Dr. Meltzer hypothesizes that the pathophysiology of negative symptoms of schizophrenia may include three elements:
1) Decreased dopamine binding in the prefrontal cortex,
2) Decreased cholinergic stimulation of the prefrontal cortex, and
3) Dysfunction of glutamatergic pyramidal neurons.

He believes that the superior efficacy of atypical antipsychotics (compared with typical antipsychotics) for negative schizophrenic symptoms may derive from their ability to:
1) Increase dopamine release in the prefrontal cortex,
2) Increase cholinergic stimulation (both directly and indirectly), and
3) Modulate glutamatergic function.

Many researchers initially believed that weaker dopaminergic activity alone (via dopamine-2 receptor blockade) was sufficient to produce an atypical antipsychotic. Recent evidence contradicts this and highlights the importance of cholinergic and glutamatergic systems. Recent evidence also suggests that a combination of potent 5-HT_2A receptor blockade and weaker dopamine-2 receptor blockade may be essential for "atypicality" of antipsychotics.

Dr. Meltzer first focused on a hypothesis involving "fast dissociation from the dopamine-2 receptor." Previously, researchers believed that both low affinity for and fast dissociation from the dopamine-2 receptor sufficed to produce an atypical antipsychotic. However, kinetic studies of drug dissociation from the dopamine-2 receptor for the atypical antipsychotics sertindol and olanzapine, and the typical antipsychotic haloperidol all show slow rates of dissociation from dopamine-2 receptors. The atypical antipsychotics clozapine and quetiapine have much higher rates of dissociation from dopamine-2 receptors. Thus, dopamine-2 dissociation alone is not sufficient to identify atypicality in antipsychotics.

In contrast, the 5-HT₂ hypothesis states that atypicality derives from high affinity for the 5-HT_2A receptor plus low affinity for the dopamine-2 receptor. These criteria in combination identify the current atypical antipsychotics with a 90% success rate. Adding 5-HT_2C and 5-HT₆ receptor affinity to this model increases the power of identification to100%. Moreover, the 5-HT to dopamine-2 ratio accurately distinguishes different atypical antipsychotics.

Dr. Meltzer's group examined negative symptoms of schizophrenia and hypothesized that low dopaminergic function in the prefrontal cortex is essential to its pathophysiology. In animal models, each of the atypical antipsychotics increases dopamine release in the prefrontal cortex while decreasing dopamine release in the limbic system. This contrasts with the effects of haloperidol, which minimally increases dopamine release in the prefrontal cortex and robustly increases dopamine release in the limbic system. Dr. Meltzer's work with 5-HT agonists and antagonists prompt him to conclude that 5-HT receptors modulate cortical and subcortical dopamine release, and also affect glutamate and GABA function. Combined, these effects modulate both positive and negative schizophrenic symptoms.

Dr. Meltzer also highlighted the potential importance of cholinergic neurotransmission in that each of the atypical antipsychotics (and none of the typical antipsychotics) induces a dose-dependent increase in acetylcholine in the prefrontal cortex. He hypothesized that negative symptoms may devolve from reduced cholinergic funtion in the prefrontal cortex, and pointed out, consistently, that clozapine is a partial agonist of muscarinic M1 and M2 receptors.