Dr. Jennifer Keller is a clinical psychologist who specializes in the assessment of psychiatric conditions. She conducts evaluations for adults on a wide-variety of conditions, including attention deficits (ADHD), cognitive and memory changes or impairments, mood and anxiety disorders, thought disorders, and effects of trauma. She has practiced as a psychologist for more than 15 years. Dr. Keller has a special interest in working with women with interpersonal trauma.
Clinical Associate Professor, Psychiatry and Behavioral Sciences
Boards, Advisory Committees, Professional Organizations
Research Professor, Palo Alto University (2009 - Present)
Board Member, No Means No Worldwide (2013 - Present)
Advisor, WOMEN SV (2012 - Present)
PhD Training:University of Illinois Department of Psychology (1999) IL
Fellowship:Stanford University School of Medicine Registrar (2001) CA
Internship:VA Medical Center Palo Alto (2000) CA
Ph.D., U of Illinois Urbana-Champaign, Clinical Psychology (1999)
Community and International Work
Family Health and Well-being, India
Opportunities for Student Involvement
Empowerment of Adolescent girls
Skills for safety and healthy living
Notre Dame San Jose
Opportunities for Student Involvement
Life Skills and Physical Empowerment Training in Women with a history of Interpersonal Trauma, Stanford
Interpersonal Trauma and abuse; skills training
Opportunities for Student Involvement
Expression of Mental Health Symptoms in Pakistan, Pakistan
Mental health and treatment
Aga Khan University
Opportunities for Student Involvement
Current Research and Scholarly Interests
My current work focuses on the prevention and intervention of interpersonal violence and abuse in women. Recent research from the CDC (2011) finds that 1 in 5 women in the U.S. experience rape in their lifetime and more than 1 in 3 women experience violence from a partner. Recent estimates put the cost of childhood violence on par with medical conditions such as diabetes and stroke (Fang, 2012). Much of this abuse is preventable. The toll of interpersonal violence on women includes reduced psychological, interpersonal, physical, occupational, and economic functioning; all of which reduce her quality of life. We are researching an adjunctive therapeutic class which provides psychoeducation, psychological skill development, and physical empowerment training to women who have a history of interpersonal trauma. In addition, we are piloting a program to promote positive health behaviors, personal safety, and empowerment for adolescent girls, partnering with a local high school.
The plight of women is even more severe in other parts of the world. Over the last few years, I have been developing several collaborations with researchers and Non-Governmental Organizations (NGOs) in South Asia, including India and Pakistan. I have begun working with a non-profit in Kenya to examined the efficacy of their girls empowerment program as well. Collectively, our vision is to improve the status of women in these countries, focusing on womens mental health and the prevention of violence.
I am also very interested in the biological links between interpersonal trauma and depression. Several studies have suggested relationships between dysfunctional hypothalamic-pituitary adrenal (HPA) activity and trauma, as well as distinct links between HPA dysfunction and depression. Previous research suggests that early life stress makes the HPA axis more stress reactive and therefore leads to dysfunction in cognition, cortisol, and even brain volume. We are examining these relationships between trauma, depression, cognition, and biological factors, including HPA activity, genetic expression, and brain structure and function.
Identifying Biological Markers for Severe Depression
The primary objective of this study is to investigate the biological components of major depression. The investigators are particularity interested in genetic variation and how it contributes to cortisol (because cortisol is higher in severe depression than mild depression or healthy controls) and how it contributes to clinical symptoms, especially suicidal ideation/behavior and psychosis.
Clinical and Biological Characteristics of Psychotic Depression
The primary objective of this study is to investigate the relationships among findings in structural and functional neuroimaging, cognitive testing and HPA (hypothalamic-pituitary-adrenal) axis dysregulation in psychotic depression.
Stanford is currently not accepting patients for this trial. For more information, please contact Lakshika Tennakoon, 650-723-3305.
Effects of Growth Hormone on Cognition and Cerebral Metabolism in Adults With Growth Hormone Deficiency
Patients with Growth hormone (GH) deficiency often report impaired quality of life and difficulty with mental functioning. It has been suggested that GH replacement in such patients leads to improvement in cognitive function. The aim of this study is to elucidate the effects of GH replacement in patients with GH deficiency on cognitive function using structural and functional neuroimaging and cognitive testing.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurence Katznelson, MD, 650-721-1020.
