Analyzing Non-verbal Behavior Throughout Recovery in a Sample of Depressed Patients Receiving Deep Brain Stimulation.

BACKGROUND: Traditional rating scales for depression rely heavily on patient self-report, and lack detailed measurement of non-verbal behavior. However, there is evidence that depression is associated with distinct non-verbal behaviors, assessment of which may provide useful information about recovery. This study examines non-verbal behavior in a sample of patients receiving Deep Brain Stimulation (DBS) treatment of depression, with the purpose to investigate the relationship between non-verbal behaviors and reported symptom severity. METHODS: Videotaped clinical interviews of twelve patients participating in a study of DBS for treatment-resistant depression were analyzed at three time points (before treatment and after 3 months and 6 months of treatment), using an ethogram to assess the frequencies of 42 non-verbal behaviors. The Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS-17) were also collected at all time points. RESULTS: Factor analysis grouped non-verbal behaviors into three factors: react, engage/fidget, and disengage. Two-way repeated measures ANOVA showed that scores on the three factors change differently from each other over time. Mixed effects modelling assessed the relationship between BDI score and frequency of non-verbal behaviors, and provided evidence that the frequency of behaviors related to reactivity and engagement increase as BDI score decreases. LIMITATIONS: This study assesses a narrow sample of patients with a distinct clinical profile at limited time points. CONCLUSIONS: Non-verbal behavior provides information about clinical states and may be reliably quantified using ethograms. Non-verbal behavior may provide distinct information compared to self-report.

Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.

OBJECTIVE: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression. METHODS: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years. RESULTS: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides. CONCLUSIONS: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions.

BACKGROUND: The dissociative anesthetic agent ketamine is increasingly being utilized to treat depression, despite not having FDA (Food and Drug Administration) approval for this indication. There are many questions about the potential risks of this treatment and hence the proper setting and degree of monitoring required to ensure patient safety. There is limited data about the cardiovascular safety of ketamine when administered at subanesthetic doses to treat depression. METHODS: 66 patients in the Department of Psychiatry at Emory University received a total of 684 ketamine infusions between 2014 and 2016. Ketamine was dosed at 0.5 mg/kg body weight and infused over 40 min. Blood pressure was measured every 10 min during the infusions and every 15 min thereafter. RESULTS: Mean age of the patients was 56.7 years, 87.9% had unipolar depression and 36.1% had essential hypertension. No infusions were discontinued due to instability of vital signs, adverse physiological consequences or acute psychotomimetic effects. The biggest increases in blood pressure were measured at 30 min (systolic 3.28 mmHg, diastolic 3.17 mmHg). Hypertensive patients had higher blood pressure peaks during the infusions. Blood pressures returned to baseline during post-infusion monitoring. There was no development of tolerance to the blood pressure elevating effects of ketamine between the first and sixth infusions. LIMITATIONS: This is a single site, retrospective analysis, of patients who were spontaneously seeking clinical care. CONCLUSIONS: The blood pressure changes observed when ketamine is administered over 40 min at 0.5 mg/kg for the treatment of depression are small, well tolerated and clinically insignificant.

Assessing Residents' Confidence in the Context of Pharmacotherapy Competence.

OBJECTIVE: We aimed to determine whether residents' confidence initiating medications increased with the number of times they prescribed individual medications and to quantify the relationship between prescription frequency and gains in confidence. METHODS: From July 2011 to June 2014, PGY-3 residents completed a survey of confidence levels at their psychopharmacology clinic orientation and then again 12 months later. The Emory Healthcare electronic medical record was used to identify all medications prescribed by each resident during their 12-month rotation and the frequency of these prescriptions. RESULTS: Confidence in initiating treatment with all medicines/medication classes increased over the 12-month period. For three of the medication classes for which residents indicated they were least confident at orientation, the number of prescriptions written during the year was significantly associated with an increase in confidence. CONCLUSIONS: Measuring resident confidence is a relevant and achievable outcome and provides data for educators regarding the amount of experience needed to increase confidence.

Use of Expert Consultation in a Complex Case of Neuroleptic Malignant Syndrome Requiring Electroconvulsive Therapy.

Our team at Emory University Hospital contacted experts at the National Network of Depression Centers (NNDC) for clinical guidance concerning a patient with schizophrenia hospitalized in the intensive care unit with a complex case of prolonged delirium secondary to neuroleptic malignant syndrome (NMS). Through the NNDC, leading psychiatrists across the United States with expertise in electroconvulsive therapy (ECT) provided us with treatment strategies based on experience in our area of concern. This report describes our use of ECT to treat severe NMS in this patient with schizophrenia, utilizing the recommendations made by the NNDC's ECT experts concerning electrode position, number and frequency of treatments, and selection of anesthetic induction agents. This case report highlights the utility of expert consultation in the treatment of rare diseases and provides guidance on how to treat NMS in the intensive care unit setting.

Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests.

Glucocorticoid challenge tests such as the dexamethasone suppression test (DST) and the combined dexamethasone/corticotropin-releasing hormone (dex-CRH) test are considered to be able to sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in stress-related psychiatric and endocrine disorders. We used mass-spectrometry to assess the relationship of plasma dexamethasone concentrations and the outcome of these tests in two independent cohorts. Dexamethasone concentrations were measured after oral ingestion of 1.5mg dexamethasone in two cohorts that underwent a standard (dexamethasone at 23:00h) as well as modified (18:00h) DST and dex-CRH test. The first study population was a case/control cohort of 105 depressed patients and 133 controls in which peripheral blood mRNA expression was also measured. The second was a cohort of 261 depressed patients that underwent a standard dex-CRH test at baseline and after 12 weeks' treatment with cognitive-behavioral therapy or antidepressants. Dexamethasone concentrations explained significant proportions of the variance in the DST in both the first (24.6%) and the second (5.2%) cohort. Dexamethasone concentrations explained a higher proportion of the variance in the dex-CRH test readouts, with 41.9% of the cortisol area under the curve (AUC) in the first sample and 24.7% in the second sample. In contrast to these strong effects at later time points, dexamethasone concentrations did not impact cortisol or ACTH concentrations or mRNA expression 3hours after ingestion. In the second sample, dexamethasone concentrations at baseline and week 12 were highly correlated, independent of treatment type and response status. Importantly, a case/control effect in the Dex-CRH test was only apparent when controlling for dexamethasone concentrations. Our results suggest that the incorporation of plasma dexamethasone concentration or measures of earlier endocrine read-outs may help to improve the assessment of endocrine dysfunction in depression.

Characterizing the therapeutic response to deep brain stimulation for treatment-resistant depression: a single center long-term perspective.

The number of depressed patients treated with deep brain stimulation (DBS) is relatively small. However, experience with this intervention now spans more than 10 years at some centers, with study subjects typically monitored closely. Here we describe one center's evolving impressions regarding optimal patient selection for DBS of the subcallosal cingulate (SCC) as well as observations of short- and long-term patterns in antidepressant response and mood reactivity. A consistent time course of therapeutic response with distinct behavioral phases is observed. Early phases are characterized by changes in mood reactivity and a transient and predictable worsening in self ratings prior to stabilization of response. It is hypothesized that this characteristic recovery curve reflects the timeline of neuroplasticity in response to DBS. Further investigation of these emerging predictable psychiatric, biological, and psychosocial patterns will both improve treatment optimization and enhance understanding and recognition of meaningful DBS antidepressant effects.

Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression.

BACKGROUND: Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response. METHODS: Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. RESULTS: Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months (n = 6) and 2 years (n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. CONCLUSIONS: Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection.

Provide optimized antidepressant monotherapy with multiple drugs before considering antidepressant polypharmacy.

Many patients with chronic or recurring major depressive disorder have suboptimal responses to the wide range of antidepressant medications available. When confronted with these patients, clinicians may augment the original antidepressant with other medications, including adjunctive treatment with a second or third antidepressant. Although it is a widely-used practice among psychiatrists and primary care physicians in high-income countries, evidence for the benefits of this type of antidepressant polypharmacy is limited. Care should be taken to utilize this approach only after failure of optimized monotherapy with different classes of antidepressants.

Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder.

OBJECTIVE: Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. METHODS: Research subjects were adult outpatients with minor depressive disorder (N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. RESULTS: Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. CONCLUSIONS: Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment.

Practical considerations in the development and refinement of subcallosal cingulate white matter deep brain stimulation for treatment-resistant depression.

BACKGROUND: Deep brain stimulation has been investigated in the past decade as a viable intervention for treatment-resistant depression. METHODS: Several anatomic targets have been tested, with the most extensive published experience found for the subcallosal cingulate (SCC) white matter. RESULTS: This article reviews the current state of clinical research of SCC deep brain stimulation for treatment-resistant depression, including an overview of the rationale for targeting SCC, practical considerations for subject recruitment and evaluation, surgical planning, and stimulation parameters. CONCLUSION: Clinical management of patients in the initial and long-term naturalistic phases of treatment, including the potential role for psychotherapeutic rehabilitation, is discussed.

