Is it important to consider the sex of the patient when using lithium or valproate to treat the bipolar disorder? Mónica Flores-Ramos a,d, ⁎, Philippe Leff b , Alonso Fernández-Guasti c , Claudia Becerra Palars d a Consejo Nacional de Ciencia y Tecnología (CONACYT), Av. Insurgentes Sur 1582, Col. Crédito Constructor, Del. Benito Juárez, C.P. 03940 Ciudad de México, México b Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Montes Urales 800, Col. Lomas Virreyes, Deleg. Miguel Hidalgo, C.P. 11000 Ciudad de México, México c Centro de Investigación y de Estudios Avanzados del I.P.N., Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, C.P. 07360 Ciudad de México, México d Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada Mexico-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, C.P. 14370, Ciudad de México, México 1. Introduction Bipolar disorder (BD) is a psychiatric disorder characterized by de- pressive episodes accompanied by hypomanic, manic and mixed epi- sodes. According to the kind of episodes present in specific patients, we can classify BD as type I, type II or not specified. BD constitutes an important medical, economic and social burden around the world. Peo- ple who suffer from the disease present important cognitive and func- tional impairments. Merikangas and colleagues estimated the 12 month prevalence of BD type I, BD type II and subthreshold BD to be 0.6%, 0.8% and 1.14%, respectively. Even though women and men are affected by BD with similar frequency, some differences have been observed in the clinical presentation of BD according to sex. Type I and subthreshold BD are more common in males than type II BD, while in women, the opposite pattern is seen, with type II BD diagnosed more frequently (Merikangas et al., 2011). In addition to differences in the fre- quency of BD subtypes, women more frequently report mixed states (Secunda et al., 1987) and rapid cycling (Altshuler et al., 2010). The na- ture of the first episode may also differ depending on the sex of the pa- tient: men more often have a manic first episode, while women more commonly initiate with a depressive episode (Kawa et al., 2005). The clinical course of BD may also differ by sex, with women more prone to having depressive episodes and a depressive polarity. No consensus exists regarding whether there are sex differences in age at first episode. Some authors suggest that women initiate earlier than men, but other reports indicate that the first episode in women tends to be later than it is in men (Arnold, 2003). In addition to these gender differences in BD, the comorbidity of medical and psychiatric diseases differs accord- ing to sex, particularly with regard to thyroid disease, obesity, migraine and anxiety disorders. Women with BD are more likely to suffer central obesity and metabolic syndrome (Baskaran et al., 2014), as well as thyroid disease (Bauer et al., 2014). These findings highlight that women experience the disease differently than men. However, data ex- ploring sex differences in responses to pharmacological treatment of BD are scarce. 2. Treatment of bipolar disorder The focuses of treatment for patients with BD are stabilization and maintenance or relapse prevention. The acute stabilization goal is to lead patients with acute mania or depression into a euthymic mood. In the case of maintenance treatment, it is important to prevent re- lapses, reduce subthreshold symptoms, and enhance the functioning of the patient (Jann, 2014). These treatment goals are pursued through the use of mood stabilizers and antipsychotics. Mood stabilizers are de- fined as drugs that have a therapeutic and prophylactic effect against both psychopathological poles of BD. Classic mood stabilizers are lithi- um, valproic acid (VPA), and carbamazepine (Rybakowski, 2007). Atyp- ical antipsychotics are also useful for both the stabilization and maintenance phases of treatment (Singh et al., 2012). In the case of acute mania, controversies about the use of a mood stabilizer or antipsy- chotic monotherapy vs a combination of both have surged between ex- perts in the field. A systematic review and meta-analysis conclude that there is currently no robust evidence to judge whether mood stabilizer and antipsychotic combination therapy is more efficacious than mood stabilizer monotherapy as the initial therapy for acutely manic patients without prior medication (Ogawa et al., 2014). Treatment for depressive episodes or for patients with depressive polarity is also a challenge for clinicians due to the risk of patients switching to mania and to the rela- tively poor efficacy of antidepressants when used for bipolar depression compared with their use for unipolar depression. The use of atypical an- tipsychotics or a combination of an atypical antipsychotic and a selec- tive serotonin reuptake inhibitor (SSRI) is appropriate for bipolar depression (Nierenberg et al., 2015). Antidepressant monotherapy is not justified for bipolar depression, but the use of antidepressants should be considered when mood stabilizers or atypical antipsychotics have failed (McInerney and Kennedy, 2014). Clinical treatment guides include vast arrays of pharmacological op- tions that can be used as a first line, second line or third line of Pharmacology, Biochemistry and Behavior 152 (2017) 105–111 ⁎ Corresponding author at: Consejo Nacional de Ciencia y Tecnología (CONACYT), Av. Insurgentes Sur 1582, Col. Crédito Constructor, Del. Benito Juárez, C.P. 03940 Ciudad de México, México. E-mail addresses: flores_ramos@hotmail.com, monica.flores@imp.edu.mx (M. Flores-Ramos), pleff@ymail.com (P. Leff), jfernand@cinvestav.mx (A. Fernández-Guasti). http://dx.doi.org/10.1016/j.pbb.2016.02.003 0091-3057/© 2016 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh