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Aim: Bipolar disorder (BP) is a mood disorder with a prevalence of 1-2% in the general population. Lithium is the most widely used and best characterized long-term treatment for BP. The aim of this study is the evaluation of the effectiveness of lithium treatment in a naturalistic setting. Moreover we investigated if a number of clinical markers were positively or negatively associated with treatment response., Methods: We evaluated 199 outpatients affected by BP (according to DSM-IV criteria), who had continuously received lithium for at least one year. Life course of illness in each patient was graphically depicted with the NIMH Life Chart method which allowed us to apply the Retrospective Evaluation of Prophylactic Treatment Response Scale in order to assess the treatment outcome. This scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment, rather than other factors., Results: Full Responders to lithium were 29% of the sample. Bipolar II (BPII) patients were significantly overrepresented in the Full Responders group (p = 0.035). In addition, psychotic symptoms were significantly associated to a poorer treatment outcome (p = 0.0197)., Conclusions: This study supports the effectiveness of lithium treatment in a naturalistic setting, suggesting that BPII patients could also benefit from lithium treatment. Finally, it suggests that the use of another mood stabilizer or of a combination treatment could represent a valuable therapeutic choice in the management of bipolar patients with psychotic symptoms.