Machine Learning Prediction of Quality of Life Improvement During Antidepressant Treatment of Patients With Major Depressive Disorder: A STAR*D and CAN-BIND-1 Report.

Background: Quality of life (QoL) is an important patient-centric outcome to evaluate in treatment of major depressive disorder (MDD). This work sought to investigate the performance of several machine learning methods to predict a return to normative QoL in patients with MDD after antidepressant treatment.Methods: Several binary classification algorithms were trained on data from the first 2 weeks of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (n = 651, conducted from 2001 to 2006) to predict week 9 normative QoL (score ≥ 67, based on a community normative sample, on the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form [Q-LES-Q-SF]) after treatment with citalopram. Internal validation was performed using a STAR*D holdout dataset, and external validation was performed using the Canadian Biomarker Integration Network in Depression-1 (CAN-BIND-1) dataset (n = 175, study conducted from 2012 to 2017) after treatment with escitalopram. Feature importance was calculated using SHapley Additive exPlanations (SHAP).Results: Random Forest performed most consistently on internal and external validation, with balanced accuracy (area under the receiver operator curve) of 71% (0.81) on the STAR*D dataset and 69% (0.75) on the CAN-BIND-1 dataset. Random Forest Classifiers trained on Q-LES-Q-SF and Quick Inventory of Depressive Symptomatology-Self-Rated variables had similar performance on both internal and external validation. Important predictive variables came from psychological, physical, and socioeconomic domains.Conclusions: Machine learning can predict normative QoL after antidepressant treatment with similar performance to that of prior work predicting depressive symptom response and remission. These results suggest that QoL outcomes in MDD patients can be predicted with simple patient-rated measures and provide a foundation to further improve performance and demonstrate clinical utility.Trial Registration: ClinicalTrials.gov identifiers NCT00021528 and NCT01655706.

Effects of nutritional interventions on the severity of depressive and anxiety symptoms of women in the menopausal transition and menopause: a systematic review, meta-analysis, and meta-regression.

IMPORTANCE: Depression and anxiety may significantly affect women during the menopausal transition. In addition to traditional treatment strategies such as hormone therapy, antidepressants, and psychotherapy, nutritional interventions have been increasingly studied, but there is no consensus about their role in this patient population. OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the effect of nutritional interventions on the severity of depressive (DS) and anxiety (AS) symptoms in women during the menopausal transition or menopausal years. EVIDENCE REVIEW: Electronic search using databases PubMed, Cochrane, and Embase to identify articles indexed until January 31, 2021, focusing on randomized placebo-controlled trials documenting the effect of diet, food supplements, and nutraceuticals on DS and AS. FINDINGS: Thirty-two studies were included (DS, n = 15; AS, n = 1; DS and AS combined, n = 16). We found two studies that demonstrated data combined with other interventions: one with lifestyle interventions (vitamin D plus lifestyle-based weight-loss program) and another with exercise (omega 3 plus exercise). The pooled effect size favored the intervention group over placebo for both DS and AS (DS: standardized mean difference, -0.35 [95% confidence interval, -0.68 to -0.03; P = 0.0351]; AS: standardized mean difference, -0.74 [95% CI, -1.37 to -0.11; P = 0.0229]). There was significant heterogeneity in the pooled results, which can be attributed to differences in assessment tools for depression and anxiety as well as the variety of nutritional interventions studied. The subgroup analysis showed a statistically significant effect of menopausal status (perimenopausal or menopausal) but not the type or duration of nutritional intervention. Older age was the only significant predictor of the effect size of nutritional interventions in the meta-regression. CONCLUSIONS AND RELEVANCE: Nutritional interventions are promising tools for the management of mood/anxiety symptoms in women during the menopausal transition and in postmenopausal years. Because of significant heterogeneity and risk of bias among studies, the actual effect of different approaches is still unclear.

Hypothalamus volume and DNA methylation of stress axis genes in major depressive disorder: A CAN-BIND study report.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.

Non-hormonal treatment strategies for vasomotor symptoms: a critical review.

Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60-90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be able to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life.

Effects and management of the menopausal transition in women with depression and bipolar disorder.

