Jerrold Rosenbaum | Harvard Medical School (original) (raw)

Papers by Jerrold Rosenbaum

Biological Psychiatry, Jul 1, 2000

Background: Stress predisposes to major depression, and hyperactivity of the stress-activated hyp... more Background: Stress predisposes to major depression, and hyperactivity of the stress-activated hypothalamic-pituitary-adrenal (HPA) axis occurs in this disease. Thymopentin, an active fragment of thymopoietin (TP), reduces endocrine and behavioral responses to experimental stress, possibly by lowering plasma TP (pTP) levels. Methods: Plasma TP and the HPA hormones arginine vasopressin (pAVP), adrenocorticotropic hormone (pACTH), and plasma cortisol (pCORT) were measured in 21 untreated depressed patients and 21 matched control subjects. Clinical responses to antidepressants were evaluated in 17 depressed patients. Results: Plasma TP was elevated in depression (p Ͻ .002), with in 8 out of 21 (38%) depressed patients having significant elevations (p Ͻ .03). For 17 patients whose antidepressant responses were evaluated, nonresponsiveness occurred in 6 out of 7 (86%) with elevated pTP (Ͼ7.5 pg/mL) versus 3 out of 10 (30%) with normal pTP (p Ͻ .05). Conclusions: The significant association of elevated pTP with nonresponsiveness to antidepressant drugs may signify a distinct pathogenesis for the depression of patients with elevated pTP.

Comprehensive Psychiatry, 1996

The purpose of this study was to compare outpatients who met DSM-III-R versus DSM-IV criteria for... more The purpose of this study was to compare outpatients who met DSM-III-R versus DSM-IV criteria for melancholia. Of 176 consecutive outpatients with unipolar depression, 40 (22.7%) met DSM-III-R criteria and 29 (16.5%) met DSM-IV criteria for melancholia. Patients with DSM-IV melancholia had higher mean scores on measurements of clinical severity as compared with those who qualified for a DSM-III-R diagnosis. These results suggest that the criteria for melancholia proposed in the DSM-IV are more restrictive and define a more severely depressed population than criteria in the DSM-III-R.

The Journal of Clinical Psychiatry, Jun 15, 2000

Many patients treated for major depression require more than one antidepressant trial to achieve ... more Many patients treated for major depression require more than one antidepressant trial to achieve or sustain response. However, the literature provides few treatment algorithms or effectiveness studies that empirically support "next-step" options available to clinicians. We conducted a survey of psychiatrists and other medical specialists who treat depression to ascertain what clinicians actually do when faced with patients who suboptimally respond to an adequate course of selective serotonin reuptake inhibitor (SSRI) therapy. Attendees at a psychopharmacology course (N = 801) were queried about their top choices for antidepressant-treatment nonresponders: a minimal responder after 4 weeks of adequate SSRI treatment, a partial responder after 8 weeks of adequate SSRI therapy, a nonresponder after 8 weeks of adequate SSRI therapy, and a relapser on long-term SSRI maintenance therapy. Choices included raising the dose, augmenting or combining with another agent, switching to a second SSRI. or switching to a non-SSRI agent. 432 (54%) of the surveys were returned. Raising the dose was the most frequently reported next-step strategy for a patient with minimal response after 4 weeks of adequate SSRI therapy, partial response after 8 weeks of adequate SSRI therapy, and relapse on long-term SSRI therapy. Switching to a non-SSRI agent was the most frequently chosen option for nonresponders to an adequate trial of SSRI therapy. Our findings suggest that clinicians select different next-step strategies when patients are nonresponders versus when patients are partial responders or relapsers.

