Charles DeBattista
Professor of Psychiatry and Behavioral Sciences (General Psychiatry and Psychology - Adult)
Clinical Focus
- Psychiatry
- Clinical Psychopharmacology
- Resistant Depression
- Neuromodulation
Academic Appointments
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Professor - University Medical Line, Psychiatry and Behavioral Sciences
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Member, Wu Tsai Neurosciences Institute
Honors & Awards
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Fellow, American College of Psychiatrists (2022)
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Nancy C.A. Roeske, M.D. Award for Excellence in Medical Student Education, American Psychiatric Association (2018)
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Teacher of the Year, Dept. Of Psychiatry (1998, 2000, 2001)
Professional Education
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Board Certification: American Board of Psychiatry and Neurology, Psychiatry (2007)
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Fellowship: Stanford University Psychiatry and Behavioral Sciences (1993) CA
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Residency: Stanford University Adult Psychiatry Residency (1993) CA
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Internship: Stanford University Adult Psychiatry Residency (1990) CA
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Medical Education: University of California at San Francisco School of Medicine (1989) CA
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DMH, UCSF/UC Berkeley, Mental Health (1986)
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MD, UCSF, Medicine (1989)
Current Research and Scholarly Interests
Treatment resistant depression.
Novel biological interventions in the treatment of mental illness.
Anti-glucocorticoid drugs in the treatment of mood disorders.
Augmentation strategies in the treatment of depression.
Clinical Trials
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Tianeptine for Treatment Resistant Depression
Recruiting
The studies will be conducted in parallel at two sites: the the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai (MSSM), and Stanford Depression Research Clinic at Stanford University School of Medicine (SUSM). In addition, MRI studies for the MSSM patients will be carried out at the New York State Psychaitric Institute (NYSPI). The following procedures will be approved by the local Institutional Review Boards (IRBs) at each site, where the site PIs (Alla Landa, PhD, NYSPI, James Murrough, MD at MSSM, and Alan Schatzberg, MD at SUSM) will be responsible for overseeing conduct of the study at their respective site. Dr. Jonathan Javitch is the scientific leader of this program and holds the IND for tianeptine use in this study. Investigators will recruit 75 participants with current unipolar MDD, non-delusional, between 21-60, who have failed at least 2 two adequate treatment trials with a standard antidepressant. Patients will receive an 8-week treatment trial of tianeptine. MSSM patients will also undergo structural and task-based magnetic resonance imaging (MRI) that will be performed under Dr. Landa's direction at NYSPI in order to maintain the internal validity of the data set. MSSM subjects will be transported to NYSPI to complete neuroimaging procedures as described below. Participants will be screened for MRI clearance during their screening visit and again at NYSPI on the day of the scan. Subjects will be asked MRI screening questions to ensure that are scanning eligible. Participants will also have additional tubes of blood drawn for human whole-genomic testing. This microarray will be used to identify regions of the human genome that contribute to disease susceptibility and phenotypes. The Illumina human whole-genome array will be used to provide a comprehensive view of the genome, detects single nucleotide polymorphisms and other variations across the genome.
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Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With TRD
Not Recruiting
This is a multi-site, randomized, open-label, effectiveness trial comparing three treatment arms for Major Depressive Disorder (MDD) patients with TRD who are currently on ongoing, stable and adequate antidepressant therapy (ADT). Adequate ADT is defined as a therapeutically sufficient dose for a sufficient treatment period, which would be expected to be effective as listed in the MGH Antidepressant Treatment Response Questionnaire (ATRQ). Patients will be randomized in a 1:1:1 fashion to one of three open-label treatment arms: a) aripiprazole augmentation, b) rTMS augmentation, and c) switching to venlafaxine XR or Duloxetine.
Stanford is currently not accepting patients for this trial.
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Functional MRI Before and After Treatment for Depression
Not Recruiting
The purpose of this study is to help us understand how depression changes brain activity and how this relates to mood, anxiety, and cognitive functions like memory. We also hope to develop a brain imaging test that will predict either before or within two weeks of starting a medicine whether the treatment will work.
Stanford is currently not accepting patients for this trial. For more information, please contact Maureen H Chang, B.S., 650-725-4620.
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Investigate Efficacy & Safety of RO4995819 vs. Placebo as Adjunct Tx in Patients w/Major Depressive Disorder
Not Recruiting
The purpose of the study is to explore the efficacy of 6 weeks treatment of an investigational medication, RO4995819, versus placebo as adjunctive therapy in patients with major depression.
Stanford is currently not accepting patients for this trial. For more information, please contact Maureen Chang, B.S., 650-725-4620.
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Radiosurgical Neuromodulation for Refractory Depression
Not Recruiting
This study is designed to evaluate the safety and effectiveness of an investigational procedure for treating people with treatment resistant bipolar depression (TRD). Precise dose delivery of radiation to the predetermined targets in the brain will be accomplished with known Cyberknife stereotactic radiosurgery methods. This technology is considered to be noninvasive (does not physically invade your body). We will be studying if the Cyberknife influences the sensitivity of certain nerves of your brain. Although many clinical treatments for psychiatric conditions have been done using stereotactic radiosurgery, the present study is experimental, because we are seeking to use more moderate doses of radiation that are intended not to destroy any brain cells, but to normalize or modulate their function.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
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Ropinirole Controlled Release (CR) as an Adjunctive Agent in the Treatment of Major Depression
Not Recruiting
This is an 8 week study for patients who are currently taking antidepressant medication but not fully responding. Ropinirole CR would be taken in conjunction with current antidepressant medication. Patients come into the clinic once a week when starting on the medication and then once every other week for the remainder of the 8 weeks.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
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Treatment Trial for Psychogenic Nonepileptic Seizures
Not Recruiting
The investigators propose that patients who receive targeted pharmacotherapy (sertraline) or focused psychotherapy (cognitive behavioral therapy-informed psychotherapy (CBT-ip) for NES) or combined treatment (CBT-ip + sertraline) will report fewer nonepileptic seizures (NES) compared to patients who receive community care / treatment as usual (TAU). The purpose of this study is to provide pilot testing and data to inform the future multicenter randomized controlled trial based on the hypothesis.
Stanford is currently not accepting patients for this trial. For more information, please contact Jessica Hawkins, (650) 723 - 8323.
2024-25 Courses
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Independent Studies (5)
- Directed Reading in Psychiatry
PSYC 299 (Aut, Win, Spr, Sum) - Graduate Research
PSYC 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
PSYC 370 (Aut, Win, Spr, Sum) - Teaching in Psychiatry
PSYC 290 (Aut, Win, Spr, Sum) - Undergraduate Research, Independent Study, or Directed Reading
PSYC 199 (Aut, Win, Spr, Sum)
- Directed Reading in Psychiatry
All Publications
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Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2023
Abstract
Major depressive disorder (MDD) is a mental health disorder that can cause disability and functional impairment that standard-of-care (SOC) antidepressant therapies (ADTs) can take weeks to treat. Zuranolone is a neuroactive steroid and positive allosteric modulator of synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors approved as an oral, once-daily, 14-day treatment course in adults with postpartum depression and under investigation in adults with MDD. The phase 3 CORAL Study (NCT04476030) evaluated the efficacy and safety of zuranolone 50 mg co-initiated with SOC ADT (zuranolone+ADT) vs placebo co-initiated with SOC ADT (placebo+ADT) in adults with MDD. Patients were randomized 1:1 to once-daily, blinded zuranolone+ADT or placebo+ADT for 14 days, then continued open-label SOC ADT for 28 more days. The primary endpoint was change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score at Day 3. Among 425 patients in the full analysis set, CFB in HAMD-17 total score at Day 3 was significantly improved with zuranolone+ADT vs placebo+ADT (least squares mean [standard error], -8.9 [0.39] vs -7.0 [0.38]; p = 0.0004). The majority of patients receiving zuranolone+ADT that experienced treatment-emergent adverse events (TEAEs) reported mild or moderate events. The most common TEAEs present in ≥10% of patients in either zuranolone+ADT or placebo+ADT groups were somnolence, dizziness, headache, and nausea. These results demonstrate that zuranolone+ADT provided more rapid improvement in depressive symptoms compared with placebo+ADT in patients with MDD, with a safety profile consistent with previous studies. Clinical trial registration: ClinicalTrials.gov identifier: NCT04476030.
View details for DOI 10.1038/s41386-023-01751-9
View details for PubMedID 37875578
View details for PubMedCentralID 3163615
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Efficacy of Ketamine in Unmedicated Adults With OCD: A Randomized Controlled Trial
ELSEVIER SCIENCE INC. 2023: S83
View details for Web of Science ID 000993018500200
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Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.
Journal of affective disorders
2023
Abstract
COMP360 is a proprietary, synthetic formulation of psilocybin being developed for treatment-resistant depression (TRD), a burdensome, life-threatening illness with high global impact. Here, we expand upon the previous report of primary outcomes from a phase 2 study of COMP360 in individuals with TRD-the largest randomised controlled clinical trial of psilocybin-to discuss findings of the exploratory efficacy endpoints.In this phase 2, double-blind trial, 233 participants with TRD were randomised to receive a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), administered alongside psychological support from trained therapists. Efficacy measures assessed patient-reported depression severity, anxiety, positive and negative affect, functioning and associated disability, quality of life, and cognitive function.At Week 3, psilocybin 25 mg, compared with 1 mg, was associated with greater improvements from Baseline total scores in all measures. The 10 mg dose produced smaller effects across these measures.Interpretation of this trial is limited by the absence of an active comparator and the possibility of functional unblinding in participants who received a low dose of psilocybin.Three weeks after dosing, psilocybin 25 mg and, to a lesser degree, 10 mg improved measures of patient-reported depression severity, anxiety, affect, and functioning. These results extend the primary findings from the largest randomised clinical trial of psilocybin for TRD to examine other outcomes that are of importance to patients.
