Rodrigo da Silva Dias

Sex hormones and biomarkers of neuroprotection and neurodegeneration: implications for female reproductive events in bipolar disorder

Previous studies have suggested that women with bipolar disorder are at higher risk for mood episodes during periods of intense hormonal fluctuation (e.g., premenstrual, postpartum, perimenopause). There is converging literature showing that estrogen and progesterone can modulate neurotransmitter systems and intracellular signaling pathways known to be affected by mood stabilizing agents. Here, we critically review clinical aspects of reproductive cycle events in women with bipolar disorder and preclinical studies, with a focus on the functional interactions between sex hormones and biomarkers of neuroprotection and neurodegeneration that are thought to be involved in the neurobiology of bipolar disorder: brain‐derived neurotrophic factor, oxidative stress, and inflammation.

Longitudinal Follow-Up of Bipolar Disorder in Women With Premenstrual Exacerbation: Findings From STEP-BD

OBJECTIVE The impact of hormonal fluctuation during the menstrual cycle on the course of bipolar disorder is poorly understood. The authors determined the course of illness and time to relapse of bipolar disorder in prospectively followed women with premenstrual exacerbation. METHOD Participants were 293 premenopause-age women with bipolar disorder who were followed prospectively for 1 year as part of the Systematic Treatment Enhancement Program for Bipolar Disorder. Frequency of mood episodes was compared between 191 women with premenstrual exacerbation (65.2%) and 102 women without. Among 129 women who were in recovered status at baseline, time to relapse was compared between 66 women with premenstrual exacerbation (51.2%) and 63 without. RESULTS During follow-up, the group with premenstrual exacerbation had more episodes (primarily depressive) than did the group without, but they were not more likely to meet criteria for rapid cycling during this period. In contrast, they were more likely to report rapid cycling retrospectively. Women with premenstrual exacerbation had a shorter time to relapse and were at greater risk for relapse, but this association was not significant after adjustment for retrospectively reported rapid cycling. Women with premenstrual exacerbation had more depressive and mood elevation symptoms overall. CONCLUSIONS Women with bipolar disorder and premenstrual exacerbation have a worse course of illness, a shorter time to relapse, and greater symptom severity, but they are not more likely to meet criteria for rapid cycling. Premenstrual exacerbation may be a clinical marker predicting a more symptomatic and relapse-prone phenotype in reproductive-age women with bipolar disorder.

Social Dysfunction in Bipolar Disorder: Pilot Study:

Objective: The purpose of the present study was to assess the social skills of euthymic patients with bipolar disorder. Methods: A group of 25 outpatients with bipolar disorder type I were evaluated in comparison with a group of 31 healthy volunteers who were matched in terms of level of education, age, sex and intelligence. Both groups were assessed using a self-report questionnaire, the Brazilian Inventário de Habilidades Sociais (IHS, Social Skills Inventory). Two Wechsler Adult Intelligence Scale subtests (Picture Arrangement and Comprehension) were also used in order to assess subject ability to analyse social situations and to make judgements, respectively. Results: Patients with bipolar disorder had lower IHS scores for the domains that assessed conversational skills/social self-confidence and social openness to new people/situations. Patients with anxiety disorders had high scores for the domain that assessed self-confidence in the expression of positive emotions. No differences were found between patients and controls in performance on the Wechsler Adult Intelligence Scale Picture Arrangement and Comprehension subtests. Conclusions: Euthymic patients with bipolar disorder present inhibited and overattentive behaviour in relation to other people and their environment. This behaviour might have a negative impact on their level of social functioning and quality of life.

Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: A double-blind controlled pilot study

Objective: This study evaluated the augmentation of venlafaxine with hormone therapy in the treatment of postmenopausal depression. The hormones evaluated were estrogen (0.625 mg) in combination with medroxyprogesterone acetate (2.5 mg) and methyltestosterone (2.5 mg). Design: Seventy-two menopausal women (mean age: 53.6 ± 4.27 years) diagnosed with depression (Montgomery-Åsberg Depression Rating Scale [MADRS] scores ≥ 20) were treated with venlafaxine and one of the following hormone therapy combinations, in a double-blind regimen: estrogen + medroxyprogesterone + methyltestosterone (group 1, n = 20); estrogen + medroxyprogesterone acetate (group 2, n = 20); methyltestosterone only (group 3, n = 16); and no hormone therapy (group 4, n = 16). Study duration was 24 weeks. Primary efficacy outcome was remission according to the MADRS, whereas secondary efficacy measures included the Clinical Global Impression (CGI), Blatt-Kupperman Index, and Women’s Health Questionnaire (WHQ). Results: Forty-eight patients completed the study. All groups showed significant improvement from baseline. Group 3 demonstrated significant improvement on the MADRS compared with placebo (group 4) at weeks 20 (P = 0.048) and 24 (P = 0.030); effect size 8.04 (0.83; 15.26) (P = 0.029), but also had the highest dropout rate. Groups 1 and 3 had significant CGI improvement rates compared with placebo: 42.23% (P = 0.012) and 44.45% (P = 0.08), respectively. There were no differences in the WHQ or BKI scores among the groups. Conclusions: Methyltestosterone 2.5 mg had the highest effect size compared with placebo, but the high dropout rate prevented its efficacy from being determined. Estrogen plus medroxyprogesterone, combined with methyltestosterone or otherwise, demonstrated a trend toward increased efficacy of venlafaxine. Further larger-scale clinical trials are needed to elucidate the findings of this pilot study.

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry (‘0-weeks’ group) or (ii) at 24 weeks after entry (‘24-weeks’ group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (‘52-weeks’ group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

O ciúme enquanto sintoma do transtorno obsessivo-compulsivo

Morbid jealousy (MJ) is an important problem in psychiatry, which involves some risks and much distress, and may occur in many mental disorders. Phenomenologically, it can be manifested in different ways, such as an obsessional, overvalued or delusional idea of infidelity. However, its manifestation in obsessive-compulsive disorder (OCD), as an obsession usually associated with checking rituals, is not much documented. To address this specific issue, considering that little has been published about MJ in OCD, this article describes and discusses four selected clinical cases, emphasizing diagnostic and therapeutic aspects. The comprehension of some cases of MJ as a manifestation of OCD, even when not clearly ego-dystonic, enhances therapeutic possibilities and may improve the prognosis.

Obesity and metabolic syndrome in Brazilian patients with bipolar disorder.

Objective: We aimed to determine the prevalence of obesity and metabolic syndrome (O/MetS) in a sample of Brazilian outpatients with bipolar disorder. Methods: Eighty-four patients with bipolar disorder were evaluated. We used the definition of MetS established in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, modified by the American Heart Association (AHA). Patients were classified as obese if their body mass index (BMI) was ≥ 30 kg/m2. Results: We found that 28.6% of our sample met the AHA criteria for MetS and 35.7% were obese. The percentage of patients meeting each criterion of the AHA was as follows: 46% for abdominal obesity; 44% for hypertriglyceridemia or cholesterol-lowering medication use; 26% for low high-density lipoprotein cholesterol or being on a lipid-lowering medication; 45% for hypertension; and 20% for high fasting glucose or anti-diabetic medication use. Conclusions: The prevalence of obesity in our sample of outpatients with bipolar disorder was higher than that observed for the general population of Brazil. The rate of MetS was similar to that observed for the general population. Our data indicate the need for prevention, early detection and treatment of O/MetS in patients with bipolar disorder.