Imaging the Nucleus Accumbens in Major Depressed Patients 'Treated With Pramipexole
We hope to learn how a brain circuit that is important to the understanding of depression, anhedonia and positive affect responds to a novel pharmaceutical treatment for depression and related symptoms. Adults who have a diagnosis of major depression and are not completely responsive to antidepressant medication will be sought out for participation; as will an equal number of adults not suffering from the disorder. Those suffering from depression will be given pramipexole, an investigational medication for eight weeks during which information will be collected about mood, cognition, and brain function. Adults not suffering from depression will also be evaluated with these measures.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Keller, PHD, 650-724-0070.
Self-Defense Training in Women With Trauma
Previous research has shown that self-defense training can lead to gains in women's assertiveness, self-esteem, self-efficacy, and physical competence, and decreases in anxiety, helplessness, fear, and avoidant behaviors. However, most of this research has been conducted with healthy women who had not previously experienced physical or sexual violence. The investigators believe that women with such trauma histories require additional care because of potential triggering symptoms. As such, the investigators are mindful of the potential for triggering trauma symptoms and will work with the women so that they feel safe and comfortable in their participation. This pilot study aims to examine whether similar psychological gains from self-defense training are made in women who have previous experiences of physical and/or sexual violence.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Keller, (650) 724 - 0070.
Treatment of Schizoaffective Disorder Using Mifepristone
This study tests the hypothesis that mifepristone will diminish cognitive distortion and alleviate psychosis in patients with schizoaffective disorder.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
- A 6-Week School Curriculum Improves Boys' Attitudes and Behaviors Related to Gender-Based Violence in Kenya JOURNAL OF INTERPERSONAL VIOLENCE 2017; 32 (4): 535-557
Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways.
Journal of psychiatric research
2013; 47 (10): 1319-1328
Anhedonia is the inability to experience pleasure from normally pleasant stimuli. Although anhedonia is a prominent feature of many psychiatric disorders, trait anhedonia is also observed dimensionally in healthy individuals. Currently, the neurobiological basis of anhedonia is poorly understood because it has been mainly investigated in patients with psychiatric disorders. Thus, previous studies have not been able to adequately disentangle the neural correlates of anhedonia from other clinical symptoms. In this study, trait anhedonia was assessed in well-characterized healthy participants with no history of Axis I psychiatric illness. Functional magnetic resonance imaging with musical stimuli was used to examine brain responses and effective connectivity in relation to individual differences in anhedonia. We found that trait anhedonia was negatively correlated with pleasantness ratings of music stimuli and with activation of key brain structures involved in reward processing, including nucleus accumbens (NAc), basal forebrain and hypothalamus which are linked by the medial forebrain bundle to the ventral tegmental area (VTA). Brain regions important for processing salient emotional stimuli, including anterior insula and orbitofrontal cortex were also negatively correlated with trait anhedonia. Furthermore, effective connectivity between NAc, VTA and paralimbic areas, that regulate emotional reactivity to hedonic stimuli, was negatively correlated with trait anhedonia. Our results indicate that trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and related limbic and paralimbic systems involved in reward processing. Critically, this association can be detected even in individuals without psychiatric illness. Our findings have important implications both for understanding the neurobiological basis of anhedonia and for the treatment of anhedonia in psychiatric disorders.