The Journal of Clinical Psychiatry, Aug 15, 2004

In the present study, we assessed the relationship between serum folate, vitamin B12, and homocys... more In the present study, we assessed the relationship between serum folate, vitamin B12, and homocysteine levels and clinical response in patients with major depressive disorder (MDD) who had previously failed to respond to open treatment with fluoxetine 20 mg/day and were enrolled in a 4-week, double-blind trial of either (1) fluoxetine dose increase, (2) lithium augmentation of fluoxetine, or (3) desipramine augmentation of fluoxetine. METHOD: Fifty-five outpatients (mean +/-SD age = 41.7 +/-10.6 years; 50.9% women) with MDD as assessed with the Structured Clinical Interview for DSM-III-R who were enrolled in the double-blind trial had serum folate, vitamin B12, and homocysteine measurements completed at baseline (prior to fluoxetine treatment initiation). Folate levels were classified as either low (< or = 2.5 ng/mL) or normal. Vitamin B12 levels were classified as either low (< or = 200 pg/mL) or normal. Homocysteine levels were classified as either elevated (> or = 13.2 micromol/L) or normal. With the use of a logistic regression, we then assessed the relationship between (1) low or normal folate levels, (2) normal or low B12 levels, and (3) elevated or normal homocysteine levels and clinical response to double-blind treatment. The study was conducted from November 1992 to January 1999. RESULTS: Low serum folate levels (chi2=3.626, p =.04), but not elevated homocysteine (p >.05) or low vitamin B12 levels (p >.05), were associated with poorer response to treatment. The response rates for patients with (N = 14) and without (N = 38) low folate levels were 7.1% versus 44.7%, respectively. CONCLUSION: Low serum folate levels were found to be associated with further treatment resistance among patients with fluoxetine-resistant MDD.

Journal of Consulting and Clinical Psychology, 2010

To examine the efficacy of a developmentally appropriate parent-child cognitive behavioral therap... more To examine the efficacy of a developmentally appropriate parent-child cognitive behavioral therapy (CBT) protocol for anxiety disorders in children ages 4-7 years. Randomized wait-list controlled trial. Conduct: Sixty-four children (53% female, mean age 5.4 years, 80% European American) with anxiety disorders were randomized to a parent-child CBT intervention (n = 34) or a 6-month wait-list condition (n = 30). Children were assessed by interviewers blind to treatment assignment, using structured diagnostic interviews with parents, laboratory assessments of behavioral inhibition, and parent questionnaires. Chi-square analyses of outcome rates and linear and ordinal regression of repeated measures, examining time by intervention interactions. The response rate (much or very much improved on the Clinical Global Impression Scale for Anxiety) among 57 completers was 69% versus 32% (CBT vs. controls), p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .01; intent-to-treat: 59% vs. 30%, p = .016. Treated children showed a significantly greater decrease in anxiety disorders (effect size [ES] = .55) and increase in parent-rated coping (ES = .69) than controls, as well as significantly better CGI improvement on social phobia/avoidant disorder (ES = .95), separation anxiety disorder (ES = .82), and specific phobia (ES = .78), but not on generalized anxiety disorder. Results on the Child Behavior Checklist Internalizing scale were not significant and were limited by low return rates. Treatment response was unrelated to age or parental anxiety but was negatively predicted by behavioral inhibition. Gains were maintained at 1-year follow-up. Results suggest that developmentally modified parent-child CBT may show promise in 4- to 7-year-old children.

Biological Psychiatry, Sep 1, 2007

Objective-"Behavioral disinhibition" refers to a temperamental tendency to exhibit boldness, appr... more Objective-"Behavioral disinhibition" refers to a temperamental tendency to exhibit boldness, approach, and spontaneity in unfamiliar situations. We previously found it to be associated with childhood disruptive behavior and mood disorders as well as with parental bipolar disorder. In the present study, our objective was to examine the diagnostic outcome in middle childhood of behavioral disinhibition assessed at preschool-age among offspring at risk for anxiety and mood disorders. Method-The sample consisted of 284 children including offspring of parents with panic disorder or major depression and comparison offspring of parents without these disorders, who had been assessed with laboratory observations of temperament at ages 21 months-6 years. We reassessed 215 of the children (77%) at 5-year follow-up (mean age 9.6 years) with structured diagnostic interviews. Results-Compared with non-inhibited, non-disinhibited controls, behaviorally disinhibited children had higher lifetime rates of comorbid mood plus disruptive behavior disorders, and higher current rates of any disruptive behavior disorder and of oppositional defiant disorder. Conclusion-Behavioral disinhibition appears to be a temperamental antecedent of disruptive behavior disorders and their comorbidity with mood disorders in middle childhood, which may be targeted for preventive intervention.