View details for DOI 10.1016/j.jad.2023.01.108
View details for PubMedID 36740140
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Efficacy of Ketamine in Unmedicated Adults With Obsessive-Compulsive Disorder: A Randomized Controlled Trial
SPRINGERNATURE. 2022: 302-303
View details for Web of Science ID 000897934700574
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Efficacy of Ketamine in Unmedicated Adults With Obsessive-Compulsive Disorder: A Randomized Controlled Trial
SPRINGERNATURE. 2022: 302-303
View details for Web of Science ID 000929613800574
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Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study.
The Journal of clinical psychiatry
2022; 84 (1)
Abstract
Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam.Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n=44) were compared to those who were not (n=55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage.Results: Benzodiazepine users did not differ from non-users on the original study's primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P=.018) and Clinical Global Impressions-Severity of Illness scale (CGI-S; P=.008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1.Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.Trial Registration: ClinicalTrials.gov identifier: NCT01920555.
View details for DOI 10.4088/JCP.22m14491
View details for PubMedID 36383742
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Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.
The New England journal of medicine
2022; 387 (18): 1637-1648
Abstract
Psilocybin is being studied for use in treatment-resistant depression.In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits).A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).
View details for DOI 10.1056/NEJMoa2206443
View details for PubMedID 36322843
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A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings.
Journal of affective disorders
1800
Abstract
BACKGROUND: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices.METHODS: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days.RESULTS: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to <5). The effect size was d=1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions.CONCLUSION: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.
View details for DOI 10.1016/j.jad.2021.12.097
View details for PubMedID 35027209
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Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.
Psychiatry research
1800; 308: 114354
Abstract
Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.
View details for DOI 10.1016/j.psychres.2021.114354
View details for PubMedID 34986431
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Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.
The American journal of psychiatry
2021: appiajp202120101429
Abstract
OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of 90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Asberg Depression Rating Scale (MADRS) 4 weeks after treatment.RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.
View details for DOI 10.1176/appi.ajp.2021.20101429
View details for PubMedID 34711062
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The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
2021; 49: 122-132
Abstract
This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59vs. 3.00±1.41, t-test p=0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555.
View details for DOI 10.1016/j.euroneuro.2021.04.024
View details for PubMedID 34090255
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Safety of Using a Combinatorial Pharmacogenomic Test for Patients with Major Depressive Disorder in the GUIDED trial.
CNS spectrums
2021; 26 (2): 169-170
Abstract
BACKGROUND: Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).MATERIALS AND METHODS: Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.RESULTS: Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41-2.83) and RR 2.25 (95% CI 1.39-3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15-0.99, p=0.048). No other significant differences in risk were observed at week 8.CONCLUSION: These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.FUNDING: Myriad Neuroscience/Assurex Health.
View details for DOI 10.1017/S1092852920002746
View details for PubMedID 34127099
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The Black Book of Psychotropic Dosing and Monitoring.
Psychopharmacology bulletin
2021; 51 (1): 8–58
View details for PubMedID 33897062
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Raising the Quality of Psychopharmacology Clinical Psychiatric Practice: Elements of Good Psychopharmacology Care.
Journal of clinical psychopharmacology
2021; 42 (1): 3-6
View details for DOI 10.1097/JCP.0000000000001499
View details for PubMedID 34928556
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Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression.
Psychiatry research
2020; 296: 113649
Abstract
We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.
View details for DOI 10.1016/j.psychres.2020.113649
View details for PubMedID 33360967
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Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD) (vol 25, pg 1592, 2020)
MOLECULAR PSYCHIATRY
2020; 25 (7): 1604
View details for DOI 10.1038/s41380-018-0311-2
View details for Web of Science ID 000541097500022
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Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)
MOLECULAR PSYCHIATRY
2020; 25 (7): 1592–1603
View details for DOI 10.1038/s41380-018-0256-5
View details for Web of Science ID 000541097500021
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Combinatorial PharmacogenomicTesting Improves Outcomes for Older Adults With Depression.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
2020
Abstract
OBJECTIVE: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD).DESIGN: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms.SETTING: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites.PARTICIPANTS: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode.INTERVENTION: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU).OUTCOMES: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis.RESULTS: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (chi2 = 19.3, df = 2; p <0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities.CONCLUSIONS: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression.
View details for DOI 10.1016/j.jagp.2020.05.005
View details for PubMedID 32513518
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Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.
Psychiatry research
2020; 290: 113017
Abstract
Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.
View details for DOI 10.1016/j.psychres.2020.113017
View details for PubMedID 32485484
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COMBINATORIAL PHARMACOGENETIC TESTING IMPROVES RESPONSE AND REMISSION FOR PATIENTS OVER 65 WITH DEPRESSION WHO HAVE FAILED ONE MEDICATION TRIAL
ELSEVIER SCIENCE INC. 2020: S151–S152
View details for Web of Science ID 000520017700165
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Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression.
The American journal of psychiatry
2020: appiajp201919070720
Abstract
New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.
View details for DOI 10.1176/appi.ajp.2019.19070720
View details for PubMedID 32252538
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150 HAM-D6 Outcomes in a Randomized, Controlled Trial Evaluating the Utility of Combinatorial Pharmacogenomics in Depression.
CNS spectrums
2020; 25 (2): 295–96
Abstract
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: 'use as directed', 'moderate gene-drug interactions', or 'significant gene-drug interactions.' Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.Assurex Health, Inc.
View details for DOI 10.1017/S1092852920000668
View details for PubMedID 32331038
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Impact of Pharmacogenomics on Clinical Outcomes for Patients Taking Medications With Gene-Drug Interactions in a Randomized Controlled Trial.
The Journal of clinical psychiatry
2019; 80 (6)
Abstract
OBJECTIVE: The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.METHODS: Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response (≥ 50% decrease in HDRS-17 score), and remission (HDRS-17 score ≤ 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented.RESULTS: Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission).CONCLUSIONS: By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02109939.
View details for DOI 10.4088/JCP.19m12910
View details for PubMedID 31721487
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COMBINATORIAL PHARMACOGENOMIC TESTING IMPROVES OUTCOMES FOR PATIENTS TAKING MEDICATIONS WITH GENE-DRUG INTERACTIONS IN A RANDOMIZED, CONTROLLED TRIAL
ELSEVIER. 2019: S132–S133
View details for DOI 10.1016/j.euroneuro.2019.08.037
View details for Web of Science ID 000488216600242
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Response to: Goldberg et al. and Severance et al. letters to the editor the clinical significance of improving remission over standard of care - The reality of treatment resistant-based therapies.
Journal of psychiatric research
2019
View details for DOI 10.1016/j.jpsychires.2019.04.027
View details for PubMedID 31101328
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Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study
JOURNAL OF PSYCHIATRIC RESEARCH
2019; 111: 59–67
View details for DOI 10.1016/j.jpsychires.2019.01.003
View details for Web of Science ID 000466252700009
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Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression
JOURNAL OF PSYCHIATRIC RESEARCH
2019; 110: 166–71
View details for DOI 10.1016/j.jpsychires.2019.01.010
View details for Web of Science ID 000458711100021
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Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression
DEPRESSION AND ANXIETY
2019; 36 (3): 235–43
View details for DOI 10.1002/da.22875
View details for Web of Science ID 000460690700004
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Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression.
Journal of psychiatric research
2019; 110: 166–71
Abstract
BACKGROUND: While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women.METHODS: A randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori-planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women.RESULTS: Analyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55).CONCLUSIONS: Results do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results.
View details for PubMedID 30641350
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Correction: Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
Molecular psychiatry
2019
Abstract
Supplementary Figure 1 and Supplementary Tables 1-4 have been re-uploaded so as to reflect the versions supplied during proofs stage. The publisher apologizes for the error in versioning. The HTML version of the paper has been updated.
View details for PubMedID 30617276
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Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study.
Journal of psychiatric research
2019; 111: 59–67
Abstract
Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial - a rater- and patient-blind randomized controlled trial. Patients were randomized to treatment as usual (TAU) or a pharmacogenomics-guided intervention arm in which clinicians had access to a pharmacogenomic test report to inform medication selections (guided-care). Medications were considered congruent ('use as directed' or 'use with caution' test categories) or incongruent ('use with increased caution and with more frequent monitoring' test category) with test results. Unblinding occurred after week 8. Primary outcome was symptom improvement [change in 17-item Hamilton Depression Rating Scale (HAM-D17)] at week 8; secondary outcomes were response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. At week 8, symptom improvement for guided-care was not significantly different than TAU (27.2% versus 24.4%, p = 0.107); however, improvements in response (26.0% versus 19.9%, p = 0.013) and remission (15.3% versus 10.1%, p = 0.007) were statistically significant. Patients taking incongruent medications prior to baseline who switched to congruent medications by week 8 experienced greater symptom improvement (33.5% versus 21.1%, p = 0.002), response (28.5% versus 16.7%, p = 0.036), and remission (21.5% versus 8.5%, p = 0.007) compared to those remaining incongruent. Pharmacogenomic testing did not significantly improve mean symptoms but did significantly improve response and remission rates for difficult-to-treat depression patients over standard of care (ClinicalTrials.gov NCT02109939).
View details for PubMedID 30677646
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Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial.
BMC psychiatry
2019; 19 (1): 420
Abstract
Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6.At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms.The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms.Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.
View details for DOI 10.1186/s12888-019-2410-2
View details for PubMedID 31881956
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Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression.
