The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine, the olanzapine-fluoxetine combination and recently lurasidone are officially FDA-approved against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lurasidone fit to a previously developed model which was the first to be derived on the basis of the strict combination of clinical and preclinical data with no input from theory or opinion. The authors performed a complete and systematic review of the literature to identify the pharmacodynamic properties of lurasidone. The original model suggests that a constellation of effects on different receptors are necessary but the serotonin reuptake inhibition does not seem to play a significant role for bipolar depression. On the contrary norepinephrine activity seems to be very important. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition is essential in order to sustain it. Overall the properties of lurasidone fit well the model and add to its validity. A point that needs clarification is norepinephrine reuptake inhibition which is not yet studied for lurasidone.