 dopamine receptor.

Researchers at Lundbeck believe that Lu AF35700 will be advantageous over current-market antipsychotics in that it has a strong binding affinity to the D1 receptor.  Some speculate that it will be similar to the drug clozapine, but with significantly less side effects such as weight gain and metabolic abnormalities.  Should it prove efficacious, the drug may be widely utilized by individuals that don’t derive significant benefit from medications that target D2 receptors.

The drug may elicit some effect at D2 and 5-HT2A receptors, but this is solely speculation.  As more information surfaces regarding Lu AF35700’s mechanism of action, we’ll get a better idea of its secondary targets.  It could take many years before this drug fully advances through the development pipeline.

  • Source: http://www.euroinvestor.dk/pdf/cse/2015/02/13101242/Lundbeck%20FY2014%20Results.pdf

Other antipsychotics in development (List)

There are significantly more than 20 drugs in development for treating symptoms of schizophrenia.  Below is a list of other medications that are in early stage clinical trials for those with schizophrenia.  Understand that certain drugs may solely target cognitive deficits and are intended to be utilized as adjuncts, while others are attempting to get approval as first-line treatments for positive and/or negative symptoms.

AMG 581

  • Mechanism: N/A
  • Status: Phase I clinical trials
  • Company: Amgen

There is currently minimal information available in regards to the drug profile of AMG 581.  The mechanism of action hasn’t been released, and Phase I clinical trials were slated to begin in August 2015.  It is unclear as to whether the Phase I trials have started with AMGen’s (Applied Molecular Genetics) latest development.

  • Source: http://www.amgenpipeline.com/pipeline/


  • Mechanism: PDE9 inhibitor
  • Status: Phase I clinical trials (complete)
  • Company: Boehringer Ingelheim Pharmaceuticals

BI-409306 is currently in Phase II clinical trials for the treatment of Alzheimer’s disease.  It functions as a PDE9 inhibitor, which is thought to enhance signaling of glutamate.  Enhanced glutamatergic signaling via PDE9 inhibition is thought to improve various aspects of cognitive function including learning and memory.

Despite showing preliminary efficacy for the treatment of Alzheimer’s, it is also under investigation for the treatment of cognitive impairment among those with schizophrenia.  The drug’s safety and tolerability are being evaluated before larger scale trials determine its efficacy.

  • Source: https://clinicaltrials.gov/ct2/show/NCT01892384


  • Mechanism: PDE10 inhibitor
  • Status: Phase I clinical trials
  • Company: Forum Pharmaceuticals

This drug is being developed to target positive, negative, and cognitive symptoms in patients with both acute and chronic schizophrenia.  The drug will function as a PDE10 inhibitor, targeting the condition with a novel approach.  In animal models, it has demonstrated preclinical efficacy.

The development of PDE inhibitors has increased in recent years with the aim of improving cognitive function among those with pathology-related deficits.  Assuming this drug is effective, it may be utilized for the treatment of other neurological conditions such as Huntington’s disease.  Other PDE10 inhibitors are being tested for the treatment of CIAS (cognitive impairment associated with schizophrenia) and Huntington’s.


  • Mechanism: PDE1 inhibitor
  • Status: Phase I clinical trials (completed)
  • Company: Intra-Cellular Therapies / Takeda Pharmaceuticals

ITI-214 is another drug under development by Intra-Cellular Therapies in conjunction with Takeda Pharmaceuticals for the treatment of cognitive impairment associated with schizophrenia.  The drug is designed to act as a selective PDE1 inhibitor, meaning it targets the enzyme phosphodiesterase 1.  Like most therapeutic PDE inhibitors, the ability to improve cognitive function stems from decrease breakdown of cAMP and cGMP.

Studies have shown that increased levels of cAMP (cyclic adenosine monophosphate) improve signaling between neurons.  The improved neuronal communication as a result of elevated cAMP levels improves certain facets of learning and memory.  Should ITI-214 advance through clinical trials and receive FDA approval, it will likely be used to ameliorate cognitive deficits associated with a variety of other conditions besides schizophrenia.