Journal of affective disorders
2019; 260: 131–39
Abstract
To examine the rate and time to relapse for remitters and responders to ketamine in treatment-resistant depression (TRD).Subjects with TRD were randomized to a single infusion of one of several doses of intravenous ketamine, or midazolam. Using Kaplan-Meier survival function, the current report examines the rate and time to relapse, defined as MADRS ≥ 22, over a period of 30 days, in subjects who achieved remission (MADRS ≤ 10) or response (≥ 50% reduction in MADRS) on day three post-infusion of intravenous ketamine 0.1, 0.5, or 1.0 mg/kg.Of the 60 randomized participants who received a single ketamine (0.1, 0.5, or 1.0 mg/kg) infusion, 19 (34%) met criteria for remission and 27 (48%) for response, on day 3 post-infusion. A numerical dose-response relationship was observed, with remitters/responders on ketamine 1.0 mg/kg having the lowest relapse rate, followed by ketamine 0.5 mg/kg and 0.1 mg/kg, respectively (% of remitters who relapsed by day 14: 38% with 1.0 mg/kg, 50% with 0.5 mg/kg, 100% with 0.1 mg/kg;% of responders who relapsed by day 14: 30% with 1.0 mg/kg, 50% with 0.5 mg/kg, 80% with 0.1 mg/kg).The sample size was small. No MADRS measurements at day one post-infusion. The study was not powered to assess differences in relapse prevention between different doses of ketamine.Time to relapse after successful treatment with a single infusion of ketamine appears to follow a dose-response relationship, where higher dosage leads to increased time to relapse.
View details for DOI 10.1016/j.jad.2019.09.017
View details for PubMedID 31494365
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Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression.
Depression and anxiety
2018
Abstract
OBJECTIVE: To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD).METHODS: In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0mg/kg, or midazolam 0.045mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion.RESULTS: N=45 subjects had anxious TRD, compared to N=54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84)=0.02, P=0.88; Day 3: F(1, 82)=0.12, P=0.73).CONCLUSION: In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.
View details for PubMedID 30597688
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Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD).
Molecular psychiatry
2018
Abstract
Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5mg/kg over 40min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1mg/kg (n=18), a single dose of ketamine 0.2mg/kg (n=20), a single dose of ketamine 0.5mg/kg (n=22), a single dose of ketamine 1.0mg/kg (n=20), and a single dose of midazolam 0.045mg/kg (active placebo) (n=19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group*time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5mg/kg) and high dose (1mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1mg/kg) was significant only prior to adjustment (p=0.02, p-adj=0.14, d=-0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5mg/kg and 1.0mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine.TRIAL REGISTRATION: NCT01920555.
View details for PubMedID 30283029
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Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein
AMERICAN JOURNAL OF PSYCHIATRY
2018; 175 (3): 251–61
View details for DOI 10.1176/appi.ajp.2017.17020172
View details for Web of Science ID 000437289900011
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The Black Book of Psychotropic Dosing and Monitoring.
Psychopharmacology bulletin
2018; 48 (1): 64–153
View details for PubMedID 29382960
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Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.
The American journal of psychiatry
2018; 175 (3): 251–61
Abstract
Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.
View details for PubMedID 29241359
View details for PubMedCentralID PMC5832545
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Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.
The lancet. Psychiatry
2017; 4 (11): 839–49
Abstract
Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162.Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.Abbott (previously St Jude Medical).
View details for PubMedID 28988904
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Psychostimulants and Wakefulness-Promoting Agents
AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 5TH EDITION
2017: 1083–1103
View details for Web of Science ID 000550981300038
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Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression
TRANSLATIONAL PSYCHIATRY
2016; 6
Abstract
Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.
View details for DOI 10.1038/tp.2016.61
View details for Web of Science ID 000377305600005
View details for PubMedID 27138798
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Utility of event-related potentials in predicting antidepressant treatment response: An iSPOT-D report
EUROPEAN NEUROPSYCHOPHARMACOLOGY
2015; 25 (11): 1981-1990
Abstract
It is essential to improve antidepressant treatment of major depressive disorder (MDD) and one way this could be achieved is by reducing the number of treatment steps by employing biomarkers that can predict treatment outcome. This study investigated differences between MDD patients and healthy controls in the P3 and N1 component from the event-related potential (ERP) generated in a standard two-tone oddball paradigm. Furthermore, the P3 and N1 are investigated as predictors for treatment outcome to three different antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D)--a multi-center, international, randomized, prospective practical trial--1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression. P3 and N1 latencies and amplitudes were analyzed using a peak-picking approach and further replicated by using exact low resolution tomography (eLORETA). A reduced P3 was found in MDD patients compared to controls by a peak-picking analysis. This was validated in a temporal global field power analysis. Source density analysis revealed that the difference in cortical activity originated from the posterior cingulate and parahippocampal gyrus. Male non-responders to venlafaxine-XR had significantly smaller N1 amplitudes than responders. This was demonstrated by both analytical methods. Male non-responders to venlafaxine-XR had less activity originating from the left insular cortex. The observed results are discussed from a neural network viewpoint.
View details for DOI 10.1016/j.euroneuro.2015.07.022
View details for Web of Science ID 000369152500014
View details for PubMedID 26282359
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ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression
PHARMACOGENOMICS JOURNAL
2015; 15 (4): 332-339
Abstract
The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.
View details for DOI 10.1038/tpj.2014.72
View details for Web of Science ID 000358448500007
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Frontal and rostral anterior cingulate (rACC) theta EEG in depression: Implications for treatment outcome?
EUROPEAN NEUROPSYCHOPHARMACOLOGY
2015; 25 (8): 1190-1200
Abstract
In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram (EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.
View details for DOI 10.1016/j.euroneuro.2015.03.007
View details for Web of Science ID 000359875500014
View details for PubMedID 25936227
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ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial
AMERICAN JOURNAL OF PSYCHIATRY
2015; 172 (8): 751-759
Abstract
The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.
View details for DOI 10.1176/appi.ajp.2015.14050680
View details for Web of Science ID 000359274700015
View details for PubMedID 25815420
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Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report
JOURNAL OF AFFECTIVE DISORDERS
2015; 176: 141-150
Abstract
Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception.MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history.Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity.Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task.Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior.
View details for DOI 10.1016/j.jad.2015.01.061
View details for Web of Science ID 000350975500019
View details for PubMedID 25710095
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The International Study to Predict Optimized Treatment in Depression (iSPOT-D): Outcomes from the acute phase of antidepressant treatment.
Journal of psychiatric research
2015; 61: 1-12
Abstract
We aimed to characterize a large international cohort of outpatients with MDD within a practical trial design, in order to identify clinically useful predictors of outcomes with three common antidepressant medications in acute-phase treatment of major depressive disorder (MDD). The international Study to Predict Optimized Treatment in Depression has presently enrolled 1008 treatment-seeking outpatients (18-65 years old) at 17 sites (five countries). At pre-treatment, we characterized participants by symptoms, clinical history, functional status and comorbidity. Participants were randomized to receive escitalopram, sertraline or venlafaxine-extended release and managed by their physician following usual treatment practices. Symptoms, function, quality of life, and side-effect outcomes were assessed 8 weeks later. The relationship of anxiety to response and remission was assessed by comorbid Axis I diagnosis, presence/absence of anxiety symptoms, and dimensionally by anxiety symptom severity. The sample had moderate-to-severe symptoms, but substantial comorbidity and functional impairment. Of completers at week 8, 62.2% responded and 45.4% reached remission on the 17-item Hamilton Rating Scale for Depression; 53.3% and 37.6%, respectively on the 16-item Quick Inventory of Depressive Symptoms. Functional improvements were seen across all domains. Most participants had side effects that occurred with a frequency of 25% or less and were reported as being in the "none" to minimal/mild range for intensity and burden. Outcomes did not differ across medication groups. More severe anxiety symptoms at pre-treatment were associated with lower remission rates across all medications, independent of depressive severity, diagnostic comorbidity or side effects. Across medications, we found consistent and similar improvements in symptoms and function, and a dimensional prognostic effect of comorbid anxiety symptoms. These equivalent outcomes across treatments lay the foundation for identifying potential neurobiological and genetic predictors of treatment outcome in this sample.
View details for DOI 10.1016/j.jpsychires.2014.12.018
View details for PubMedID 25586212
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Impairment and distress patterns distinguishing the melancholic depression subtype: An iSPOT-D report.
Journal of affective disorders
2015; 174: 493-502
Abstract
This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress.Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress.Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants.Due to the cross-sectional nature of this study, causal pathways cannot be concluded.Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.
View details for DOI 10.1016/j.jad.2014.10.046
View details for PubMedID 25554994
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ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression.
The pharmacogenomics journal
2014
Abstract
The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.The Pharmacogenomics Journal advance online publication, 9 December 2014; doi:10.1038/tpj.2014.72.
View details for DOI 10.1038/tpj.2014.72
View details for PubMedID 25487678
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ABCB1 Genetic Variants and Neurocognitive Function Predict Antidepressant Outcomes
NATURE PUBLISHING GROUP. 2014: S521–S522
View details for Web of Science ID 000345905002075
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Measuring severe adverse events and medication selection using a "PEER Report" for nonpsychotic patients: a retrospective chart review
NEUROPSYCHIATRIC DISEASE AND TREATMENT
2012; 8: 277-284
Abstract
We previously reported on an objective new tool that uses quantitative electroencephalography (QEEG) normative- and referenced-electroencephalography sampling databases (currently called Psychiatric EEG Evaluation Registry [PEER]), which may assist physicians in determining medication selection for optimal efficacy to overcome trial-and-error prescribing. The PEER test compares drug-free QEEG features for individual patients to a database of patients with similar EEG patterns and known outcomes after pharmacological interventions. Based on specific EEG data elements and historical outcomes, the PEER Report may also serve as a marker of future severe adverse events (eg, agitation, hostility, aggressiveness, suicidality, homicidality, mania, hypomania) with specific medications. We used a retrospective chart review to investigate the clinical utility of such a registry in a naturalistic environment.This chart review demonstrated significant improvement on the global assessment scales Clinical Global Impression - Improvement and Quality of Life Enjoyment and Satisfaction - Short Form as well as time to maximum medical improvement and decreased suicidality occurrences. The review also showed that 54.5% of previous medications causing a severe adverse event would have been raised as a caution had the PEER Report been available at the time the drug was prescribed. Finally, due to the significant amount of off-label prescribing of psychotropic medications, additional, objective, evidence-based data aided the prescriber toward better choices.The PEER Report may be useful, particularly in treatment-resistant patients, in helping to guide medication selection. Based on the preliminary data obtained from this chart review, additional studies are warranted to establish the safety and efficacy of adding PEER data when making medication decisions.
