Sarah M. Szymkowicz

A 12-month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment-resistant depression.

BACKGROUND Acute administration of subanesthestic doses of intravenous ketamine have been shown to elicit a rapid antidepressant response in patients with treatment-resistant depression. However, it remains to be seen if repeated doses over a longer period of time will have the same effects. Here, we assess the long-term efficacy of repeated intravenous ketamine infusions in three patients with high treatment-resistant depression via a naturalistic observation study. METHOD Three patients consented to intravenous ketamine infusions as a therapy for their treatment-resistant depression. Patients were administered ketamine at 0.5mg/kg of ideal body weight over 40 min followed by a saline flush until discharge. Severity of depressive symptoms was rated with the Montgomery-Asberg Depression Rating Scale. RESULTS All three patients responded to the ketamine infusions, but each went through an individualized course of treatment based on their own response. LIMITATIONS This was an open-label naturalistic observation without blinding, randomization, or a placebo control. CONCLUSIONS These cases add to the literature supporting the therapeutic effect of low-dose repeated intravenous ketamine for patients with treatment-resistant depression. Further study is needed to define the risks, benefits, indications, and contraindications of this potential treatment.

Unique and Interactive Effect of Anxiety and Depressive Symptoms on Cognitive and Brain Function in Young and Older Adults

OBJECTIVE Depression and anxiety and are associated with cognitive deficits and brain changes, especially in older adults. Despite the frequent co-occurrence of these conditions, cognitive neuroscience studies examining comorbid depression and anxiety are limited. The goal of the present study was to examine the unique and combined effect of depressive and anxiety symptoms on cognitive and brain functioning in young and older adults. METHODS Seventy-one healthy, community-dwelling adults between the ages of 18 and 81 were administered a neuropsychological battery and completed the Center for Epidemiologic Studies Depression Scale (CES-D) and the trait form of the State-Trait Anxiety Inventory (STAI-T). A subset of 25 participants also underwent functional magnetic resonance imaging (fMRI) scanning while completing the n-back working memory task. RESULTS Total depressive symptoms, depressed mood symptoms, and somatic symptoms were associated with deficits in speed, working memory and executive functions, especially in older adults. Symptoms of lack of well-being were not associated with any neuropsychological test. Anxiety was associated with better attention and working memory. Moreover, anxiety modified the relationship between depressive symptoms and executive functioning in older adults, as elevated depressive symptoms were associated with worse performance at low levels of anxiety, but not at higher anxiety levels. Similarly, analysis of fMRI data showed that total depressive symptoms and depressed mood symptoms were associated with decreased activity in the superior frontal gyrus at low anxiety levels, but not at high anxiety levels. CONCLUSION Results confirm previous reports that subthreshold depression and anxiety impact cognitive and brain functioning and suggest that the interaction of depression and anxiety results in distinct cognitive and brain changes. Findings highlight the importance of assessing and controlling for symptoms of depression and anxiety in research studies of either condition.

Age Differences in Prefrontal Surface Area and Thickness in Middle Aged to Older Adults

Age is associated with reductions in surface area and cortical thickness, particularly in prefrontal regions. There is also evidence of greater thickness in some regions at older ages. Non-linear age effects in some studies suggest that age may continue to impact brain structure in later decades of life, but relatively few studies have examined the impact of age on brain structure within middle-aged to older adults. We investigated age differences in prefrontal surface area and cortical thickness in healthy adults between the ages of 51 and 81 years. Participants received a structural 3-Tesla magnetic resonance imaging scan. Based on a priori hypotheses, primary analyses focused on surface area and cortical thickness in the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex. We also performed exploratory vertex-wise analyses of surface area and cortical thickness across the entire cortex. We found that older age was associated with smaller surface area in the dorsolateral prefrontal and orbitofrontal cortices but greater cortical thickness in the dorsolateral prefrontal and anterior cingulate cortices. Vertex-wise analyses revealed smaller surface area in primarily frontal regions at older ages, but no age effects were found for cortical thickness. Results suggest age is associated with reduced surface area but greater cortical thickness in prefrontal regions during later decades of life, and highlight the differential effects age has on regional surface area and cortical thickness.