Transtorno bipolar do humor e gênero

Embora o transtorno bipolar (TB) ocorra quase igualmente em ambos os sexos, a fenomenologia e o curso da doenca diferem no homem e na mulher. No entanto, ha evidencias de que mulheres bipolares, mais que os homens, apresentariam inicio mais tardio (em especial na quinta decada de vida), ciclagem rapida, mais episodios depressivos, mais mania disforica que euforica, estados mistos e evolucao do tipo bipolar II, ainda que os achados nem sempre sejam consistentes. Embora o risco de comorbidades no TB inclua, para ambos os generos, abuso de alcool e drogas, homens bipolares teriam maior probabilidade de ser alcoolistas, nao procurar tratamento e de se suicidar. Hipoteses sugeridas para explicar tais diferencas variam daquelas centradas em aspectos culturais ou psicologicos para as que focalizam os sistemas hormonais, como os esteroides gonadais ou o eixo tireoidiano, e ate mesmo a anatomia cerebral. A influencia do ciclo reprodutivo (ciclo menstrual, gravidez e menopausa) sobre as opcoes terapeuticas no tratamento do TB e apresentada na ultima parte desta revisao.

Association between history of suicide attempts and family functioning in bipolar disorder.

OBJECTIVES To investigate the association between history of suicide attempts (SA) and family functioning in bipolar disorder (BD) patients. METHODS Thirty-one BD type I patients with lifetime history of SA, 31 BD type I with no lifetime history of SA, participating in the Outpatient Clinic of the Bipolar Disorder Program at the Institute of Psychiatry of the University of São Paulo Medical School were recruited for this study. We used the Family Assessment Device (FAD) to evaluate family functioning. We compared these two groups on demographic and clinical variables to identify which variables were associated with family functioning impairment. Fifty-one relatives of the same patients were also asked to complete a FAD. RESULTS BD patients with SA presented more psychiatric hospitalizations, higher frequency of psychotic symptoms, and higher scores on depressive, manic, and suicidal ideation than BD patients without SA. BD patients with SA presented significantly higher scores in several subscales of the FAD, including Problem Solving (p=0.042), Communication (p=0.009), Roles (p=0.006), and General Functioning (p=0.025), when compared with BD patients without SA. Relatives of BD patients with SA presented significantly higher scores in Communication, Roles, Affective Responsiveness, and General Functioning than relatives of BD patients without SA. LIMITATIONS Cross-sectional study and long time elapsed since last SA. CONCLUSION History of SA in BD is associated with worse family functioning in several domains of FAD, including Problem Solving, Communication, Roles, and General Functioning. As suicide attempts are routinely assessed in clinical practice, these findings may help to identify patients with poorer family functioning and may suggest a role for environmental risk factors in suicidal behavior among BD patients.

A clinical study comparing manic and mixed episodes in patients with bipolar disorder

OBJECTIVE Mixed episodes have been described as more severe than manic episodes, especially due to their longer duration and their association with higher rates of suicide attempts, hospitalization and psychotic symptoms. The purpose of this study was to compare the severity between mixed and pure manic episodes according to DSM-IV criteria, through the evaluation of sociodemographic data and clinical characteristics. METHOD Twenty-nine bipolar I patients presenting acute mixed episodes were compared to 20 bipolar I patients with acute manic episodes according to DSM-IV criteria. We analyzed (cross-sectionally) episode length, presence of psychotic symptoms, frequency of suicide attempts and hospitalization, Young Mania Rating Scale scores, Hamilton Depression Rating Scale scores and the Clinical Global Assessment Scale scores. RESULTS Young Mania Rating Scale scores were higher in manic episodes than in mixed episodes. There were no differences in gender frequency, CGI scores and rates of hospitalization, suicide attempts and psychotic symptoms, when mixed and manic episodes where compared. Patients with mixed episodes were younger. CONCLUSION In our sample, mixed states occurred at an earlier age than manic episodes. Contrary to previous reports, we did not find significant differences between manic and mixed episodes regarding severity of symptomatology, except for manic symptoms ratings, which were higher in acute manic patients. In part, this may be explained by the different criteria adopted on previous studies.