View details for DOI 10.2147/NDT.S31665
View details for Web of Science ID 000305552300001
View details for PubMedID 22802691
View details for PubMedCentralID PMC3395405
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Response to Dr. Tsai's letter to the Editor - The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression
JOURNAL OF PSYCHIATRIC RESEARCH
2011; 45 (1): 134–35
View details for DOI 10.1016/j.jpsychires.2010.09.011
View details for Web of Science ID 000287075200021
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The use of referenced-EEG (rEEG) in assisting medication selection for the treatment of depression
JOURNAL OF PSYCHIATRIC RESEARCH
2011; 45 (1): 64-75
Abstract
To evaluate the efficacy of rEEG(®)-guided pharmacotherapy for the treatment of depression in those circumstances where rEEG and STAR*D provided different recommendations.This was a randomized, single-blind, parallel group, 12 center, US study of rEEG-guided pharmacotherapy vs. the most effective treatment regimens reported in the NIH sponsored STAR*D study. Relatively treatment-resistant subjects ≥18 years who failed one or more antidepressants were required to have a QIDS-16-SR score ≥13 and a MADRS score ≥26 at baseline. All subjects underwent a washout of all current medications (with some protocol-specified exceptions) for at least five half-lives before receiving a QEEG and rEEG report. Subjects randomized to rEEG were assigned a regimen based on the rEEG report. Control subjects who had failed only SSRI's in their current episode were randomized to receive venlafaxine XR. Control subjects who had failed antidepressants from ≥2 classes of antidepressants were randomized to receive a regimen from Steps 2-4 of the STAR*D study. Treatment lasted 12 weeks. The primary outcome measures were change from baseline for self-rated QIDS-SR16 and Q-LES-Q-SF.A total of 114 subjects were randomized and 89 subjects were evaluable. rEEG-guided pharmacotherapy exhibited significantly greater improvement for both primary endpoints, QIDS-SR16 (-6.8 vs. -4.5, p<0.0002) and Q-LES-Q-SF (18.0 vs. 8.9, p<0.0002) compared to control, respectively, as well as statistical superiority in 9 out of 12 secondary endpoints.These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression. If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice.
View details for DOI 10.1016/j.jpsychires.2010.05.009
View details for Web of Science ID 000287075200011
View details for PubMedID 20598710
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Safety considerations of the use of second generation antipsychotics in the treatment of major depression: extrapyramidal and metabolic side effects.
Current drug safety
2010; 5 (3): 263-266
Abstract
Second generation antipsychotics (SGAs) are increasingly employed in the treatment of depression. Adjunctive aripiprizole and olanzapine/ fluoxetine combination (OFC) have been approved in the US in the treatment of depression. Quetiapine also appears to be poised for an FDA approval as an adjunctive treatment for resistant depression. Historically, first generation antipsychotics were thought to carry an enhanced risk of certain side effects in the treatment of mood disorders, including an enhanced risk of extrapyramidal symptoms (EPS). The second generation antipsychotics are also known to be associated with a variety of metabolic side effects. The use of SGA in a depressed population may pose risks that differ from use in other conditions such as bipolar disorder and schizophrenia. In this paper, the risk of extrapyramidal and metabolic side effects is reviewed in depressed patients treated with second generation antipsychotics.
View details for PubMedID 20394571
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A Multisite Trial of Mifepristone for the Treatment of Psychotic Depression: A Site-by-Treatment Interaction (vol 30, pg 284, 2009)
CONTEMPORARY CLINICAL TRIALS
2010; 31 (1): 134-134
View details for DOI 10.1016/j.cct.2009.10.001
View details for Web of Science ID 000274576400020
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Safety Considerations of the Use of Second Generation Antipsychotics in the Treatment of Major Depression: Extrapyramidal and Metabolic Side Effects
CURRENT DRUG SAFETY
2010; 5 (3): 263–66
View details for DOI 10.2174/157488610791698325
View details for Web of Science ID 000218277000011
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A Multisite Trial of Mifepristone for the Treatment of Psychotic Depression: A Site-by-Treatment Interaction (vol 30, pg 284, 2009)
CONTEMPORARY CLINICAL TRIALS
2009; 30 (5): 497-497
View details for DOI 10.1016/j.cct.2009.06.010
View details for Web of Science ID 000270073800019
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Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function
PSYCHONEUROENDOCRINOLOGY
2009; 34 (7): 1012-1018
Abstract
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
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A multisite trial of mifepristone for the treatment of psychotic depression: A site-by-treatment interaction
CONTEMPORARY CLINICAL TRIALS
2009; 30 (4): 284-288
Abstract
Major Depression with Psychotic Features (psychotic depression) is a common, debilitating psychiatric disease. We hypothesized that mifepristone, a cortisol receptor (GRII) antagonist, would significantly reduce psychotic symptoms in psychotic depression. Two hundred fifty-eight patients with psychotic depression enrolled at 29 sites were randomized to mifepristone or placebo for 7 days. The primary outcome was rapid and sustained response, defined as a 50% or greater decrease in Brief Psychiatric Rating Scale - Positive Symptom Subscale scores at the end of treatment (day7) and 49 days later (day 56). Cochran-Mantel-Haenszel compared proportions of responders to mifepristone versus placebo adjusting for site. Exploratory analyses compared response of patients with mifepristone plasma concentrations of > or =1800 ng/ml to placebo. The primary endpoint was not statistically significant. However, the Breslow-Day test indicated a statistically significant site-by-treatment interaction. Mifepristone produced significantly higher response among the twenty sites who participated from the trial onset (p<.05), whereas no difference was observed at the nine sites added late in the trial. Patients with mifepristone plasma levels > or =1800 ng/ml were significantly more likely to respond than placebo patients (Intent-to-Treat: OR=2.4, p=.03; Initial 20 sites: OR=4.1, p=.002). The results of this trial are instructive in two respects. First, while statistical adjustments for [corrected] site are common in multisite clinical trials, this study reminds trialists to formally evaluate the interaction of site by treatment.Second, the association between increased mifepristone plasma concentration levels and greater clinical response, detected despite the site-by-treatment interaction, suggests that higher plasma levels may be needed for maximizing the probability of a positive response.
View details for DOI 10.1016/j.cct.2009.03.001
View details for Web of Science ID 000266853900002
View details for PubMedID 19318138
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Utility of Atypical Antipsychotics in the Treatment of Resistant Unipolar Depression
CNS DRUGS
2009; 23 (5): 369-377
Abstract
Many patients fail to achieve an adequate response to antidepressant medication. Growing evidence suggests that atypical antipsychotics may augment antidepressant effects, resulting in a greater potential for response. Atypical antipsychotics possess pharmacological actions that are associated with antidepressant properties, including serotonin 5-HT(2) receptor antagonist and 5-HT(1A) and dopamine receptor partial agonist activity. In fact, the term 'atypical antipsychotic' is an unfortunate remnant of the early indication of these drugs in the treatment of schizophrenia. Soon after their introduction, the usefulness of atypical antipsychotics in bipolar disorder was firmly established and their use in the treatment of mood disorders has far outpaced their use in schizophrenia and other psychotic disorders. Aripiprazole has become the first agent to receive US FDA approval for the adjunctive treatment of unipolar depression. Most recently, Symbyax, a fluoxetine/olanzapine combination, received FDA approval for the acute treatment of treatment-resistant depression. This is the first medication to be FDA approved for this indication. In the present article, the usefulness of antipsychotics in the treatment of resistant unipolar depression is reviewed.
View details for Web of Science ID 000266961000002
View details for PubMedID 19453199
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Sildenafil treatment of women with antidepressant-associated sexual dysfunction - A randomized controlled trial
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2008; 300 (4): 395-404
Abstract
Antidepressant-associated sexual dysfunction is a common adverse effect that frequently results in premature medication treatment discontinuation and for which no treatment has demonstrated efficacy in women.To evaluate the efficacy of sildenafil for sexual dysfunction associated with selective and nonselective serotonin reuptake inhibitors (SRIs) in women.An 8-week prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 1, 2003, and January 1, 2007, at 7 US research centers that included 98 previously sexually functioning, premenopausal women (mean [SD] age 37.1 [6] years) whose major depression was remitted by SRIs but who were also experiencing sexual dysfunction.Forty-nine patients were randomly assigned to take sildenafil or placebo at a flexible dose starting at 50 mg adjustable to 100 mg before sexual activity.The primary outcome measure was the mean difference in change from baseline to study end (ie, lower ordinal score) on the Clinical Global Impression sexual function scale. Secondary measures included the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale-female version, the University of New Mexico Sexual Function Inventory-female version, a sexual activity event log, and the Hamilton Depression Rating scale. Hormone levels were also assessed.In an intention-to-treat analysis, women treated with sildenafil had a mean Clinical Global Impression-sexual function score of 1.9 (95% confidence interval [CI], 1.6-2.3) compared with those taking placebo (1.1; 95% CI, 0.8-1.5), with a mean end point difference of 0.8 (95% CI, 0.6-1.0; P = .001). Assigning baseline values carried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6-1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3-0.8; P = .03). Baseline endocrine levels were within normal limits and did not differ between groups. The mean (SD) Hamilton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treatment, but no patients withdrew because of serious adverse effects.In this study population, sildenafil treatment of sexual dysfunction in women taking SRIs was associated with a reduction in adverse sexual effects.clinicaltrials.gov Identifier: NCT00375297.
View details for Web of Science ID 000257831200017
View details for PubMedID 18647982
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Depression and smoking cessation: does the evidence support psychiatric practice?
