Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder.

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P<0.0001). In addition, a significant positive correlation between change in IL-1ß and change in depression symptom scores was observed (P=0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1ß to positive depression treatment outcomes.

Does exercise improve self-reported sleep quality in non-remitted major depressive disorder?

BACKGROUND: Sleep disturbances are persistent residual symptoms following remission of major depressive disorder (MDD) and are associated with an increased risk of MDD recurrence. The purpose of the current study was to examine the effect of exercise augmentation on self-reported sleep quality in participants with non-remitted MDD. Method Participants were randomized to receive selective serotonin reuptake inhibitor (SSRI) augmentation with one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. Depressive symptoms were assessed using the clinician-rated Inventory of Depressive Symptomatology (IDS-C). The four sleep-related items on the IDS-C (Sleep Onset Insomnia, Mid-Nocturnal Insomnia, Early Morning Insomnia, and Hypersomnia) were used to assess self-reported sleep quality. RESULTS: Significant decreases in total insomnia (p < 0.0001) were observed, along with decreases in sleep onset, mid-nocturnal and early-morning insomnia (p's <0.002). Hypersomnia did not change significantly (p = 0.38). Changes in total, mid-nocturnal and early-morning insomnia were independent of changes in depressive symptoms. Higher baseline hypersomnia predicted a greater decrease in depression severity following exercise treatment (p = 0.0057). No significant moderating effect of any baseline sleep on change in depression severity was observed. There were no significant differences between exercise treatment groups on total insomnia or any individual sleep item. CONCLUSIONS: Exercise augmentation resulted in improvements in self-reported sleep quality in patients with non-remitted MDD. Given the prevalence of insomnia as a residual symptom following MDD treatment and the associated risk of MDD recurrence, exercise augmentation may have an important role in the treatment of MDD.

Dyadic discord at baseline is associated with lack of remission in the acute treatment of chronic depression.

BACKGROUND: Dyadic discord, while common in depression, has not been specifically evaluated as an outcome predictor in chronic major depressive disorder. This study investigated pretreatment dyadic discord as a predictor of non-remission and its relationship to depressive symptom change during acute treatment for chronic depression. METHOD: Out-patients with chronic depression were randomized to 12 weeks of treatment with nefazodone, the Cognitive Behavioral Analysis System of Psychotherapy or their combination. Measures included the Marital Adjustment Scale (MAS) and the Inventory of Depressive Symptomatology - Self Report (IDS-SR30). Of 681 original patients, 316 were partnered and 171 of these completed a baseline and exit MAS, and at least one post-baseline IDS-SR30. MAS scores were analysed as continuous and categorical variables ('dyadic discord' v. 'no dyadic discord' defined as an MAS score >2.36. Remission was defined as an IDS-SR30 of 14 at exit (equivalent to a 17-item Hamilton Rating Scale for Depression of 7). RESULTS: Patients with dyadic discord at baseline had lower remission rates (34.1%) than those without dyadic discord (61.2%) (all three treatment groups) (chi2=12.6, df=1, p=0.0004). MAS scores improved significantly with each of the treatments, although the change was reduced by controlling for improvement in depression. Depression remission at exit was associated with less dyadic discord at exit than non-remission for all three groups [for total sample, 1.8 v. 2.4, t(169)=7.3, p<0.0001]. CONCLUSIONS: Dyadic discord in chronically depressed patients is predictive of a lower likelihood of remission of depression. Couple therapy for those with dyadic discord may increase remission rates.

Anticipated Benefits of Care (ABC): psychometrics and predictive value in psychiatric disorders.

BACKGROUND: Attitudes and expectations about treatment have been associated with symptomatic outcomes, adherence and utilization in patients with psychiatric disorders. No measure of patients' anticipated benefits of treatment on domains of everyday functioning has previously been available. METHOD: The Anticipated Benefits of Care (ABC) is a new, 10-item questionnaire used to measure patient expectations about the impact of treatment on domains of everyday functioning. The ABC was collected at baseline in adult out-patients with major depressive disorder (MDD) (n=528), bipolar disorder (n=395) and schizophrenia (n=447) in the Texas Medication Algorithm Project (TMAP). Psychometric properties of the ABC were assessed, and the association of ABC scores with treatment response at 3 months was evaluated. RESULTS: Evaluation of the ABC's internal consistency yielded Cronbach's alpha of 0.90-0.92 for patients across disorders. Factor analysis showed that the ABC was unidimensional for all patients and for patients with each disorder. For patients with MDD, lower anticipated benefits of treatment was associated with less symptom improvement and lower odds of treatment response [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.87, p=0.0011]. There was no association between ABC and symptom improvement or treatment response for patients with bipolar disorder or schizophrenia, possibly because these patients had modest benefits with treatment. CONCLUSIONS: The ABC is the first self-report that measures patient expectations about the benefits of treatment on everyday functioning, filling an important gap in available assessments of attitudes and expectations about treatment. The ABC is simple, easy to use, and has acceptable psychometric properties for use in research or clinical settings.

