Schizophrenia

Affecting 1 out of every 100 people, schizophrenia is one of the most tragic psychotic disorders.

Its debilitating symptoms often appear when individuals are just on the threshold of young adulthood.  The overwhelming disturbances in cognition, altered perception of reality, and uncontrollable paranoia cause normal functioning to suddenly and completely deteriorate.  Untreated schizophrenia can make work, along with personal and social relationships, virtually impossible to maintain.

Sadly, at least 10% of all people diagnosed with schizophrenia end up either homeless or in prison, and the suicide rate among them is at least 15%.  Moreover, the incidence of drug use is astonishingly high with nicotine and alcohol being the most commonly abused drugs.  These individuals often self-sooth with drugs only to find that substance abuse worsens their symptoms.

There are three categories of symptoms in people diagnosed with schizophrenia – positive, negative, and psychomotor.  The positive symptoms consist of bizarre additions to an individual’s behavior, thought, and emotion.  Hallucinations, delusions, and disorganized speech are the most often encountered.  In contrast, negative symptoms are profound deficiencies in behavior, thought, and emotion such as:   alogia (reduction in speech), flat effect (blunted mood), and social withdrawal.  Finally, people diagnosed with schizophrenia may exhibit involuntary psychomotor movements such as awkward grimaces and gestures.  They may also become catatonic during which they stop responding to the environment, remain motionless for hours, and resist efforts to be moved.

There are several theories which attempt to explain the complex pathology of schizophrenia, and much of the current research focuses on its neurological basis.  Numerous studies have directly linked schizophrenia to the dopaminergic and serotonergic pathways in the brain.  In particular, the dopamine D2 and the serotonin 5-HT2A receptors are involved in the positive, negative, and psychomotor symptoms of schizophrenia.

Treatment for schizophrenia has become more specific and effective with the development of second-generation antipsychotic medications, commonly known as “atypical” antipsychotics.  These medications, which block D2 and 5-HT2A, significantly reduce all of the characteristic symptoms of schizophrenia.  In fact, more than 80% of diagnosed patients with schizophrenia are treated with second-generation antipsychotics, and the global market is currently estimated at $13 billion. Moreover, second-generation antipsychotics are the top selling class of medications in the United States.

However, these medications have very serious and intolerable side effects which cause high rates of discontinuation among patients.  For example, a common side effect of clozapine, Zyprexa, Abilify, Seroquel and Risperdal is excessive weight gain.  Even more disturbing is that patients can still develop extrapyramidal symptoms such as akathesis (involuntary restlessness), dystonia (slow, involuntary movements of the limbs), and Parkinsonism (muscle tremors, shakiness, and immobility) while taking second-generation antipsychotics.

DAYA has discovered a new and highly potent small molecule (DDD-016) which significantly reduces the symptoms of schizophrenia and with the potential to reduce extrapyramidal side effects.  A 2-week in vivo study with rats also revealed that DDD-016 is not toxic to the liver.  Most importantly, DDD-016 did not cause weight gain in rats.

DDD-016 is now ready to be put through a full preclinical evaluation for IND submission, and DAYA is seeking suitable commercial partners to introduce this promising medication into the market.