All Publications

  • Cognitive Effects of Hormone Therapy Continuation or Discontinuation in a Sample of Women at Risk for Alzheimer Disease. American journal of geriatric psychiatry Wroolie, T. E., Kenna, H. A., Williams, K. E., Rasgon, N. L. 2015; 23 (11): 1117-1126


    Use of estrogen-based hormone therapy (HT) as a protection from cognitive decline and Alzheimer disease (AD) is controversial, although cumulative data support HT use when initiated close to menopause onset with estrogen formulations containing 17β-estradiol preferable to conjugated equine estrogen formulations. Little is known regarding specific populations of women who may derive benefit from HT.Women with heightened risk for AD (aged 49-69), all of whom were taking HT for at least 1 year and most of whom initiated HT close to menopause onset, underwent cognitive assessment followed by randomization to continue or discontinue HT. Assessments were repeated at 2 years after randomization.Women who continued HT performed better on cognitive domains composed of measures of verbal memory and combined attention, working memory, and processing speed measures. Women who used 17β-estradiol versus conjugated equine estrogen, whether randomized to continue or discontinue HT, showed better verbal memory performance at the 2-year follow-up assessment. An interaction was also found with HT randomization and family history of AD in a first-degree relative. All female offspring of patients with AD declined in verbal memory; however, women who continued HT declined less than women who discontinued HT. Women without a first-degree relative with AD showed verbal memory improvement (likely because of practice effects) with continuance and declined with discontinuance of HT.Continuation of HT use appears to protect cognition in women with heightened risk for AD when initiated close to menopause onset.

    View details for DOI 10.1016/j.jagp.2015.05.009

    View details for PubMedID 26209223

    View details for PubMedCentralID PMC4654994

  • From Networking to Next-Working: How an Academic Department "Retreated" and Advanced at the Same Time ACADEMIC PSYCHIATRY Yager, J., Kenna, H., Hantke, M. 2015; 39 (2): 220-224


    Department-wide retreats conducted at periods of transition can enrich and benefit academic departments in several ways. Here, the authors describe the organization, conduct, and immediate outcomes of a department-wide retreat in a university department of psychiatry intended to (1) foster networking and communication among faculty who often work in "silos" and (2) invite the faculty to provide "internal consultations" regarding aspirational strategic goals and recommendations for short-term actionable tactics to address these goals. The retreat featured an evening networking and socializing poster session followed by a day-long event consisting of small group and large group interactive sessions. Participants were 120 faculty members including 44 new and younger faculty members who prepared and presented posters about themselves and their work. A variety of aspirational goals and specific recommendations for follow-up emerged from small groups were discussed in plenary sessions and were subsequently summarized and distributed to the faculty to be addressed by ongoing workgroups. Immediate informal feedback suggests that conducting and acting on recommendations ensuing from academic department retreats can foster at least a short-term sense of shared community and purpose, network faculty, identify commonly held values and aspirational goals, and potentially stimulate formation of innovative affinity groups and collaborations. Longer-term workgroup efforts and outcome assessments are required to assess the enduring results and value of such undertakings.

    View details for DOI 10.1007/s40596-014-0139-2

    View details for Web of Science ID 000351433800019

    View details for PubMedID 24789482

  • Lamotrigine and GABAA receptor modulators interact with menstrual cycle phase and oral contraceptives to regulate mood in women with bipolar disorder. Journal of affective disorders Robakis, T. K., Holtzman, J., Stemmle, P. G., Reynolds-May, M. F., Kenna, H. A., Rasgon, N. L. 2015; 175: 108-115


    To examine the occurrence of menstrually-entrained mood cycling in women with treated bipolar disorder as compared to healthy controls, and to explore whether there is a specific effect of lamotrigine in dampening menstrually-entrained cyclicity of mood.Observational comparison study of daily self-ratings of mood, sleep, and insomnia obtained over a mean of four menstrual cycles in 42 women with bipolar disorder taking lamotrigine as part of their treatment, 30 women with bipolar disorder receiving mood stabilizing regimens without lamotrigine, and 13 healthy controls, all with physiological menstrual cycles. Additional exploratory analysis of interactions between psychopharmacological regimen and hormonal contraceptive use in the group of women with bipolar disorder, with the addition of 19 women with bipolar disorder who were using hormonal contraceptives.Women treated for bipolar disorder manifested lower average mood, longer average nightly sleep duration, and greater fluctuations in mood and sleep across menstrual cycle phases than healthy controls. Women with bipolar disorder who were taking lamotrigine had less fluctuation in mood both within and across menstrual cycle phases, and were more similar to the control group than to women with bipolar disorder who were not taking lamotrigine in this respect. In addition, medications with GABA-A receptor modulating effects were found to result in improved mood ratings when combined with hormonal contraceptives.Menstrually-entrained mood fluctuation is present in women treated for bipolar disorder to a greater degree than in healthy controls. Lamotrigine may be of use in mitigating this fluctuation. GABA-A receptor modulators in general may act synergistically with hormonal contraceptives to enhance mood in women with bipolar disorder; this hypothesis merits further study.