LY03004 (Risperidone CR)

  • Mechanism: D2 & 5-HT2A antagonist
  • Status: Phase I clinical trials
  • Company: Luye America Pharmaceuticals

Ly03004 is a reengineered formulation of the time-tested drug Risperdal.  It will be manufactured in the form of “extended release microspheres” that can be injected intramuscularly for the treatment of schizophrenia or schizoaffective disorder.  Luye America Pharmaceuticals believes that the product Ly03004 will carve out a unique niche as an improvement upon a past antipsychotic.

That said, it appears as though there are a variety of other risperidone reformulations taking place, meaning significantly more competition for Luye America.  The company believes that this drug can be successfully marketed throughout Europe and Japan.

  • Source: https://clinicaltrials.gov/ct2/show/NCT02186769


  • Mechanism: AMPA receptor modulator
  • Status: Phase I clinical trials
  • Company: Pfizer

PF-04958242 is a drug being developed by Pfizer for the treatment of cognitive deficits associated with schizophrenia.  It functions as an AMPA receptor modulator, meaning it regulates glutamate activity via its action on AMPA receptors.  Those with schizophrenia are thought to display abnormal glutamatergic activity, specifically hyperexcitability of glutamate.

Glutamatergic hyperexcitability can be neurotoxic and is known to impair aspects of learning, memory, and synaptic plasticity.  By modulating activity at the AMPA receptors, this drug may act as a neuroprotective agent and minimize the killing of brain cells as a result of glutamatergic dysfunction.  It is unclear as to whether PF-04958242 is capable of stabilizing glutamate levels (e.g. decreasing when high, increasing when low).

On a side note, this drug has also been tested in a trial for adults with age-related hearing loss.  Results suggested that the drug may improve certain aspects of hearing, although it wasn’t more effective than a placebo.  Assuming this drug is safe, it may protect neurons and the brain from atrophy associated with glutamatergic neurotoxicity, while simultaneously enhancing cognitive function.

  • Source: https://clinicaltrials.gov/ct2/show/NCT02332798
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25997115


  • Mechanism: PDE10 inhibitor
  • Status: Phase II clinical trials
  • Company: Pfizer

PF-02545920 is a drug under development by Pfizer to treat cognitive impairment associated with schizophrenia (and Huntington’s disease).  It functions by acting as a PDE10 inhibitor, meaning it inhibits enzymatic breakdown of phosphodiesterase 10.  It is thought that by inhibiting the breakdown of phosphodiesterase, levels of cAMP (cyclic adenosine monophosphate) increase.

Increased cAMP levels are conducive to cognitive function – specifically learning and memory.  A 26-week trial of this drug is currently underway to evaluate its efficacy, safety, and tolerability.  There appears to be an emergence of potent, selective PDE inhibitors in clinical trials for cognitive impairment – PF-02545920 is yet another example.

  • Source: https://clinicaltrials.gov/ct2/show/NCT02197130


  • Mechanism: N/A
  • Status: Phase I clinical trials
  • Company: Pfizer

PF-06412562 is a new drug under development by Pfizer and is currently in Phase I clinical trials.  The drug is suggested to treat cognitive impairment associated with schizophrenia, as well as cognitive deficits associated with neurological conditions.  The drug’s mechanism of action hasn’t been publically released and Pfizer and its safety and efficacy are currently being tested among healthy volunteers.

  • Source: https://clinicaltrials.gov/ct2/show/NCT01914796


  • Mechanism: D2 & 5-HT2A antagonist
  • Status: Phase I clinical trials
  • Company: DURECT / Zogenix

Like RBP-7000, Relday is a once-monthly injectable formulation of risperidone that provides controlled-release.  It is under development by the companies DURECT and Zogenix.  Developers of this drug believe that it will provide a superior pharmacokinetic profile and reduction in injection volume compared to competing formulations.  Another major appeal is that this injectable form of risperidone will incorporate technology called “SABER,” allowing for the drug to be released in a controlled manner.

The controlled-release (CR) format may be appealing as to ensure that the drug isn’t released at uneven intervals.  The approval of Relday could mean trouble for existing versions of injectable Risperdal.  That said, it is unclear as to whether individuals will be willing to spend the extra money on a newly repackaged Risperdal when they’ll have access to less expensive injectable and non-injectable options.

Assuming the SABER controlled-release technology triggers less unwanted side effects than existing formulations, Relday could be a popular option.  That said, it may not be an economical option compared to others.  It still has a long ways to advance throughout clinical trials, and is essentially just another tweaked version of risperidone.