American Journal of Psychiatry, Mar 1, 2010

The gold standard for evidence in psychiatry, as elsewhere in medicine, is often considered to be... more The gold standard for evidence in psychiatry, as elsewhere in medicine, is often considered to be the randomized, placebo-controlled, double-blind study. The use of blinding or masking plays a key role in these designs by addressing the problem of expectancy. First, if participants anticipate greater benefit from a particular treatment, they may be more likely to respond to it, which is considered a component of placebo response. Not surprisingly, participants have been found to report greater anticipated benefits when they were randomized to enter an active-comparator, versus a placebo-comparator, study (1). Likewise, raters may anticipate greater benefit from active drug and thus favor it in their ratings, whether consciously or unconsciously. Greater response rates in both active and placebo arms occur when a greater proportion of participants receive active treatment-that is, when patients (1) or raters (2) expect more participants to benefit. Double-blinding, typically by providing drug and placebo in identical capsules, is intended to minimize the impact of expectancy and the related concept of credibility. The blind may be compromised in a variety of ways, however, beginning with differences in medication taste or smell. Of particular concern may be the emergence of adverse effects, particularly when those adverse effects are known to be associated with a specific medication. The requirement that informed consent forms delineate common adverse effects may increase this risk (3). Indeed, when the degree of unblinding is assessed in antidepressant trials, multiple reports suggest that it is extensive: at least three-quarters of patients are typically able to correctly guess at their treatment assignment (4, 5). Moreover, even the sudden absence of adverse effects may contribute to unblinding, as might occur when a participant stabilized on a sedating medication is abruptly switched to placebo at randomization in a relapse-prevention study. If such unblinding occurs, does it meaningfully affect trial results? A meta-analysis of antidepressant trials using active placebos, such as those with antihistaminergic or anticholinergic effects, suggested smaller effect sizes than those observed in the presumably less blinded trials with inert placebo (6). Estimating the potential impact in published studies is difficult, but certain findings when results are stratified by potentially unblinding adverse effects raise concern. In a trial of quetiapine in bipolar depression (7), for example, when investigators examined only the groups reporting sedation, mean change in the Montgomery-Åsberg Depression Rating Scale total score at week 8 was-18.8 in the quetiapine groups (N=195) and-18.9 in the placebo group (N=24). Conversely, when the subset of participants without sedation were examined, the mean change in the Montgomery-Åsberg Depression Rating Scale total score was-19.3 and-11.7 in the quetiapine and placebo groups, respectively. While only a small subset of patients were in the placebo/sedation arm, the disparity in placebo response might suggest that clinical raters were attempting to "guess" at treatment assignment. Unfortunately, for psychotropic drugs, CNS side effects may be inevitable. Therefore, we call for more uniform application of standards in the design, reporting, and review of clinical trials. 1. Consistent with CONSORT (8) and international guidelines (9), participants and raters should be asked to guess treatment assignment, and the degree of true and false unblinding should be reported in the primary publication of results. Statistical tech

Neuropsychopharmacology, Aug 21, 2015

Although lithium preparations remain first-line treatment for bipolar disorder, risk for developm... more Although lithium preparations remain first-line treatment for bipolar disorder, risk for development of renal insufficiency may discourage their use. Estimating such risk could allow more informed decisions and facilitate development of prevention strategies. We utilized electronic health records from a large New England health-care system between 2006 and 2013 to identify patients aged 18 years or older with a lithium prescription. Renal insufficiency was identified using the presence of renal failure by ICD9 code or laboratory-confirmed glomerular filtration rate below 60 ml/min. Logistic regression was used to build a predictive model in a random two-thirds of the cohort, which was tested in the remaining one-third. Risks associated with aspects of pharmacotherapy were also examined in the full cohort. We identified 1445 adult lithium-treated patients with renal insufficiency, matched by risk set sampling 1 : 3 with 4306 lithium-exposed patients without renal insufficiency. In regression models, features associated with risk included older age, female sex, history of smoking, history of hypertension, overall burden of medical comorbidity, and diagnosis of schizophrenia or schizoaffective disorder (po0.01 for all contrasts). The model yielded an area under the ROC curve exceeding 0.81 in an independent testing set, with 74% of renal insufficiency cases among the top two risk quintiles. Use of lithium more than once daily, lithium levels greater than 0.6 mEq/l, and use of first-generation antipsychotics were independently associated with risk. These results suggest the possibility of stratifying risk for renal failure among lithiumtreated patients. Once-daily lithium dosing and maintaining lower lithium levels where possible may represent strategies for reducing risk.