    View details for DOI 10.1016/j.jad.2014.12.040

    View details for PubMedID 25601310

    View details for PubMedCentralID PMC4352404

  • Optimistic outlook regarding maternity protects against depressive symptoms postpartum ARCHIVES OF WOMENS MENTAL HEALTH Robakis, T. K., Williams, K. E., Crowe, S., Kenna, H., Gannon, J., Rasgon, N. L. 2015; 18 (2): 197-208


    The transition to motherhood is a time of elevated risk for clinical depression. Dispositional optimism may be protective against depressive symptoms; however, the arrival of a newborn presents numerous challenges that may be at odds with initially positive expectations, and which may contribute to depressed mood. We have explored the relative contributions of antenatal and postnatal optimism regarding maternity to depressive symptoms in the postnatal period. Ninety-eight pregnant women underwent clinician interview in the third trimester to record psychiatric history, antenatal depressive symptoms, and administer a novel measure of optimism towards maternity. Measures of depressive symptoms, attitudes to maternity, and mother-to-infant bonding were obtained from 97 study completers at monthly intervals through 3 months postpartum. We found a positive effect of antenatal optimism, and a negative effect of postnatal disconfirmation of expectations, on depressive mood postnatally. Postnatal disconfirmation, but not antenatal optimism, was associated with more negative attitudes toward maternity postnatally. Antenatal optimism, but not postnatal disconfirmation, was associated with reduced scores on a mother-to-infant bonding measure. The relationships between antenatal optimism, postnatal disconfirmation of expectations, and postnatal depression held true among primigravidas and multigravidas, as well as among women with prior histories of mood disorders, although antenatal optimism tended to be lower among women with mental health histories. We conclude that cautious antenatal optimism, rather than immoderate optimism or frank pessimism, is the approach that is most protective against postnatal depressive symptoms, and that this is true irrespective of either mood disorder history or parity. Factors predisposing to negative cognitive assessments and impaired mother-to-infant bonding may be substantially different than those associated with depressive symptoms, a finding that merits further study.

    View details for DOI 10.1007/s00737-014-0446-3

    View details for Web of Science ID 000351476400006

    View details for PubMedID 25088532

  • Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Sudheimer, K., Keller, J., Gomez, R., Tennakoon, L., Reiss, A., Garrett, A., Kenna, H., O'Hara, R., Schatzberg, A. F. 2015; 40 (4): 849-860


    Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

    View details for DOI 10.1038/npp.2014.259

    View details for PubMedID 25292261

    View details for PubMedCentralID PMC4330499

  • Association between insulin resistance and cognition in patients with depressive disorders: Exploratory analyses into age-specific effects JOURNAL OF PSYCHIATRIC RESEARCH Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72
  • Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects. Journal of psychiatric research Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72


    The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes.Clinical Trial NCT01106313.

    View details for DOI 10.1016/j.jpsychires.2014.10.001

    View details for PubMedID 25455511

  • Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy. Psychiatry research Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., DeMuth, B. N., Silverman, D. H. 2014; 223 (1): 28-36


    Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

    View details for DOI 10.1016/j.pscychresns.2014.04.004

    View details for PubMedID 24819305

  • Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., DeMuth, B. N., Silverman, D. H. 2014; 223 (1): 28-36
  • Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. Journal of psychiatric research Yuen, K. W., Garner, J. P., Carson, D. S., Keller, J., Lembke, A., Hyde, S. A., Kenna, H. A., Tennakoon, L., Schatzberg, A. F., Parker, K. J. 2014; 51: 30-36


    The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.

    View details for DOI 10.1016/j.jpsychires.2013.12.012

    View details for PubMedID 24405552

  • Blood levels of brain derived neurotrophic factor in women with bipolar disorder and healthy control women. Journal of affective disorders Kenna, H. A., Reynolds-May, M., Stepanenko, A., Ketter, T. A., Hallmayer, J., Rasgon, N. L. 2014; 156: 214-218


    Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

    View details for DOI 10.1016/j.jad.2013.01.054

    View details for PubMedID 24398043

  • Evaluation of reproductive function in women treated for bipolar disorder compared to healthy controls. Bipolar disorders Reynolds-May, M. F., Kenna, H. A., Marsh, W., Stemmle, P. G., Wang, P., Ketter, T. A., Rasgon, N. L. 2014; 16 (1): 37-47


    The purpose of the present study was to investigate the reproductive function of women with bipolar disorder (BD) compared to healthy controls.Women diagnosed with BD and healthy controls with no psychiatric history, aged 18-45 years, were recruited from a university clinic and surrounding community. Participants completed a baseline reproductive health questionnaire, serum hormone assessment, and ovulation tracking for three consecutive cycles using urine luteinizing hormone (LH)-detecting strips with a confirmatory luteal-phase serum progesterone.Women with BD (n = 103) did not differ from controls (n = 36) in demographics, rates of menstrual abnormalities (MAs), or number of ovulation-positive cycles. Of the women with BD, 17% reported a current MA and 39% reported a past MA. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone levels were higher in controls (p = 0.052 and 0.004, respectively), but there were no other differences in biochemical levels. Medication type, dose, or duration was not associated with MA or biochemical markers, although those currently taking an atypical antipsychotic agent indicated a greater rate of current or past MA (80% versus 55%, p = 0.013). In women with BD, 22% reported a period of amenorrhea associated with exercising or stress, versus 8% of controls (p = 0.064). Self-reported rates of bulimia and anorexia nervosa were 10% and 5%, respectively.Rates of MA and biochemical levels did not significantly differ between women with BD and controls. Current atypical antipsychotic agent use was associated with a higher rate of current or past MA and should be further investigated. The incidence of stress-induced amenorrhea should be further investigated in this population, as should the comorbid incidence of eating disorders.

    View details for DOI 10.1111/bdi.12149

    View details for PubMedID 24262071

  • Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PloS one Rasgon, N. L., Geist, C. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., Silverman, D. H. 2014; 9 (3)


    The objective of this study was to examine the effects of estrogen-based hormone therapy (HT) on regional cerebral metabolism in postmenopausal women (mean age = 58, SD = 5) at risk for development of dementia. The prospective clinical trial design included pre- and post-intervention neuroimaging of women randomized to continue (HT+) or discontinue (HT-) therapy following an average of 10 years of use. The primary outcome measure was change in brain metabolism during the subsequent two years, as assessed with fluorodeoxyglucose-18 positron emission tomography (FDG-PET). Longitudinal FDG-PET data were available for 45 study completers. Results showed that women randomized to continue HT experienced relative preservation of frontal and parietal cortical metabolism, compared with women randomized to discontinue HT. Women who discontinued 17-β estradiol (17βE)-based HT, as well as women who continued conjugated equine estrogen (CEE)-based HT, exhibited significant decline in metabolism of the precuneus/posterior cingulate cortical (PCC) area. Significant decline in PCC metabolism was additionally seen in women taking concurrent progestins (with either 17βE or CEE). Together, these findings suggest that among postmenopausal subjects at risk for developing dementia, regional cerebral cortical metabolism is relatively preserved for at least two years in women randomized to continue HT, compared with women randomized to discontinue HT. In addition, continuing unopposed 17βE therapy is associated specifically with preservation of metabolism in PCC, known to undergo the most significant decline in the earliest stages of Alzheimer's NCT00097058.

