Clinical Outcomes of Intravenous Ketamine Treatment for Depression in the VA Health System.

Objective/Background: Intravenous (IV) ketamine is effective for reducing symptoms of major depressive disorder in short-term clinical trials; this study characterized clinical outcomes of repeated infusions in routine clinical practice and the frequency and number of infusions used to sustain symptom improvement.Methods: Records of IV ketamine infusions for depression and associated Patient Health Questionnaire-9 (PHQ-9) scores were identified from Veterans Health Administration (VA) electronic medical records for patients treated in Fiscal Year 2020 and up to 12 months following the date of their first infusion.Results: Sample patients (n = 215) had a mean baseline PHQ-9 score of 18.6 and a mean of 2.1 antidepressant medication trials in the past year and 6.1 antidepressant trials in the 20 years prior to their first ketamine infusion. Frequency of infusions decreased from every 5 days to every 3-4 weeks over the first 5 months of infusions, with a mean of 18 total infusions over 12 months. After 6 weeks of treatment, 26% had a 50% improvement in PHQ-9 score (response) and 15% had PHQ-9 score ≤ 5 (remission). These improvements were similar at 12 and 26 weeks. No demographic characteristics or comorbid diagnoses were associated with 6-week PHQ-9 scores.Conclusions: While only a minority of patients treated with IV ketamine for depression experienced response or remission, symptom improvements achieved within the first 6 weeks were sustained over at least 6 months with decreasing infusion frequency. Further study is needed to determine optimal infusion frequency and potential for adverse effects with repeated ketamine infusions for depression.

Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events. OBJECTIVE/HYPOTHESIS: To examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individual's alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD. METHODS: Six-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD17) ≥ 17. RESULTS: 202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (N = 59), however, had significantly greater mean decrease in HamD17 than sham (N = 60) (-9.00 vs. -6.56, P = 0.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs. -4.25, P = 0.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS. CONCLUSIONS: Results suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended.

Quantitative electroencephalogram biomarkers for predicting likelihood and speed of achieving sustained remission in major depression: a report from the biomarkers for rapid identification of treatment effectiveness in major depression (BRITE-MD) trial.

OBJECTIVE: Clinical trials in major depressive disorder (MDD) commonly assess remission at a single endpoint. Complementary, clinically relevant metrics include the likelihood and speed of achieving sustained remission. A neurophysiologic measure, the Antidepressant Treatment Response (ATR) index, previously predicted 8-week outcomes of pharmacotherapy. We retrospectively examined data from the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) trial to evaluate this biomarker's properties in predicting sustained remission and time to achieve sustained remission. METHOD: In the BRITE-MD trial, 67 adults with DSM-IV MDD received escitalopram continuously for 13 weeks. The 17-item Hamilton Depression Rating Scale (HDRS17) was used to define sustained remission as achieving remission (HDRS17 score ≤ 7) at a series of consecutive assessments, including week 13. The onset of sustained remission was defined as the earliest time from which all subsequent HDRS17 assessments were ≤ 7. The ATR was evaluated by using frontal quantitative electroencephalogram recordings at baseline and week 1. Subjects were stratified based on ATR status (ie, ATR+/ATR-). Kaplan-Meier survival analysis evaluated group differences in time to sustained remission. Higher ATR was hypothesized to predict sustained remission and time to sustained remission. Subjects participated between January 2006 and July 2007. RESULTS: Of 67 subjects, 36 achieved remission by week 13, and ATR predicted this single endpoint in receiver operating characteristic analyses (P = .016; sensitivity, 52.8%; positive predictive value, 76.0%). Remitters had a higher mean (SD) ATR value than those who did not remit (57.9 [10.0] vs 51.9 [8.7], P = .012). Sixteen of the 31 individuals with sustained remission had ATR+ status, while 28 of the 36 who were not sustained remitters had ATR- status (P = .012). The mean time to reach sustained remission was significantly shorter among ATR+ subjects than ATR- individuals (38 vs 53 days, P = .038). CONCLUSIONS: The ATR index predicted remission at 13 weeks as well as the speed of achieving sustained remission with antidepressant monotherapy. This finding suggests that the ATR biomarker may predict stable longer-term outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00289523.