View details for DOI 10.1016/j.jpsychires.2013.05.015
View details for PubMedID 23791396
Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression
AMERICAN JOURNAL OF PSYCHIATRY
2008; 165 (7): 872-880
The limbic system is thought to underlie dysfunctional affective and cognitive processes in individuals with depression. Neuroanatomical studies of subjects with depression have often examined hippocampal and amygdalar structures, since they are two key structures of the limbic system. Research has often but not always found reduced hippocampal volume in patients with major depression. The purpose of the present study was to examine differences in hippocampal and amygdalar volumes in patients with depression subtypes relative to healthy comparison subjects.Participants were 1) patients with major depression with psychosis, 2) patients with major depression without psychosis, and 3) healthy comparison subjects. To examine hippocampal and amygdalar volumes, all participants underwent structural magnetic resonance imaging (MRI). The authors further examined the effects of clinical and chronicity data on these two brain structures.After age, gender, and total brain volume were controlled, depressed patients with psychosis had a significantly smaller mean amygdala volume relative to depressed patients without psychosis and healthy comparison subjects. There were no differences between depressed patients without psychosis and healthy comparison subjects. Correlational analyses suggested that age of depression onset was strongly associated with amygdala volume. No group differences in hippocampal volume were found.There were no differences between depressed patients and healthy comparison subjects in hippocampal volume. However, psychotic but not nonpsychotic depression was associated with reduced amygdala volume. Reduced amygdala volume was not associated with severity of depression or severity of psychosis but was associated with age at onset of depression. Smaller amygdala volume may be a risk factor for later development of psychotic depression. In addition, chronicity of depression and depression subtype might be two important factors associated with hippocampal and amygdalar volumes in depression.
View details for DOI 10.1176/appi.ajp.2008.07081257
View details for Web of Science ID 000257320100016
View details for PubMedID 18450931
View details for PubMedCentralID PMC3733673
Cortisol circadian rhythm alterations in psychotic major depression
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
High-Dose Spaced Theta-Burst Transcranial Magnetic Stimulation as a Rapid-Acting Anti- Depressant in Highly Refractory Depression
ELSEVIER SCIENCE INC. 2018: S191
View details for Web of Science ID 000432466300476
- High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain : a journal of neurology 2018
Corticotropin-releasing factor 1 receptor haplotype and cognitive features of major depression.
2018; 8 (1): 5
Corticotropin-releasing factor signaling through CRF receptor type 1 (CRF1) has been shown to contribute to learning and memory function. A haplotype of alleles T-A-T in a set of common polymorphisms in the gene encoding for CRF1(CRHR1) has been associated with both depression vulnerability and alterations in cognitive functioning. The present study investigated the relations between the TAT haplotype and specific symptoms of depression, self-reported ruminative behaviors, and neuropsychological performance on a learning and memory task. Participants were adults with major depression with and without psychotic features (N = 406). Associations were examined between TAT haplotype and endorsement of depression symptoms from diagnostic interviews, scores on the rumination response scale (RRS), and verbal memory performance on the California Verbal Learning Test-II (CVLT-II). All analyses included depression subtype, age, and sex as covariates; CVLT-II analyses also included evening cortisol levels. Across the entire sample, carriers of more copies of the TAT haplotype reported greater endorsement of the symptom describing difficulty concentrating and making decisions. In separate subsamples, TAT homozygotes had higher rumination scores on the RRS, both brooding and reflection subscales, and more TAT copies were associated with poorer CVLT-II performance in both total learning and free recall trials. These data demonstrate that the CRHR1 TAT haplotype is associated with cognitive features of depression including difficulty with decision-making, higher rumination, and poorer learning and memory. It will be important in future research to identify the specific molecular mechanisms for CRF1signaling that contribute to depression-related cognitive dysfunction.
View details for DOI 10.1038/s41398-017-0051-0
View details for PubMedID 29317606
View details for PubMedCentralID PMC5802461
Increased Intra-Limbic Functional Connectivity to Insula, Thalamus, Caudate, Putamen, and Cingulate Cortex in Patients With Major Depression
NATURE PUBLISHING GROUP. 2017: S172–S173
View details for Web of Science ID 000416846301094
Resting-state connectivity biomarkers define neurophysiological subtypes of depression
2017; 23 (1): 28-38
Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82-93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.
View details for DOI 10.1038/nm.4246
View details for Web of Science ID 000391646800011
View details for PubMedID 27918562
Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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
Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol.
Journal of psychiatric research
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
Insular cortex abnormalities in psychotic major depression: relationship to gender and psychotic symptoms.
