Faculty Bibliography

BACKGROUND: Antidepressant therapies have been associated with a variety of side effects of both physical and psychological nature. Until recently, however, the majority of the studies focusing on side effects of antidepressants have not routinely included assessment of cognitive side effects. The purpose of the present work is to examine cross-sectionally the prevalence of cognitive and physical side effects of antidepressants during long-term treatment of depression. METHOD: Patients at least 18 years of age who were deemed responders to antidepressant therapy following at least 3 months of treatment for major depressive disorder (MDD) (diagnosed according to DSM-IV criteria) and whose MDD was considered to be in partial or full remission were eligible for inclusion in this study. Eligible patients were enrolled between January 2003 and December 2004. Study participants were administered the Harvard Department of Psychiatry/National Depression Screening Day (HANDS) scale, the Epworth Sleepiness Scale, the Brief Fatigue Inventory, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), and a study-specific questionnaire inquiring about the emergence of specific side effects such as apathy, fatigue, and inattentiveness. RESULTS: 117 MDD patients (mean +/- SD age: 43.4 +/- 12.6 years; women: N = 78 [66.7%]) met criteria for response according to the HANDS (score < 9). Cognitive symptoms (apathy, inattentiveness, forgetfulness, word-finding difficulty, and mental slowing) were each reported on both the CPFQ and the study-specific questionnaire by more than 30% of the responders on antidepressants. The physical symptoms of fatigue and sleepiness/sedation were reported by over 40% of the responders on both the CPFQ and the study-specific questionnaire. A significant, positive relationship was found between the CPFQ and the severity of residual depressive symptoms as measured by the HANDS total score (F = 15.3, p = .0002). CONCLUSION: Physical and cognitive symptoms are frequently reported by MDD patients who have responded to antidepressants and are treated in the long term with these agents. It is likely that these symptoms are both side effects of the antidepressants as well as residual symptoms of MDD.

BACKGROUND: Studies investigating the performance of instruments to detect major depressive disorder (MDD) have reported inconsistent results. Subsyndromal depression (SD) has also been associated to increased morbidity, and little is known about its detection in primary care setting. This study aimed to investigate the performance of the Primary Care Evaluation of Mental Disorders (PRIME-MD) to detect MDD and any depression (threshold at SD) in an outpatient unit of a teaching general hospital. METHODS: Nineteen primary care physicians using the PRIME-MD evaluated 577 patients, 240 of them (75% female; mean age, 40.0 +/- 14.4), including all with MDD and a randomly subset of those without MDD, were evaluated by 11 psychiatrists using the Structured Clinical Interview Axis I Disorders, Patient Version (SCIDI/P) for DSM-IV as the standard instrument. RESULTS: The kappa between the PRIME-MD and the SCID was 0.42 for the diagnosis of any depression and 0.32 for MDD. The distribution of the number of depressive symptoms per patient suggested the existence of a continuum between SD and MDD, and a high frequency of subjects with 4-6 symptoms (close to the cutoff for the diagnosis of MDD). LIMITATIONS: The sample has a modest size and is a subset of an original one. CONCLUSION: A continuum between SD and MDD may in part explain the relatively low agreement for the diagnosis of MDD in our sample and possibly in other studies. Studies investigating the performance of screening instruments to detect MDD, should consider the relevance of identifying SD, and the influence of the distribution of the number of depressive symptoms in their results.

BACKGROUND: An increased incidence of brain white-matter hyperintensities has been described in major depressive disorder, butthe impact of such hyperintensities on treatment outcome is still controversial. AIMS: To investigate the relationship of brain white-matter hyperintensities with cardiovascular risk factors and with treatment outcome in younger people with major depressive disorder. METHOD: We assessed brain white-matter hyperintensities and cardiovascular risk factors in 84 people with major depressive disorder prior to initiating antidepressant treatment. We also assessed hyperintensities in 35 matched controls. RESULTS: We found no significant difference in the prevalence of white-matter hyperintensities between the depression and the control groups. Left-hemisphere subcortical hyperintensities correlated with lower rates of treatment response. We found no correlation between global hyperintensity measures and clinical outcome. Brain white-matter hyperintensities correlated with hypertension and age and withtotal cardiovascular risk score. CONCLUSIONS: Subcortical white-matter hyperintensities in the left hemisphere (but notin other brain areas) maybe associated with poor response to antidepressant treatment in major depression.