The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder.

OBJECTIVE: To determine whether the combination of triiodothyronine (T3) plus sertraline at treatment initiation confers greater antidepressant efficacy than sertraline plus placebo in patients with major depressive disorder. METHOD: Eight-week, double blind, randomized placebo controlled clinical trial of 153 adult outpatients between 18 and 60 years of age, with DSM-IV defined major depressive disorder. Patients were treated with sertraline flexibly adjusted for tolerability and in a double blind fashion with placebo or T3 (25 µg/day in week 1 and increasing to 50 µg/day in week 2). Response was defined categorically as 50% reduction and total score less than 15 in 21-item Hamilton Rating Scale for Depression (HRSD-21) at week 8 and remission as HRSD-21 less than 8. RESULTS: There was no difference between treatment groups at final assessment; 65% of placebo and 61.8% of T3 treated subjects achieved response and 50.6% of placebo and 40.8% of T3 treated patients achieved remission. The mean daily dose at final assessment of sertraline and T3, respectively was 144.7 mg (± 48.7 mg) and 48.2 µg (± 7 µg). Median time to response did not differ between treatment groups. Baseline thyroid function tests did not predict response to sertraline treatment or T3 augmentation. CONCLUSIONS: These results do not support the routine use of T3 to enhance or accelerate onset of antidepressant response in patients with major depressive disorder.

Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.

CONTEXT: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. OBJECTIVE: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). DESIGN: Open-label trial with a sham lead-in phase. SETTING: Academic medical center. Patients  Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention  Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. MAIN OUTCOME MEASURES: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. RESULTS: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. CONCLUSIONS: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration  clinicaltrials.gov Identifier: NCT00367003.

Peak window of suicides occurs within the first month of diagnosis: implications for clinical oncology.

OBJECTIVE: A diagnosis of cancer can provoke painful emotional reactions and possibly suicidal thoughts in a patient. Consequently, cancer patients carry a twofold increased lifetime risk of suicide. This risk is much higher within 1 year of diagnosis. However, it remains largely unknown whether suicide frequency remains constant within the first year. Therefore, we sought to characterize the distribution of suicides in order to potentially identify a clinically important window of peak suicide risk. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for cancer patients 20 + years old with diagnosed with a single malignancy from 1973 to 2005 and known cause of death, including whether a patient committed suicide. Initial frequency analysis was performed to identify the period of maximum suicide risk. One-way ANOVA was performed to assess the relationship between year of diagnosis and suicide completions within 1 month of diagnosis. RESULTS: The cohort consisted of 3,678,868 patients. Of the total cohort, 0.2% (5875 patients) committed suicide, 36% (2111 patients) within 1 year of diagnosis. One in three (701 of the patients) who committed suicide in the first year did so within 1 month of diagnosis. No change in this distribution occurred over time. CONCLUSIONS: Cancer patients carry an increased risk of suicide. However, this risk peaks with the month following diagnosis. Clinicians should be aware of this increased risk and include assessments of mood state and suicidality at the time of initial diagnosis of the malignancy and be prepared to provide referral to mental health treatment providers.

The effects of sertraline on psychopathic traits.

We examined whether antidepressants alter expression of psychopathic personality traits in patients with major depressive disorder (MDD). Data were collected from a double-blind, placebo-controlled 8-week trial evaluating the efficacy of sertraline (50-200 mg/day) combined with either tri-iodothyronine (T3) or matching placebo in adult outpatients with major depressive disorder. Administration of sertraline was open-label; T3/placebo was double-blind. At the baseline and week 8 visits, patients completed the short form of the Psychopathic Personality Inventory (PPI), a well-validated self-report measure assessing two major factors of psychopathy: Fearless Dominance (PPI-1) and Self-Centered Impulsivity (PPI-2). Change in PPI scores were assessed using paired t-tests for all participants who completed a baseline and postrandomization PPI. Ninety patients (84 completers and six who terminated the trial early) were eligible for the analysis. Both PPI factors changed significantly from baseline to endpoint, but in opposing directions. The mean score on PPI-1 increased significantly during treatment; this change was weakly correlated with change in depression scores. In contrast, the mean score on PPI-2 decreased significantly, but these changes were not correlated with changes in depression scores. Independent of their effects on depression, antidepressants increase adaptive traits traditionally observed in psychopathic individuals, such as social charm and interpersonal and physical boldness. Antidepressants reduce other, more maladaptive, traits associated with psychopathy, including dysregulated impulsivity and externalization.