2013; 75 (4): 331-339
Recent data suggests that psychotic major depression (PMD) may be a discrete disorder distinguishable from nonpsychotic major depression (NPMD), and that patients with PMD may be more similar to individuals with schizophrenia than individuals with NPMD. The insula is a brain region in which morphometric changes have been associated with psychotic symptom severity in schizophrenia and affective psychosis. It was hypothesized that insular volumes would be reduced in PMD compared to NPMD and controls, and insular volumes would correlate with psychosis but not depression severity. Insular gray matter volumes were measured in PMD and NPMD patients and matched healthy controls using magnetic resonance images and manual morphometry. Clinical measures of illness severity were obtained to determine their relationship with insular volume. Posterior insular volumes were significantly reduced in PMD compared to HC. There were also significant group-by-gender interactions for total, anterior and posterior insular volumes. Using Pearson product-moment correlations, anterior insular volumes did not correlate with depression severity. Left anterior insular volume was significantly correlated with total and positive symptom psychosis severity in the PMD group. Atypical insular morphometry may be related to the inability to distinguish between internally and externally generated sensory inputs characteristic of psychosis.
View details for DOI 10.1016/j.neures.2013.02.005
View details for PubMedID 23471015
View details for PubMedCentralID PMC3662543
Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression.
2013; 211 (2): 119-126
Psychotic major depression (PMD) is associated with deficits in verbal memory as well as other cognitive impairments. This study investigated brain function in individuals with PMD during a verbal declarative memory task. Participants included 16 subjects with PMD, 15 subjects with non-psychotic major depression (NPMD) and 16 healthy controls (HC). Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed verbal memory encoding and retrieval tasks. During the explicit encoding task, subjects semantically categorized words as either "man-made" or "not man-made." For the retrieval task, subjects identified whether words had been presented during the encoding task. Functional MRI data were processed using SPM5 and a group by condition ANOVA. Clusters of activation showing either a significant main effect of group or an interaction of group by condition were further examined using t-tests to identify group differences. During the encoding task, the PMD group showed lower hippocampus, insula, and prefrontal activation compared to HC. During the retrieval task, the PMD group showed lower recognition accuracy and higher prefrontal and parietal cortex activation compared to both HC and NPMD groups. Verbal retrieval deficits in PMD may be associated with deficient hippocampus function during encoding. Increased brain activation during retrieval may reflect an attempt to compensate for encoding deficits.
View details for DOI 10.1016/j.pscychresns.2012.06.008
View details for PubMedID 23149036
- Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression PSYCHIATRY RESEARCH-NEUROIMAGING 2013; 211 (2): 119-126
The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression
2013; 38 (1): 115-121
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs).Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed.There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009).Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans.
View details for DOI 10.1016/j.psyneuen.2012.05.006
View details for Web of Science ID 000313761000011
View details for PubMedID 22727477
The relationships of positive and negative symptoms with neuropsychological functioning and their ability to predict verbal memory in psychotic major depression
2012; 198 (1): 34-38
Neuropsychological functioning, in relation to positive and negative symptoms in psychotic major depression (PMD), has not been as thoroughly studied as it has been in schizophrenia. Thus, the current study investigated the associations between positive and negative symptoms with cognitive functioning, with an emphasis on verbal memory in PMD. Attention, working memory, and the executive functioning domains were analyzed among 49 PMD participants. Positive symptoms did not correlate significantly with any measures of verbal memory but did correlate with one measure of attention, working memory, and executive functioning. Negative symptoms correlated significantly with two California Verbal Learning Test-II (CVLT-II) measures of verbal memory and three measures of executive function. Hierarchical regressions were conducted to determine if negative symptoms could predict verbal memory performance after controlling for depression. Of the two verbal memory measures, negative symptoms significantly explained additional variance for CVLT Recognition, but not for CVLT Trials 1-5 total score. Our results provide some evidence that, consistent with the schizophrenia literature, negative symptoms contributed more to verbal memory deficits in PMD than positive symptoms, regardless of depression severity.