Both diabetes and depression are highly prevalent. Patients with diabetes experience higher rates of depression compared to the general population. When present, depression is associated with an increase in the morbidity and mortality of diabetes, suggesting the importance of treatment in this population. The objective of the present study was to characterize depressive characteristics in depressed patients with and without comorbid diabetes. Seventeen patients with type 1 or type 2 diabetes were drawn from outpatient clinical trials. Depressed patients without diabetes were identified from the same studies. Unpaired t-tests and multiple chi-square analyses were used to compare demographic and clinical characteristics between the samples. Diabetic patients in our sample were more depressed and reported lower levels of somatic well-being and contentment compared to non-diabetic patients. The samples did not differ significantly along other dimensions of depression, including course of illness, response to previous treatments and comorbid conditions. These findings suggest that depressed diabetic patients are more similar than not to non-diabetic depressed patients, although important differences exist.

Patients with bipolar disorder are among the most challenging to treat. These patients frequently present with complex mood and other symptoms that change over time, complex psychiatric and medical comorbid conditions, and multiple medications. Clinicians rarely systematically assess or measure all of these factors and instead rely on memory and general impressions. It is imperative that clinicians systematically track and monitor these relevant variables to ensure treatment decisions are based on precise clinical data. By integrating measurement and management, clinicians and patients can collaborate to assess the effectiveness of treatments and to make joint decisions about critical points at which to adjust treatment. This method was shown to be successful in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).

Our objective was to assess the effectiveness and safety of the combination of duloxetine and bupropion for treatment-resistant major depressive disorder (TRD). A retrospective chart review was conducted to identify patients with major depressive disorder (MDD) who had not experienced full remission of symptoms following an adequate trial of either duloxetine (n = 3) or bupropion (n = 7), and who then received the combination of these two antidepressants for TRD. Ten patients [37.2 +/- 11.3 years of age, five women, baseline Clinical Global Impressions (CGI) scale score 4.4 +/- 1.1], seven of whom had not remitted following treatment with bupropion (330 +/- 67 mg, 20.5 +/- 12.2 weeks), and three of whom had not remitted following treatment with duloxetine (90 +/- 30 mg, 18 +/- 2 weeks) received at least 4 weeks of combination treatment. The CGI was administered when the combination was first prescribed, and following 8.8 +/- 4.0 (range, 4-16) weeks of treatment. There was a significant decrease in CGI-S (Severity) scores (4.4 +/- 1.1 to 2.1+/-0.9, P <.0001) following combination treatment. Three (30%) patients were remitters at follow-up, and six (60%) were responders who did not achieve full symptom remission. The mean maximum adjunctive duloxetine and bupropion doses were 60.0 +/- 17.3 mg and 175.0 +/- 114.5 mg, respectively. Side effects reported during combination treatment were nausea (n = 2), dry mouth (n = 2), jitteriness/agitation (n = 2), fatigue/drowsiness (n = 2), increased blood pressure (n = 1), increased sweating (n = 1), insomnia (n = 1), pruritus (n = 1), headache (n = 1), sexual dysfunction (n = 1), and weight gain (n = 1). Although preliminary, these results suggest a possible role for the combination of duloxetine and bupropion for TRD.

The objective of the present work was to study the interrelationship between white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle including serum folate, vitamin B12, and homocysteine levels in a relatively young sample of outpatients with major depressive disorder (MDD), and to compare the severity of white matter hyperintensities in MDD patients and healthy volunteers. Fifty MDD outpatients (34% women, age 40.6+/-10.3 years), free of psychotropic medications for at least 2 weeks before enrollment, underwent magnetic resonance imaging (MRI) scans of the brain to detect T2 WMHs and also had (1) serum folate, vitamin B12, homocysteine and cholesterol levels measured, and (2) cardiovascular risk factors assessed during the same study visit. Thirty-five healthy comparison subjects (40% women, age 39.2+/-9.8 years) also underwent brain MRI scans. Hypofolatemia, hypertension and age independently predicted a greater severity of total brain WMHs. Separately, the same factors also predicted a greater severity of subcortical WMHs. Hypofolatemic and hypertensive patients had more severe WMHs than normal controls. In light of the adverse impact of WMHs on a number of health-related outcomes later in life, hypofolatemia and hypertension may represent modifiable risk factors to prevent the occurrence of such adverse outcomes.

