Although a large variety of biochemical effects have been reported for lithium (Li) and carbamazepine (Cbm), the final molecular mechanism underlying their therapeutic efficacy for recurrent affective disorders is still unknown. The data presented here clearly indicate that therapeutic concentrations of both drugs inhibit sodium nitroprusside-induced accumulation of cGMP in human lymphocytes to about the same extent. The effect is not seen for other antidepressants, and shows pronounced interindividual variations in healthy volunteers. A similar effect of lithium and carbamazepine can also be demonstrated for the cGMP accumulation of central neurons using the model of dissociated cells of the mouse brain. The results are discussed in view of a common mechanism of action of both drugs. Furthermore, it is speculated that the individual sensitivity of the cGMP generating system of human lymphocytes to both drugs might be used to predict therapeutic response or nonresponse of the individual patient.