View details for DOI 10.1016/j.psychres.2011.12.001
View details for Web of Science ID 000313848200007
View details for PubMedID 22410589
Aberrant Brain Activation During a Working Memory Task in Psychotic Major Depression
AMERICAN JOURNAL OF PSYCHIATRY
2011; 168 (2): 173-182
The authors sought to better understand the neural circuitry associated with working memory deficits in psychotic major depression by examining brain function during an N-back task.Study subjects were 16 patients with psychotic major depression, 15 patients with nonpsychotic major depression, and 19 healthy comparison subjects. Functional MRI data were collected while participants responded to letter stimuli that were repeated from the previous trial (1-back) or the one before that (2-back).Relative to the healthy comparison group, both the psychotic and nonpsychotic major depression groups had significantly greater activation in the right parahippocampal gyrus during the 2-back task, and the psychotic major depression group showed this overactivation during the 1-back task as well. The nonpsychotic major depression group showed significantly lower activation than other groups in the right dorsolateral prefrontal cortex and greater activation than the healthy comparison group in the superior occipital cortex. The psychotic major depression group was unique in showing greater activation than both other groups in the right temporoparietal junction, a cluster that also demonstrated connectivity with activation in the left prefrontal cortex.The psychotic major depression group showed aberrant parahippocampal activation at a lower demand level than observed in nonpsychotic major depression. While the nonpsychotic major depression group showed abnormalities in frontal executive regions, the psychotic major depression group showed abnormalities in temporoparietal regions associated with orienting to unexpected stimuli. Considering the functional connectivity of this cluster with left dorsolateral prefrontal cortex regions, these findings may reflect neural compensation for sensory gating deficits in psychotic major depression.
View details for DOI 10.1176/appi.ajp.2010.09121718
View details for Web of Science ID 000286972800011
View details for PubMedID 21078708
Preliminary evidence that plasma oxytocin levels are elevated in major depression
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
Semantic processing of emotional words in depression and schizophrenia
INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY
2010; 75 (2): 211-215
Major depressive disorder is associated with dysfunction in brain regions involved in language and emotion processing. Despite evidence of emotion processing biases in depression, neurophysiological evidence of language dysfunction for emotional words in depression has been inconsistent. This series of three studies evaluated whether depressed individuals exhibited abnormal semantic processing of emotionally-valenced words. During the passive viewing of sentences with mood congruent and incongruent sentence endings, the N400 component of the event-related brain potential was measured in patients with depression, dysthymia, or schizophrenia and in healthy controls. In each study, results revealed normal semantic processing in depression. That is, N400 was similar for both mood-incongruent (positive and neutral) endings and mood-congruent (negative) endings. In contrast, the small sample of individuals with schizophrenia exhibited a significantly exaggerated N400 for negative word endings compared to the depressed and healthy control groups. These data suggest anomalies in semantic network interactions with emotion processing in schizophrenia.
View details for DOI 10.1016/j.ijpsycho.2009.12.004
View details for Web of Science ID 000275700800016
View details for PubMedID 20006969
CURRENT ISSUES IN THE CLASSIFICATION OF PSYCHOTIC MAJOR DEPRESSION
Conference on Deconstructing Psychosis
AMER PSYCHIATRIC PRESS, INC. 2010: 29–44
View details for Web of Science ID 000294244000004
Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function
2009; 34 (7): 1012-1018
Although many studies have examined separately the effects of depression and cortisol on cognition, no study has examined their relative or potentially additive effects. Our study simultaneously investigated the contributions of clinical status [major depression (MD) versus psychiatrically healthy controls (HC)] and cortisol on a hippocampal/mediotemporal mediated verbal memory task (Paragraph Recall) and a prefrontal cortex/cingulate mediated executive functioning task (Stroop). Thirty-seven unmedicated nondelusional MDs and 18 HCs underwent psychiatric ratings, hourly assessments of cortisol activity over 24 h, and neuropsychological assessments. Hierarchical multiple regressions indicated a significant effect of cortisol but not of diagnosis on verbal memory. Greater cortisol levels were related to poorer memory performance independent of group. In contrast, a significant interaction between cortisol and diagnosis was found for a color-word index of response inhibition. This interaction suggests that the detrimental effect of elevated cortisol level on this type of executive functioning exists only in the healthy control group but not in MDs. On an Interference score, another measure of response inhibition, cortisol had a significant independent effect, but neither the effects of diagnosis and the interaction attained full significance. Our study suggests that cortisol has an independent effect on verbal memory. Also, our study produced evidence of an interaction between diagnosis and cortisol on response inhibition.