The objective of this study was to investigate the relative impact of brain white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle metabolism (including serum folate, vitamin B12 and homocysteine levels) on the outcome of antidepressant treatment in non-elderly subjects with major depressive disorder (MDD). Fifty MDD subjects were administered brain magnetic resonance imaging (MRI) scans at 1.5 T to detect T2 WMHs. The severity of brain WMHs was classified with the Fazekas scale (range=0-3). We assessed cardiovascular risk factors in all MDD subjects (age, gender, smoking, diabetes, family history, hypertension, cholesterol). MDD patients also had serum folate, vitamin B12 and homocysteine levels measured. All MDD subjects received treatment with fluoxetine 20 mg/day for 8 weeks. In a logistic regression, the severity of subcortical WMHs and the presence of hypofolatemia were independent predictors of lack of clinical response to antidepressant treatment. Separately, hypofolatemia also predicted lack of remission to antidepressant treatment. These associations were independent of the presence of smoking, diabetes, family history, hypercholesterolemia, hyperhomocysteinemia and low B12 levels. Although preliminary, the results of the present work suggest that subcortical brain WMHs and hypofolatemia may have an independent negative impact on the likelihood of responding to antidepressant treatment in non-geriatric subjects with MDD.

OBJECTIVE: An increased association between depression and cardiovascular disease, as well as cardiovascular risk factors, led to the "vascular depression" hypothesis. This subtype of depression is postulated to have a different clinical presentation and to be more treatment-resistant. In this study, we measured the impact of cardiovascular risk factors on the outcome of antidepressant treatment in major depressive disorder (MDD). METHOD: We enrolled 348 MDD subjects, ages 19 to 65 years, in an 8-week treatment study with 20 mg fluoxetine per day. We recorded for each subject 6 cardiovascular risk factors: age (male > or =45, female > or =55), smoking, family history, hypertension, diabetes, hypercholesterolemia; and we defined a cardiovascular risk score (range, 0-6) by the number of risk factors present. Treatment outcome was measured as response (> or =50% improvement on the 17-item Hamilton Rating Scale for Depression [Ham-D-17]) and remission (final Ham-D-17< or =7). RESULTS: In logistic regression analyses, the cardiovascular risk score was significantly associated with treatment nonresponse and lack of remission when adjusting for age of onset of MDD and baseline severity of depression. The cardiovascular risk score remained significantly associated with treatment nonresponse when we additionally controlled for overall medical burden (measured with the Cumulative Illness Rating Scale). Among individual cardiovascular risk factors, elevated total cholesterol was a significant predictor of treatment nonresponse and lack of remission. CONCLUSION: Cardiovascular risk factors may have negative effects on the course of treatment in MDD. These results support the concept of "vascular depression" in younger subjects.

OBJECTIVE: In an open trial, we investigated the efficacy of triiodothyronine (T(3)) adjuvant to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder (MDD) resistant to SSRI treatment. METHOD: Twenty subjects who met DSM-IV criteria for MDD (mean +/- SD age = 44.3 +/- 10.3 years; 55% [N = 11] women) and had failed to respond to a course of treatment of at least 8 weeks with an SSRI antidepressant were enrolled in a 4-week open-label augmentation treatment with T(3) 50 microg/day. Atypical and melancholic sub-types of MDD were diagnosed using Structured Clinical Interview for DSM-IV Axis I Disorders criteria. We administered the 17-item Hamilton Rating Scale for Depression (HAM-D-17) 4 times during the study (which was conducted between 2001 and 2003). RESULTS: During T(3) augmentation, the severity of depression decreased from an initial mean +/- SD HAM-D-17 score of 20.5 +/- 3.6 to a final HAM-D-17 score of 14.0 +/- 7.1 (p < .001). Seven subjects (35.0%) were treatment responders (HAM-D-17 reduction >or= 50%), and 6 subjects (30.0%) achieved clinical remission (final HAM-D-17

PMID: 16086620

ISSN: 0160-6689

CID: 2389802