Effects of acute tryptophan depletion on mood and cognitive functioning in older recovered depressed subjects.

OBJECTIVE: Previous studies show that acute tryptophan depletion (ATD), by administration of an amino acid drink lacking tryptophan, can produce clinically significant depressive symptoms in subjects who have recovered from major depression. This is more likely in female patients who have had suicidal ideation, recurrent depression, and treatment with specific serotonin reuptake inhibitors. These risk factors are frequent in older recovered depressed people. The authors investigated the effects of ATD on mood and cognitive functioning in this group. METHODS: Sixteen recovered depressed (RD) subjects and 17 healthy-comparison subjects, over 60 years old, participated in a double-blind, placebo-controlled, crossover study involving administration of a tryptophan-depleting and a placebo drink. Mood ratings scales were administered at baseline and at 4 and 7 hours post-drink on each test day. A battery of neuropsychological tests, including the modified Mini-Mental State Examination (MMSE) was administered between 4 and 6 hours post-drink. RESULTS: Depletion of plasma free tryptophan was 71% at 4 and 7 hours after the active drink. There was no evidence of mood change at any time in either group. On the MMSE, however, the ATD/RD group showed a significant decrease compared with placebo. CONCLUSIONS: There was no evidence of mood disturbance during ATD in any subject. This may imply less sensitivity to acute disturbance of the 5HT system than in younger recovered patients.     

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635

Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.     

Late-life depression as a risk factor for mild cognitive impairment or Alzheimer's disease in 30 US Alzheimer's disease centers

Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer's Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer's disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score ≥5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR = 2.35; 95% CI 1.93-3.08) versus never depressed. Normal subjects, identified as depressed at first visit but subsequently improved, were found to have lower risk of progression (RR 1.40 (1.01-1.95)). The 'always depressed' had only a modest increased risk of progression from MCI to AD (RR = 1.21 (1.00-1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI.     

Cognitive impairment and depression outcomes in the IMPACT study.

INTRODUCTION: It is unclear whether cognitive impairment affects acute and long-term treatment response in geriatric depression. In addition, little is known about the long-term outcome of depression among older individuals who experience cognitive decline during a course of treatment for depression. The authors examined both of these issues using data from the IMPACT trial. METHODS: The sample consisted of 1,684 participants in the IMPACT study who had baseline and two-year follow-up data. Subjects were randomized to one year of active intervention with a depression care manager or usual care. After one year, all subjects had usual care for another year. Data were collected for two years. The authors used the Six-Item Cognitive Screener to examine acute and long-term effects on depression outcome of baseline cognitive impairment and of cognitive decline. Depression measures included the HSCL-20 and an estimation of depression-free days. Outcomes were determined using both linear regression and repeated-measures analyses. RESULTS: Depressed subjects in the active intervention group had better depression outcomes at one year regardless of baseline cognitive impairment. Cognitively impaired subjects within each treatment group had similar outcomes to subjects without cognitive impairment. Subjects who experienced decline in cognitive score over two years had worse 24-month depression outcomes compared with subjects whose cognitive score did not change. CONCLUSIONS: Cognitively impaired depressed patients can experience significant improvement in depression with appropriate acute and continuation-phase management. Older depressed adults experiencing ongoing cognitive decline may be at higher risk for poor depression outcomes and may require more careful clinical monitoring and management of both cognitive and affective symptoms.     

Personality and clinical predictors of recurrence of depression

OBJECTIVE: To help clinicians more accurately predict outcomes of treatment for depression, variables associated with recurrence of depression in the year after treatment were examined in a group of patients who completed treatment for an index episode of depression. METHODS: Forty-two depressed patients who participated in a double-blind pharmacological treatment study were followed for one year after treatment was discontinued. Length of treatment for the index episode was determined by clinicians and ranged from eight to 76 consecutive weeks. Eighteen patients who had a recurrent episode (43 percent) and 24 patients who did not (57 percent) were compared on sociodemographic and clinical variables, including scores on the Eysenck Personality Questionnaire (EPQ). RESULTS: A combination of three variables predicted recurrence of depression in 90 percent of cases. They were an elevated EPQ score on the neuroticism subscale, a short duration of treatment of the index episode, and a slow onset of response to treatment of the index episode. CONCLUSIONS: The findings suggest that personality traits, treatment duration, and variations in response to treatment might have an impact on long-term treatment outcome. Clinicians should consider these factors when making treatment decisions for depressed patients.     

Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907

OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.     

Risk factors for depression in elderly people: a prospective study.

In 1982-1983 a random sample of 1486 people aged 65 years and above was generated from general practitioner lists; 1070 were interviewed in the community using the Geriatric Mental State and a Social History questionnaire. The cohort was followed up by interview 3 years later. At year 3 the diagnostic computer program AGECAT diagnosed 44 incident cases of depression. Information from the depressed group's initial and further interviews was compared with a control group (which excluded cases of affective or organic mental illness). Univariate analysis yielded three factors that were significantly associated with the development of depression 3 years later: a lack of satisfaction with life; feelings of loneliness; and smoking. Multivariate analysis confirmed their independent effects and revealed 2 further factors attaining significance: female gender and a trigger factor, bereavement of a close figure within 6 months of the third-year diagnosis. Some other factors traditionally associated with depression, such as poor housing, marital status and living alone, failed to attain significance as risk factors.     

Stepped collaborative care for primary care patients with persistent symptoms of depression: a randomized trial

BACKGROUND: Despite improvements in the accuracy of diagnosing depression and use of medications with fewer side effects, many patients treated with antidepressant medications by primary care physicians have persistent symptoms. METHODS: A group of 228 patients recognized as depressed by their primary care physicians and given antidepressant medication who had either 4 or more persistent major depressive symptoms or a score of 1.5 or more on the Hopkins Symptom Checklist depression items at 6 to 8 weeks were randomized to a collaborative care intervention (n = 114) or usual care (n = 114) by the primary care physician. Patients in the intervention group received enhanced education and increased frequency of visits by a psychiatrist working with the primary care physician to improve pharmacologic treatment. Follow-up assessments were completed at 1, 3, and 6 months by a telephone survey team blinded to randomization status. RESULTS: Those in the intervention group had significantly greater adherence to adequate dosage of medication for 90 days or more and were more likely to rate the quality of care they received for depression as good to excellent compared with usual care controls. Intervention patients showed a significantly greater decrease compared with usual care controls in severity of depressive symptoms over time and were more likely to have fully recovered at 3 and 6 months. CONCLUSIONS: A multifaceted program targeted to patients whose depressive symptoms persisted 6 to 8 weeks after initiation of antidepressant medication by their primary care physician was found to significantly improve adherence to antidepressants, satisfaction with care, and depressive outcomes compared with usual care.     

Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study

The aim of the study was to investigate cognitive impairment in major depression both acutely and after 6 months. All patients were investigated within a neurocognitive experimental setting at two testing sessions: at inclusion and after 6 months. Automatic and effortful information processing was investigated with a visual search paradigm. Twenty-one patients with recurrent major depression according to DSM-IV and a Hamilton Depression Rating Scale score >18 were included in the study. Healthy subjects, matched for age and gender, were used as a control group. The results showed that the depressed patients performed equal to the control group on trials requiring automatic information processing at both sessions. However, the patients were impaired compared to the control group on trials requiring effortful information processing, also at both sessions. The depressed patients showed no improvement in cognitive performance from test 1 to test 2. The results indicate that the depressed patients had an impaired performance for effortful, but not automatic, visual search performance, and that the impairment remained after 6 months, despite significant improvement in their depression scores.     

Recognition and treatment of depression in Parkinson's disease

Depression in Parkinson's disease (PD) is common, but little is known about its recognition and treatment. The authors report the antidepressant experience (N = 100) and outcome of depression assessment (n = 77) of a convenience sample of patients at a PD center. Subjects were assessed with a psychiatric and neurological battery, and information was gathered on depression treatment. One third (34%) of subjects met criteria for a depressive disorder, and two thirds (65%) of them were not currently receiving antidepressant treatment. Approximately one quarter (23%) of subjects were taking an antidepressant, but almost half (47%) of them still met criteria for a depressive disorder. Few antidepressant users with persistent depression had received either antidepressant treatment at dosages within the highest recommended range (11%) or more than 1 antidepressant trial (33%). Most depressed patients are untreated, and half of antidepressant users remain depressed, suggesting that even when delivered, treatment is often inadequate or ineffective.     