Unipolar and bipolar disorders are major causes of disease burden for women in the United States. For some women, the menopausal transition can represent a time of increased vulnerability to depression, a greater risk of recurrence or instability of bipolar disorder, and an overall poorer quality of life (QOL). The physical and psychological changes of menopause and symptoms of depression may overlap, but QOL is affected doubly for women experiencing menopause-related complaints concomitantly with a unipolar or bipolar disorder. Treatments for the symptoms of menopause and for unipolar or bipolar disorder need to be chosen with careful consideration for the different stages of the menopausal transition, as well as safety, tolerability, and impact on QOL. Menopausal-related symptoms can be treated with hormonal therapies, antidepressants, and herbal supplements, but a critical window of opportunity may exist for these interventions. Bipolar disorder presents differently in women than in men and may require different medication. For instance, in women, lithium may be less effective for patients who have rapid cycling; adjuvant antidepressant medication may be required with valproate or carbamazepine; and lamotrigine may also be effective. Most of the medications that are standard treatment for bipolar disorder affect bone mineral density, and the risk for impaired QOL should be considered when choosing medication for women during this period. Insufficient information is available, however, to assess the best strategy to treat women with bipolar disorder and depression as they age.

Insônia na menopausa e perimenopausa: características clínicas e opções terapêuticas / Insomnia during menopause and perimenopause: clinical characteristics and therapeutic options

Transtornos do sono e insônia são mais freqüentemente observados entre as mulheres do que entre os homens durante a vida adulta. Entre outros fatores, especula-se que alta comorbidade psiquiátrica para transtornos afetivos e ansiosos entre as mulheres contribua para maior ocorrência de insônia. Além disso, períodos de intensa variabilidade hormonal (por exemplo, gestação e puerpério, perimenopausa) parecem estar relacionados com maior incidência de insônia e de transtornos respiratórios do sono entre as mulheres. Estudos populacionais sugerem que a transição menopausal constitue um período de maior risco para o desenvolvimento de sintomas depressivos, vasomotores e de insônia. Este artigo examina os fatores clínicos e hormonais que contribuem para a ocorrência de insônia durante a peri e a pós-menopausa. Opções terapêuticas são discutidas, incluindo técnicas cognitivo-comportamentais, tratamentos hormonais, agentes hipnótico-sedativos, antidepressivos e tratamentos de medicina alternativa.

Sleep disturbances and insomnia are more commonly observed in adult females than in adult males. It has been speculated that comorbid depression and anxiety among females may contribute to a higher incidence of insomnia. In addition, periods of intense hormonal variability (e.g.; pregnancy/postpartum, menopause transition) appear to be associated with higher incidence of sleep disturbances in females. Epidemiologic studies suggest that the menopausal transition constitutes a period of heightened risk for the occurrence of depressive symptoms and vasomotor complaints, as well as insomnia. This article reviews the clinical and hormone factors that may play a role for the development of insomnia during the menopausal transition and postmenopause. Treatment options are critically reviewed, including cognitive-behavioral techniques, hormonal treatments, hypnotics, antidepressants, and complimentary/alternative medicine.

Treatment of menopause-related mood disturbances.

More than 1.7 million American women are expected to reach menopause each year. Recent Canadian statistics show that a 50-year-old woman can now expect to live until her mid-80s, which implies living at least one-third of her life after menopause. The menopausal transition is typically marked by intense hormonal fluctuations, accompanied by vasomotor symptoms (eg, hot flashes, night sweats), sleeps disturbance, and changes in sexual function, as well as increased risk for osteoporosis, cardiovascular disease, and cognitive decline. More importantly, recent studies have demonstrated a significant association between menopausal transition and a higher risk for developing depression. In the post-Women's Health Initiative Study era, physicians and patients are questioning the safety and efficacy of long-term hormone therapy use. This article reviews the current literature on the benefits and risks of using hormone therapy for the treatment of menopause-related mood disturbances and alternate strategies currently available for the management of menopause-related problems, including antidepressants, complementary and alternative medicine, and selective estrogen receptor modulators.

Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause.

Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.