Rationale: Abnormalities of serotonin (5HT) function have been implicated in mood disorders, and lithium treatment may produce its beneficial effects by modifying serotonergic mechanisms. It has also been observed that 5HT 2A receptors are upregulated both in the postmortem brain and platelets of patients with depression and suicidal behavior. However, the role of 5HT2A receptors in bipolar disorders and in the mechanism of action of lithium is unclear. Objective: The major objective of this study was to examine if abnormalities of 5HT2A receptors are associated with bipolar or schizoaffective disorders and if treatment with lithium would cause changes in the 5HT2A receptors. Methods: 5HT2A receptors were studied in the platelets obtained from drug-free normal control subjects and patients with bipolar (n=41) or schizoaffective (n=20) disorders during a drug-free washout period and after treatment (4.0∓0.44 weeks) with lithium (n=16). The Bmax and KD of 5HT2A receptors were quantitated by binding techniques using [125I] lysergic acid diethylamide (LSD) as a ligand. Results: We observed that the 5HT2A receptor Bmax was increased in platelets obtained from drug-free bipolar or schizoaffective patients as compared with normal control subjects. The 5HT2A receptor density was even more increased in bipolar or schizoaffective suicidal patients, and the 5HT2A receptor Bmax in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control subjects. Treatment with lithium caused a significant increase in the Bmax of platelet 5HT2A receptors in bipolar or schizoaffective patients. Conclusions: Our studies indicate that increased 5HT2A receptors may be associated with the pathophysiology of bipolar illness and that treatment with lithium further increases the density of 5HT2A receptors. Whether this increase in 5HT2A receptors caused by lithium is associated with its therapeutic mechanism of action is unclear. It is also not clear whether the increase in 5HT2A receptors in bipolar or schizoaffective patients, or in suicidal bipolar or schizoaffective patients, is a trait or state marker.