    View details for DOI 10.1371/journal.pone.0089095

    View details for PubMedID 24622517

    View details for PubMedCentralID PMC3951184

  • Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PloS one Rasgon, N. L., Geist, C. L., Kenna, H. A., Wroolie, T. E., Williams, K. E., Silverman, D. H. 2014; 9 (3)

    View details for DOI 10.1371/journal.pone.0089095

    View details for PubMedID 24622517

  • High Rates of Comorbid Depressive and Anxiety Disorders Among Women with Premutation of the FMR1 Gene AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS Kenna, H. A., Tartter, M., Hall, S. S., Lightbody, A. A., Quynh Nguyen, Q., de los Angeles, C. P., Reiss, A. L., Rasgon, N. L. 2013; 162 (8): 872-878
  • High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Kenna, H. A., Tartter, M., Hall, S. S., Lightbody, A. A., Nguyen, Q., de los Angeles, C. P., Reiss, A. L., Rasgon, N. L. 2013; 162 (8): 872-878


    Phenotypic variations are emerging from investigations of carriers of the fragile X mental retardation 1 (FMR1) premutation gene (55 to 200 CGG repeats). Initial studies suggest elevated psychiatric and reproductive system dysfunction, but have largely used self-reports for assessment of psychiatric history. The present study used diagnostic psychiatric interviews and assessed reproductive and menstrual history in women with FMR1 premutation. History of psychiatric diagnoses and data on reproductive functioning were collected in 46 women with FMR1 premutation who were mothers of at least one child with the fragile X full mutation. Results showed a significantly earlier age of menopause (mean age = 45.6 years) relative to the national average age of menopause (mean age = 51 years) and a high rate (76%) of lifetime depressive or anxiety history, with 43% of the overall sample reporting a comorbid history of both diagnoses. Compared to those free of psychiatric history, significantly longer premutation length was observed among women with psychiatric history after adjusting for age, with comorbid women having the highest number of CGG repeats (mean = 95.8) compared to women free of psychiatric history (mean = 79.9). Psychiatric history did not appear significantly related to reproductive system dysfunction, though results may have been obscured by the high rates of psychiatric dysfunction in the sample. These data add to the growing evidence base that women with the FMR1 premutation have an increased risk of psychiatric illness and risk for early menopause. Future investigations may benefit from inclusion of biochemical reproductive markers and longitudinal assessment of psychiatric and reproductive functioning. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.b.32196

    View details for PubMedID 24003006

  • Fasting plasma insulin and the default mode network in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Kenna, H., Hoeft, F., Kelley, R., Wroolie, T., Demuth, B., Reiss, A., Rasgon, N. 2013; 34 (3): 641-649


    Brain imaging studies in Alzheimer's disease research have demonstrated structural and functional perturbations in the hippocampus and default mode network (DMN). Additional evidence suggests risk for pathological brain aging in association with insulin resistance (IR). This study piloted investigation of associations of IR with DMN-hippocampal functional connectivity among postmenopausal women at risk for Alzheimer's disease. Twenty middle-aged women underwent resting state functional magnetic resonance imaging. Subjects were dichotomized relative to fasting plasma insulin levels (i.e., > 8 μIU/mL [n = 10] and < 8 μIU/mL [n = 10]), and functional connectivity analysis contrasted their respective blood oxygen level-dependent signal correlation between DMN and hippocampal regions. Higher-insulin women had significantly reduced positive associations between the medial prefrontal cortex and bilateral parahippocampal regions extending to the right hippocampus, and conversely, between the left and right hippocampus and medial prefrontal cortex. Neuropsychological data (all within normal ranges) also showed significant differences with respect to executive functioning and global intelligence. The results provide further evidence of deleterious effects of IR on the hippocampus and cognition. Further imaging studies of the IR-related perturbations in DMN-hippocampal functional connectivity are needed.

    View details for DOI 10.1016/j.neurobiolaging.2012.06.006

    View details for Web of Science ID 000313117900001

    View details for PubMedID 22770543

  • Accelerated Cell Aging in Female APOE-epsilon 4 Carriers: Implications for Hormone Therapy Use PLOS ONE Jacobs, E. G., Kroenke, C., Lin, J., Epel, E. S., Kenna, H. A., Blackburn, E. H., Rasgon, N. L. 2013; 8 (2)


    Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

    View details for DOI 10.1371/journal.pone.0054713

    View details for Web of Science ID 000315970300020

    View details for PubMedID 23418430

    View details for PubMedCentralID PMC3572118

  • Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use. PLoS One Jacobs, E., Kroenke, C., Lin, J., Epel, E., Kenna, H., Blackburn, E., Rasgon, N. 2013; 8 (2): e54713
  • Insulin resistance and hippocampal volume in women at risk for Alzheimer's disease NEUROBIOLOGY OF AGING Rasgon, N. L., Kenna, H. A., Wroolie, T. E., Kelley, R., Silverman, D., Brooks, J., Williams, K. E., Powers, B. N., Hallmayer, J., Reiss, A. 2011; 32 (11): 1942-1948


    Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-ε4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