  • Mechanism: PDE10 inhibitor
  • Status: Phase I clinical trials
  • Company: Hoffmann-La Roche

RO5545965 is a drug under development by Hoffmann-La Roche for the treatment of cognitive deficits associated with schizophrenia.  The drug functions as a PDE10 inhibitor which drives up levels of cAMP and cGMP and would be used as an adjunct to an antipsychotic.  Assuming the drug effectively increases cAMP and cGMP, it may improve neuronal signaling and enhance processes of learning and memory.

  • Source: http://www.roche-trials.com/resultsByProductGet.action?productName=RO5545965


  • Mechanism: N/A
  • Status: Phase I clinical trials
  • Company: Sunovion

SEP-363856 is an antipsychotic drug that was developed by Sunovion.  It is currently in Phase I clinical trials for the treatment of schizophrenia.  Preclinical reports suggest that it is highly effective for treating negative symptoms of schizophrenia with minimal side effects – particularly extrapyramidal effects.  Its mechanism of action hasn’t been publicly released but has been described as “novel.”

  • Source: http://onlinelibrary.wiley.com/doi/10.1002/fps.109/pdf
  • Source: http://www.ds-pharma.com/rd/clinical/pipeline_profile.html

5 Newest Antipsychotics

Many companies have worked to develop antipsychotics with favorable side effect profiles compared to older medications.  While most of these drugs still target dopaminergic and serotonergic receptors, formulations have been revised for superior tolerability compared to older medications.  Most recently, the FDA approved Rexulti (Brexpiprazole) for the treatment of schizophrenia in 2015.

  • Rexulti (2015)
  • Latuda (2010)
  • Saphris (2009)
  • Fanapt (2009)
  • Invega (2006)

Progress is relatively slow in development of antipsychotics, but many new drugs are in development.  There is big money in getting the next big antipsychotic approved, especially since many also end up getting approved as antidepressant augmentation options.  There are 30+ drugs being developed for schizophrenia, but many are solely targeting cognitive symptoms, while others are merely tweaks of older drugs.

In reality, there are less than 10 novel drugs in development that seek to target the core positive and negative symptoms of schizophrenia.  As drug delivery technology continues to improve and pharmacological targets of schizophrenia are better understood, a new class of drugs will emerge.  Until then, most patients will be stuck with “revised” versions of older antipsychotics or similar-functioning (questionably “novel”) drugs.

Which of the new pipeline drugs for schizophrenia are most appealing?

Many drugs under development are marketed as “novel” new treatments, when in reality they’re nothing more than uncreative revisions of past-drugs.  There’s definitely a place and a market for minor tweaks to older formulas.  Patients are hoping that these tweaks provide similar efficacy to proven antipsychotics with less side effects and/or an improved modalities of administration.

Several developments are clearly piggybacking off of time-tested antipsychotics and will likely have success.  These include the drugs: RBP-7000 (an improved injectable version of Risperdal), Aripiprazole Lauroxil (an improved injectable version of Abilify), and ALKS 3831 (a drug that combines Zyprexa and Samidorphan).  Nearly all of these formulations should serve as slight improvements over previous medications.

Drugs in development that may be equally as effective as current-market atypical antipsychotics for management of positive and negative symptoms include: Cariprazine (targeting the D2 and D3 receptors), ITI-007 (targeting 5-HT2A receptors significantly more than D2), and MIN-101 (targeting 5-HT2A and Sigma-2 receptors).  The drug ADX-1149 may be the first of a new class of antipsychotics that modulate glutamatergic activity.

In addition to the development of new antipsychotics, most pharmaceutical companies are investing money for the development of drugs that reverse cognitive impairment associated with schizophrenia.  The drugs in development for the treatment of cognitive impairment vary in their targets.  A majority of these “cognitive enhancers” are targeting the alpha-7 nicotinic acetylcholine receptors as agonists.

A few are focused on inhibiting PDE (phosphodiesterase) at various PDE receptors including: PDE10, PDE10A (specifically), or PDE1.  Other unique targets for enhancing cognitive function among those with schizophrenia-induced deficits include: 5-HT6 receptors, AMPA receptors, glyT1 receptors, and H3 histamine receptors.  Another agent that may improve depression as an adjunct is NW-3509, which functions as a VGSC (voltage-gated sodium channel) modulator.