Acta Psychiatrica Scandinavica, May 1, 1997

We studied the sensitivity in detecting changes of the 6-item version of the original 17-item Ham... more We studied the sensitivity in detecting changes of the 6-item version of the original 17-item Hamilton Depression Rating Scale (HAM-D) and compared it with the more widely used versions among 164 depressed outpatients with and without atypical features before and after treatment with fluoxetine. The 6-item HAM-D was shown to be as sensitive as the 17-, 21and 24-item versions of this scale. In addition, the different versions of the HAM-D were strongly correlated with each other at baseline and at the endpoint. It appears that the 6-item version of the HAM-D allows the assessment of severity of depression with comparable sensitivity to the

Biological Psychiatry, Nov 1, 1993

Significant antidepressant effects have been reported after administration of dexamethasone and t... more Significant antidepressant effects have been reported after administration of dexamethasone and thyrotropin-releasing hormone (TRH). The purpose of this study was to evaluate whether or not the administration of the dexamethasone suppression test (DST) and TRH test in depressed patients, just before their entering clinical trials, has any impact on their symptoms. The Hamilton Rating Scale for Depression was administered to 166 subjects at screen visit, 1 week later (baseline visit), and I week after beginning treatment with fluoxetine 20 mglday (week.l). Between screen and baseline visits, 62 patients were administered the DST alone, 6 underwent the TRH test alone, and 26 received both the DST and the TRH test. Seventytwo patients were not administered either test. No statistically significant differences in depression scores were found at screen, baseline and week.! visits between patients who underwent neuroendocrine tests and those who did not. Our data suggest that the administration of neuroendocrine tests such as the DST and the TRH test does not have a statistically significant effect on depressive symptoms and, therefore, does not interfere with study results and interpretation.

Acta Psychiatrica Scandinavica, Jul 1, 1992

ABSTRACT

The Journal of Clinical Psychiatry, Sep 15, 1999

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome co... more Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared with major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in depressive symptoms and anxiety levels in outpatients with major depression with comorbid anxiety disorder following 12 weeks of open treatment with fluvoxamine. We enrolled 30 outpatients (mean +/- SD age = 39.4 +/- 11.3 years; 16 women and 14 men) with DSM-IV major depressive disorder accompanied by one or more current comorbid DSM-IV anxiety disorders in our study. Patients were treated openly with fluvoxamine initiated at 50 mg/day, with an upward titration to a maximum of 200 mg/day (mean +/- SD dose = 143 +/- 45 mg/day). Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales for both depression and anxiety. Intent-to-treat analysis was used to assess outcome. The mean +/- SD number of comorbid anxiety disorders per patient was 2.1 +/- 1.1. Following fluvoxamine treatment, the mean +/- SD HAM-D-17 score dropped from 20.2 +/- 3.3 to 1 1.0 +/- 7.0 (p &amp;lt; .0001). The mean +/- SD depression CGI-S score dropped from 4.0 +/- 0.6 to 2.4 +/- 1.1 (p &amp;lt; .0001), and the mean +/- SD anxiety CGI-S score decreased from 4.1 +/- 0.8 to 2.5 +/- 1.2 (p &amp;lt; .0001). Eighteen (60%) of the 30 patients had CGI-I scores &amp;lt; or = 2 for both anxiety and depression at endpoint, with 53% showing a &amp;gt; or = 50% reduction in HAM-D-17 scores at endpoint. Although preliminary, our findings suggest that fluvoxamine is effective in treating outpatients with major depression with comorbid anxiety disorder, having a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are needed, in a larger sample, to confirm our findings.