    View details for DOI 10.1016/j.neurobiolaging.2009.12.005

    View details for Web of Science ID 000295220700003

    View details for PubMedID 20031276

    View details for PubMedCentralID PMC2891925

  • Differences in Verbal Memory Performance in Postmenopausal Women Receiving Hormone Therapy: 17 beta-Estradiol Versus Conjugated Equine Estrogens AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Khaylis, A., Rasgon, N. L. 2011; 19 (9): 792-802


    Much controversy exists and many questions remain unanswered about the effects of hormone therapy (HT) on cognition in postmenopausal women. There is growing evidence suggesting that HT compounds containing conjugated equine estrogen (CEE) have negative effects on cognition whereas 17β-estradiol (17β-E) either has positive or neutral effects. The present study sought to further examine this issue in a sample of postmenopausal women with risk factors for Alzheimer's disease (AD).Cross-sectional neuropsychological evaluation.Academic research clinic.68 healthy postmenopausal women (aged 49-68) receiving either 17β-E or CEE for at least one year with increased risk for AD.Neuropsychological test battery of the cognitive domains of attention/working memory/processing speed, verbal memory, visual memory, and executive functioning.Multivariate analyses of variance (MANOVA) showed significantly better verbal memory performance in women receiving 17β-E compared to women receiving CEE regardless of age, IQ, years of education, risk factors for AD (including APOE-ε4 carriership), duration of endogenous and exogenous estrogen exposure, concurrent progesterone use, or natural versus surgical menopause status.Verbal memory performance was better in postmenopausal women receiving 17β-E compared to CEE in a sample population of women with risk factors for AD. Genetic risk for AD as well as other confounds did not affect this finding. The results suggest a differential effect of HT type on verbal memory, with 17β-E being a preferential compound. Further evaluation of HT types, regimens and duration of use on cognitive performance in postmenopausal women in a controlled longitudinal design is warranted.

    View details for DOI 10.1097/JGP.0b013e3181ff678a

    View details for Web of Science ID 000294415800006

    View details for PubMedID 21873835

  • Gender-specific lipid profiles in patients with bipolar disorder JOURNAL OF PSYCHIATRIC RESEARCH Vemuri, M., Kenna, H. A., Wang, P. W., Ketter, T. A., Rasgon, N. L. 2011; 45 (8): 1036-1041


    High rates of dyslipidemia and insulin resistance (IR) are reported in patients with bipolar disorder (BD). We assessed gender effects upon rates of dyslipidemia/IR in outpatients with BD.Data from 491 outpatients (ages 18-88) seen in the Stanford Bipolar Disorders clinic between 2000 and 2007 were evaluated. Patients were followed longitudinally and received naturalistic treatment. BD patients (n = 234; 61% female; 42% Type I, 47% Type II, 11% NOS) with a mean age of 40.3 ± 14.0 years, mean BMI 26.8 ± 6.4, and 81% Caucasian, who had one of four lipid measures (total cholesterol, LDL, HDL, TG) at clinicians' discretion, a psychiatry clinic visit within 2 months of laboratory, and were not medicated for dyslipidemia were included. IR was imputed from TG/HDL ratio.Women, compared with men, had significantly lower mean triglycerides (105.58 ± 64.12 vs. 137.99 ± 105.14, p = 0.009), higher mean HDL cholesterol (60.17 ± 17.56 vs. 46.07 ± 11.91 mg/dl, p < 0.001), lower mean LDL cholesterol (109.84 ± 33.47 vs. 123.79 ± 35.96 mg/dl, p = 0.004), and lower TG/HDL ratio (1.98 ± 1.73 vs. 3.59 ± 3.14 p < 0.001). Compared to men, women had a significantly lower prevalence of abnormal total cholesterol, LDL, TG, HDL, and TG/HDL ratio. No significant differences were found between men and women with regard to age, BMI, ethnicity, educational attainment, smoking habits, bipolar illness type, illness severity or duration, or weight-liable medication exposure.In outpatients with BD, women had more favorable lipid profiles than men despite similar demographic variables. This sample of primarily Caucasian and educated patients, receiving vigilant clinical monitoring, may represent a relatively healthy psychiatric population demonstrating gender differences similar to those in the general population.

    View details for DOI 10.1016/j.jpsychires.2011.02.002

    View details for Web of Science ID 000293938900006

    View details for PubMedID 21377167

  • Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD PSYCHONEUROENDOCRINOLOGY Silverman, D. H., Geist, C. L., Kenna, H. A., Williams, K., Wroolie, T., Powers, B., Brooks, J., Rasgon, N. L. 2011; 36 (4): 502-513


    Differential cerebral metabolic effects of various hormone therapy formulations, and their associations with cognitive status, remain to be established. The principal aim of the current study was to assess relationships between regional cerebral metabolism and estrogen-based hormone therapies. Postmenopausal women (n=53) at elevated risk for Alzheimer's disease (AD) were on estrogen-containing hormone therapy for at least one year prior to enrollment in a prospective, randomized clinical trial. Subjects underwent an FDG-PET scan, along with neuropsychological, medical, and demographic assessments at time of enrollment, to be repeated one year following randomization to hormone therapy continuation versus discontinuation, and results from analyses of the baseline assessments are reported here. Across all subjects, years of endogenous estrogen exposure correlated most closely with metabolism in right superior frontal gyrus (p<0.0005). Women taking 17β-estradiol (E) performed three standard deviations higher in verbal memory than women taking conjugated equine estrogen (CEE), and their verbal memory performance positively correlated with metabolism in Wernicke's (p=0.003) and auditory association (p=0.002) areas. Women taking progesterone-plus-estrogen had lower metabolism than women taking unopposed estrogen within the mesial and inferior lateral temporal regions (p<0.0005) and the inferior frontal cortex, contralateral to Broca's area (p<0.0005). In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects.

    View details for DOI 10.1016/j.psyneuen.2010.08.002

    View details for Web of Science ID 000288922300008

    View details for PubMedID 20810219

    View details for PubMedCentralID PMC3021636

  • Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline Workshop on Window of Opportunity Lin, J., Kroenke, C. H., Epel, E., Kenna, H. A., Wolkowitz, O. M., Blackburn, E., Rasgon, N. L. ELSEVIER SCIENCE BV. 2011: 224–231


    Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized β=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized β=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.