Neuropsychiatric disease and treatment
2007; 3 (4): 487-493
Abstract
Depression and smoking are highly comorbid. The vast majority of psychiatrists treating depressed patients do not target or treat nicotine dependence, and many inpatient psychiatric facilities implicitly condone smoking by providing 'smoke breaks'. The reasons for failure to treat are unclear, but are probably linked to the notion that depressed smokers are neither willing nor able to quit, and will become more depressed if they try. We review the clinical evidence on depression and smoking cessation, and find little support for current psychiatric practice. Although quitting smoking does appear to pose a risk for the development of depression, this risk is not clearly higher in those with a past history of depression than those without. Depressed smokers are as capable as nondepressed smokers of quitting smoking, and at least one-quarter of depressed smokers is willing to try. Sustained abstinence may even lead to improvement in depressive disorders. More research is needed to understand the relationship between depression and quitting smoking, but current clinical evidence suggests more resiliency among depressed smokers than common clinical wisdom would dictate.
View details for PubMedID 19300577
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Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness.
Annals of clinical psychiatry
2007; 19 (3): 153-159
Abstract
Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue.This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4).Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI.Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.
View details for PubMedID 17729016
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Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression
43rd Annual Meeting of the American-College-of-Neuropsychopharmacology
ELSEVIER SCIENCE INC. 2006: 1343–49
Abstract
Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD.221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment.Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression.A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.
View details for DOI 10.1016/j.biopsych.2006.05.034
View details for Web of Science ID 000242735700011
View details for PubMedID 16889757
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The neuropsychological profile of psychotic major depression and its relation to cortisol
BIOLOGICAL PSYCHIATRY
2006; 60 (5): 472-478
Abstract
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
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The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats
BEHAVIOURAL BRAIN RESEARCH
2006; 171 (2): 225-229
Abstract
Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.
View details for DOI 10.1016/j.bbr.2006.03.039
View details for Web of Science ID 000239197500006
View details for PubMedID 16782211
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Augmentation and combination strategies for depression
158th Annual Scientific Meeting of the American-Psychiatric-Association
SAGE PUBLICATIONS LTD. 2006: 11–18
Abstract
Treatment-resistant depression represents a common problem, with the vast majority of depressed patients showing incomplete response to antidepressant trials. Augmentation and combination strategies are commonly employed to address this problem, but there are few randomized, controlled studies to guide treatment choice. Indeed, some of the most common augmentation strategies in depression are those with the least controlled evidence. The popularity of bupropion, psychostimulants and atypical antipsychotics as augmentors may not be warranted by existing controlled studies, whereas two less commonly used augmentors-lithium and thyroid hormone- have substantial controlled evidence to support their use. This paper summarizes the state of the evidence for commonly used augmenting strategies and explores preliminary findings for more investigational approaches.
View details for DOI 10.1177/13597868064310
View details for Web of Science ID 000237852000003
View details for PubMedID 16644767
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Serious adverse events and the Modafinil Augmentation Study - Reply
CNS SPECTRUMS
2006; 11 (5): 340-342
View details for Web of Science ID 000237649700003
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An open maintenance trial using low frequency transcranial magnetic stimulation for treatment resistant unipolar and bipolar depression
61st Annual Convention of the Society-of-Biological-Psychiatry
ELSEVIER SCIENCE INC. 2006: 170S–170S
View details for Web of Science ID 000236767301130
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The use of mifepristone in the treatment of neuropsychiatric disorders
TRENDS IN ENDOCRINOLOGY AND METABOLISM
2006; 17 (3): 117-121
Abstract
Mifepristone is a potent glucocorticoid and progesterone receptor antagonist. The pathophysiology of a number of neuropsychiatric disorders implicates abnormalities in glucocorticoid function. These include mood disorders such as psychotic major depression and bipolar depression. In addition, cognitive disorders such as Alzheimer's disease might also be partially mediated by abnormalities in the hypothalamic-pituitary-adrenal axis. Preliminary studies suggest that mifepristone might have a role in the treatment of a number of neuropsychiatric disorders.
View details for DOI 10.1016/j.tem.2006.02.006
View details for Web of Science ID 000237145300007
View details for PubMedID 16530421
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Detecting psychotic major depression using psychiatric rating scales
JOURNAL OF PSYCHIATRIC RESEARCH
2006; 40 (1): 22-29
Abstract
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
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Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study
CNS SPECTRUMS
2006; 11 (2): 93-102
Abstract
Many patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitors have residual symptoms (eg, persistent fatigue, excessive sleepiness) despite an overall antidepressant response. Placebo-controlled studies indicate that modafinil, a wake-promoting agent, may relieve residual symptoms.This 12-week, open-label, dose titration, extension study followed an 8-week placebo-controlled study of modafinil augmentation in patients with MDD. The dose was 100-400 mg/day. The median stable dose was 300 mg/day. Assessments were the Epworth Sleepiness Scale, Brief Fatigue Inventory, Clinical Global Impression of Improvement scale, 17-item Hamilton Rating Scale for Depression, and Montgomery-Asberg Depression Rating Scale.Of the 245 patients treated, 194 completed the study; 70% reported Clinical Global Impression of Improvement scale responses of "much improved" or "very much improved" between open-label baseline and final visit (previous randomized modafinil group: 74%; placebo group: 66%). When data were analyzed for four subsets of patients (former modafinil responders, placebo responders, modafinil nonresponders, and placebo nonresponders), improvements in scores on all outcome measures were at least twice as great among former modafinil and placebo nonresponders compared with responders. Most common adverse events were headache (18%), nausea (9%), and dizziness (7%); all were generally mild to moderate in severity.Twelve weeks of modafinil augmentation relieved excessive sleepiness, reduced fatigue, and improved patients' overall clinical condition, including mood.
View details for Web of Science ID 000235789200009
View details for PubMedID 16520686
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Update on augmentation of antidepressant response in resistant depression.
Current psychiatry reports
2005; 7 (6): 435-440
Abstract
Most patients in acute depression trials fail to achieve remission with antidepressant monotherapy. Many patients seem to require more than one medication to achieve remission or adequate response. Augmentation strategies are commonly used in clinical practice, but most have been poorly studied. In addition, better-studied strategies, such as the use of lithium and thyroid augmentation, have not been well investigated in combination with newer antidepressants. Various novel strategies are being investigated as augmenting agents, including selective dopamine agonists, sex steroids, norepinephrine reuptake inhibitors, glucocorticoid-specific agents, and newer anticonvulsants. We review the status of augmentation strategies in the treatment of depression.
View details for PubMedID 16318821
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The efficacy of divalproex sodium in the treatment of agitation associated with major depression
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2005; 25 (5): 476-479
Abstract
Agitation is both a feature of major depression and a common side effect of antidepressant treatment. Depressive agitation correlates with overall severity of illness and suicide risk, whereas treatment-emergent agitation may contribute to early discontinuation of pharmacotherapy. Thus, agitation merits investigation as a treatment target in clinical depression.In this study, adults with major depression were evaluated for change in agitation and other mood symptoms during adjunctive treatment with divalproex sodium. Twelve patients on antidepressants, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, were given low doses of divalproex sodium and evaluated repeatedly for symptoms of depression, anxiety, and agitation. Agitation severity was evaluated using the Overt Agitation Severity Scale and the Stanford Scale for Agitation Symptoms. Mood symptoms were assessed with the Hamilton Anxiety and the Hamilton Depression Rating Scales.Nine of 12 patients completed 4 weeks of treatment. All agitation scores decreased sharply, whereas depression (Hamilton Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale) symptoms decreased only modestly. Decreased agitation was not merely a function of decreases on the Hamilton Depression or Hamilton Anxiety Rating Scales. Relatively low doses of divalproex sodium appear to be useful in the treatment of agitation associated with major depression.The observation that decreases in agitation were not simply an artifact of overall change in depressive or anxiety symptoms is in keeping with the previous clinical impression that divalproex sodium has a specific effect on depressive agitation. Controlled clinical trials are needed to fully evaluate the utility and symptom specificity of divalproex sodium in depression.
View details for DOI 10.1097/01.jcp.0000177552.21338.b0
View details for Web of Science ID 000232287500015
View details for PubMedID 16160625
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A placebo-controlled, randomized, double-blind study of adjunctive bupropion sustained release in the treatment of SSRI-induced sexual dysfunction
JOURNAL OF CLINICAL PSYCHIATRY
2005; 66 (7): 844-848
Abstract
Sexual side effects are among the common reasons patients discontinue selective serotonin reuptake inhibitors (SSRIs). While many antidotes have been proposed, few have been subjected to double-blind trials. Some evidence has suggested that bupropion may be an effective antidote for SSRI-induced sexual dysfunction. In this double-blind trial, the efficacy of a standard dose of bupropion sustained release (SR) is evaluated in the treatment of SSRI-induced sexual dysfunction.Patients with a history of SSRI-induced sexual side effects were randomly assigned to adjunctive treatment with either bupropion SR 150 mg daily or placebo for 6 weeks. Assessments of sexual function and interest included the Arizona Sexual Experiences Scale (ASEX), Brief Index of Sexual Functioning, and a 10-point visual analogue scale. Efficacy was defined as a 50% improvement on the ASEX at the end of 6 weeks. Data were collected from January 1999 to March 2001.Forty-one patients entered the study and completed the 6-week trial. No significant differences were seen between placebo and bupropion SR on the ASEX or on any measure of sexual functioning at the end of the trial.A fixed dose of 150 mg/day of bupropion SR taken in the morning does not appear to be effective in the treatment of SSRI-induced sexual dysfunction. Additional trials will be required to define what role, if any, bupropion might have in the treatment of SSRI-induced sexual side effects.
View details for Web of Science ID 000230663800006
View details for PubMedID 16013899
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C-1073 (mifepristone) in the adjunctive treatment of Alzheimer's disease.