Journal of Anxiety Disorders, Jul 1, 2000

There is a growing body of evidence that social phobia may be treated effectively by either pharm... more There is a growing body of evidence that social phobia may be treated effectively by either pharmacologic or cognitive-behavioral interventions. but few studies have examined the relative benefits of these treatments. In this study, we examined the relative efficacy of pharmacotherapy with clonazepam and cognitive-behavioral group therapy (CBGT) for treating social phobia. In addition, we examined potential predictors of differential treatment response. Outpatients meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for social phobia were randomly assigned to treatment. Clinician-rated and patient-rated symptom severity was examined at baseline and after 4, 8, and 12 weeks of treatment. All clinician-rated assessments were completed by individuals blind to treatment condition. Patients in both conditions improved significantly, and differences between treatment conditions were absent, except for greater improvement on clonazepam on several measures at the 12-week assessment. Symptom severity was negatively associated with treatment success for both methods of treatment, and additional predictors-sex, comorbidity with other anxiety or mood disorders, fear of anxiety symptoms, and dysfunctional attitudes-failed to predict treatment outcome above and beyond severity measures. In summary, we found that patients randomized to clinical care with clonazepam or CBGT were equally likely to respond to acute treatment, and pretreatment measures of symptom severity provided no guidance for the selection of one treatment over another.

American Journal of Psychiatry, Nov 1, 2006

This report describes the participants and compares the acute and longer-term treatment outcomes ... more This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N= 3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR 16) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD 17 ]) defined remission; a QIDS-SR 16 total score of ≥11 (HRSD 17 ≥14) defined relapse. Results: The QIDS-SR 16 remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps.

American Journal of Psychiatry, Oct 1, 1999

Studies have identified two types of antidepressant response: true drug response and placebo patt... more Studies have identified two types of antidepressant response: true drug response and placebo pattern response. This study examined the relationship between true drug response and choline-creatine ratios in the basal ganglia of depressed patients treated with fluoxetine. The authors evaluated drug-free outpatients with major depression before (N = 41) and after (N = 15) 8 weeks of fluoxetine treatment, 20 mg/day, by using proton magnetic resonance spectroscopy. There was a significant difference in the degree of change from baseline to week 8 in choline-creatine ratios between the true drug response group (N = 8) and the placebo pattern response/nonresponse group (N = 7); the true drug response patients had a 20% increase in choline-creatine ratios, and the placebo pattern response/nonresponse patients had a 12% decrease in choline-creatine ratios. These data suggest that true drug response to fluoxetine treatment in depression may be associated with an increase in choline-creatine ratios in the basal ganglia.

Psychiatric Clinics of North America, Jun 1, 2003

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinica... more Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinical information gaps and to evaluate the theoretical principles and clinical beliefs that currently guide pharmacotherapy of major depressive disorder. The study is conducted in representative participant groups and settings using clinical management tools that easily can be applied in daily practice. Outcomes include clinical outcomes and health care utilization and cost estimates. Research findings should be immediately applicable to, and easily implemented in, the daily primary and specialty care practices. This article provides the overall rationale for STAR*D and details the rationale for key design, measurement, and analytic features of the study.

American Journal of Psychiatry, Oct 1, 1995

European Neuropsychopharmacology, Sep 1, 1997

for all patients with a diagnosis of depression and/or prescription for an antidepressant were ob... more for all patients with a diagnosis of depression and/or prescription for an antidepressant were obtained. Episodes of antidepressant use following initiation of therapy with selective serotonin re-uptake inhibitors and tricyclic antidepressants are described with respect to duration of use, dose titration, prior and post co-morbidities, overall drug use and resource utilization in the two classes of antidepressants. We consider how antidepressant utilization compares to recommended treatment guidelines in Belgium (Commission de Transparence, 1994). These results will be generally considered in comparison to findings in similar and differently structured health care systems.

Psychiatric Clinics of North America, Sep 1, 1993

The importance of psychotropic drug interactions has become increasingly evident in recent years.... more The importance of psychotropic drug interactions has become increasingly evident in recent years. Although drug interactions may lead to therapeutic benefits, they also may result in diminished efficacy of drug therapy or may cause toxic or life-threatening reactions. To avoid these unwanted effects, it is important for the clinician to be aware of the basic principles that govern drug interactions.