    View details for DOI 10.1016/j.brainres.2010.10.033

    View details for Web of Science ID 000288844300022

    View details for PubMedID 20965155

    View details for PubMedCentralID PMC3057451

  • Psychiatric complications of treatment with corticosteroids: Review with case report PSYCHIATRY AND CLINICAL NEUROSCIENCES Kenna, H. A., Poon, A. W., de los Angeles, C. P., Koran, L. M. 2011; 65 (6): 549-560


    Corticosteroids are widely used in modern medicine but can result in troubling psychiatric side-effects. Physicians and other medical professionals should be aware of the potential for these side-effects, possible means of prevention, and efficacious treatments. Herein, we review adult case report data published during the past quarter-century on adverse corticosteroid-induced psychiatric effects, and present a case of corticosteroid-induced psychotic depression. PubMed and PsychLit databases were searched using the terms 'corticosteroids', 'steroids', and the generic names of corticosteroid medications with terms for psychiatric symptoms or syndromes, including psychosis, mania, hypomania, depression, apathy, anxiety, panic, depersonalization, delirium, confusion, hallucinations, delusions, paranoia, cognitive impairment and dementia. Fifty-five cases and a number of clinical trials investigating the incidence and treatment of these psychiatric symptoms and syndromes were identified. Data on incidence, drug dose, risk factors, course of illness and treatment (when present) were tabulated. We conclude that the cumulative data indicate that psychiatric complications of corticosteroid treatment are not rare and range from clinically significant anxiety and insomnia, to severe mood and psychotic disorders, delirium and dementia. While tapering or discontinuation of the corticosteroid treatment may remedy these adverse side-effects, psychotropic medications are often required because of the medical necessity of the corticosteroid or the severity of the psychiatric symptom. Further studies are needed to better understand the deleterious psychiatric effects associated with corticosteroids.

    View details for DOI 10.1111/j.1440-1819.2011.02260.x

    View details for Web of Science ID 000296045500002

    View details for PubMedID 22003987

  • Metabolic dysfunction in women with bipolar disorder: the potential influence of family history of type 2 diabetes mellitus BIPOLAR DISORDERS Rasgon, N. L., Kenna, H. A., Reynolds-May, M. F., Stemmle, P. G., Vemuri, M., Marsh, W., Wang, P., Ketter, T. A. 2010; 12 (5): 504-513


    Overweight/obesity, insulin resistance (IR), and other types of metabolic dysfunction are common in patients with bipolar disorder (BD); however, the pathophysiological underpinnings of metabolic dysfunction in BD are not fully understood. Family history of type 2 diabetes mellitus (FamHxDM2), which has been shown to have deleterious effects on metabolic function in the general population, may play a role in the metabolic dysfunction observed in BD.Using multivariate analysis of variance, the effects of BD illness and/or FamHxDM2 were examined relative to metabolic biomarkers in 103 women with BD and 36 healthy, age-matched control women.As a group, women with BD had higher levels of fasting plasma insulin (FPI) and fasting plasma glucose (FPG), higher homeostatic assessment of IR (HOMA-IR) scores, body mass index (BMI), waist circumference (WC), and hip circumference (HC) compared to control women. FamHxDM2 was associated with significantly worse metabolic biomarkers among women with BD but not among healthy control women. Among women with BD, there was a significant main effect of FamHxDM2 on FPI, HOMA-IR, BMI, WC, and HC, even after controlling for type of BD illness, duration of medication exposure, and depression severity. Metabolic biomarkers were not influenced by use of weight-liable psychotropic medication (WLM), even after controlling for type of BD illness, duration of medication exposure, and depression severity.Women with BD have overall worse metabolic biomarkers than age-matched control women. The use of WLM, duration of medication use, type of BD illness, and depression severity did not appear to be associated with more pronounced metabolic dysfunction. FamHxDM2 may represent a risk factor for the development of IR in women with BD. Further, focused studies of the endocrine profiles of families of BD patients are needed.

    View details for DOI 10.1111/j.1399-5618.2010.00839.x

    View details for Web of Science ID 000280987800005

    View details for PubMedID 20712751

    View details for PubMedCentralID PMC2941396

  • Preliminary evidence that plasma oxytocin levels are elevated in major depression PSYCHIATRY RESEARCH Parker, K. J., Kenna, H. A., Zeitzer, J. M., Keller, J., Blasey, C. M., Amico, J. A., Schatzberg, A. F. 2010; 178 (2): 359-362


    It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.

    View details for DOI 10.1016/j.psychres.2009.09.017

    View details for Web of Science ID 000279988900025

    View details for PubMedID 20494448

    View details for PubMedCentralID PMC2902664

  • Brain volume abnormalities and neurocognitive deficits in diabetes mellitus: Points of pathophysiological commonality with mood disorders? ADVANCES IN THERAPY McIntyre, R. S., Kenna, H. A., Nguyen, H. T., Law, C. W., Sultan, F., Woldeyohannes, H. O., Alsuwaidan, M. T., Soczynska, J. K., Adams, A. K., Cheng, J. S., Lourenco, M., Kennedy, S. H., Rasgon, N. L. 2010; 27 (2): 63-80


    It is hypothesized that diabetes mellitus (DM) and mood disorders share points of pathophysiological commonality in the central nervous system.A PubMed search of all English-language articles published between 1966 and March 2009 was performed with the following search terms: depression, mood disorders, hippocampus, amygdala, central nervous system, brain, neuroimaging, volumetric, morphometric, and neurocognitive deficits, cross-referenced with DM. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. The primary author was principally responsible for adjudicating the merit of articles that were included.Volumetric studies indicate that individuals with Type 1/2 DM exhibit regional abnormalities in both cortical and subcortical (e.g., hippocampus, amygdala) brain structures. The pattern of neurocognitive deficits documented in individuals with Type 1 DM overlap with Type 2 populations, with suggestions of discrete abnormalities unique to each phenotype. The pattern of volumetric and neurocognitive deficits in diabetic populations are highly similar to that reported in populations of individuals with major depressive disorder.The prevailing models of disease pathophysiology in DM and major depressive disorder are distinct. Notwithstanding, the common abnormalities observed in disparate effector systems (e.g., insulin resistance, immunoinflammatory activation) as well as brain volume and neurocognitive performance provide the nexus for hypothesizing that both conditions are subserved by overlapping pathophysiology. This conception provides a novel framework for disease modeling and treatment development in mood disorder.