Current Alzheimer research
2005; 2 (2): 125-129
Abstract
Alzheimer's disease is frequently associated with abnormalities in the hypothalamic pituitary adrenal axis. Elevated cortisol levels in Alzheimer's disease may in turn be associated with a more rapid progression of the illness. In addition, elevated cortisol levels may directly contribute to cognitive deficits in Alzheimer's disease. Mifepristone is a potent antagonist of the glucocorticoid receptor and blocks the central actions of cortisol. The purpose of this study is to determine the effects of glucocorticoid receptor blockade with mifepristone on cognition in Alzheimer's disease.
View details for PubMedID 15974908
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Executive dysfunction in major depressive disorder.
Expert review of neurotherapeutics
2005; 5 (1): 79-83
Abstract
Executive dysfunction is commonly seen in major depression. The types of executive deficits seen in depression include problems with planning, initiating and completing goal-directed activities. Executive dysfunction may vary as a function of the severity of depression. In addition, a subset of geriatric depression is also characterized by prominent deficits in executive functioning. The presence of executive dysfunction in depression is associated with vocational disability and possibly poorer treatment response. While few studies have examined the treatment of executive dysfunction in depression, preliminary work suggests that both pharmacologic interventions and psychosocial interventions such as problem solving therapy may be efficacious.
View details for PubMedID 15853477
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A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness
JOURNAL OF CLINICAL PSYCHIATRY
2005; 66 (1): 85-93
Abstract
Up to one half of depressed patients have partial or no response to antidepressant monotherapy. This multicenter, placebo-controlled study evaluated the efficacy of modafinil augmentation in major depressive disorder (MDD) patients with fatigue and excessive sleepiness despite selective serotonin reuptake inhibitor (SSRI) monotherapy.Patients (18-65 years) with a DSM-IV diagnosis of MDD and partial response to SSRI monotherapy (> or = 8 weeks) at a stable dose for > or = 4 weeks were eligible. Patients had screening/baseline 31-item Hamilton Rating Scale for Depression (HAM-D) scores of 14 to 26, Epworth Sleepiness Scale (ESS) scores > or = 10, and Fatigue Severity Scale (FSS) scores > or = 4. Patients were randomly assigned to augmentation therapy with modafinil 200 mg/day or placebo for 8 weeks. Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS).Of 311 enrolled patients who received > or = 1 dose of study drug, 158 were randomly assigned to modafinil (70% women) and 153 to placebo (72% women); 85% of each treatment group completed the study. At final visit, modafinil significantly improved patients' overall clinical condition compared with placebo on the basis of CGI-I scores (p = .02), and there were trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores versus placebo. Modafinil significantly reduced BFI scores for worst fatigue at final visit (p < .05 vs. placebo). There were no significant differences between modafinil and placebo at final visit in FSS or BFI total scores. Adverse events significantly more common during modafinil compared with placebo treatment were nausea (9% vs. 2%; p = .01) and feeling jittery (4% vs. 1%; p = .03).These findings suggest that modafinil is a well-tolerated and potentially effective augmenting agent for SSRI partial responders with fatigue and sleepiness.
View details for Web of Science ID 000226493200012
View details for PubMedID 15669893
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A double-blind, placebo controlled trial of C-1073 (mifepristone) in the treatment of psychotic major depression
43rd Annual Meeting of the American-College-of-Neuropsychopharmacology
NATURE PUBLISHING GROUP. 2004: S98–S98
View details for Web of Science ID 000225588000287
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HPA axis activation in major depression and response to fluoxetine: a pilot study
PSYCHONEUROENDOCRINOLOGY
2004; 29 (9): 1198-1204
Abstract
Hypothalamic-pituitary-adrenal (HPA) axis activation is a frequently observed phenomenon in major depression. However, whether this activation has any implications for treatment is unknown. To address this question, we examined baseline response to metyrapone and 6-week response to fluoxetine. Premenopausal women (n = 20) who met criteria for major depression with no other confounding Axis I disorders, medications, or medical illnesses and were not taking hormonal contraceptives were evaluated with an evening metyrapone challenge before the onset of treatment. Twenty-one normal women were also studied with the evening metyrapone challenge. The depressed patients then entered an open label treatment with fluoxetine for 6 weeks. Subjects were classified as responders if they demonstrated a 50% or greater decrease in Hamilton Depression Rating Scale rating. As a group, the depressed women demonstrated significantly increased ACTH secretion compared to control women before the onset of treatment, during the metyrapone challenge. Before treatment, women who were non-responders to fluoxetine showed increased HPA axis activation compared to controls, while the fluoxetine responders did not differ significantly from normal subjects in their ACTH levels during metyrapone challenge. These results suggest that overactivity of the HPA axis may be one factor associated with slower response to fluoxetine. This may reflect the greater severity of subjects with HPA axis dysregulation or the need to normalize the HPA axis with medications for optimal response.
View details for DOI 10.1016/j.psyneuen.2004.02.002
View details for Web of Science ID 000223107600012
View details for PubMedID 15219644
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Modafinil as antidepressant augmentation therapy in major depressive disorder
ELSEVIER SCIENCE BV. 2004: S210–S211
View details for DOI 10.1016/S0924-977X(04)80175-5
View details for Web of Science ID 000225460400176
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Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder
PSYCHONEUROENDOCRINOLOGY
2004; 29 (9): 1129-1137
Abstract
Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.
View details for DOI 10.1016/j.psyneuen.2004.01.004
View details for Web of Science ID 000223107600004
View details for PubMedID 15219636
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Modulators of the HPA axis
ELSEVIER SCIENCE BV. 2004: S9
View details for Web of Science ID 000220594100013
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A prospective trial of modafinil as an adjunctive treatment of major depression
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2004; 24 (1): 87-90
Abstract
Modafinil is a wake-promoting agent approved by the Federal Drug Administration for the treatment of narcolepsy. Preliminary evidence indicates that modafinil may improve fatigue and excessive sleepiness associated with a variety of conditions. The purpose of this study was to investigate the utility of modafinil as an adjunctive treatment of depressed patients. Subjects with a history of major depression with partial response on a stable therapeutic dose of an antidepressant were eligible to participate. All subjects endorsed complaints of significant fatigue and/or excessive sleepiness on clinical assessment. Modafinil was added to their existing regimen at a dose of 100 to 400 mg/d for 4 weeks. Subjects were assessed at 2-week intervals for improvement using the standard depression scales (HDRS, BDI, CGI), fatigue scales (VASF, FSI), and a neuropsychologic battery. Thirty-five subjects were entered and 31 subjects completed the 4-week trial. Significant improvements were seen across all 3 measures of depression (HDRS, BDI, CGIS) and both measures of fatigue (VASF, FSI). On the neurocognitive battery, significant gains in the Stroop Interference Test were seen at 4 weeks, whereas the other cognitive tests showed no change. Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression.
View details for DOI 10.1097/01.jcp.0000104910.75206.b9
View details for Web of Science ID 000188093400015
View details for PubMedID 14709953
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Seizure duration with remifentanil/methohexital vs. methohexital alone in middle-aged patients undergoing electroconvulsive therapy
ACTA ANAESTHESIOLOGICA SCANDINAVICA
2003; 47 (9): 1064-1066
Abstract
The object of this study was to test whether substituting part of the methohexital dose with the short-acting opioid remifentanil would prolong seizure duration in middle-aged patients while providing a similar depth of anesthesia as with methohexital alone. This has been reported for the combined use of methohexital and remifentanil in elderly patients, but has not been investigated in middle-aged patients likely to require a higher total dose of methohexital for inducing anesthesia.Seven patients (42+/-10 years; mean +/-SD) receiving electroconvulsive therapy (ECT) were anesthetized with methohexital (1.25 mg kg-1) or with methohexital (0.625 mg kg-1) plus remifentanil (1 micro g kg-1) in this randomized, double blind, crossover study. Additional methohexital was given as needed until loss of eyelash reflex was observed. Suxamethonium (1 mg kg-1) was used for muscular paralysis.Motor and EEG seizure durations were significantly longer after induction with methohexital plus remifentanil (45+/-14 and 58+/-15 s) than with methohexital alone (31+/-11 and 42+/-18 s). A methohexital dose of 1.2+/-0.3 and 1.9+/-0.3 mg was necessary to achieve loss of eyelash reflex if methohexital was used with and without remifentanil. Peak heart rate after ECT was significantly higher if remifentanil was coadministered with methohexital (148+/-12 vs. 126+/-24 b.p.m).Substituting part of the methohexital dose with remifentanil is a useful anesthetic technique to prolong seizure duration in middle-aged patients requiring a 1.5-fold higher induction dose of methohexital than elderly patients, the only population studied to date for the combined use of methohexital and remifentanil in ECT.
View details for PubMedID 12969096
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Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary double-blind, placebo-controlled study
JOURNAL OF CLINICAL PSYCHIATRY
2003; 64 (9): 1057-1064
Abstract
Fatigue and sleepiness are primary symptoms of depression that may not resolve with antidepressant therapy. Modafinil is a novel agent that has been shown to improve wakefulness and lessen fatigue in a variety of conditions. In this study, we examined the utility of modafinil as an adjunct therapy to treat fatigue and sleepiness in patients with major depression who are partial responders to antidepressants.Patients with partial response to anti-depressant therapy given for at least a 6-week period for a current major depressive episode (DSM-IV criteria) were enrolled in this 6-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Patients received once-daily doses (100-400 mg) of modafinil or matching placebo as adjunct treatment to ongoing antidepressant therapy. The effects of modafinil were evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Fatigue Severity Scale (FSS), the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Change (CGI-C), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Adverse events were monitored throughout the study.One hundred thirty-six patients were randomized to treatment, with 118 patients (87%) completing the study. Most patients (82%) were fatigued, and one half of patients (51%) were sleepy. Modafinil rapidly improved fatigue and daytime wakefulness, with significantly greater mean improvements from baseline than placebo in fatigue (FSS) scores at week 2 (p < .05) and sleepiness (ESS) scores at week 1 (p < .01); the differences between modafinil and placebo at week 6 were not statistically significant. Assessment of the augmentation effects of modafinil (HAM-D, CGI-C, and SF-36) did not significantly distinguish modafinil from placebo. Modafinil was well tolerated in combination with a variety of antidepressants.Modafinil may be a useful adjunct therapy for the short-term management of residual fatigue and sleepiness in patients who are partial responders to antidepressant therapy.