A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state.

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542.

Mixed depression: a study of its phenomenology and relation to treatment response.

BACKGROUND: Mixed depression reflects the occurrence of a major depressive episode with subsyndromal manic symptoms. Not recognized in DSM-IV, it is included in the proposed changes for DSM-5. Observational and cross-sectional studies have suggested that mixed depression is present in up to one-half of major depressive episodes, whether in MDD or bipolar disorder. Based on observational studies, antidepressants appear to be less effective, and neuroleptics more effective, in mixed than pure depression (major depressive episodes with no manic symptoms). In this report, we examine the specific manic symptoms that are most present in mixed depression, especially as they correlate with prospectively assessed treatment response. METHODS: In 72 patients treated in a randomized clinical trial (ziprasidone versus placebo), we assessed the phenomenology of manic symptom type at study entry and their influence as predictors of treatment response. RESULTS: The most common symptom presentation was a clinical triad of flight of ideas (60%), distractibility (58%), and irritable mood (55%). Irritable mood was the major predictor of treatment response. DSM-based diagnostic distinctions between MDD and bipolar disorder (type II) did not predict treatment response. CONCLUSION: In this prospective study, mixed depression seems to be most commonly associated with irritable mood, flight of ideas, and distractibility, with irritability being an important predictor of treatment outcome with neuroleptic agents. If these data are correct, in the presence of mixed depression, the DSM-based dichotomy between MDD and bipolar disorder does not appear to influence treatment response.

Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study.

BACKGROUND: Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE: We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS: Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS: Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS: These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: results of the BRITE-MD study.

Patients with Major Depressive Disorder (MDD) may not respond to antidepressants for 8 weeks or longer. A biomarker that predicted treatment effectiveness after only 1 week could be clinically useful. We examined a frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, as a predictor of response to escitalopram, and compared ATR with other putative predictors. Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study. After 1 week of treatment with escitalopram, 10 mg, a second QEEG was performed, and the ATR was calculated. Subjects then were randomly assigned to continue with escitalopram, 10 mg, or change to alternative treatments. Seventy-three evaluable subjects received escitalopram for a total of 49days. Response and remission rates were 52.1% and 38.4%, respectively. The ATR predicted both response and remission with 74% accuracy. Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors. Responders had larger decreases in Hamilton Depression Rating Scale (Ham-D(17)) scores at day 7 (P=0.005), but remitters did not. Clinician prediction based upon global impression of improvement at day 7 did not predict outcome. Logistic regression showed that the ATR and early Ham-D(17) changes were additive predictors of response, but the ATR was the only significant predictor of remission. Future studies should replicate these results prior to clinical use.

Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder.

We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications.

A double-blind, placebo-controlled pilot study of galantamine to improve cognitive dysfunction in minimally symptomatic bipolar disorder.

OBJECTIVE: There is increasing evidence that cognitive impairment is common in patients with bipolar disorder. The purpose of this study was to determine whether galantamine augmentation improved cognition in patients with euthymic bipolar disorder. In addition, the effect of galantamine on clinical measures of functioning and psychopathology was assessed. METHOD: This study was a randomized double-blind, placebo-controlled, parallel design examining the impact of galantamine augmentation on cognition and other clinical measures in 30 patients during the course of 3 months. Sixteen subjects who completed baseline and follow-up second neuropsychological testing were evaluable (10 with galantamine and 6 with placebo). RESULTS: The galantamine group showed improved performance on the California Verbal Learning Test total learning and the placebo group showed improved performance on the 2 Delis-Kaplan Executive Functioning System trail-making conditions and category fluency. CONCLUSIONS: Episodic memory performance was improved in the galantamine treatment group but did not improve in the placebo group. In contrast, performance on 2 of the processing speed measures showed significant improvement in the placebo condition, whereas that of the patients treated with galantamine did not improve. Galantamine may thus have specific benefits for episodic memory, but not processing speed, in patients with cognitive impairment as part of bipolar disorder.

Sociodemographic, clinical, and treatment characteristics associated with worsened depression during treatment with citalopram: results of the NIMH STAR(*)D trial.