    View details for DOI 10.1007/s12325-010-0011-z

    View details for Web of Science ID 000277095200001

    View details for PubMedID 20390390

  • Rosiglitazone Add-On in Treatment of Depressed Patients with Insulin Resistance: a Pilot Study THESCIENTIFICWORLDJOURNAL Rasgon, N. L., Kenna, H. A., Williams, K. E., Powers, B., Wroolie, T., Schatzberg, A. F. 2010; 10: 321-328


    A number of cross-sectional studies have suggested an association between insulin resistance (IR) and affective disorders. However, limited data exist on potential changes in IR in a prospective treatment of depression. The present pilot study tested the hypothesis that improvement of IR with the addition of an insulin-sensitizing agent would improve mood in nondiabetic patients with unipolar or bipolar depression, who had surrogate blood markers suggestive of IR. Surrogate IR-criteria blood markers were fasting plasma glucose >100 mg/dl or triglyceride (TG) to high density lipoprotein (HDL) ratio >3.0. Open-label rosiglitazone, titrated to a dose of 8 mg/day, was administered for 12 weeks to 12 patients with depressive disorder receiving treatment as usual (TAU). Eight patients who completed the 12-week study exhibited significant declines in both depression severity by the Hamilton Depression Rating Scale and the Clinical Global Impression scale, with moderate effect sizes noted. Modest improvement in Matsuda Index scores was also noted at 12 weeks, yet declines in depression severity scores were not associated with improvements in the endocrine markers (Matsuda Index, TG/HDL ratio, and body mass index). These results suggest the potential novel use for an insulin-sensitizing agent in the treatment of depressive disorders. Larger placebo-controlled studies are warranted.

    View details for DOI 10.1100/tsw.2010.32

    View details for Web of Science ID 000274935000007

    View details for PubMedID 20191245

  • Genetic overlap between polycystic ovary syndrome and bipolar disorder: The endophenotype hypothesis MEDICAL HYPOTHESES Jiang, B., Kenna, H. A., Rasgon, N. L. 2009; 73 (6): 996-1004


    Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.

    View details for DOI 10.1016/j.mehy.2008.12.056

    View details for Web of Science ID 000272923000032

    View details for PubMedID 19556071

  • Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study ACTA NEUROLOGICA SCANDINAVICA Wroolie, T. E., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M., Lazzeroni, L., Rasgon, N. L. 2009; 119 (3): 172-179


    To determine the effects of memantine on cognition in a normal population of postmenopausal women with putative risk factors for Alzheimer's disease (AD) using a built-in control for the genetic risk factor for AD (apoE-epsilon4 status).A prospective, open-label, 6-month pilot medication trial with memantine and follow-up after discontinuance conducted at the Center for Neuroscience in Women's Health, Stanford University School of Medicine. Neuropsychological data were collected on 22 community-dwelling postmenopausal women (11 apoE-epsilon4 carriers and 11 apoE-epsilon4 non-carriers) with at least one putative risk factor for AD.ApoE-epsilon4 status was not a significant predictor of change in neuropsychological performance. Changes associated with memantine treatment for entire sample included significant declines in some variables associated with verbal learning and memory that improved upon medication withdrawal. A positive medication effect was noted with executive functions and possibly category fluency. Trend-level improvements were seen in motor dexterity of the non-dominant hand and maintained even after drug discontinuance.Treatment with memantine appeared to have differential effects on cognitive performance in a population of women with putative risk factors for AD. ApoE-epsilon4 carrier status did not account for observed changes in cognition.

    View details for DOI 10.1111/j.1600-0404.2008.01084.x

    View details for Web of Science ID 000262949100005

    View details for PubMedID 18705678

  • Thalamo-Basal Ganglia Connectivity in Postmenopausal Women Receiving Estrogen Therapy NEUROCHEMICAL RESEARCH Kenna, H. A., Rasgon, N. L., Geist, C., Small, G., Silverman, D. 2009; 34 (2): 234-237


    Cumulative data on the effects of estrogen therapy (ET) on brain function in postmenopausal women suggests that ET influences cerebral metabolism and may protect against age-related declines in various domains of cognitive function. The beneficial cognitive effects of ET may relate to its modulation of the thalamic-striatum cholinergic and dopaminergic systems, as the activity of both neurotransmitter systems in the thalamus appears to be positively influenced by estrogen. In the current study, we attempted to evaluated regional cerebral brain metabolism utilizing [18F]-fluorodeoxyglucose positron emission tomography in 11 healthy recently-postmenopausal women on ET (ET+) in comparison to 11 recently-postmenopausal and ET-naïve women (ET-) in order to assess the effects of ET on cholinergic and dopaminergic system regulation. Results showed thalamo-basal ganglia connectivity among ET+ women but not among ET- women. The presence of connectivity in the thalamo-striatal pathway in recently postmenopausal women suggests estrogen effects in preserving integrity of the cholinergic and dopaminergic systems. The results also suggest that ET initiated at or near the menopausal transition may modulate brain aging by mediating complex sensory-motor functions.

