Dopamine D2 and serotonin 5-HT2A receptors (antagonist); mu-opioid receptor (antagonist)

Class

Fixed-dose combination of olanzapine (atypical antipsychotic, multi-receptor antagonist) and samidorphan (opioid receptor antagonist); the samidorphan component is intended to attenuate olanzapine-associated weight gain without reducing antipsychotic efficacy

Pathway

Olanzapine's antagonism of dopamine D2 and serotonin 5-HT2A receptors is proposed to underlie antipsychotic efficacy; the co-formulated opioid receptor antagonist samidorphan is proposed to mitigate olanzapine-induced weight gain via effects on reward/homeostatic feeding circuitry

This mechanism combines two receptor-blocking actions in one medicine. The first component blocks dopamine D2 receptors and serotonin 5-HT2A receptors, a combination characteristic of atypical antipsychotics. Excess dopamine signaling in certain brain circuits is associated with the hallucinations and disordered thinking seen in psychotic illness, and blocking D2 receptors dampens this signaling; the added 5-HT2A blockade is thought to preserve dopamine tone in other brain regions, softening movement-related side effects and possibly aiding mood and cognitive symptoms. This receptor profile is used broadly across schizophrenia and bipolar disorder. A well-known drawback of this class of antipsychotic is substantial weight gain, driven partly by effects on appetite and metabolism. The second component of this combination blocks mu-opioid receptors, which participate in reward and appetite circuits in the brain. The rationale for pairing it with the antipsychotic is to blunt the drive toward increased food intake and reward-driven eating that the antipsychotic component can produce, without interfering with the receptor actions responsible for its psychiatric benefit. This pairing represents an attempt to preserve therapeutic effect while addressing a major long-term tolerability and cardiometabolic concern associated with this drug class.