Faculty Bibliography

BACKGROUND: An increasing amount of attention has been paid to treatment resistant depression. Although it is quite common to observe nonremission to not just one but consecutive antidepressant treatments during a major depressive episode, a relationship between the likelihood of achieving remission and one's degree of resistance is not clearly known at this time. This study was undertaken to empirically test 2 recent models for staging treatment resistance. MATERIALS AND METHODS: Psychiatrists from 2 academic sites reviewed charts of patients on their caseloads. Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scales were used to measure severity of depression and response to treatment, and 2 treatment-resistant staging scores were classified for each patient using the Massachusetts General Hospital staging method (MGH-S) and the Thase and Rush staging method (TR-S). RESULTS: Out of the 115 patient records reviewed, 58 (49.6%) patients remitted at some point during treatment. There was a significant positive correlation between the 2 staging scores, and logistic regression results indicated that greater MGH-S scores, but not TR-S scores, predicted nonremission. CONCLUSIONS: This study suggests that the hierarchical manner in which the field has typically gauged levels of treatment resistance may not be strongly supported by empirical evidence. This study suggests that the MGH staging model may offer some advantages over the staging method by Thase and Rush, as it generates a continuous score that considers both number of trials and intensity/optimization of each trial.

BACKGROUND: There is a paucity of naturalistic studies from depression specialty clinics describing the next-step (augmentation versus switching) practices of clinicians for outpatients with major depressive disorder (MDD) resistant to an antidepressant trial of adequate dose and duration. METHODS: Eighty-five MDD outpatients enrolled in one of two specialty clinics, who had not achieved remission after a first adequate prospective antidepressant trial conducted at the clinic underwent either augmentation (n = 36) or switching (n=49) of their antidepressant regimen. Outcome was defined with the use of the Clinical Global Impressions (CGI) Scale. RESULTS: Nonresponders (CGI-I>3) following the first antidepressant trial were more likely to have their treatment switched than patients who experienced incomplete response (CGI-I<4, CGI-S>1) (67.2% versus 28.5%, p = 0.001). Incomplete responders during the first trial who went on to receive augmentation had higher remission rates (60.0% versus 0%, p=0.01), lower endpoint depression severity scores (1.8 +/- 1.1 versus 3.3 +/- 0.8, p = 0.01) and greater clinical improvement scores (1.6 +/- 1.1 versus 3.0 +/- 0.0, p=0.03) than incomplete responders who had their antidepressant regimen switched. Although nonresponders to the first treatment who were switched experienced greater symptom improvement than nonresponders who were augmented (2.7 +/- 1.1 versus 3.4 +/- 1.2, p=0.03), there was no significant difference (p>0.05) between these two groups with respect to remission rates (18.6% versus 14.2%, respectively) and endpoint depressive severity (3.0 +/- 1.4 versus 3.4 +/- 1.4, respectively). CONCLUSIONS: In this nonrandomized, naturalistic treatment setting, nonresponders to an adequate, prospective antidepressant trial were more likely to have their antidepressant regimen switched, while patients with incomplete response during the first trial were more likely to have their regimen augmented. In addition, patients with incomplete response who had their treatment augmented had better outcome than patients with incomplete response who had their treatment switched.

Studies focusing on the prevalence of obesity in Major Depressive Disorder (MDD), or the impact of excess body fat on the treatment of MDD are lacking. The aim of the present work is to systematically study obesity in MDD outpatients. A total of 369 MDD outpatients enrolled in an 8-wk trial of 20 mg fluoxetine had height and weight measured at baseline. We then examined: (1) the prevalence of being overweight or obese, (2) the relationship between obesity and a number of demographic and clinical variables, and, (3) the relationship between relative body weight and obesity with clinical response. We found that more than 50% of patients were overweight [body mass index (BMI) > or =2 5 kg/m2], while 20% were obese (BMI > or = 30 kg/m2). Obese patients presented with worse somatic well-being scores than non-obese MDD patients, but they did not differ with respect to depression severity, anxiety, somatic complaints, hopelessness or hostility. Greater relative body weight, but not obesity, predicted non-response. In conclusion, greater relative body weight was found to place MDD outpatients at risk for fluoxetine resistance.

OBJECTIVE: We used the Tridimensional Personality Questionnaire (TPQ) to study the relationship between temperamental traits and comorbid anxiety disorders as well as age of onset of major depressive disorder (MDD) in 263 patients with MDD. METHODS: Patients recruited for a large clinical study on MDD underwent a Structured Clinical Interview for DSM-III-R assessment and were administered the self-rated TPQ [mean age = 39.5 +/- 10.5 years, women = 138 (53%), initial 17-item Hamilton Rating Scale for Depression (HAM-D-17) score = 19.6 +/- 3.4]. The TPQ was scored for three previously identified factors -- harm avoidance (HA), novelty seeking (NS), and reward dependence (RD). Multiple linear regression methods were used to evaluate the relationship between TPQ factors and each comorbid anxiety disorder as well as between early-- vs. late-onset MDD, after controlling for age, gender and initial HAM-D-17 score (when these were related to the dependent variable in simple regressions). RESULTS: Social anxiety disorder in MDD was strongly associated with higher scores on HA and lower scores on NS and RD (t = 5.4, p < 0.0001; t = 2.6, p = 0.009; t = 2.2, p = 0.028, respectively). A diagnosis of generalized anxiety disorder in MDD was significantly related to higher HA scores (t = 2.8, p = 0.006). The presence of comorbid obsessive-compulsive disorder was associated with lower NS scores (t = 2.3, p = 0.023) as was that of comorbid panic disorder (t = 2.0, p = 0.051). Finally, the presence of simple phobias was associated with lower scores on RD (t = 2.4, p = 0.016). HA scores were higher in patients with early onset of MDD (adjusted p = 0.05). Early versus late onset of MDD was not significantly related to NS or RD scores. LIMITATIONS: Since our sample consisted of moderately depressed outpatients, our ability to generalize our findings to other populations is limited. CONCLUSIONS: Features of temperament are related to patterns of anxiety disorder comorbidity and age of onset among patients with MDD. Higher levels of HA and lower levels of RD and NS were associated with an increased risk of anxiety disorder comorbidity in our sample. HA may also be related to early onset of depression.