Factors associated with 1-year outcome of major depression in the community

Evidence from outcome studies of major depression indicates a high rate of relapse and chronicity, and that prior chronicity, recurrent episodes, and the presence of psychosocial stressors are associated with a poor outcome. However, the generalizability of these findings is limited because most studies have focused on treated samples; thus, these studies may have been biased toward more chronic or severe illnesses. In prospectively surveying a large probability sample of the general population, the Epidemiologic Catchment Area program offers the opportunity to investigate prognosis without selection bias. In this study, the Epidemiologic Catchment Area subjects with a diagnosis of Major Depressive Disorder at first interview (n = 423) were categorized according to their diagnostic status 1 year later. The results confirmed a high rate of nonrecovery, with clinical features associated with a poor outcome that resembled those identified in previous clinical studies. Overall, clinical factors were more important prognostically than were sociodemographic characteristics. However, there was some evidence that a poorer outcome in older women may partially explain the greater female prevalence of depression in the community.     

Stability of DSM-IV criterion symptoms for major depressive disorder

Given the chronic and recurrent nature of major depressive disorder (MDD), it is important to understand whether specific symptoms are stable over time or vary over the course of the disorder. This is the first longitudinal investigation examining the stability of the nine criterion symptoms of depression, as specified in the DSM-IV, among diagnosed depressed adults who were not recovered at follow-up. In this study, participants were assessed twice, ten months apart, with the structured clinical interview for DSM-IV, and stability of the nine criterion symptoms of MDD was examined. Findings indicate strong stability in individuals' symptom profiles. Among individuals who were clinically depressed at both assessments, there were no statistically significant fluctuations in specific symptoms endorsed. Changes in symptom endorsement among individuals who no longer met diagnostic criteria for MDD at Time 2 were attributable to reduced severity (i.e., number of symptoms) rather than to inconsistency of symptom endorsement. These results indicate that depressed individuals experience essentially the same pattern of specific symptoms over the course of a year. Variation in clinical course is likely to be attributable more to fluctuations in overall severity than to changes in specific symptoms of depression.     

Inflammatory markers in depressed post-myocardial infarction patients

BACKGROUND: Depressive disorder in the post-myocardial infarction (MI) period has been associated with increased cardiac morbidity and mortality. Possible pathophysiological mechanisms behind this association are not clear. Major depression in physically healthy subjects has been related to immune abnormalities including increased plasma levels of interleukin-6 (IL-6), tumor necrosis factor alfa (TNF-alpha) and C-reactive protein (CRP). In patients with MI, increased inflammatory markers, such as CRP and TNF-alpha, have been associated with increased cardiovascular events. It was the aim of this study to test the hypothesis that depression in post-MI patients is associated with increased inflammation as compared to non-depressed post-MI patients. METHODS: The cytokines IL-6 and TNF-alpha ; the soluble cytokine receptors sIL-6R, sTNF-RI and sTNF-RII; neopterin; and the inflammation-sensitive plasma proteins (ISPs) CRP and haptoglobin were assessed in a group of 57 patients with a diagnosis of depression post-MI and in a control group of 46 non-depressed post-MI patients, matched for age, gender and time elapsed since MI. RESULTS: Cytokine, neopterin and ISP levels were not statistically different in the depressed post-MI group as compared to the non-depressed post-MI group. Several inflammatory markers were however elevated in both cohorts when compared with levels reported in healthy subjects, indicating persistent inflammation several months after MI. CONCLUSIONS: There was no indication of increased inflammation in depressed post-MI patients as compared to non-depressed post-MI patients.     

Cortisol hypersecretion in depressed school-aged children and adolescents

A prospective longitudinal study has been carried out to determine the secretory pattern of cortisol in children (n = 10) with major depressive disorder. Salivary cortisol samples were collected at 4-hourly intervals over 24 hours when the subjects were depressed and again when they were recovered. Group comparison indicated that significant increases in mean cortisol output occurred during illness as compared with recovery. This difference occurred only at three points (midnight, 4 a.m., 8 a.m.) of six measured. Not all cases were showed hypersecretion, but when hypersecretion was present, it occurred in cases with more severe symptoms. In addition, marked differences existed within individuals in the depressed state vs. the recovered state. Hypersecretion appeared to be associated with a significant alteration in diurnal rhythm in some, but not all, cases. The degree of cortisol responsivity and the shape of the curve over 24 hours during the depressed state deserve further investigation and may have implications for the course and outcome of major depression in this age group.     