Which new schizophrenia drugs are you most excited about?

If you have schizophrenia, study schizophrenia, and/or know someone with schizophrenia – is there any particular drug that you’re most excited about compared to the rest?  Mention which drug you’re most excited about in the comments section below.  Discuss whether you believe certain substances will be safer and more effective than currently available treatments.

When considering the significant number of cognitive enhancers being developed for schizophrenia, which target do you think will provide the greatest benefit with the fewest side effects?  The pharmaceutical companies seem to have gone “all in” on targeting the alpha-7 nACh receptor and are ramping up production of PDE inhibitors.  It is hoped that some of these developments will significantly improve the quality of life for those with schizophrenia.

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{ 7 comments… add one }
  • Minnii September 22, 2015, 11:20 am

    I’m looking forward to ITI-007, just waiting for it to be approved and available in the EU.

    • NIRAJ FAFLE(far_cryo) February 2, 2016, 9:14 am

      I am waiting for MIN-101 and SEP-865 for negative symptoms of schizophrenia. I hope they pass through phase 2 and phase 3.

  • Talis Abolins December 2, 2015, 4:44 pm

    Sodium Nitroprusside (Nitropress): This drug is already FDA approved, and showed impressive long lasting (one month) impact on negative, positive and cognitive symptoms of schizophrenia. There are at least two trials ongoing, and several animal based studies confirmed efficacy. Has anyone tried off label use?

    There was an article warning ER doctors to be cautious when using Nitropress to control psychotic symptoms — which suggests there are folks out there already using it. The drug is administered through an infusion at low levels which reduce the risk of side effects. Is there any recent report — anecdotal or otherwise — confirming the promising results of the early studies?

    • Katarina Piljanovic June 24, 2016, 1:36 pm

      There is an on-going trial in Boston, General Hospital in cooperation with Harvard University, the study will finish this year and the first results are expected next year (2017). They are not publishing anything before then.

  • Vikas Kumar February 8, 2016, 3:10 am

    I hope most of these antipsychotics have minimal side effects.

  • Muhammad August 8, 2016, 10:42 pm

    I was really disappointed when encenicline failed it was my only hope (I have schizophrenia) of curing my cognitive deficits. I really want a drug to come out that treats negative symptoms specifically alogia, alogia is the one symptom I still have after getting sick a year ago and it is still very bad. Did they discontinue aqw051? That was my next hope for an a7nachr drug that will swoop in and wipe away the illness.

    It really gets on my nerves that the pipeline is progressing so slowly and the drugs aren’t coming out very soon. We’ll likely have to wait decades for many of these promising drugs to come out. It really makes you wonder what pharma companies have been doing for the past 50 yrs. No innovation whatsoever.

    Enough of antipsychotics, they all work by the same mechanism and no matter how much you delude yourself they do not have enough of an impact on negative and cognitive symptoms. I would like to go back to school and get my life together but the damn cognitive impairment and alogia make it difficult for me to function; its virtually impossible to make friends/relationships with alogia.

    And enough of this business of recycling meds to make more money off them after the patent is finished. These companies don’t seem to care about the schizophrenia sufferers. Or maybe they just lack the intelligence or initiative to cure the different symptom domains.

    Thats why Lumateperone pisses me off, why is everyone getting so excited about YET ANOTHER antipsychotic? Wheres the originality? Wheres the innovation? People want their lives back, why is it so impossible to get new transformative medications out? I was born in the wrong decade I guess.

    • Andrey August 27, 2016, 2:04 pm

      I second that, Muhammad. The innovation process is painstakingly slow and we need better treatments NOW. I struggle with negative symptoms too, can’t exercise, can’t enjoy music or sex, my imagination has faded etc etc. I’m waiting for Vraylar to become available in my country, but my hopes are still slim because it only hits the dopamine receptors…

      Have you tried Sarcosine or Pregnenolone? Many people swear by these two substances, it seems they can improve cognition and negative symptoms to some extent. I’m trying pregnenolone right now, 50 mg/day, and I noticed some effects after a few weeks. Will keep taking it and possibly increase the dose. Don’t lose hope Muhammad, you’re not alone in this struggle!!

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