The authors examined the impact of comorbid medical illness on the rate of relapse of major depressive disorder during continuation therapy. Subjects (N = 128) with major depressive disorder (according to DSM-III-R criteria) achieved clinical remission (a 17-item Hamilton Depression Rating Scale score < or = 7) after 8 weeks of treatment with fluoxetine and entered the continuation phase of antidepressant treatment. They used the Cumulative Illness Rating Scale to measure the severity of comorbid medical illness. Eight patients (6.3%) relapsed during the 28-week continuation phase. With logistic regression, the total burden and the severity of comorbid medical illness significantly predicted the relapse of major depressive disorder during continuation therapy with fluoxetine. Greater medical comorbidity was also associated with higher increases in self-reported symptoms of depression, anxiety, and anger during the follow-up.

A major factor in evaluating and treating depression is the presence of comorbid medical problems. In this paper, the authors will first evaluate studies showing that medical illness is a risk factor for depression. The authors will review a series of randomized, controlled studies of antidepressant treatment in subjects with major depressive disorder (MDD) and comorbid medical illnesses (myocardial infarction, stroke, diabetes, cancer, and rheumatoid arthritis). Most of these studies report an advantage for an active antidepressant over placebo in improvement of depressive symptoms. The authors also will review a series of studies in which the outcome of antidepressant treatment is compared between subjects with MDD with and without comorbid medical illness. In these studies, subjects with medical illness tend to have lower improvement of depressive symptoms and higher rates of depressive relapse with antidepressant treatment compared with MDD subjects with no medical comorbidity. In addition, the authors will review hypotheses on the mechanism of the interaction between medical illness and clinical response in MDD. The paper will conclude that medical comorbidity is a predictor of treatment resistance in MDD.

This study assessed the effect of general medical comorbidity on response to next-step antidepressant treatments among subjects with major depressive disorder whose depression failed to respond to an 8-week open trial of 20 mg/day of fluoxetine. Of the 386 outpatients in the open trial, 101 who remained depressed were randomly assigned to double-blind treatment with either an increased dose of fluoxetine or lithium or desipramine augmentation for 4 weeks. The Cumulative Illness Rating Scale (CIRS) was used to assess baseline general medical comorbidity, and the Hamilton Depression Rating Scale was used to assess depressive symptoms. Logistic regression analysis showed that CIRS score was not associated with likelihood of remission or premature study discontinuation. Medical comorbidity thus does not appear to be associated with significantly poorer outcome among patients whose major depressive disorder failed initially to respond to an initial trial of 20 mg/day of fluoxetine.

OBJECTIVE: In the present study we assessed the relationship between somatic symptoms and the time to onset of clinical response to fluoxetine in patients with major depressive disorder (MDD). METHOD: 87 outpatients (mean age = 41.4 +/- 10.2 years; 59.8% women) with DSM-III-R MDD who had sustained acute response to fluoxetine completed the Symptom Questionnaire (SQ) at baseline. Onset of response was defined as a 30% decrease in the total score for the 17-item Hamilton Rating Scale for Depression that led to a 50% decrease by week 8. With the use of 2 separate multiple regressions, controlling for the severity of depression at baseline, we then assessed the relationship between the number of somatic symptoms as assessed by the SQ subscale for somatic symptoms (SQ-SS) and both the time to onset of clinical response and the time to clinical response. The study was conducted between November 1992 and January 1999. RESULTS: A greater number of somatic symptoms at baseline predicted a greater amount of time to onset of clinical response to fluoxetine (p =.0233). The relationship between SQ-SS scores and time to response was not found to be statistically significant (p >.05). CONCLUSION: Somatic symptoms of depression were found to be associated with a delayed onset of antidepressant response to fluoxetine in MDD.

Cholesterol plays an integral role in the structure and function of the cell membrane and may also affect neurotransmission in the central nervous system. Previous work has identified abnormalities in serum cholesterol levels in patients with mood and anxiety disorders as well as in suicidal patients. However, the biological significance of these abnormalities remains to be clarified. An understanding of how serum cholesterol relates to the pathophysiology of mood disorders may generate biological markers that predict treatment response as well as targets for novel therapeutic strategies. In this article, we review the literature studying the significance of cholesterol in mood and anxiety disorders, with an emphasis on new studies focusing on the adverse impact of hypercholesterolemia on the treatment of major depressive disorder (MDD). We then propose possible mechanisms that would account for the relationship between elevated cholesterol and treatment non-response in MDD.