Verbal learning and memory in depression: a 9-year follow-up study

Memory impairment is often associated with depression. However, the literature is not uniform whether such impairment constitutes state and/or trait characteristics. One-hundred-and-twelve clinically depressed (CDs), previously depressed (PDs), and never depressed (NDs) subjects (T2 diagnostic status),were assessed with the California Verbal Learning Test (CVLT) at T1 and re-assessed 9 years later with the revised version, CVLT-II. At T1 no deficit in verbal memory between CDs and PDs compared to NDs was found, in which the majority of the subjects were younger adults. At follow-up the majority of CDs and PDs had suffered one or several recurrent depressive episodes. Repeated-measures analysis of variance showed, in particular and irrespective of group, a significant decline in recall measures over time. CDs, PDs and NDs showed the same pattern of verbal memory performance over time with the exception of Short Delayed Free Recall, in which CDs and PDs showed a significant decline in performance at follow-up compared to NDs. Likewise, subjects with recurrent depression performed comparable to subjects with a single episode over the course of follow-up. Our results suggest that individuals with mild to moderate unipolar depression may not be significantly affected by verbal memory impairments over the long-term course. The comparability of the versions of the CVLT is addressed.     

Incidence of psychiatric disorder in offspring at high and low risk for depression.

First onsets (incidence) of suicide attempts and DSM-III psychiatric disorders, including major depression, any anxiety disorder, conduct disorder, or substance abuse were determined in a 2-year longitudinal study of 174 offspring at high and low risk for major depression. All of the suicide attempts, the first onsets of major depression, and anxiety disorders were in offspring of depressed parents. Compared with asymptomatic offspring, offspring with subclinical manifestations of major depression, conduct disorder, and substance abuse at the initial interview were significantly more likely to become incident cases of the same disorder over the next 2 years. Either conduct disorder or substance abuse at initial interview were highly predictive of first onset of each other, but not of any other disorders 2 years later. Family risk factors (such as poor marital adjustment, parent-child discord, low cohesion, and affectionless control) at initial interview were associated with increased incidence of substance abuse, or conduct disorder, but not major depression or anxiety disorder. Combining both retrospective and prospective data, the overall suicide attempt rate was 7.8% in the offspring of depressed parents as compared with 1.4% in the offspring of nondepressed parents. By age 20, over 50% of the offspring of depressed patients reported a major depression.     

The Zurich study

Summary The purpose of this study was to investigate antecedents of first incidence of major depressive disorder and recurrent brief depression with the help of a cohort of 20 year-old Swiss, who was interviewed four times up to age 30. Cases diagnosed as depressed at the third or fourth interview (age 28 or 30) were compared with never diagnosed controls for antecedents at the first and second interview (age 21 and 23). Besides retrospectively assessed childhood precursors, later depressives showed slight differences in their relationship to parents and friends and early symptoms of subclinical depression, persistent helplessness and a surplus of life events. These antecedents were mainly found in females. The most persistent antecedent of later depression for both sexes was a higher score than controls' on the SCL-90R (negative affectivity). Whether this finding signifies that proneness to the milder depressions in young adults is rooted in personality is subject to discussion.Supported by grant 32-9502/3.873-0.88 from the Swiss National Science Foundation     

Cognitive function in unipolar major depression: a comparison of currently depressed, previously depressed, and never depressed individuals

There is a lack of consensus upon a conclusive cognitive profile characterizing unipolar major depression. Currently depressed (n?=?37), recovered previously depressed (n?=?81), and never depressed controls (n?=?50) underwent assessment of executive functions, working memory, attention, and psychomotor speed. Currently depressed yielded significantly lower test scores than previously and never depressed subjects on a measure of working memory. Both currently depressed and previously depressed scored significantly lower than never depressed subjects on measures of processing speed. Recurrent depressed performed similarly to subjects with a single depressive episode. These findings indicate a mild and limited cognitive impairment during the course of a mild to moderate major depressive disorder among relatively young adults. Impaired processing speed should be considered in further studies as a potential irreversible marker for recurrent depression.