Five patients (three bipolars and two unipolars) affected by a major depressive episode with psychotic features were treated with total sleep deprivation (TSD) without concurrent psychotropic medication. After TSD we observed a worsening in psychotic as well as in depressive symptoms as rated on the Dimension of Delusional Experience Rating Scale and on Hamilton Rating Scale for Depression, respectively. TSD is known to markedly enhance the activity of brain monoaminergic pathways. Given the interaction between brain serotonergic and dopaminergic systems in delusional depression, it is possible that an enhancement in dopaminergic activity may be responsible of the symptomatological worsening in delusional depressives observed after TSD.