Axis III disorders in treatment-resistant major depressive disorder

A number of naturalistic studies have found that medical co-morbidity conveys a worse long-term prognosis in the treatment of major depressive disorder (MDD). The purpose of this study was to test whether the presence of co-morbid medical conditions can predict clinical response in patients with treatment-resistant MDD (TRD) treated with open-label nortriptyline (NT). Ninety-two patients with TRD entered a 6-week open trial of NT. The presence of co-morbid medical disorders was assessed during the screen visit. The degree of medical co-morbidity during the screen visit was then quantified with the use of the Cumulative Illness Rating Scale-Geriatric Version (CIRS(G)). We tested whether CIRS(G) scores predicted clinical response or depression severity at endpoint. CIRS scores at baseline did not significantly predict treatment response. The results of this study fail to confirm the relationship between co-morbid medical conditions and poor outcome in the treatment of MDD for patients with TRD. Patients with TRD and co-morbid medical conditions can be expected to respond to antidepressants as well as their counterparts without concurrent axis III co-morbidity. The CIRS(G) scores for this TRD sample were lower than those reported for geriatric depression, or for depressed patients with severe medical illness, common in medical and surgical wards and in most specialty clinics of large academic centers. Thus, the present results cannot be generalized to such populations.     

Hopelessness and suicidal ideation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome

Depression and hopelessness are risk factors for suicide. The purpose of this study was to examine the extent of suicidal ideation and hopelessness in outpatients with treatment-resistant depression (TRD) and to study the impact of suicidal ideation and hopelessness on treatment with nortriptyline (NT). The degree of suicidal ideation and hopelessness was assessed during the screen visit with the use of items #3 and #30 of the Hamilton Depression Rating Scale (HAM-D) in 89 patients with TRD who entered a 6-week open trial of NT. Forty of these patients also completed the Beck Hopelessness Index (BHI) during the screen visit. In separate logistic regressions, the scores from the BHI and the two HAM-D items were then tested as predictors of clinical response to the 6-week trial with NT, controlling for the severity of depression. More than half of patients reported thoughts or wishes of death to self and significant hopelessness. A greater degree of hopelessness before treatment in completers, reflected by the score on the HAM-D item #30, predicted response to NT. More than half of patients with prominent hopelessness who completed the trial responded. Patients with TRD are more likely than not to report prominent suicidal ideation and hopelessness. Furthermore, a full 6-week trial of NT, a relatively noradrenergic tricyclic antidepressant, may be particularly useful in patients who have failed to respond to several antidepressants and also report significant hopelessness.     

Somatic symptoms as predictors of time to onset of response to fluoxetine in major depressive disorder

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.     

Functioning and interpersonal relationships as predictors of response in treatment-resistant depression

The purpose of this study was to examine whether occupational functioning or the quality of interpersonal relationships is predictive of clinical response to a 6-week open trial of nortriptyline (NT) in patients with treatment-resistant depression (TRD). Ninety-two subjects with TRD were treated openly with NT for 6 weeks. The longitudinal interval follow-up evaluation (LIFE) scale was administered at baseline. A logistic regression was performed using occupational functioning and interpersonal relationships (over the past month and over the past 5 years) as predictors of treatment response. Unpaired t tests were performed to examine mean composite LIFE score values between responders and nonresponders. The composite scores that were statistically significant were used as single predictors of treatment status in separate logistic regression equations. Better occupational function over the past 5 years predicted better response to treatment with NT in patients with TRD. Beyond a history of nonresponse to antidepressants, long-term occupational function may be a predictor of outcome in the treatment of TRD.     

Anxiety and somatic symptoms as predictors of treatment-related adverse events in major depressive disorder

The purpose of this study was to examine the relationship between the degree of anxiety or somatic symptoms present before treatment with the subsequent diagnosis of treatment-related adverse events (TRAEs) in patients with major depressive disorder (MDD) enrolled in an 8-week open trial of fluoxetine (20 mg). Baseline symptom questionnaires (SQ) were completed by 170 MDD patients enrolled in the trial. We then tested whether pre-treatment scores for anxiety and somatic symptoms predicted (1) whether patients were subsequently diagnosed with TRAEs; (2) whether they were subsequently diagnosed with moderate or severe TRAEs; or (3) whether a greater number of TRAEs were diagnosed during the trial. We found that depressed patients who presented with prominent somatic symptoms were significantly more likely to report at least one moderate or severe side effect during the course of treatment, but not more likely to report a greater number of side effects. Pre-treatment anxiety was not related to the development of side effects.     