Failed response to repeat intravenous ketamine infusions in geriatric patients with Major Depressive Disorder

Geriatric depression has reported prevalence rates of 1.6 to 15% of the population1. New effective fast-acting treatment modalities in this population would be cost saving and alleviate suffering and disability for the patients and their families. The rapid onset of antidepressant effect produced by subanesthetic intravenous (IV) ketamine provides such a promise. Single2, 3 and repeat 4-7 ketamine infusions have been shown to produce an antidepressant effect within hours with a sustained effect lasting days to weeks. But not all depressed patients who are administered ketamine have a response. Using a 50% reduction in baseline symptoms as the response criteria, response rates of 43-90% are reported within 40 minutes, 24 hours, and 72 hours post-infusion8. Although a large number of patients do respond, studies to accurately predict who responds are at an early stage. Here, we report a case series where IV ketamine infusions in geriatric patients with Treatment Resistant Depression (TRD) did not prove beneficial. Four patients (mean (± SD) age, 72.25 (± 5.38) years) admitted to an inpatient psychiatric unit due to a relapse in their Major Depressive Disorder (MDD), with histories of multiple failed medication trials and failed electroconvulsive therapy (ECT), were offered IV ketamine treatments, as described elsewhere9. An Institutional Review Board approved retrospective chart review was conducted for this case series. After the initial inpatient infusion demonstrated no physiological concerns, the infusions were continued on an outpatient basis. Prescribed medications were continued throughout the infusions.

Admixture analysis of age at onset in major depressive disorder

OBJECTIVES This study aimed to determine the distributions of the age at onset (AAO) in patients with major depressive disorder (MDD) using admixture analysis and to determine the clinical differences between subgroups with different AAO. METHODS Participants were administered the Mini-International Neuropsychiatric Interview to obtain clinical data. Admixture analysis was performed using the STATA module DENORMIX to identify subgroups characterized by differences in AAO. RESULTS The best fit model was the three-component model with the following means, standard deviations and proportions: 14.60 (3.75) years (49.1%), 29.15 (6.75) years (34.1%) and 46.96 (6.06) years (16.8%) (χ(2)=3.64, 2 df, P=.162). The three subgroups were divided by AAO of 22 and 40. After controlling for duration of illness, there were no significant differences between the three AAO subgroups in terms of gender and psychiatric family history. However, the early-onset subgroup was significantly more likely to report being single compared to the intermediate- and late-onset groups. The proportion of individuals meeting criteria for lifetime comorbid panic disorders and obsessive-compulsive disorder did not differ significantly between the AAO groups. However, the early-onset group reported a higher incidence of attention-deficit/hyperactivity disorder (5.1% vs. 1.7% and 1.2%, P=.086), although this was not statistically significant. CONCLUSIONS Our study identified three characteristically different AAO subgroups in individuals suffering from MDD. The subgroups may reflect different underlying neurobiological mechanisms involved.

Dimensions of depressive symptoms and cingulate volumes in older adults

Clinical depression and subthreshold depressive symptoms in older adults have been linked to structural changes in the cingulate gyrus. The cingulate comprises functionally distinct subregions that may have distinct associations with different types, or symptom dimensions, of depression. This study examined the relationship between symptom dimensions of depression and gray matter volumes in the anterior cingulate, posterior cingulate and isthmus of the cingulate in a nonclinical sample. The study included 41 community-dwelling older adults between the ages of 55 and 81. Participants received a structural magnetic resonance imaging scan and completed the Center for Epidemiologic Studies Depression Scale. Subscale scores for depressed mood, somatic symptoms and lack of positive affect were calculated, and Freesurfer was used to extract cingulate gray matter volumes. Regression analyses were conducted to examine the relationship between depressive symptoms and volumes of cingulate subregions while controlling for sex, age and estimated total intracranial volume. Higher scores on the depressed mood subscale were associated with larger volumes in the left posterior cingulate and smaller volumes in the isthmus cingulate. Higher scores on the somatic symptoms subscale were significantly related to smaller volumes in the posterior cingulate. A trend was observed for a positive relationship between higher scores on the lack of positive affect subscale and larger volumes in the anterior cingulate cortex. These results are consistent with previous findings of altered cingulate volumes with increased depressive symptomatology and suggest specific symptom dimensions of depression may differ in their relationship with subregions of the cingulate.