Diagnostic utility of the Quick Inventory of Depressive Symptomatology (QIDS-C16 and QIDS-SR16) in the elderly.

OBJECTIVE: To evaluate psychometric properties and comparability ability of the Montgomery-Asberg Depression Rating Scale (MADRS) vs. the Quick Inventory of Depressive Symptomatology-Clinician-rated (QIDS-C(16)) and Self-report (QIDS-SR(16)) scales to detect a current major depressive episode in the elderly. METHOD: Community and clinic subjects (age >or=60 years) were administered the Mini-International Neuropsychiatric Interview (MINI) for DSM-IV and three depression scales randomly. Statistics included classical test and Samejima item response theories, factor analyzes, and receiver operating characteristic methods. RESULTS: In 229 elderly patients (mean age = 73 years, 39% male, 54% current depression), all three scales were unidimensional and with nearly equal Cronbach alpha reliability (0.85-0.89). Each scale discriminated persons with major depression from the non-depressed, but the QIDS-C(16) was slightly more accurate. CONCLUSION: All three tests are valid for detecting geriatric major depression with the QIDS-C(16) being slightly better. Self-rated QIDS-SR(16) is recommended as a screening tool as it is least expensive and least time consuming.

IL-1ß and BDNF are associated with improvement in hypersomnia but not insomnia following exercise in major depressive disorder.

Given the role of sleep in the development and treatment of major depressive disorder (MDD), it is becoming increasingly clear that elucidation of the biological mechanisms underlying sleep disturbances in MDD is crucial to improve treatment outcomes. Sleep disturbances are varied and can present as insomnia and/or hypersomnia. Though research has examined the biological underpinnings of insomnia in MDD, little is known about the role of biomarkers in hypersomnia associated with MDD. This paper examines biomarkers associated with changes in hypersomnia and insomnia and as predictors of improvements in sleep quality following exercise augmentation in persons with MDD. Subjects with non-remitted MDD were randomized to augmentation with one of two doses of aerobic exercise: 16 kilocalories per kilogram of body weight per week (KKW) or 4 KKW for 12 weeks. The four sleep-related items on the clinician-rated Inventory of Depressive Symptomatology (sleep onset insomnia, mid-nocturnal insomnia, early morning insomnia and hypersomnia) assessed self-reported sleep quality. Inflammatory cytokines (tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6) and brain-derived neurotrophic factor (BDNF) were assessed in blood samples collected before and following the 12-week intervention. Reduction in hypersomnia was correlated with reductions in BDNF (ρ = 0.26, P = 0.029) and IL-1ß (ρ = 0.37, P = 0.002). Changes in these biomarkers were not associated with changes in insomnia; however, lower baseline levels of IL-1ß were predictive of greater improvements in insomnia (F = 3.87, P = 0.050). In conclusion, improvement in hypersomnia is related to reductions in inflammatory markers and BDNF in persons with non-remitted MDD. Distinct biological mechanisms may explain reductions in insomnia.

Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline.

Our objective was to determine if pretreatment anxiety levels were associated with preferential response to bupropion sustained release (n = 122) or sertraline (n = 126) during a 16-week randomized acute phase treatment study. Both agents had comparable antidepressant activity, and comparable anxiolytic effects using the intent-to-treat sample. Baseline anxiety levels were not related to antidepressant efficacy, and they did not differentiate responders to each agent. Time to clinically significant anxiolysis did not differentiate between treatment groups or between responders to each agent. These results contradict the commonly held, but unsubstantiated, belief that in clinically depressed anxious patients, serotonergic antidepressants are especially anxiolytic and that such patients preferentially benefit from the antidepressant or anxiolytic effects of selective serotonin reuptake inhibitors. Thus, the clinical decision to select between these two agents when treating depressed outpatients cannot rest on either levels of pretreatment anxiety or on anticipation of more rapid or more complete anxiolysis.

Shock liver. Case report with long-term survival.

