The diagnostic entity of Major Depressive Episode includes both simple and agitated or mixed Depression. Mixed Depression is characterized by a full depressive episode with symptoms of excitatory nature. Psychic and motor agitation, racing or crowded thoughts, irritability and unprovoked feelings of rage, talkativeness, mood lability and early insomnia are clearly symptoms of nervous excitability and when they are mixed in the picture of a major depressive episode, they constitute a mixed depressive episode. Psychomotor and psychic agitations are equally important for the diagnosis. We propose that the traditional term ‘agitated Depression’ be reserved for those cases with motor agitation and the term ‘mixed Depressions for those without such agitation. They correspond to the two forms of depressive mixed states named by Kraepelin (1913) ‘excited (agitated) Depression’ and ‘Depression with flight of ideas’. The adverse response of these states to antidepressant drugs, above all the increase of agitation and of suicidality, makes a clear distinction between simple and mixed Depression necessary and urgent. The suicidality induced by antidepressants is related to manifest or latent agitation. The concept of latent mixed Depression will be introduced for those major depressive episodes that become agitated following antidepressant treatment.The following clinical forms can be distinguished: Psychotic agitated Depression, Agitated Depression (nonpsychotic) with psychomotor agitation, Mixed Depression with psychic agitation. The term Melancholia Agitata is proposed for Agitated and Psychotic Depressions. Diagnostic Criteria of Agitated Depression and Mixed Depression Full depressive syndrome and inner unrest are both essential elements of this syndrome. The presence of motor agitation is sufficient to make the diagnosis of agitated Depression, as in the RDC criteria. It also confirms the presence of psychic agitation. The absence of motor agitation creates the diagnostic problem of distinguishing anxiety from the particular inner unrest of mixed Depression. In order to distinguish between anxiety and inner agitation, we used the following criteria: along with major Depression at least 3 of the following symptoms must be present: 1) inner agitation, 2) racing or crowded thoughts, 3) irritability or unprovoked feelings of rage, 4) absence of signs of retardation, 5) talkativeness, 6) dramatic descriptions of suffering or frequent spells of weeping, 7) mood lability and marked emotional reactivity, 8) early insomnia, 9) occasional hypersexuality and 10) high diastolic blood pressure. Such symptoms are of excitatory, not depressive, nature and indicate the absence of depressive inhibition. We consider misleading the use of the term manic for these symptoms. The main problem is the nature of depressive mixed states. It is generally considered an admixture of manic symptoms into a clinical picture of Depression. We believe that excitatory processes are the cause of the depressive syndrome. This brilliant intuition was first advanced by W.Griesinger in 1861 and, although neglected by modern psychiatry, we think it is today one of the foremost and urgent issues for research We have reviewed the clinical charts of 2141 patients treated at the Centro Lucio Bini of Rome from 1999 to June 2006. These patients were diagnosed according to DSM-IV criteria. RDC criteria were applied for agitated Depression with motor agitation and author’s diagnostic criteria for mixed Depression without motor agitation. 1026 patients had a depressive episode as index episode. 346 (33%) were agitated and mixed depressive states. 138 (44%) of them were spontaneous; in 173 cases, the onset of the mixed Depression was associated with antidepressants. The great use of antidepressants today to treat all forms of Depression makes the problem of the real nature of agitated Depression a crucial issue. We have observed that many of these patients, if treated with antidepressant drugs, have negative outcomes such as growing agitation, uncontrollable anxiety, increased risk of suicide, manifestation of psychotic symptoms and worsening of the subsequent course of the illness. The inability to recognize mixed Depression as a mixed state may be responsible for many unsatisfactory, often dramatic results of the treatment In mixed or agitated Depression, treatment should initiate with neuroleptics, anti-psychotics, anti-epileptics, lithium and benzodiazepines and when agitation has subsided, and if simple Depression follows, antidepressants may be used cautiously. Electroconvulsive therapy is very effective throughout its course.