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Because the causes of schizophrenia are still unknown, treatments focus on eliminating the symptoms of the disease. Treatments include antipsychotic medications and various psychosocial treatments.

News From NIH --Schizophrenia's strongest known genetic risk deconstructed--- Suspect gene may trigger runaway synaptic pruning during adolescence – NIH-funded study.

"...The gene, called C4 (complement component 4), sits in by far the tallest tower on schizophrenia's genomic "skyline" of more than 100 chromosomal sites harboring known genetic risk for the disorder. Affecting about 1 percent of the population, schizophrenia is known to be as much as 90 percent heritable, yet discovering how specific genes work to confer risk has proven elusive, until now." --Steam McCarroll and a team, including Harvard colleagues Beth Stevens, Ph.D., Michael Carroll, Ph.D., and Aswin Sekar , reported on their findings online Jan. 27, 2016 in the journal Nature.--Schizophrenia risk from complex variation of complement component 4

"Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function," explained Thomas Lehner, Ph.D., director of the Office of Genomics Research Coordination of the NIH's National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components. "It could help explain schizophrenia's delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain's working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.



Approved antipsychotic medications

Antipsychotic medications have been available since the mid-1950's. The older types are called conventional or "typical" antipsychotics. Some of the more commonly used typical medications include:


Drug Name
Molecular Structure
Mechanism of Action
Chlorpromazine (Thorazine) Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic receptors Chlorpromazine is classified as a low-potency antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder as well as amphetamine-induced psychoses.
Haloperidol (Haldol) strong central antidopaminergic action Used in the treatment of schizophrenia and, more acutely, in the treatment of acute psychotic states and delirium.
Perphenazine (Trilafon) Binds to the dopamine D1 and dopamine D2 receptors and inhibits their activity. Perphenazine also binds the alpha adrenergic receptor. Perphenazine is used to treat psychosis (e.g. in schizophrenics) and the manic phases of bipolar disorder.
Fluphenazine (Prolixin). Fluphenazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain as a long acting injection given once every two or three weeks to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness.

In the 1990's, new antipsychotic medications were developed. These new medications are called second generation, or "atypical" antipsychotics. These compounds share a receptor-blocking profile of less robust dopamine blockade combined with greater serotonin blockade in comparison with standard antipsychotic medications (i.e., dopamine D2 blockers).

Existing drugs are reasonably good at treating the hallucinations and delusions of schizophrenia. They are however far less effective treating the negative symptoms of the disease e.g., the lack of motivation and emotion that leave many patients unable to work or have normal social relationships. The side effects of existing medicines, are also severe. The older drugs like Chlorpromazine can cause movement disorders; the newer atypicals have fewer movement dissorders but can cause weight gain and other metabolic changes


Drug Name
Molecular Structure
Mechanism of Action
Risperidone (Risperdal) actions at several 5-HT (serotonin) receptor subtypes,5-HT2C, 5-HT2A, high affinity for D2 dopaminergic receptors used to treat schizophrenia (including adolescent schizophrenia), the mixed and manic states associated with bipolar disorder, and irritability in children with autism.
Olanzapine (Zyprexa) It is a selective monoaminergic antagonist with high affinity binding to serotonin 5-HT2A and 5-HT2C, dopamine D1-4, muscarinic M1-5, histamine H1- and alpha1-adrenergic receptor sites. schizophrenia; treatment of acute mania episodes associated with bipolar disorder (as monotherapy or in combination with lithium or valproate); maintenance treatment of bipolar disorder; acute agitation (patients with schizophrenia or bipolar mania)
Quetiapine (Seroquel) D1 and D2 dopamine receptor, the alpha-1 and alpha-2 adrenergic receptor, and 5-HT1A and 5-HT2 serotonin receptor subtypes are antagonized Quetiapine is indicated for the treatment of schizophrenia, depressive episodes associated with bipolar disorder, acute manic episodes associated with bipolar I disorder
Ziprasidone (Geodon) antagonism at dopamine receptors, specifically D2. Serotonin agonism may also play a role treatment of schizophrenia, acute treatment of mania and mixed states associated with bipolar disorder
Aripiprazole (Abilify) Rather than antagonizing the D2 receptor, aripiprazole acts as a D2 partial agonist. Aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics displays an antagonist profile at the 5-HT2A receptor used in the treatment of schizophrenia, bipolar disorder, and clinical depression.
Paliperidone (Invega) therapeutic effect may be due to a combination of D2 and 5-HT2A receptor antagonism
Clozapine (Clozaril) Blocks dopamine4 receptors, serotonin2 receptors, norepinephrine receptors, acetylcholine receptors, and histamine receptors -- weakly blocks D2 receptors used principally in treating treatment-resistant schizophrenia --as a last resort medication.Clozapine can sometimes cause a serious problem called agranulocytosis
Iloperidone (Fanapt) new

block the sites of noradrenaline (a2C), dopamine (D2A and D3), and serotonin (5-HT1A and 5-HT6) receptors.


