Many discussions have been made related to diagnosis of bipolar disorder in recent years. Especially, much attention has been devoted to the activation syndrome induced by antidepressants and the bipolar spectrum disorder proposed by Gahemi. Differential diagnosis between bipolar depression and monopolar depression is extremely important when planning treatment strategy, but it is difficult to differentiate between them using symptomatic information alone. Therefore, if an easily-accessible biological marker can differentiate between them, it is expected to be extremely useful in clinical practice. Several trait biological markers associated with the pathophysiology of bipolar disorder have been identified with a high evidence level. Abnormality of cellular calcium signaling is regarded as one such replicable trait marker. Especially because human platelets are easily accessible, increasingly numerous reports describe studies of intracellular calcium concentration increase induced by various agonists in patients with bipolar disorder. Summarizing previous reports, the agonist-stimulated calcium response is enhanced significantly in patients with bipolar disorder compared to normal subjects, although resting intraplatelet calcium concentration does not differ between them. Moreover, serotonin-induced calcium response in monopolar depression and the other psychiatric diseases is not significantly different from that in normal subjects, which suggests that the enhanced calcium response to serotonin is specific to bipolar disorder among various diseases. However, several problems arise in using this marker as a supplemental tool of clinical diagnosis. First, the calcium response has a fairly common distribution between bipolar depression and monopolar depression groups although the means of the responses are significantly different. Consequently, it is difficult to differentiate clearly between bipolar depression and monopolar depression merely by setting a discriminating value. Second, it is necessary to measure calcium response as soon as possible after blood collection. Third, drugs taken at the time of blood collection might affect the calcium response. Finally little evidence exists showing whether functions in peripheral tissue actually reflect brain function. Therefore, many obstacles remain to be solved before using this marker in clinical practice.