Schizophrenia is a serious mental disorder that causes a range of problems with thinking (cognition), behavior and emotions. People with schizophrenia interpret reality abnormally in a way that is often disabling. Signs and symptoms vary but people with schizophrenia may experience some combination of hallucinations, delusions, and extremely disordered thinking and behavior that impairs their daily functioning. Hallucinations and delusions in schizophrenia may result from increased subcortical release of dopamine, which increases activity of D1 receptor expressing neurons and decreases activity of D2 receptor expressing neurons in striatum, increasing the amount of “noise” propagated through the basal ganglia circuit.
Second-generation (atypical) antipsychotics are the first-line treatment for schizophrenia. There are significant side effects that occur in patients receiving atypical antipsychotics, including weight gain, diabetes mellitus, hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataract.
Although the abnormalities in neural circuitry in schizophrenia remain elusive, much progress has been made. At MapLight, we employ a targeted approach. Hallucinations and delusions in schizophrenia may result from increased subcortical release of dopamine, which augments D2 receptor activation, thought to be due to a disturbed cortical pathway through the nucleus accumbens. Atypical antipsychotics block both serotonin 5-HT2a and dopamine D2 receptors, but do not directly alter activity in D1 receptor expressing neurons. MapLight is therefore focusing its therapeutic strategy on targeting both D1 and D2 expressing neuronal circuits, using non-dopaminergic targets in these neurons. By targeting both populations of neurons that become dysfunctional during schizophrenia without directly blocking dopamine D2 receptors, our treatments will have both improved efficacy and may lack the side effects seen with atypical antipsychotics.