A case of reversible hepatic failure due to cardiogenic shock following acute myocardial infarction is described. The hepatic failure was characterized by portal systemic encephalopathy and markedly abnormal results of liver function tests. Concomitant renal failure required peritoneal dialysis. Long-term survival (nine years) and return of normal liver function were observed.

Which depressed patients respond to nefazodone and when?

BACKGROUND: Retrospective data analyses were conducted of a single-blind trial of 993 outpatients with nonpsychotic major depression (DSM-III-R) treated for 12 weeks with nefazodone to provide a more specific picture of the nature and timing of response or remission to acute-phase treatment. METHOD: All patients participated in a single-blind, 16-week lead-in to obtain responders eligible for a subsequent double-blind, randomized continuation phase trial. Outcomes were defined by the 17-item Hamilton Rating Scale for Depression (HAM-D). A > or = 50% reduction from baseline defined response, and a total HAM-D exit score of < or =8 defined remission. RESULTS: Of all patients who entered the trial, 41.8% (last observation carried forward) responded at or before week 4 (early responders), and an additional 25.2% responded thereafter; 18.3% achieved remission at or before week 4; 33.6% achieved remission after week 4. Thus, 77.3% of those responding ultimately remitted. On average, remission followed response by 2 weeks. The average end-of-treatment dose was 376 mg/day at exit (last observation carried forward). Responders or remitters (as opposed to nonresponders or nonremitters) had lower baseline depressive symptomatology and were more likely to be married or cohabiting. CONCLUSION: The full symptomatic benefit of antidepressant medication may not be apparent until completion of an 8- to 10-week trial. A high number of responders ultimately attained remission. Baseline demographic and clinical features were not highly predictive of who would or would not benefit from nefazodone. For routine care, a minimal acute-phase trial, using a 50% reduction in baseline symptom severity to define response, should be 8 weeks. Whether ultimate nonresponders can be identified earlier than 8 weeks deserves further study.

Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients?

OBJECTIVE: To examine the effects of bupropion sustained release (SR) and sertraline on anxiety in outpatients with recurrent DSM-IV-defined major depressive disorder. METHOD: This retrospective analysis was conducted using pooled data from 2 identical, 8-week, acute-phase, double-blind, placebo-controlled, parallel-group studies of bupropion SR (N = 234), sertraline (N = 225), and placebo (N = 233). Symptoms of anxiety and depression were measured using the 14-item Hamilton Rating Scale for Anxiety (HAM-A) and the 21-item Hamilton Rating Scale for Depression (HAM-D-21), respectively. Percentage reduction in baseline HAM-A total score for each treatment week was calculated to determine whether the time to onset of anxiolytic activity differed among antidepressant responders to each agent. Central nervous system (CNS) adverse events were tabulated. RESULTS: Bupropion SR and sertraline were comparably effective, both were superior to placebo in reducing depressive symptoms. and they did not differ in their effect on anxiety symptoms. Antidepressant responders (> 50% reduction in baseline HAM-D-21 score) in both groups showed marked and comparable reductions in HAM-A scores (baseline to exit). There were no differences between bupropion SR and sertraline in the median time (4 weeks) to reach a clinically significant anxiolytic effect (> or = 50% reduction in baseline HAM-A score). CNS adverse events were comparable for bupropion SR and sertraline, except for somnolence, which was more common in sertraline-treated patients. CONCLUSION: Bupropion SR and sertraline had comparable antidepressant and anxiolytic effects and an equally rapid onset of clinically significant anxiolytic activity. There was no difference in the activating effects between the 2 antidepressants. Selection between these 2 agents cannot be based on either anticipation of differential anxiolytic activity or differential CNS side effect profiles.

Technique for construction of an in vivo model of simulated pulmonary metastases.

RATIONALE AND OBJECTIVES: Existing methods used to simulate pulmonary metastases are unsatisfactory. The aim of this study was to create a simple in vivo model of pulmonary metastases by endobronchial deployment of small high-density beads in anesthetized dogs. METHODS: Commercially available decorative beads measuring 2 and 4 mm in diameter and of high density (600 to 1200 Hounsfield units) were deployed in the peripheral airways of anesthetized dogs using catheter and guide wire manipulations through an endotracheal tube. RESULTS: A total of 65 beads were placed in five dogs. Computed tomography demonstrated that 41 (63%) were satisfactorily located in the lung periphery, 9 (14%) were unsatisfactorily located in large airways, and 15 (23%) were not visible. CONCLUSIONS: The endobronchial deployment of small high-density beads in the peripheral airways of anesthetized dogs is a novel and effective technique for creation of an in vivo model of pulmonary metastases.