CONTEXT: Outcomes of antidepressant medication treatment for major depressive disorder include remission, response, and nonresponse. But nonresponse can include depression that worsened over the course of treatment, an outcome that has received scant attention. OBJECTIVE: To describe baseline sociodemographic, clinical, and treatment characteristics associated with worsened depression during a trial of citalopram. DESIGN, PARTICIPANTS, AND SETTINGS: Open-label clinical trial of 2,876 adult outpatients seen in 18 primary and 23 psychiatric-care settings. INTERVENTION: Citalopram was delivered using measurement-based care and flexible dosing with the aim of achieving symptom remission. Symptom and side effect ratings were obtained at each treatment visit. MAIN OUTCOME MEASURES: Worsened depression was defined as an exit score >or=3 points above the pretreatment (baseline) score on the 16-item QIDS-SR. Baseline sociodemographic, clinical, and treatment characteristics were examined for association with worsened depression. RESULTS: Of 2,864 outpatients who returned for >or=2 post baseline visits, 150 (5.2%) had worsened depression at study exit. Baseline characteristics independently associated with increased worsened depression included African-American race (OR=2.02), having less than a college education (OR=2.36), posttraumatic stress disorder (OR=1.78), drug abuse (OR=1.97), hypochondriasis (OR=2.74). Participants with worsened depression spent less time in treatment; had fewer treatment visits; exited the study sooner; had more frequent, intense, and burdensome adverse effects; and were more intolerant of medication. CONCLUSIONS: The presence of certain baseline characteristics indicated a greater likelihood of worsened depression during antidepressant treatment. Patients with these characteristics should be monitored closely during treatment and may be candidates for more aggressive treatment.

Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial.

Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery-Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.

Does the duration of index episode affect the treatment outcome of major depressive disorder? A STAR*D report.

OBJECTIVE: This article aims to identify baseline sociodemographic and clinical characteristics associated with the duration of the index major depressive episode (MDE) and to assess the effect of the current MDE duration on response and remission rates with up to 14 weeks of citalopram. METHOD: Eligible participants met DSM-IV criteria for nonpsychotic major depressive disorder, scored >or= 14 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and were not resistant to adequate antidepressant treatment in the current episode. The first patient was enrolled in July 2001 and the last visit for the last patient in follow-up was in March 2006. The evaluable sample (N = 2851) was divided into 4 groups based on the index MDE duration at study entry: acute (or= 42 months, N = 394). These 4 groups were compared in terms of baseline sociodemographic and clinical characteristics and treatment outcomes. Citalopram was generally begun at 20 mg/day and raised to 40 mg/day by weeks 2 through 4 and to 60 mg/day (final dose) by weeks 4 through 6. Logistic regression models with adjusted post hoc analyses were used to control for associated baseline characteristics. Response was defined as >or= 50% reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores at exit. Remission was defined as

Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study.

OBJECTIVE: To determine the efficacy of divalproex (extended release) in the treatment of acute nonrefractory bipolar depression. METHOD: In a stratified, double-blind, randomized, placebo-controlled trial, 18 acutely depressed bipolar outpatients (DSM-IV criteria) received either divalproex monotherapy (target dose level, 70-90 ng/dL) (N = 9) or placebo (N = 9) for 6 weeks. Patients were recruited between January 2004 and May 2005. Clinical assessment on the Montgomery-Asberg Depression Rating Scale (MADRS) determined primary efficacy. RESULTS: The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo (group x time interaction, p = .0078). Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo (p = .003, linear growth curve model). Standardized effect size was large (Cohen d = 0.81). MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms. There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group (r = 0.29, df = 51, p = .03), but not in the placebo group (r = -0.15, df = 35, p = .36). CONCLUSIONS: Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression, which is consistent with previous small randomized studies. Some evidence of benefit in the depressive mixed state was observed. Confirmation or refutation with larger randomized clinical trials is warranted. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00226343.

Effect of age at onset on the course of major depressive disorder.