    View details for DOI 10.1007/s11064-008-9756-z

    View details for Web of Science ID 000262811300005

    View details for PubMedID 18535904

  • Reproductive and Metabolic Abnormalities Associated with Bipolar Disorder and Its Treatment HARVARD REVIEW OF PSYCHIATRY Kenna, H. A., Jiang, B., Rasgon, N. L. 2009; 17 (2): 138-146


    Women with mood disorders, especially bipolar disorder (BD), have been shown to have high rates of reproductive and metabolic dysfunction. The available data on the functional, anatomic, and clinical neuroendocrine abnormalities in women with BD suggest a two-tiered relationship with mood pathology. First, many of the medications commonly used in the treatment of BD can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. Studies that have specifically addressed the association between psychotropic medications and menstrual abnormalities, polycystic ovary syndrome, and overall reproductive endocrine function in women with BD have found high rates of HPG irregularities in women with BD. Second, there is evidence of reproductive dysfunction in women with BD prior to treatment. In addition, many of the psychotropic medications used in the treatment of BD are associated with weight gain, insulin resistance, and dyslipidemia. These metabolic side effects further compound the neuroendocrine system dysregulation in women with BD. Current understanding of the reproductive and metabolic function in women with BD points to vulnerability, which in turn increases the risk of later-life cardiovascular disease and diabetes, among other morbidities, for women with BD.

    View details for DOI 10.1080/10673220902899722

    View details for Web of Science ID 000265294600006

    View details for PubMedID 19373621

  • Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder PSYCHIATRY RESEARCH-NEUROIMAGING Rasgon, N. L., Kenna, H. A., Geist, C., Small, G., Silverman, D. 2008; 164 (1): 77-80


    Cerebral metabolic rates were assessed using [(18)F]-fluorodeoxyglucose positron emission tomography in six naturally postmenopausal women with untreated unipolar depression and 11 matched controls. All subjects were hormone therapy-naive and medication-free. Findings include hypermetabolism in the middle frontal gyrus and Broca regions, and hypometabolism in the pons among depressed compared with non-depressed women.

    View details for DOI 10.1016/j.psychresns.2007.12.006

    View details for Web of Science ID 000261023800007

    View details for PubMedID 18707852

  • Resting-state functional connectivity in major depression: Abnormally increased contributions from subgenual cingulate cortex and thalamus BIOLOGICAL PSYCHIATRY Greicius, M. D., Flores, B. H., Menon, V., Glover, G. H., Solvason, H. B., Kenna, H., Reiss, A. L., Schatzberg, A. F. 2007; 62 (5): 429-437


    Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls.Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity.Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate.This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

    View details for DOI 10.1016/j.biopsych.2006.09.020

    View details for Web of Science ID 000249042800009

    View details for PubMedID 17210143

  • Hypothalamic-pituitary-end organ function in women with bipolar depression 61st Annual Convention of the Society-of-Biological-Psychiatry Rasgon, N. L., Kenna, H. A., Wong, M., Whybrow, P. C., Bauer, M. PERGAMON-ELSEVIER SCIENCE LTD. 2007: 279–86


    Disturbance of each of the three hypothalamic-pituitary-end organ systems [hypothalamic-pituitary-thyroid (HPT), -adrenal (HPA), and -gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900 h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15 min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples.

    View details for DOI 10.1016/j.psyneuen.2006.12.014

    View details for Web of Science ID 000245741300007

    View details for PubMedID 17317022

  • Dissociable intrinsic connectivity networks for salience processing and executive control JOURNAL OF NEUROSCIENCE Seeley, W. W., Menon, V., Schatzberg, A. F., Keller, J., Glover, G. H., Kenna, H., Reiss, A. L., Greicius, M. D. 2007; 27 (9): 2349-2356


    Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a "salience network," anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an "executive-control network" that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

    View details for DOI 10.1523/JNEUROSCI.5587-06.2007

    View details for Web of Science ID 000244758500023

    View details for PubMedID 17329432

  • The neuropsychological profile of psychotic major depression and its relation to cortisol BIOLOGICAL PSYCHIATRY Gomez, R. G., Fleming, S. H., Keller, J., Flores, B., Kenna, H., DeBattista, C., Solvason, B., Schatzberg, A. F. 2006; 60 (5): 472-478


    Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits.Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained.PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory.While PMDs' ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory.

    View details for DOI 10.1016/j.biopsych.2005.11.010

    View details for Web of Science ID 000240506000007

    View details for PubMedID 16483550

  • Cortisol circadian rhythm alterations in psychotic major depression BIOLOGICAL PSYCHIATRY Keller, J., Flores, B., Gomez, R. G., Solvason, H. B., Kenna, H., Williams, G. H., Schatzberg, A. F. 2006; 60 (3): 275-281


    Increased hypothalamic-pituitary-adrenal axis activity is well described in psychotic depression with an emphasis on 24-hour, urinary free cortisol levels or dexamethasone suppression tests. There are limited data on cortisol levels during specific times of the day.Patients with depression with (PMD) and without (NPMD) psychosis and healthy control subjects were studied using rating scales of depression and psychosis and measures of HPA activity, including overnight cortisol and adrenocorticotropin levels. We used analysis of variance to determine group differences and regression analyses to assess contributions of specific measures to cortisol levels.PMDs had higher cortisol during the evening hours than did NPMDs or control subjects, who did not differ from one another. Regression analyses suggest that depression and the combination of depressive and psychotic symptoms were important contributors to variance in evening cortisol.PMD is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing's syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.