The impact of written exposure on worry: a preliminary investigation

The main goal of this study was to examine the effect of written exposure on generalized anxiety disorder (GAD)-related symptoms in high worriers. Thirty nonclinical high worriers were randomly assigned to either a written exposure condition or a control writing condition. Self-report measures were used to assess worry, GAD somatic symptoms, depression, and intolerance of uncertainty at four time points during the study. Using hierarchical linear modeling (HLM), the authors found that all symptoms (i.e., worry, GAD somatic symptoms, and depression) significantly decreased over time in the written exposure group (although GAD somatic symptoms also decreased in the control group). Moreover, consistent with previous findings that intolerance of uncertainty preceded changes in worry over the course of treatment, intolerance of uncertainty scores predicted subsequent scores on all symptom measures in the experimental group. In contrast, worry and depression scores predicted subsequent intolerance of uncertainty scores in the control group.     

Psychic and somatic anxiety symptoms as predictors of response to fluoxetine in major depressive disorder

The purpose of this study was to examine whether the presence/severity of psychic and somatic anxiety symptoms predicted clinical response following a 12-week, flexible-dose (20-60 mg daily), open-label trial of fluoxetine for major depressive disorder (MDD). The presence and severity of psychic and somatic anxiety symptoms were assessed with the use of select subscales of the Symptom Questionnaire and the Hopkins Symptom Checklist among 518 outpatients with MDD. With the use of separate logistic regressions, we tested for the relationship between clinical response, baseline Hamilton Depression Rating Scale (HAM-D-17) scores, and subscale scores at baseline entered separately as independent variables Overall completion, response and remission rates for the trial were 64.2%, 55.4%, and 48.9%, respectively. All subscale scores selected for this analysis significantly predicted treatment response to fluoxetine. The presence/severity of psychic and somatic anxiety symptoms of MDD at baseline predicted an increased likelihood of non-response to fluoxetine in MDD. Studies examining whether specific treatment strategies are more effective than the selective serotonin reuptake inhibitors for MDD patients with high levels of co-morbid psychic and somatic anxiety symptoms are warranted.     

Longitudinal analysis of nortriptyline side effects in elderly depressed patients.

Forty-five depressed elderly patients were closely monitored in a research setting during treatment with nortriptyline and interpersonal psychotherapy for 7 consecutive months of acute and continuation treatment. Overall, nortriptyline was efficacious and well tolerated in this group. The frequency of somatic complaints measured by the Rating Scale for Side Effects declined by 50% during the acute phase of treatment, suggesting that many somatic complaints that may be attributed to side effects of nortriptyline are actually somatic symptoms of depression. The authors discuss the implications of these findings and offer practical advice for the treating clinician.     

难治性抑郁症患者MECT治疗前后血清VEGF水平的变化

目的探讨难治性抑郁症(TRD)患者血清血管内皮生长因子(VEGF)水平在改良电抽搐治疗(MECT)治疗前后的变化情况。方法采用酶联免疫吸附法检测26例TRD患者MECT治疗前后及27例正常对照者的血清VEGF浓度;采用汉密尔顿抑郁量表17项(HAMD-17)评估TRD患者的临床症状。组间血清VEGF浓度比较采用Wilcoxon符号秩和检验,治疗前后血清VEGF浓度变化与HAMD总评分的相关性分析使用Speaman秩相关。结果 TRD患者MECT治疗后24例(92.3%)达到治疗有效标准。TRD组MECT治疗前血清VEGF水平与对照组差异无统计学意义(P0.05);MECT治疗后血清VEGF水平有升高趋势,但差异无统计学意义(P0.05)。治疗前后血清VEGF浓度与HAMD总评分变化的相关性有统计学意义(r=-0.663,P0.01)。结论血清VEGF水平变化可能对临床疗效的评估有一定参考价值。     

Brain-derived neurotrophic factor and subcallosal deep brain stimulation for refractory depression