View details for Web of Science ID 000185457600011
View details for PubMedID 14628981
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Safety of antidepressants in the elderly.
Expert opinion on drug safety
2003; 2 (4): 367-383
Abstract
Until the 1980s, the two major classes of antidepressants, the tricyclics and the monoamine oxidase inhibitors (MAOIs), were effective but had severe side effects, requiring monitoring by psychiatrists. The past several years have brought new classes of antidepressants that are safer for the patient to take and far easier for the non-psychiatrist to prescribe. Whilst this is of enormous value, it leaves the physician with the dilemma of which one to prescribe. These new antidepressants cannot safely be used interchangeably. This paper will discuss each of the antidepressants presently available, with particular emphasis on safety in the elderly. Drug interactions, side effects and particular challenges to the older patient will be described. The authors will then advise a general strategy for prescribing antidepressants.
View details for PubMedID 12904093
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A prospective trial of bupropion SR augmentation of partial and non-responders to Serotonergic antidepressants
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2003; 23 (1): 27-30
Abstract
Many patients fail to achieve an adequate response to a given antidepressant trial. The best-studied augmentation agents, lithium and thyroid supplementation are less commonly used. Augmenting antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Several case reports and 2 open label studies suggest efficacy of this strategy. The purpose of this study is to further examine the utility of bupropion sustained release (SR) augmentation in patients with inadequate response to selective serotonin reuptake inhibitors. Patients who met DSM-IV criteria for major depression and had failed to achieve adequate response to an SSRI were considered for this study. Eligible patients were required to have a score of 16 on the 24-item Hamilton Depression Rating Scale (HDRS). Patients were treated openly for 6 weeks with bupropion SR added to their existing antidepressant. The dose range of bupropion was 150 to 300 mg per day. At each visit, patients were assessed using the Beck Depression Inventory (BDI), the Hamilton Depression Ratings Scale (HDRS), and the Clinical Global Impression (CGI). Twenty-eight patients (12 men, 16 women) entered the study. Twenty-five patients completed the six-week trial. With respect to the clinical benefit of bupropion SR augmentation, 15 out of 28, or 54% of patients, were classified as responders, showing a decrease in their HDRS or BDI scores of 50% or more between baseline and Week 6. This prospective, open-label trial supports the use of bupropion SR in the augmentation of SSRIs and venlafaxine. Placebo controlled trials should be completed to further evaluate the efficacy of this strategy.
View details for Web of Science ID 000180765000005
View details for PubMedID 12544372
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The timing of electroconvulsive therapy and bispectral index after anesthesia induction using different drugs does not affect seizure duration
JOURNAL OF CLINICAL ANESTHESIA
2003; 15 (1): 29-32
Abstract
To determine the association between bispectral index (BIS) and seizure duration obtained by electroconvulsive therapy (ECT) administered sooner or later after anesthetic induction.Prospective, randomized, crossover study.University-affiliated medical center.Nine ASA physical status I, II, and III patients undergoing a total of 31 ECTs.ECT was administered soon (<210 sec) or later (between 210 sec and 360 sec) after anesthetic induction. In each individual patient, drug regimens and ECT machine settings were identical.BIS immediately before the start of the ECT and the duration of the EEG seizure were recorded, as well as the time period between loss of consciousness and ECT administration.There was no relationship between BIS level and seizure duration. Moreover, seizure duration was not dependent on the time of ECT administration in the time window between one and 6 minutes after loss of consciousness.The hypnotic drug effect measured by the BIS is not correlated to the seizure duration obtained by ECT.
View details for DOI 10.1016/S0952-8180(02)00477-4
View details for Web of Science ID 000182004300006
View details for PubMedID 12657408
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Fetal heart rate decelerations during ECT-induced seizures: is it important?
ACTA ANAESTHESIOLOGICA SCANDINAVICA
2003; 47 (1): 101-103
Abstract
Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may offer advantages over pharmacotherapy for the patient and the fetus (1,2). However, very little data is available on the impact of epileptic or ECT-induced seizures on the fetus. We report a case of brief fetal heart rate decelerations in a fetus associated with maternal ECT-induced convulsions.
View details for Web of Science ID 000179948400019
View details for PubMedID 12492807
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Novel strategies in the treatment of psychotic major depression
PSYCHIATRIC ANNALS
2002; 32 (11): 695-698
View details for Web of Science ID 000179153800006
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The impact on cognitive function of pharmacologic treatments for late-life depression
PHYSICIANS POSTGRADUATE PRESS. 2002: 1075–76
View details for Web of Science ID 000179471900104
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The status of evidence-based guidelines and algorithms in the treatment of depression
PSYCHIATRIC ANNALS
2002; 32 (11): 658-663
View details for Web of Science ID 000179153800003
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A dynamic algorithm for the treatment of psychotic major depression
PSYCHIATRIC ANNALS
2002; 32 (11): 681-691
View details for Web of Science ID 000179153800005
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An open label trial of C-1073 (mifepristone) for psychotic major depression
BIOLOGICAL PSYCHIATRY
2002; 52 (5): 386-392
Abstract
The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained.Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days.All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group.These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.
View details for Web of Science ID 000177985100002
View details for PubMedID 12242054
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Slowing the progression of cognitive decline in Alzheimer's disease using mifepristone
JOURNAL OF MOLECULAR NEUROSCIENCE
2002; 19 (1-2): 201-206
Abstract
High circulating levels of glucocorticoid hormones adversely affect cognition. Previous studies exploring the hypothalamic-pituitary-adrenal (HPA) axis and basal cortisol levels in the elderly reported that subjects with mid-range cortisol levels outperformed subjects with high cortisol levels on assessments of memory and attention. This study examines the efficacy of mifepristone, a glucocorticoid-antagonist, in decelerating the rate of cortisol-related cognitive decline in subjects with mile-to-moderate Alzheimer's disease (AD). Rate of cognitve decline is compared in AD subjects randomized to receive 200 mg of mifepristone daily for 6 mo or placebo. The Alzheimer's Disease Assessment Scale (ADAS) and the Folstein Mini Mental Status Exam (MMSE) will be the primary measures used to assess change in cognitve function over the 6 mo period, supplemented by a neuropsychological battery testing memory and language and reasoning skills. During each visit, subjects will have samples collected for determination of plasma adrenocorticotropin (ACTH), serum cortisol and salivary cortisol levels to assess HPA axis activity. The placebo arm of this study also investigate whether subjects with high baseline cortisol levels experience greater declines in cognitive impairment over time relative to subjects with Ad who have low baseline cortisol levels. Additionally, this study test the hypothesis that AD subjects with elevated cortisol at baseline will perform more poorly on neuropsychological exams that do subjects with low cortisol.
View details for Web of Science ID 000177794700032
View details for PubMedID 12212781
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Delusional major depression: new treatment approaches
Collegium Internationale Neuro-Psychopharmacologicum (CINP)
LIPPINCOTT WILLIAMS & WILKINS. 2002: S99–S100
View details for Web of Science ID 000179199800215
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Effect of Hypericum perforatum (St John's wort) in major depressive disorder - A randomized controlled trial
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2002; 287 (14): 1807-1814
Abstract
Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated.To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder.Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States.Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20.Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks.Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores.On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo.This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.
View details for Web of Science ID 000174881700033
View details for PubMedID 11939866
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New psychopharmacologic treatment strategies - Response
ANNALS OF INTERNAL MEDICINE
2001; 135 (11): 1008
View details for DOI 10.7326/0003-4819-135-11-200112040-00022
View details for Web of Science ID 000172520000017
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Cortisol feedback during the HPA quiescent period in patients with major depression
AMERICAN JOURNAL OF PSYCHIATRY
2001; 158 (12): 2083-2085
Abstract
The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period.Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m.Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found.The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.
View details for Web of Science ID 000172452100028
View details for PubMedID 11729034
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Antidepressant effects of hydrocortisone - Dr. DeBattista replies
AMERICAN JOURNAL OF PSYCHIATRY
2001; 158 (9): 1537
View details for DOI 10.1176/appi.ajp.158.9.1537
View details for Web of Science ID 000170769900050
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Is electroconvulsive therapy effective for the depressed patient with comorbid borderline personality disorder?
JOURNAL OF ECT
2001; 17 (2): 91-98
Abstract
Among the more common current indications for electroconvulsive therapy (ECT) is treatment-resistant depression. Treatment resistance is correlated with a number of factors, including the presence of comorbid personality disorders, such as borderline personality disorder (BPD). A detailed review of the literature was undertaken and very few reports or studies have dealt specifically with ECT in borderline patients. Thirteen original reports on ECT outcome in personality disordered patients were identified. Depressed patients with a personality disorder, particularly BPD, may have a poorer outcome on some measures. However, the available data suggests that depression in these patients can be effectively treated with ECT. The depressed, borderline patient appears to have two distinct disorders, one which is responsive to ECT and the other which is not. Unfortunately, the literature is limited by lack of rigorous randomized treatment studies, lack of long-term follow-up, and other methodological weaknesses. Clinical guidelines are suggested.
View details for Web of Science ID 000169270500002
View details for PubMedID 11417933
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Sertraline versus imipramine to prevent relapse in chronic depression
JOURNAL OF AFFECTIVE DISORDERS
2001; 65 (1): 27-36
Abstract
Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study.After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment.Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment.The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates.Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.