    View details for DOI 10.1016/j.biopsych.2005.10.014

    View details for Web of Science ID 000239543800009

    View details for PubMedID 16458262

  • Mood and neuropsychological changes in women with midlife depression treated with escitalopram JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Wroolie, T. E., Williams, K. E., Keller, J., Zappert, L. N., Shelton, S. D., Kenna, H. A., Reynolds, M. F., Rasgon, N. L. 2006; 26 (4): 361-366


    This study assessed mood and neuropsychological function in a population of middle-aged women with major depressive disorder treated with escitalopram.Psychometric data measuring severity of depression were collected from 19 women and neuropsychological data were collected from 17 women aged between 45 and 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depression in a study in the Behavioral Neuroendocrinology Program at the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine. All women were treated with escitalopram in an open-label design. Mean age was 55.94 years and mean number of years of education was 16.36 years. Diagnosis of major depressive disorder was assessed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and mood was evaluated with the 21-item Hamilton Depression Rating Scale (HAM-D) at baseline and at weekly follow-ups for 12 weeks. Cognition was assessed at baseline and 3 months after treatment using a neuropsychological test battery, which included an abbreviated measure of Full Scale Intelligence Quotient, measures of attention and processing speed, verbal and nonverbal memory, executive functioning, and verbal fluency. Self-report data were collected on current menopause status and current hormone therapy use in the postmenopausal women. Paired sample t tests were used to analyze the change in total HAM-D scores and neuropsychological variables.Statistically significant improvements were found in total HAM-D score, Wechsler Memory Scale III Logical Memory 1st Recall, I, and II scores, Wechsler Memory Scale III Visual Reproduction I scores, and Trail Making Test Part B scores. There was a statistically significant decrease in Controlled Oral Word Association Test FAS scores.Treatment of depression with escitalopram in a population of middle-aged women was shown to improve mood and cognitive efficiency in complex attention, short- and long-term recall of contextual information, short-term recall of visual information, and cognitive flexibility; however, it was shown to worsen phonemic fluency.

    View details for DOI 10.1097/

    View details for Web of Science ID 000239551200003

    View details for PubMedID 16855452

  • Clinical and biological effects of mifepristone treatment for psychotic depression NEUROPSYCHOPHARMACOLOGY Flores, B. H., Kenna, H., Keller, J., Solvason, H. B., Schatzberg, A. F. 2006; 31 (3): 628-636


    Psychotic major depression (PMD) is found to be a relatively common psychiatric condition that affects up to nearly 20% of patients with major depression. Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone, in addition to restoring a more normal afternoon cortisol release. The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed. In total, 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a randomized double-blind manner. The Hamilton Depression Rating Scale (HDRS) and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment. Significantly, more patients in the mifepristone group (seven of 15) showed a 50% or greater decline on the BPRS positive symptom subscale, an index of psychotic symptoms, as compared to the placebo group (two of 15). Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo, but these differences were not statistically significant. In addition, mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo. Clinical and biological effects of mifepristone were comparable among males and females. Age was found to significantly and positively correlate with changes in cortisol and ACTH. These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may re-regulate the HPA axis. Additional blinded studies are warranted.

    View details for DOI 10.1038/sj.npp.1300884

    View details for Web of Science ID 000236141600015

    View details for PubMedID 16160710

  • Detecting psychotic major depression using psychiatric rating scales JOURNAL OF PSYCHIATRIC RESEARCH Keller, J., Gomez, R. G., Kenna, H. A., Poesner, J., Debattista, C., Flores, B., Schatzberg, A. F. 2006; 40 (1): 22-29


    The aim of this study was to assess whether individual or clusters of psychiatric symptoms can differentiate patients with psychotic major depression (PMD) from those with nonpsychotic depression (NPMD).Data were pooled from two studies investigating patients with moderate depression. A total of 129 subjects were studied. Patients in Sample 1 were unmedicated, while the majority of the patients in Sample 2 were taking psychotropic medications. Baseline rating scales were obtained for all subjects, including the Hamilton depression rating scale and the brief psychiatric rating scale (BPRS). We used discriminant function analyses, logistic regression, and ROC analyses to determine the patterns in symptoms that differentiated the groups.Psychotic patients were adequately differentiated by the unusual thought content (UTC) item of the BPRS. Even mild UTC endorsement was an indicator of PMD. Furthermore, results suggest that the positive symptom subscale of the BPRS was even better at differentiating PMD from NMPD patients. Sensitivity and specificity for this scale were 84% and 99%, respectively.Psychotic major depression is often undiagnosed and poorly treated. One reason for this trend is the failure of physicians to inquire in a more detailed manner about positive symptoms in patients with primary mood symptoms. Although physicians are not likely to have the time to conduct an entire BPRS during an evaluation, our results suggest that a few key symptoms, if assessed directly, may aid the psychiatrist to more effectively diagnose and subsequently treat their depressed patients.

    View details for DOI 10.1016/j.jpsychires.2005.07.003

    View details for Web of Science ID 000235466200002

    View details for PubMedID 16165160

  • Insulin resistance in depressive disorders and Alzheimer's disease: Revisiting the missing link hypothesis SPARK Workshop 2004 Rasgon, N. L., Kenna, H. A. ELSEVIER SCIENCE INC. 2005: S103–S107
  • Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis. Neurobiology of aging Rasgon, N. L., Kenna, H. A. 2005; 26: 103-107


    Several lines of evidence suggest an association between depressive disorders and Alzheimer's disease (AD). We previously suggested central nervous system (CNS) effects of insulin resistance (IR) to be an important link between depressive disorders and AD. Although the exact mechanism of central IR is not known, it is thought that central IR results in inadequate glucose metabolism in the brain. According to our hypothesis, inadequate glucose utilization resulting from IR underlies neuronal changes in crucial brain regions (i.e. limbic system) observed among patients with depressive disorders, the same brain regions affected in AD. Further, in patients with undetected and/or untreated IR, such changes in glucose utilization, if unresolved, may lead to neurodegeneration. Our studies have demonstrated a high prevalence of IR in patients with depressive disorders, and reciprocally, a high prevalence of depression in patients with the primary IR disorder polycystic ovary syndrome (PCOS), and we believe these populations have significantly increased risk of cognitive decline. Herein, we review the IR link in depressive disorders and AD and describe the results of our studies and others in support of this hypothesis.

    View details for PubMedID 16225963