Objectives. Subcallosal cingulate (SCC) deep brain stimulation (DBS) is a promising experimental treatment for treatment-resistant depression (TRD). Given the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity and antidepressant efficacy, we examined the effect of SCC-DBS on serum BDNF in TRD. Methods. Four patients with TRD underwent SCC-DBS treatment. Following a double-blind stimulus optimization phase of 3 months, patients received continuous stimulation in an open label fashion for 6 months. Clinical improvement in depressive symptoms was evaluated bi-weekly for 6 months using the Hamilton Depression Rating Scale (HDRS). Mature serum BDNF levels were measured before and 9–12 months after surgery. Results. Three patients responded to SCC-DBS: two showed full clinical response (50% reduction in HDRS scores) and one had partial response (35% reduction in HDRS scores) at the clinical endpoint. Interestingly, all four patients showed reduction in serum BDNF concentration from pre-DBS baseline. Conclusions. SCC-DBS for TRD may be associated with decreased levels of serum BDNF. Longitudinal studies with multiple measurements in a larger sample are required to determine the role of BDNF as a biomarker of SCC-DBS antidepressant efficacy.     

Abnormal connectivity of anterior-insular subdivisions and relationship with somatic symptom in depressive patients

Depressive patients frequently present with somatic complaints such as pain and fatigue. The anterior insula (AI) is a crucial region for somatic processing, but reported contributions of AI dysfunction to somatic symptoms have varied across studies. We speculated that functional heterogeneity among AI subdivisions may contribute to this inconsistency. To reveal the correlation between each subdivision and somatic symptoms, we investigated resting-state functional connectivity (RSFC) based on seeds within distinct AI subdivisions in 45 depressive patients and 35 matched healthy controls (HCs). Depressive and somatic symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) and the 15-item somatic symptom severity scale of the Patient Health Questionnaire (PHQ-15), respectively. The contributions of AI subregion-specific pathways to depression were further validated by examining changes in symptom severity and RSFC following electroconvulsive therapy (ECT). At baseline, depressive patients exhibited weaker RSFC between ventral AI (vAI) and right orbitofrontal cortex (rOFC) than HCs. Moreover, vAI–rOFC RSFC strength was negatively correlated with PHQ-15 and HDRS scores, indicating that weaker RSFC predicted greater symptom severity. ECT reduced depressive and somatic symptoms, and symptom mitigation was correlated with enhanced vAI–rOFC RSFC. The findings suggest that reduced vAI–rOFC RSFC underlies the somatic symptoms of depression and that enhancing vAI–rOFC RSFC can contribute to amelioration of somatic symptoms.

     

Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study

BACKGROUND: The olanzapine/fluoxetine combination has demonstrated effectiveness in treatment-resistant depression (TRD). Although this combination is being used by prescribers, this is the first study to examine long-term use. Long-term efficacy and safety were therefore investigated in a group of patients with major depressive disorder (MDD) with and without TRD. METHOD: 560 patients who met DSM-IV diagnostic criteria for MDD were enrolled in this 76-week, open-label study (Feb. 2000-July 2002). The Montgomery-Asberg Depression Rating Scale (MADRS) total score was the primary efficacy measure. Safety was assessed via adverse events, vital signs, laboratory analytes, electrocardiography, and extrapyramidal symptom measures. RESULTS: MADRS mean total scores decreased 7 points from baseline (31.6 [N = 552]) at 1/2 week of treatment, 11 points at 1 week of treatment, and 18 points at 8 weeks of treatment. This effect was maintained to endpoint with a mean decrease of 22 points at 76 weeks. Response and remission rates for the total sample were high (62% and 56%, respectively), and the relapse rate was low (15%). Response, remission, and relapse rates for TRD patients (N = 145) were 53%, 44%, and 25%, respectively. The most frequently reported adverse events were somnolence, weight gain, dry mouth, increased appetite, and headache. At endpoint, there were no clinically meaningful changes in vital signs, laboratory analytes, or electrocardiography. There were no significant increases on any measure of extrapyramidal symptoms. CONCLUSIONS: The olanzapine/fluoxetine combination showed rapid, robust, and sustained improvement in depressive symptoms in patients with MDD, including patients with TRD. The long-term safety profile of the combination was similar to that of its component monotherapies.     

Three-year outcomes of maintenance nortriptyline treatment in late-life depression: a study of two fixed plasma levels.