View details for Web of Science ID 000168910100005
View details for PubMedID 11426506
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Psychopharmacologic treatment strategies for depression, bipolar disorder, and schizophrenia
ANNALS OF INTERNAL MEDICINE
2001; 134 (1): 47-60
Abstract
Patients with serious psychiatric disorders are frequently treated by primary care physicians, who may have difficulty keeping up with recent advances in psychiatry. This paper presents an updated synopsis for three major psychiatric illnesses: major depression, bipolar disorder, and schizophrenia. Current definitions, updated diagnostic criteria, short- and long-term treatment strategies with algorithms, and special challenges for the clinician are discussed for each of these illnesses. On the basis of each illness's distinct characteristics, five treatment principles are emphasized: 1) Treatment strategies should be long-term and should emphasize adherence, 2) treatment choice should be empirical, 3) combinations of medications may be helpful, 4) a combination of psychosocial and pharmacologic treatments may be more useful than either alone, and 5) the family or "significant others" as well as a consumer organization need to be involved. Some of the new directions in dinical research to refine these strategies and meet these challenges are also described.
View details for PubMedID 11187420
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Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: A double-blind, placebo-controlled study
AMERICAN JOURNAL OF PSYCHIATRY
2000; 157 (8): 1334-1337
Abstract
The primary objective of this investigation was to examine the acute antidepressant effects of intravenous hydrocortisone and ovine corticotropin releasing hormone (CRH) infusions in patients with major depression.Twenty-two patients who met DSM-III-R criteria for nonpsychotic major depression were randomly assigned to receive intravenously 1 mg/kg of ovine CRH, 15 mg of hydrocortisone, or saline under double-blind conditions on day 1. Standard depression rating scales were completed on day 1 before the study medications were administered and again the following day (day 2).Patients treated with hydrocortisone demonstrated a significantly greater reduction in total 21-item Hamilton Depression Rating Scale scores (mean reduction=8.4 points or 37%) than patients given ovine CRH (mean=1.2 points) or placebo (mean=1.3 points).Acute hydrocortisone infusion is associated with a rapid and robust reduction in depressive symptoms. The authors discuss the therapeutic implications of these findings.
View details for Web of Science ID 000088520100027
View details for PubMedID 10910802
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24-hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression
28th Annual Meeting of the International-Society-of-Psychoneuroendocrinology
AMER MEDICAL ASSOC. 2000: 755–60
Abstract
Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients.Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours.Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices.In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.
View details for Web of Science ID 000088582000005
View details for PubMedID 10920463
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Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness
AMERICAN JOURNAL OF PSYCHIATRY
2000; 157 (7): 1095-1100
Abstract
At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions.A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale.Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test).These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.
View details for Web of Science ID 000087931200011
View details for PubMedID 10873917
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A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.
New England journal of medicine
2000; 342 (20): 1462-1470
Abstract
Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments.Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness).Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
View details for PubMedID 10816183
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A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression
NEW ENGLAND JOURNAL OF MEDICINE
2000; 342 (20): 1462-1470
Abstract
Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments.Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness).Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
View details for Web of Science ID 000087068200001
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Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
2000; 20 (2): 274-275
View details for Web of Science ID 000086302800029
View details for PubMedID 10770475
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Negative-pressure pulmonary edema: A potential mazard in patients undergoing ECT
JOURNAL OF ECT
1999; 15 (2): 168-170
View details for Web of Science ID 000084423300012
View details for PubMedID 10378160
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The Texas Medication Algorithm Project: Report of the Texas Consensus Conference Panel on medication treatment of major depressive disorder
JOURNAL OF CLINICAL PSYCHIATRY
1999; 60 (3): 142-156
Abstract
This article describes the development of consensus medication algorithms for the treatment of patients with major depressive disorder in the Texas public mental health system. To the best of our knowledge, the Texas Medication Algorithm Project (TMAP) is the first attempt to develop and prospectively evaluate consensus-based medication algorithms for the treatment of individuals with severe and persistent mental illnesses. The goals of the algorithm project are to increase the consistency of appropriate treatment of major depressive disorder and to improve clinical outcomes of patients with the disorder.A consensus conference composed of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of major depressive disorder in the Texas mental health system. After a series of presentations and panel discussions, the consensus panel met and drafted the algorithms.The panel consensually agreed on algorithms developed for both nonpsychotic and psychotic depression. The algorithms consist of systematic strategies to define appropriate treatment interventions and tactics to assure optimal implementation of the strategies. Subsequent to the consensus process, the algorithms were further modified and expanded iteratively to facilitate implementation on a local basis.These algorithms serve as the initial foundation for the development and implementation of medication treatment algorithms for patients treated in public mental health systems. Specific issues related to adaptation, implementation, feasibility testing, and evaluation of outcomes with the pharmacotherapeutic algorithms will be described in future articles.
View details for Web of Science ID 000079368100002
View details for PubMedID 10192589
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Phenomenology and treatment of agitation
Closed Symposium on the Phenomenology and Treatment of Agression Across Psychiatric Illnesses
PHYSICIANS POSTGRADUATE PRESS. 1999: 17–20
Abstract
Agitation is a troublesome, common symptom in major depression that can be difficult to manage. It is sometimes a side effect of antidepressant treatment and may occasionally represent a mixed bipolar episode. If agitation fails to respond to an antidepressant alone, treatment may be augmented with a benzodiazepine, a neuroleptic, or lithium. Preliminary evidence indicates that divalproex, which has been found useful for bipolar disorder and for agitation associated with Alzheimer's disease, may also be effective for agitated depression. A controlled trial is now underway.
View details for Web of Science ID 000081543500004
View details for PubMedID 10418809
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ECT in dissociative identity disorder and comorbid depression
JOURNAL OF ECT
1998; 14 (4): 275-279
Abstract
Dissociative identity disorder (DID), previously named multiple personality disorder, is a diagnosis often complicated by comorbid major depression. We report on four cases of DID associated with severe self-destructive behavior and comorbid major depression treated with electroconvulsive therapy (ECT). In three of the patients, ECT appeared to be helpful in treating the comorbid depression without adversely affecting the DID. The potential risks of using ECT in patients with DID are reviewed.
View details for Web of Science ID 000084422900011
View details for PubMedID 9871851
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Serotonergic synergism: The risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs
Neuroscience Discussion Forum on a Decade of Serotonin Research
ELSEVIER SCIENCE INC. 1998: 341–47
Abstract
It has become common clinical practice to combine the selective serotonin reuptake inhibitors with other serotonergic agents for augmentation or adjunctive purposes. The empirical basis for using these combinations remains limited, but is growing. Also growing is a literature that suggests that even the most apparently benign combinations of serotonergic drugs carry at least some risk of serious pharmacokinetic or pharmacodynamic drug interactions, such as a serotonin syndrome.
View details for Web of Science ID 000075793700005
View details for PubMedID 9755356
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Developing treatment algorithms for unipolar depression in cyberspace: International Psychopharmacology Algorithm Project (IPAP)
PSYCHOPHARMACOLOGY BULLETIN
1998; 34 (3): 355-359
View details for Web of Science ID 000078297300025
View details for PubMedID 9803769
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Treatment of psychotic depression
AMERICAN JOURNAL OF PSYCHIATRY
1997; 154 (11): 1625-1626
View details for Web of Science ID A1997YD36500038
View details for PubMedID 9356580
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Does ketorolac prophylaxis prevent succinylcholine induced myalgias following electroconvulsive therapy?
LIPPINCOTT WILLIAMS & WILKINS. 1997: S20–S20
View details for Web of Science ID A1997WF78000020
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Valproate in the treatment of agitation associated with depression
PSYCHIATRIC ANNALS
1996; 26 (7): S470-S473
View details for Web of Science ID A1996UY62800010
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Development of obsessive symptoms during nefazodone treatment
AMERICAN JOURNAL OF PSYCHIATRY
1996; 153 (4): 577-578
View details for Web of Science ID A1996UC47800039
View details for PubMedID 8599413
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Sertraline or imipramine for chronic depression: 7-month results
US GOVERNMENT PRINTING OFFICE. 1996: 396
View details for Web of Science ID A1996VQ76300018
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SUMATRIPTAN PROPHYLAXIS FOR POSTELECTROCONVULSIVE THERAPY HEADACHES
HEADACHE
1995; 35 (8): 502-503
Abstract
Very little has been written about headaches following electroconvulsive therapy (ECT) but the incidence has been estimated at 26%. Patients with a history of migraine occasionally have similar headaches precipitated by ECT. In addition, some patients may have headaches that persist for months after a series of ECT treatments, while some patients who have a preexisting headache problem report improvement with ECT. Serotonergic mechanisms have been proposed both for the efficacy of ECT and its tendency to produce headaches in susceptible patients. There have been no studies on the prophylaxis or treatment of post-ECT headache. While various strategies have been suggested for these headaches, even case reports documenting the efficacy of these strategies are lacking. We, therefore, report a case of severe, refractory, post-ECT headaches which responded to prophylactic treatment with sumatriptan.
View details for Web of Science ID A1995RW29600014
View details for PubMedID 7591748
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PHYSICAL SYMPTOMS ASSOCIATED WITH PAROXETINE WITHDRAWAL
AMERICAN JOURNAL OF PSYCHIATRY
1995; 152 (8): 1235-1236
View details for Web of Science ID A1995RL64200039
View details for PubMedID 7625481
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PHARMACOTHERAPY OF PERSONALITY-DISORDERS
CURRENT OPINION IN PSYCHIATRY
1995; 8 (2): 102-105
View details for Web of Science ID A1995QM15000009
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AN ALGORITHM FOR THE TREATMENT OF MAJOR DEPRESSION AND ITS SUBTYPES
PSYCHIATRIC ANNALS
1994; 24 (7): 341-347
View details for Web of Science ID A1994NX26200004
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Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder.
Journal of clinical psychopharmacology
; 40 (3): 287–92
Abstract
Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression.Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed.The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion.Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity.NCT01920555.
View details for DOI 10.1097/JCP.0000000000001209
View details for PubMedID 32332464