OBJECTIVE: This report assesses whether age at onset defines a specific subgroup of major depressive disorder in 4,041 participants who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. METHOD: The study enrolled outpatients 18-75 years of age with nonpsychotic major depressive disorder from both primary care and psychiatric care practices. At study entry, participants estimated the age at which they experienced the onset of their first major depressive episode. This report divides the population into five age-at-onset groups: childhood onset (ages <12), adolescent onset (ages 12-17), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late adult onset (ages > or =60). RESULTS: No group clearly stood out as distinct from the others. Rather, the authors observed an apparent gradient, with earlier ages at onset associated with never being married, more impaired social and occupational function, poorer quality of life, greater medical and psychiatric comorbidity, a more negative view of life and the self, more lifetime depressive episodes and suicide attempts, and greater symptom severity and suicidal ideation in the index episode compared to those with later ages at onset of major depressive disorder. CONCLUSIONS: Although age at onset does not define distinct depressive subgroups, earlier onset is associated with multiple indicators of greater illness burden across a wide range of indicators. Age of onset was not associated with a difference in treatment response to the initial trial of citalopram.

An association of intrusive, repetitive phrases with lamotrigine treatment in bipolar II disorder.

INTRODUCTION: Bipolar disorder is frequently associated with obsessional symptoms. However, no reports have identified a pattern of obsessionality that is associated with a specific mood stabilizer treatment. METHODS: A chart review was conducted on five patients with bipolar II disorder who spontaneously reported a form of obsessionality characterized by intrusive, recurrent phrases after taking lamotrigine. RESULTS: Development of the phrases occurred from 7-42 years after mood disorder onset and occurred only after initiation of lamotrigine treatment. The phrases improved with lamotrigine discontinuation or dose reduction and recurred with lamotrigine re-challenge or upon dose escalation. CONCLUSION: A possible mechanism for the development of the intrusive phrases involves the influence of lamotrigine on glutamatergic regulation in a bipolar II disorder population vulnerable to the expression of obsessionality. Limitations of this report include its observational nature, small number of cases reported, and confound of concomitant medication use.

Aripiprazole augmentation in treatment-resistant bipolar depression: early response and development of akathisia.

There is growing evidence that atypical antipsychotics may be effective in the treatment of acute bipolar depression. Results from randomized, placebo-controlled trials support the use of quetiapine monotherapy and a combination of olanzapine-fluoxetine in the depressed phase of bipolar disorder, while only limited data exists regarding the use of aripiprazole in this population. To assess the potential effectiveness of aripiprazole in treating acute bipolar depression, a chart review was conducted on 12 patients with treatment-resistant bipolar disorder (I, II, and not otherwise specified [NOS]) who received aripiprazole augmentation for the relief of an acute major depressive episode. After 8 weeks of treatment, 4 of 12 (33%) patients demonstrated a response, defined as a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score. In addition, 5 of 12 (42%) patients newly developed akathisia. This report, though limited by its small sample size and naturalistic design, suggests that the usefulness of aripiprazole in the treatment of bipolar depression may be limited by akathisia.

Human immunodeficiency virus and depression in primary care: a clinical review.

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of developing depression. Depressive syndromes in these patients pose a challenge both diagnostically and therapeutically. These syndromes reflect both the presence of preexisting mood disorders and the development of depressive syndromes subsequent to HIV infection. DATA SOURCES: A search of the literature to 2005 was performed using the PubMed and Ovid search engines. English- and Portuguese-language articles were identified using the following keywords: HIV or AIDS and depression, mental illness, suicide, fatigue, psychiatry, and drug interactions. Additional references were identified through bibliography reviews of relevant articles. DATA SYNTHESIS: The clinical presentation and differential diagnosis of depressive symptoms in HIV illness and the role of HIV in the development of these conditions are reviewed. Management issues including suicide assessment and treatment options are then discussed, and potentially important pharmacokinetic interactions are reviewed. CONCLUSIONS: Individuals with HIV show higher rates of depression. This phenomenon may be due to a preexisting psychiatric disorder or to the HIV infection. Untreated depression symptoms may lead to non-compliance with drug regimens or increased high-risk behaviors. Given the adverse sequelae of untreated depressions in HIV illness, identification and management of depression are integral components of comprehensive HIV care.