OBJECTIVE: This study compared the long-term efficacy of two fixed plasma levels of nortriptyline in preventing or delaying recurrence of major depression in elderly patients and in minimizing residual depressive symptoms and somatic complaints. METHOD: The authors randomly assigned 41 elderly patients with histories of recurrent major depression to 3-year, double-blind maintenance pharmacotherapy using nortriptyline, with controlled plasma concentrations of 80-120 ng/ml versus 40-60 ng/ml. The authors compared times to, and rates of, recurrence of major depression. They also compared frequencies of side effects, noncompliance episodes, and subsyndromal symptomatic flare-ups. RESULTS: Major depressive episodes recurred for six (29%) of 21 subjects in the 80-120-ng/ml condition and eight (40%) of 20 subjects in the 40-60-ng/ml condition, a nonsignificant difference. Most recurrences took place in the first year of maintenance treatment. Hamilton depression scores in the subsyndromal range (higher than either 10 or 7) occurred significantly more often at 40-60 ng/ml, while constipation occurred significantly more often at 80-120 ng/ml. The proportions of patients reporting missed doses did not differ. CONCLUSIONS: Maintenance pharmacotherapy with nortriptyline at 80-120 ng/ml is associated with fewer residual depressive symptoms, that is, a less variable long-term response, than pharmacotherapy at 40-60 ng/ml, but constipation is more frequent and there is no difference in recurrence of syndromal major depressive episodes. Treatment at 80-120 ng/ml may be preferable, because of fewer residual symptoms and less variability of response, as long as side effect burden can be managed successfully.     

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study

BackgroundIntermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly.ObjectiveWe compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS.Methods208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments.ResultsHRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups.ConclusionsThese results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD.Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792)     

Symptom clusters as predictors of late response to antidepressant treatment

OBJECTIVE: While there is some indication from studies in the acute phase of antidepressant treatment that there are differences in the timing of improvement in symptoms, relatively little work has explored the patterns of change for specific symptom clusters and the predictability of these changes to signal eventual response during the acute phase of treatment. This article investigates the use of clusters of symptoms on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) to define the pattern of late response versus nonresponse to antidepressant medication. METHOD: Using principal component analysis, the HAM-D-17 was divided into 4 symptom clusters (mood, sleep/psychic anxiety, appetite, and somatic anxiety/weight). Data for 996 patients with major depressive disorder (DSM-III-R criteria), who participated in a 12-week acute phase study with nefazodone, were subjected to a post hoc analysis of changes in symptom cluster scores. Patients were divided into 3 groups: early responders (< 4 weeks), late responders (4-12 weeks), and nonresponders (> 12 weeks) as defined by < 50% reduction in HAM-D-17 scores from baseline. The late-responder and nonresponder groups were subjected to the principal component analysis. Data were collected from October 1992 to November 1994. RESULTS: There were significant differences in the pattern of symptom change on the mood cluster (weeks 3-4) (p < .0001), the sleep/psychic anxiety cluster (weeks 3-4) (p < .003), and the somatic anxiety/weight cluster (weeks 3-4) (p < .01) for the late responders compared to the nonresponders. Using change scores, a discriminant function analysis correctly assigned 127 of the 182 late responders and 85 of the 133 nonresponders, or 70% of the late responders and 64% of the nonresponders, to their final response groups. CONCLUSION: Monitoring changes in symptom clusters from the HAM-D-17 during this crucial early stage (first 4 weeks) can be used to distinguish late responders (after week 4) from nonresponders. Successful identification of nonresponders based on symptom cluster change in the first 4 weeks would facilitate a shortening of an ineffective treatment trial and allow for necessary changes in treatment strategy, helping physicians more closely follow treatment guidelines.     

Frontal theta cordance predicts 6-month antidepressant response to subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) may be an effective approach for treatment-resistant depression (TRD) that otherwise fails to respond to more conventional therapies, but DBS is invasive, costly, and has potential for adverse effects. Therefore, it is important to identify potential biomarkers for predicting antidepressant response before intervention. Resting-state EEG was recorded from 12 TRD patients at pre-treatment baseline, after 4 weeks SCC DBS, and after 24 weeks SCC DBS. Lower frontal theta cordance (FTC) at baseline (and higher FTC after 4 weeks) predicted lower depression severity scores after 24 weeks. Greater FTC increases (baseline-4 weeks) predicted greater decreases in depression severity scores subsequently (4-24 weeks) and over the course of the study (baseline-24 weeks). Predictive relationships were topographically specific to theta cordance for frontal electrodes. Thus, results from this pilot study suggest that baseline FTC and changes early in treatment each have utility as biomarkers for predicting 6-month clinical response to SCC DBS for TRD.     