Meconium: a 1990s perspective on an old obstetric hazard.

OBJECTIVE: To quantify the current perinatal consequences associated with intrapartum detection of meconium in the amniotic fluid (AF). METHODS: We compared retrospectively the outcomes in 8136 term singleton cephalic pregnancies with meconium and 34,573 similar pregnancies with clear AF. RESULTS: Virtually all measures of adverse fetal-neonatal outcomes were significantly increased with meconium. For example, perinatal mortality increased from 0.3 per 1000 births with clear AF to 1.5 deaths per 1000 with meconium (P < .001). Most of these deaths resulted from meconium aspiration. Other unwanted outcomes also increased; eg, severe fetal acidemia at birth (umbilical artery blood pH 7.00 or less) increased from three per 1000 to seven per 1000 when meconium was diagnosed (P < .001). Delivery by cesarean also increased with meconium, from 7 to 14% (P < .001). CONCLUSION: Meconium in the AF is an obstetric hazard with small but significantly increased risks of adverse fetal-neonatal outcomes.

Amniotic fluid meconium: a fetal environmental hazard.

OBJECTIVE: To investigate the hypothesis that meconium aspiration syndrome, the major hazard of meconium during labor, may be associated with superimposed fetal acute acidemia. METHODS: Umbilical artery blood gases were measured in 7816 term pregnancies with meconium in the amniotic fluid (AF) and the results were correlated with intrapartum and neonatal outcomes. RESULTS: Sixty-nine (1%) infants developed meconium aspiration syndrome and 31 (45%) of these were in association with fetal acidemia at birth. Moreover, umbilical blood gas analysis and intrapartum events suggested that the fetal acidemia linked to meconium aspiration was an acute event rather than a long-duration process, which might be expected if meconium was itself a marker of an antecedent fetal asphyxial event. CONCLUSION: Meconium in the AF may be a fetal environmental hazard when acidemia supervenes rather than solely a marker of preexisting fetal compromise leading to the release of meconium.

Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder.

OBJECTIVE: To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years. METHOD: Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS). RESULTS: Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen. CONCLUSIONS: Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

Depression in radiation oncology patients: a preliminary evaluation.

BACKGROUND: Some, but not all, patients undergoing radiation therapy for cancer experience depression. Recognition of depression in these patients is complicated by the effects of cancer, chemotherapy and radiation. METHODS: Total scores of the 30-item Inventory of Depressive Symptomatology-Self Report (IDS-SR) were used to divide 52 consecutive radiation oncology outpatients into those with depressive symptoms (n = 16) and those without (n = 36). These 2 groups were compared to find which depressive symptoms occurred and what risk factors were associated with them. RESULTS: Cognitive and endogenous, but not vegetative, symptoms of depression were helpful in distinguishing the 2 groups. A personal or family history of treated depression-but not the number of radiation treatments received-was also predictive of those with depressive symptoms. LIMITATIONS: The patient population studied was small and diverse. Self-reports scores, rather than structured psychiatric interviews, were used to define clinically significant depression. CONCLUSIONS: Depressive symptoms are not inevitable with cancer. Patient reports of thoughts of death or suicide, feeling restless, or diminished mood response to good events should prompt a more thorough evaluation for depression. A personal or family history of treated depression appears to be associated with an increased risk of depressive symptoms.

Does pretreatment anxiety predict response to either bupropion SR or sertraline?

BACKGROUND: A common clinical belief is that more sedating and/or serotonin-selective antidepressants are preferred for depressed patients with symptoms of anxiety compared with more activating and/or catecholamine-selective antidepressants. The purpose of this study was to determine whether higher baseline anxiety is associated with different antidepressant responses to bupropion sustained release (SR) or sertraline. METHODS: A retrospective data analysis was conducted using pooled data from two identical 8-week, randomized, double-blind, placebo-controlled multicenter studies of bupropion SR (n=234), sertraline (n=225), and placebo (n=233) in adult outpatients with recurrent, major depressive disorder. Anxiety symptoms were measured using the 14-item Hamilton Anxiety Rating Scale scores. RESULTS: Baseline anxiety levels were not related to antidepressant response to treatment with either bupropion SR or sertraline, nor did they differentiate between responders to bupropion SR and responders to sertraline. CONCLUSIONS: Baseline anxiety levels do not appear to be a basis for selecting between bupropion SR and sertraline in the treatment of outpatients with major depressive disorder.

Prediction of response to fluoxetine and placebo in children and adolescents with major depression: a hypothesis generating study.

