In depressed patients the hypothalamo-pituitary adrenal (hpa) axis is usually activated. Until recently, the measures used for this activation, such as the dexamethason suppression test (dst), show low sensitivity and specificity. A recently developed improved test for hpaaxis activation is clearly more sensitive for depression, but its specificity has not yet been studied. Little was known about the central mechanism of hpaaxis activation in humans and virtually nothing about its specificity. Therefore, we determined the measures of the central activation in the paraventricular nucleus (pvn), such as the number of corticotrophin releasing hormone (crh) producing neurons, its fraction showing colocalization with vasopressin, the amount of crhmessenger (m)-rna and the number of neurons producing vasopressin or oxytocin, in 8 to 10 control patients and 6 to 8 depressed patients diagnosed as suffering from major depression or bipolar disorder. All these measures showed activation of the hpaaxis in depressed patients. The finding of crh neuron activation in depressed patients has shown to be relevant for clinical practice, since it resulted in rational strategies for developing antidepressants, such as crh1 receptor antagonists.