Depressive symptom severity is associated with increased cortical thickness in older adults.

Structural neuroimaging studies in older adults have consistently shown volume reductions in both major and subthreshold depression. Cortical thickness, another measure of brain structure, has not been well studied in this population. We examined cortical thickness in older adults across a range of depressive symptom (DS) severity.

Transcranial Direct Current Stimulation Use in the Treatment of Neuropsychiatric Disorders: A Brief Review

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has grown in popularity over the past two decades as an alternative treatment option for various neuropsychiatric disorders. tDCS modulates cortical excitability through the application of a weak direct current to the scalp via electrodes placed over cortical regions of interest. It has been shown to be a promising and relatively safe treatment tool with few adverse events. In this article, we will briefly review the efficacy of tDCS in depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder. We will also discuss biomarkers of tDCS efficacy in depression, as it is the most studied neuropsychiatric disorder using tDCS application. We will then offer suggestions for future directions. Although efficacy results show promise, more studies with larger samples and longer treatment periods are needed to better understand the benefits of using tDCS as an alternative treatment option for neuropsychiatric disorders.

Impact of Education on Memory Deficits in Subclinical Depression

Elevated depressive symptoms are associated with cognitive deficits, while higher education protects against cognitive decline. This study was conducted to test if education level moderates the relationship between depressive symptoms and cognitive function. Seventy-three healthy, dementia-free adults aged 18-81 completed neuropsychological tests, as well as depression and anxiety questionnaires. Controlling for age, sex, and state anxiety, we found a significant interaction of depressive symptoms and education for immediate and delayed verbal memory, such that those with a higher education level performed well regardless of depressive symptomatology, whereas those with lower education and high depressive symptoms had worse performance. No effects were found for executive functioning or processing speed. Results suggest that education protects against verbal memory deficits in individuals with elevated depressive symptoms. Further research on cognitive reserve in depression-related cognitive deficits and decline is needed to understand the mechanisms behind this phenomenon.

Associations between subclinical depressive symptoms and reduced brain volume in middle-aged to older adults

ABSTRACT Objectives: The associations between subclinical depressive symptoms, as well specific symptom subscales, on brain structure in aging are not completely elucidated. This study investigated the extent to which depressive symptoms were related to brain volumes in fronto-limbic structures in a sample of middle-aged to older adults. Method: Eighty participants underwent structural neuroimaging and completed the Beck Depression Inventory, 2nd Edition (BDI-II), which comprises separate affective, cognitive, and somatic subscales. Gray matter volumes were extracted from the caudal and rostral anterior cingulate, posterior cingulate, hippocampus, and amygdala. Hierarchical regression models examined the relationship between brain volumes and (i) total depressive symptoms and (ii) BDI-II subscales were conducted. Results: After adjusting for total intracranial volume, race, and age, higher total depressive symptoms were associated with smaller hippocampal volume (p = 0.005). For the symptom subscales, after controlling for the abovementioned covariates and the influence of the other symptom subscales, more somatic symptoms were related to smaller posterior cingulate (p = 0.025) and hippocampal (p < 0.001) volumes. In contrast, the affective and cognitive subscales were not associated with brain volumes in any regions of interest. Conclusion: Our data showed that greater symptomatology was associated with smaller volume in limbic brain regions. These findings provide evidence for preclinical biological markers of major depression and specifically advance knowledge of the relationship between subclinical depressive symptoms and brain volume. Importantly, we observed variations by specific depressive symptom subscales, suggesting a symptom-differential relationship between subclinical depression and brain volume alterations in middle-aged and older individuals.