Somatic symptoms for predicting depression: one-year follow-up study in annual health examinations

It has recently been noted that screening for depression can improve clinical outcomes. The purpose of the present study was to examine whether somatic symptoms reported at health examinations predicted depression in the following year. Subjects were 1066 Japanese workers (732 men, mean age 35 years) attending annual health examinations at an institute in two successive years. A self-administered questionnaire including items of 12 major somatic symptoms was given to all the subjects. Then clinical interviews of the DSM-IV were used to diagnose major depression and minor depression in both years. In addition, the 17-item Hamilton Depression Scale (HDS-17) was measured as one of the outcomes of depression in the following year. The prevalence of major (minor) depression was 3.7 (7.8)% at baseline and 3.4 (5.9)% for the following year, respectively. The following year's HDS-17 scores were higher (all P < 0.05) in those who had complained of each somatic symptom at baseline than in those who had not. Three somatic symptoms (low back pain, dizziness, and abdominal pain) at baseline were significant risk factors of major depression for the following year. Dizziness at baseline significantly predicted major and minor depression for the following year as well. Somatic symptoms may be good predictors to screen for depression at health examination.     

Serum cholesterol in treatment-resistant depression

OBJECTIVE: Patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared with healthy controls. A previous study by our group reported that depressed patients with elevated cholesterol levels (>or=200 mg/dl) were significantly more likely to be nonresponders to fluoxetine treatment than depressed patients with nonelevated cholesterol levels. However, very little is known regarding cholesterol in patients with treatment-resistant depression (TRD). The purpose of this study was to compare cholesterol levels at baseline between depressed patients with and without TRD and to test whether cholesterol levels at baseline can predict clinical response in patients with TRD treated with open-label nortriptyline (NT). METHODS: Ninety-two patients with TRD entered a 6-week open trial of NT. Baseline cholesterol levels were randomly collected for 59 of these patients. Controlling for age and gender, we compared baseline cholesterol and triglyceride levels for 35 patients with TRD who did not respond to NT with 205 non-TRD patients who responded to an 8-week open trial of fluoxetine. Furthermore, with the use of logistic regression, we tested whether baseline cholesterol levels predicted clinical response to NT in the patients with TRD. RESULTS: Patients with TRD had higher triglyceride levels at baseline compared with depressed patients without TRD. Cholesterol defined as a dichotomous variable being elevated if equal to or greater than 200 mg/dl, predicted poor response to a 6-week open trial of NT in patients with TRD. CONCLUSIONS: The results of this study confirm the relationship between hypercholesterolemia and poor outcome in the treatment of MDD for patients with TRD.     

Amplification and attribution styles in somatoform and depressive disorders--a study from Bangalore,India

OBJECTIVE: The present investigation aimed to study attribution styles and somatosensory amplification among patients suffering from somatoform and depressive disorders. METHODS: Two groups of 30 patients with diagnoses of somatoform disorder and depressive disorder, respectively (ICD-10 DCR), and one group of 30 normal controls were recruited. The study patients were assessed using the symptom interpretation questionnaire, somatosensory amplification scale, and scales for assessing alexithymia and illness attitudes. RESULTS: The somatoform and depressive disorder patients had greater recent symptom experience than the normal group. The somatoform disorder group had higher somatic attribution scores, the depressive disorder sample had higher psychological attribution scores, and the normal group had higher normalizing attribution scores than the two other groups. Somatoform disorder patients had higher mean amplification scores than depressed patients, who in turn had higher scores than normals. Correlation analyses showed somatic attribution and certain illness attitudes to be closely associated in all three groups. Recent symptom experience was associated with amplification in the somatoform disorder group alone. Recent symptom experience, a diagnosis of somatoform disorder and lower normalizing attribution scores predicted amplification. DISCUSSION: These findings indicate that somatoform and depressive disorder patients and normals differ from each other in their attribution styles. There is a clustering of attributes among somatoform disorder patients that include greater symptom experience, which is somatically attributed, and is associated with excessive illness worry, concern and preoccupation with bodily symptoms, and a fear of having or developing a disease. On the other hand, depressed patients and normal subjects who do have a somatic attribution style (though, as a group, they have lower somatic attribution scores than the somatoform disorder group), also harbor hypochondriacal beliefs and related attitudes.