View details for DOI 10.1016/j.psyneuen.2009.01.017
View details for Web of Science ID 000267471900008
View details for PubMedID 19261389
Impact of clinician gender on examination anxiety among female veterans with sexual trauma: A pilot study
JOURNAL OF WOMENS HEALTH
2007; 16 (9): 1291-1299
The sequelae of sexual trauma, including symptoms or diagnosis of posttraumatic stress disorder (PTSD), may impact women's anxiety and avoidance of preventive healthcare measures such as breast, pelvic, and rectal examinations. As sexual trauma is unfortunately a common occurrence among female patients, particularly veterans, understanding how it influences examination-related distress may improve provision of care to this population. We explored the impact of clinician gender and examination type (breast, pelvic, rectal, and dental) on anticipated examination-related anxiety among women veterans with a history of sexual trauma.We present a cross-sectional pilot study that examines anticipated examination-related distress among 31 female veterans with a history of sexual trauma. Sexual trauma history was verified by chart review. Self-report instruments assessed patient demographics and patients' anticipated anxiety during breast, pelvic, rectal, and dental examinations (stratified by gender of clinician). The PTSD Checklist-Civilian Version (PCL-C) assessed symptom severity.The women reported significantly more anticipated anxiety during breast, pelvic, and rectal examinations, (p < 0.05) when clinician gender was male. Severity of PTSD symptoms was generally unrelated to anticipated examination-related anxiety.Anticipated anxiety was found to be a function of both examination type and clinician gender but not of PTSD symptom severity. These findings emphasize the importance of screening for sexual trauma and the careful consideration of female veterans' unique needs during sensitive medical procedures.
View details for DOI 10.1089/jwh.2006.0208
View details for Web of Science ID 000251174900006
View details for PubMedID 18001185
Current issues in the classification of psychotic major depression
Conference on Deconstructing Psychosis
OXFORD UNIV PRESS. 2007: 877–85
Depression is one of the most common mental disorders worldwide. There are a number of depression subtypes, and there has been much debate about how to most accurately capture and organize the features and subtypes of major depression. We review the current state of categorizing unipolar major depression with psychotic features (psychotic major depression, PMD), including clinical, biological, and treatment aspects of the disorder. We then propose some improvements to the current unipolar major depression categorization system. Finally, we identify important issues in need of further research to help elucidate the subtype of unipolar PMD.
View details for DOI 10.1093/schbul/sbm065
View details for Web of Science ID 000248178800009
View details for PubMedID 17548842
Empirically assessing participant perceptions of the research experience in a randomized clinical trial: The Women's Self-Defense Project as a case example
JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS
2007; 2 (2): 11-23
A growing body of empirical literature has systematically documented the reactions to research participation among participants in traumafocused research. To date, the available data has generally presented an optimistic picture regarding participants' ability to tolerate and even find benefit from their participation. However, this literature has been largely limited to cross-sectional designs. No extant literature has yet examined the perceptions of participants with psychiatric illness who are participating in randomized clinical trials (RCTs) designed to evaluate the efficacy or effectiveness of novel trauma treatments. The authors posit that negative experiences of, or poor reactions to, the research experience in the context of a trauma-focused RCT may elevate the risk of participation. Indeed, negative reactions may threaten to undermine the potential therapeutic gains of participants and promoting early drop out from the trial. Empirically assessing reactions to research participation at the pilot-study phase of a clinical trial can both provide investigators and IRB members alike with empirical evidence of some likely risks of participation. In turn, this information can be used to help shape the design and recruitment methodology of the full-scale trial. Using data from the pilot study of the Women's Self-Defense Project as a case illustration, we provide readers with concrete suggestions for empirically assessing participants' perceptions of risk involved in their participation in behaviorally oriented clinical trials.