BACKGROUND: The results of multivariate analyses to identify potential predictors of response to fluoxetine or placebo separately in 96 child and adolescent outpatients with major depressive disorder from a recent controlled trial are presented. METHODS: A variety of clinical, demographic and laboratory factors were examined as possible predictors of response to fluoxetine or placebo using logistic regression models. RESULTS: No single variable or combination of variables strongly predicted response to fluoxetine. For the placebo group, a younger age, a shorter duration of depressive episode, and a lower socioeconomic status predicted response with an overall predictive power of 81%. CONCLUSIONS: This study is limited by the small sample size and should be considered hypothesis generating rather than confirming.

Structured diagnostic assessment and depot fluphenazine treatment of multiple suicide attempters in the emergency department.

The aim of this study was to compare the efficacy of two doses of monthly intramuscular (i.m.) injections of fluphenazine decanoate in reducing self-harm behaviours in outpatients with histories of multiple suicide attempts. Fifty-eight patients who presented to a psychiatric emergency service after an attempted suicide and who had histories of multiple suicide attempts, were randomized to receive monthly i.m. injections of fluphenazine decanoate. Thirty patients received monthly 12.5 mg ('low' dose), and 28 patients received monthly 1.5 mg ('ultra low' dose) under double-blind conditions. DSM-III-R diagnoses were obtained on all patients using the Structured Clinical Interview for DSM-III-R-Patient Version (SCID-P) and SCID for DSM-III-R Personality Disorders (SCID-II). Outcomes were assessed by the Parasuicide History Inventory and the Abnormal Involuntary Movement Scale, collected monthly for 6 months. Patients had an average of six current Axis I and 2.6 Axis II diagnoses, with borderline personality (85%) and alcohol dependence (58%) occurring most frequently in the sample. Both the low dose and ultra-low dose groups showed a marked reduction in self-harm behaviours. For 'serious' self-harm behaviours, there was a trend for a greater effect of the low dose over the ultra-low dose group, however, the differences did not reach statistical significance. A survival analysis indicated that the presence of 'acute' stressors at baseline and female sex were risk factors for continuing (post-randomization) 'serious' self-harm behaviours, while younger age and the absence of concurrent general medical conditions were risk factors for all self-harm behaviours.

A comparison of alternative assessments of depressive symptom severity: a pilot study.

This study compared the performance of an itemized symptom self-report (Inventory of Depressive Symptomatology - Self-Report; IDS-SR), patient global ratings, and clinician global ratings with an itemized clinician-rated symptom severity measure (Inventory of Depressive Symptomatology - Clinician-Rated; IDS-C) in detecting treatment effects in patients with major depressive disorder (MDD). A total of 28 inpatients (30.8% psychotic) and 34 outpatients (17.9% psychotic) with MDD began treatment that followed the Texas medication algorithm. The clinicians completed the IDS-C and a Physician Global Rating Scale (PhGRS) at each assessment visit, while the patients completed the IDS-SR and a Patient Global Rating Scale (PtGRS). Change scores from the baseline to subsequent weeks were computed for all subjects, utilizing all four measures. The IDS-SR was a significant independent predictor of the response to treatment as compared to the two global ratings. The IDS-SR was as sensitive to change as the IDS-C. While the clinician-rated itemized symptom severity rating scale remains the standard to assess the symptomatic outcome of the treatment of MDD, a self-report of identical symptomatology may be a reasonable alternative for many patients.

A comparison of alternative assessments of depressive symptom severity: a pilot study.

This study compared the performance of an itemized symptom self-report (Inventory of Depressive Symptomatology - Self-Report; IDS-SR), patient global ratings, and clinician global ratings with an itemized clinician-rated symptom severity measure (Inventory of Depressive Symptomatology - Clinician-Rated; IDS-C) in detecting treatment effects in patients with major depressive disorder (MDD). A total of 28 inpatients (30.8% psychotic) and 34 outpatients (17.9% psychotic) with MDD began treatment that followed the Texas medication algorithm. The clinicians completed the IDS-C and a Physician Global Rating Scale (PhGRS) at each assessment visit, while the patients completed the IDS-SR and a Patient Global Rating Scale (PtGRS). Change scores from the baseline to subsequent weeks were computed for all subjects, utilizing all four measures. The IDS-SR was a significant independent predictor of the response to treatment as compared to the two global ratings. The IDS-SR was as sensitive to change as the IDS-C. While the clinician-rated itemized symptom severity rating scale remains the standard to assess the symptomatic outcome of the treatment of MDD, a self-report of identical symptomatology may be a reasonable alternative for many patients.