for the treatment of schizophrenia -- less likely to cause movement disorders and weight gain

Drugs in the Pipeline

  Molecular Structure Mechanism of Action Clinical Trials
Invega Sustenna (paliperidone palmitate)

Therapeutic effect may be due to a combination of D2 and 5-HT2A receptor antagonism -- this is a once monthly formulation

July 31, 2009 Approved for Once-Monthly for the Acute and Maintenance Treatment of Schizophrenia

Saphris (asenapine)

The drug binds with both dopamine D2 receptor and a host of serotonin 5-HT receptors subtypes, with a greater antagonism to all serotonin receptor subtypes except 5-HT1a and 5-HT1b

In August of 2009, the FDA approved Saphris for the treatment of bipolar and schizophrenia.


Bifeprunox Minimal D2 receptor agonism with 5-HT receptor agonism PIII -- unapprovable letter
LY2140023 Stimulates glutamate receptors



ATI-9242 ARYx Therapeutics, Inc.

Moderate D2 receptor affinity and a high 5HT2A/D2 binding ratio


Receptor profile is targeted at the treatment of both the positive and the negative symptoms of schizophrenia as well as the improvement of cognitive function.


Blonanserin (Lonasen) 5-HT2 receptor antagonist and Dopamine receptor D2 antagonist[ http://www.ncbi.nlm.nih.gov/pubmed/19552488

Notes and Updates on Pipeline Drugs:

Comments on present drugs:

"ATI-9242 In vitro receptor profiling has demonstrated that ATI-9242 has moderate D2 receptor affinity and a high 5HT2A/D2 binding ratio characteristic of atypical antipsychotic agents. In addition, ATI-9242 binds with high affinity to the 5HT7 receptor and exhibits 5HT1A partial agonist activity. In rat cortical neurons, ATI-9242 potentiates NMDA current and facilitates GABAergic neurotransmission. In rats, it increases dopamine and acetylcholine in the prefrontal cortex, with no measurable increase in the nucleus accumbens. ATI-9242 has no antimuscarinic properties.

We believe this product will improve upon the efficacy of the best atypicals while avoiding metabolic drug-drug interactions and minimizing certain other metabolic problems associated with atypicals, including weight gain and type 2 diabetes. The receptor profile of ATI-9242 is designed to treat negative symptoms of schizophrenia - reduction in social interaction, disassociation from people or settings, monotone speech, loss of feelings of pleasure - and enhance cognitive functions". Source

"Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not seen with any dose of blonanserin throughout the study period. Blonanserin was effective in the treatment of acute schizophrenia and showed greater efficacy in negative symptoms compared with placebo and haloperidol. Blonanserin was well tolerated and its safety profile compared favourably with haloperidol, particularly with respect to prolactin elevation and EPS frequency". Source

LY2140023 - also known as mGlu2/3 -- differs from established antipsychotic drugs in that it targets glutamate rather than dopamine or serotonin receptors. There is a substantial body of evidence to suggest that glutamate, a neurotransmitter, may also be involved in the pathophysiology of schizophrenia.

For decades, psychiatrists have known that the street drug phencyclidine (PCP) can induce symptoms almost identical to those of schizophrenia. PCP acts as a NMDA glutamate receptor antagonist to non-competitively block the NMDA subtype of the glutamate receptor. LY2140023, an oral prodrug, is metabolised to the active mGlu2/3 receptor agonist LY404039, which is believed to work by reducing the presynaptic release of glutamate in those regions of the brain where mGlu2/3 receptors are expressed.

Earlier tests with LY2140023 -in about 200 patients had shown that the drug worked quickly and safely without resulting in weight gain and that the drug was effective in treating hallucinations, delusions, social withdrawal and apathy. See Nature Medicine Abstract. In the latest trial, the drug failed to outperform Zyprexa. Lilly also said the drug did not outperform a placebo. The response of patients to the placebo however, was approximately double that normally seen in schizophrenia clinical trials.

Ongoing Studies with LY2140023 -- A Safety Study Comparing LY2140023 to Atypical Antipsychotic Standard Treatment in Schizophrenic Patients.

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