View details for DOI 10.1525/JERHRE.2007.2.2.11
View details for Web of Science ID 000256385200002
View details for PubMedID 19385792
Dissociable intrinsic connectivity networks for salience processing and executive control
JOURNAL OF NEUROSCIENCE
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
View details for PubMedCentralID PMC2680293
- Reply: Clinical and biological effects of mifepristone treatment for psychotic treatment - Reply to Carroll and Rubin NEUROPSYCHOPHARMACOLOGY 2006; 31 (12): 2795-2797
The neuropsychological profile of psychotic major depression and its relation to cortisol
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
Mood and neuropsychological changes in women with midlife depression treated with escitalopram
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
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 10.1097/01.jcp.0000227699.26375.f8
View details for Web of Science ID 000239551200003
View details for PubMedID 16855452
Clinical and biological effects of mifepristone treatment for psychotic depression
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
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
Normal N400 in mood disorders
2006; 71 (1): 74-79
Individuals diagnosed with major depression have been characterized as having a variety of cognitive problems based on a number of behavioral and psychophysiological measures, but it is not clear whether there is a consistent language processing abnormality in depression. Three studies sought to determine whether diverse mood disordered samples show abnormal semantic processing, as indexed by a failure to show increased N400 event-related brain potential amplitudes to passively viewed incongruent, relative to congruent sentence endings. Individuals with major depression (N = 50) or dysthymia (N = 14) had N400 amplitudes similar to those of controls (N = 41) in this sentence processing paradigm. These results are consistent with a small behavioral literature suggesting intact semantic processing in depression and further indicate that abnormal controlled processing in some tasks does not simply reflect a generalized deficit.
View details for DOI 10.1016/j.biopsycho.2005.02.005
View details for Web of Science ID 000234530500009
View details for PubMedID 15885876
- I Got My Life Back! Making a Case for Self Defense Training for Older Women with PTSD. Clinical Gerontologist 2005; 28 (3): 113-118
Cognitive bias and emotion in neuropsychological models of depression
COGNITION & EMOTION
2001; 15 (6): 787-802
View details for Web of Science ID 000171618800005
- Cognitive bias and emotion in neuropsychological models of depression Cognition & Emotion 2001; 15 (6): 787-802
Right-posterior face processing anomaly in depression
JOURNAL OF ABNORMAL PSYCHOLOGY
2000; 109 (1): 116-121
Evidence of a right-posterior brain anomaly was found in a study of 19 individuals with major depression and 15 controls. Participants performed a recognition-memory task involving positive, neutral, and negative face and word stimuli. Scalp brain wave topography suggested a region-specific anomaly in the depressed group. Individuals with major depression demonstrated a reduction in the N200 component of the event-related brain potential to faces and not words. Furthermore, results indicate that the regional anomaly is specific to positive facial stimuli. Findings are interpreted in light of a model of regional brain specialization in emotion and psychopathology.
View details for Web of Science ID 000085841400013
View details for PubMedID 10740942
Neuropsychological differentiation of depression and anxiety
JOURNAL OF ABNORMAL PSYCHOLOGY
2000; 109 (1): 3-10
The high comorbidity of depression and anxiety is well established empirically but not well understood conceptually, in terms of either psychological or biological mechanisms. A neuropsychological model of regional brain activity in emotion provides contrasting hypotheses for depression and anxiety, with depression associated with a relative decrease and anxiety with a relative increase in right-posterior activity. These hypotheses received support in a comparison of individuals diagnosed with depression and community controls, and also in a separate study of nonpatients administered a measure of perceptual asymmetry. Hierarchical regressions revealed that depression and anxiety were uniquely and jointly associated with perceptual asymmetry. In light of consistent empirical support for the model, implications for conceptualizations of the comorbidity of depression and anxiety are discussed.
View details for Web of Science ID 000085841400001
View details for PubMedID 10740930
- Psychology and neuroscience: Making peace Current Directions in Psychological Science 2000; 9 (6): 212-215
Converging evidence for a cognitive anomaly in early psychopathology
1999; 36 (4): 511-521
Subcomponents of the N200 component of the event-related brain potential believed to be differentially sensitive to involuntary and voluntary cognitive processes were examined. Nonpatients (N = 131) identified initially by the Chapman and Depue research scales and classified later on the basis of diagnostic symptom clusters and family psychiatric history provided converging evidence for an intact mismatch negativity subcomponent. In contrast, the N2b subcomponent distinguished several groups of subjects. Results suggested abnormal voluntary cognitive processing, perhaps reflecting compensatory efforts in subjects at risk for or manifesting psychopathology, particularly those showing negative symptoms.
View details for Web of Science ID 000081470300011
View details for PubMedID 10432801