Sex difference in the progression of manic symptoms during acute hospitalization: A prospective pilot study

Abstract

Objectives: Acute mania is a serious medical condition that impacts men and women equally. Longtime presentation of manic symptoms is sex-dependent; however, little is known about acute symptoms of mania. The objective of this study is to track and compare acute manic symptoms for sex differences during inpatient hospitalization.

Methods: All patients with bipolar mania admitted to a large university hospital between January and October 2017 were invited to participate in this longitudinal naturalistic follow-up study. Manic (YMRS), depressive (MADRS), and psychotic (PAS) symptoms were tracked daily from admission to discharge.

Results: The total YMRS scores decreased significantly overtime (p < .0001) in both male (n = 34) and female (n = 23) patients (p = .7). However, male patients scored significantly higher in sexual interest (p = .01), disruptive and aggressive behavior (p = .01), and appearance (p < .001) while females had better insight into their illness (p = .01). Males and females received similar doses of lithium (p = .1), but males received significantly higher doses of valproic acid (VPA) in comparison with females (p = .003). However, plasma lithium and VPA concentrations at discharge were not significantly different between sexes.

Conclusion: Our results show sex differences in the progression of certain domains of manic symptoms in a cohort of 23 female and 34 male patients admitted to a large academic center in Turkey. Males, in this sample, exhibited more sexual interest, disruptive and aggressive behaviors, better grooming, and less insight compared to females. While these results are concordant with our preclinical findings and with anecdotal clinical observations, replication in larger samples is needed.

Keywords: Young Mania Rating Scale; aggressive and disruptive behavior; insight; mania; phenotype; sex difference; sexual interest.

Figure 1

Progression of manic symptoms as measured by YMRS over hospital LOS in male and female patients by two‐way ANOVA. (a) Total YMRS score shows significant effect of time [F (4, 220) = 149.9, p < .0001], but not sex [F (1, 55) = 0.06176, p = .8] and no interaction between time and sex [F (4, 220) = 0.2012, p = .9. (b) YMRS Q3 sexual interest shows significant effect of time [F (4, 275) = 12.69, p < .0001], and sex [F (1, 275) = 5.625, p = .01] but no interaction between time and sex [F (4, 275) = 0.1477, p = .9]. The overall sex difference was not specific to a time point by Sidak's multiple comparison test. (c) YMRS Q9 disruptive and aggressive behavior shows significant effect of time [F (4, 275) = 17.32, p < .0001], and sex [F (1, 275) = 5.614, p = .018] but no interaction between time and sex [F (4, 275) = 1.156, p = .3]. The overall sex difference was not specific to a time point. However, a nonsignificant trend for sex difference was observed at the 25% LOS time point (mean difference = −0.09488, 95% CI of difference = −1.992 to 0.0941, p = .09) by Sidak's multiple comparison test. (d) YMRS Q10 appearance shows significant effect of time [F (4, 275) = 19.78, p < .0001], and sex [F (1, 275) = 16.56, p < .0001] but no interaction between time and sex [F (4, 275) = 0.789, p = .7]. In addition to the overall sex difference, significant (**) sex difference was observed at the admission time point [mean difference = 0.6228, 95% CI of difference = 0.143 to 1.103, p = .004) by Sidak's multiple comparison test. (e) YMRS Q11 insight also shows significant effect of time [F (4, 275) = 13.39, p < .0001], and sex [F (1, 275) = 6.717, p = .01] but no interaction between time and sex [F (4, 275) = 0.0868, p = .9]. (*) Indicates significant effect of time and (#) indicates significant effect of sex in all measures. The overall sex difference was not specific to a time point by Sidak's multiple comparison test

Figure 2

Vitamin B₁₂ and folate have fundamental role in cellular metabolism. Vitamin B₁₂ is a cofactor for cytoplasmic methionine synthase (MS) and mitochondrial methylmalonyl‐CoA (MMCo‐A) mutase enzymes. MS converts homocysteine into methionine (essential to sustain adequate synthesis of myelin, proteins, DNA, and neurotransmitters) and 5‐methyl tetrahydrofolate (TH4‐folate) into tetrahydrofolate (TH4) needed for nucleic acid synthesis (Calderon‐Ospina & Nava‐Mesa, 2020; Hathout & El‐Saden, 2011; Reynolds, 2006). Methionine is transformed into S‐Adenosyl Methionine (SAM) which is converted by methyltransferase into S‐Adenosyl Homocysteine (SAH) by the enzyme methyltransferase an important step in methylation reactions which is essential for genomic and nongenomic methylation. Inside the mitochondria, vitamin B₁₂ functions as a cofactor for MMCo‐A mutase which converts methylmalonic acid to succinyl co‐enzyme A, which subsequently enters in the Krebs cycle for ATP production (Froese & Gravel, 2010; Gueant et al., 2013)

Figure 3

Brain thyroid hormone. (a) Hypothalamic–pituitary–thyroid (HPT) axis; thyrotropin‐releasing hormone (TRH) is released from the hypothalamus to stimulate anterior pituitary to secrete thyroid stimulating hormone (TSH) which in turn stimulates thyroid gland to produce mostly tetraiodothyronine (T4) and to less extent triiodothyronine (T3). (b) Transportation and brain action of plasma T3 and T4: Both T3 and T4 are present in free and protein‐bound forms. Free T4 is transported through the blood–brain barrier (BBB) by the organic anion‐transporting peptide 1c1 (OATP1c1) to astrocytes and tanycytes where it is converted into T3 by deiodinase type 2 (DIO‐2) enzyme. Astrocyte T3 is transported to neurons through monocarboxylate transporter (MCT)8. Free T3 and to less extent T4 can also be transported directly into neurons through gap junctions and MCT8. Another unknown thyroid hormone transporter (UTHT) transporters astrocytic T3 to oligodendrocytes to activate myelination genes. Within neurons, T3 (and to possibly T4) bind to nuclear thyroid hormone receptors (nTR) to influence gene expression critical for cell growth and differentiation and synaptic plasticity. Neuronal T4 and T3 are metabolized by deiodinase type 3 (DIO‐3) enzyme into inactive reverse T3 (rT3) and T2, respectively (Cheng, Leonard, & Davis, 2010; Lee & Petratos, 2016; Schroeder & Privalsky, 2014)