Adriaan Honig

A comparative study into the one year cumulative incidence of depression after stroke and myocardial infarction

Background: The high incidence of post-stroke depression has been claimed to reflect a specific, stroke related pathogenesis in which lesion location plays an important role. To substantiate this claim, post-stroke depression should occur more often than depression after another acute, life threatening, disabling disease that does not involve cerebrovascular damage. Objectives: To compare the cumulative one year incidence of depression after stroke and after myocardial infarction, taking into consideration differences in age, sex, and the level of handicap. Methods: In a longitudinal design, 190 first ever stroke patients and 200 first ever myocardial infarction patients were followed up for one year. Depression self rating scales were used as a screening instrument to detect patients with depressive symptoms. Major and minor depression was assessed at one, three, six, nine, and 12 months after stroke or myocardial infarction according to DSM-IV criteria, using the structured clinical interview from DSM-IV. The severity of depressive symptoms was measured with the Hamilton depression rating scale. Level of disability and handicap was rated with the Rankin handicap scale. Results: The cumulative one year incidence of major and minor depression was 37.8% in stroke patients and 25% in patients with myocardial infarction (hazard ratio 1.6; p = 0.06). This difference disappeared after controlling for sex, age, and level of handicap. In addition, no differences were found in the severity of depressive symptoms or in the time of onset of the depressive episode after stroke or myocardial infarction. Conclusions: Depression occurs equally often during the first year after stroke and after myocardial infarction when non-specific factors such as sex, age, and level of handicap are taken into account. Thus the relatively high incidence of post-stroke depression seems not to reflect a specific pathogenic mechanism. Further research is needed to investigate whether vascular factors play a common role in the development of depression after stroke and myocardial infarction.

Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders

BACKGROUND Acute tryptophan (TRP) depletion was evaluated in healthy volunteers with or without a family history of major affective disorder (FH+ versus FH-). METHODS Twenty-seven subjects (16 FH+, 11 FH-) received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind cross-over design and a diet devoid of TRP for the next 24 hours. RESULTS The ratio TRP/large neutral amino acids declined to 22% of baseline values after 6 hours, and increased during the night reaching 85% of baseline after 24 hours. Overall, after 6 hours, TRP depletion lead to a lowering of mood, but after 24 hours, these changes were no longer detected. Mood changes and gastrointestinal side effects were significantly more evident in FH+ subjects than in FH- subjects. CONCLUSIONS Our data support the hypothesis that subjects with a positive family history for depression are predisposed to increased vulnerability to the adverse consequences of serotonergic imbalance.

Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers.

BACKGROUND Serotonergic circuits have been proposed to mediate cognitive processes, particularly learning and memory. Cognitive impairment is often seen in bipolar disorders in relation to a possible lowered serotonergic turnover. METHODS We investigated the effects of acute tryptophan depletion (ATD) on cognitive performance in healthy first-degree relatives of bipolar patients (FH) (N= 30) and matched controls (N= 15) in a placebo-controlled, double-blind cross-over design. Performance on planning, memory and attention tasks were assessed at baseline and 5 h after ATD. RESULTS Following ATD, speed of information processing on the planning task was impaired in the FH group but not in the control group. FH subjects with a bipolar disorder type I relative (FH I) showed impairments in planning and memory, independent of ATD. In all subjects, ATD impaired long-term memory performance and speed of information processing. ATD did not affect short-term memory and focused and divided attention. CONCLUSIONS The results suggest serotonergic vulnerability affecting frontal lobe areas in FH subjects, indicated by impaired planning. Biological vulnerability in FH I subjects is reflected in impaired planning and memory performance. In conclusion, the cognitive dysfunctions in FH subjects indicate an endophenotype constituting a possible biological marker in bipolar psychopathology. Serotonin appears to be involved in speed of information processing, verbal and visual memory and learning processes.

One year cumulative incidence of depression following myocardial infarction and impact on cardiac outcome

BACKGROUND Major depression has been identified as an independent risk factor for increased morbidity and mortality in mixed patients populations with first and recurrent myocardial infarction (MI). The aim of this study was to evaluate whether incidence of major and minor depression is as high in a population with merely first-MI patients as in recurrent MI populations. Furthermore, it was evaluated whether in first-MI patients major and minor depression, and depressive symptoms, had an impact on cardiac mortality and morbidity up to 3 years post MI. METHODS A consecutive cohort of 206 patients with a first MI were included in this study. One month following MI, all patients were interviewed using the Structured Clinical Interview for DSM-IV (SCID-I-R). Three, six, nine and twelve months following MI, patients filled out three psychiatric self-rating scales for depression, the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), and the 90-item Symptom Checklist (SCL-90). Patients, exceeding a previously defined cut-off value on at least one of these scales, were reinterviewed using the SCID. The BDI was applied to assess depressive symptoms in relation to cardiac outcome as the SCL-90 and HADS showed similar results. Cardiac outcome was defined as major cardiac event, i.e., death or recurrent MI, and health care consumption, i.e., cardiac rehospitalisation and/or frequent visits at the cardiac outpatient clinic. Depression outcome was assessed from 1 month post MI up to 1 year post MI whereas cardiac outcome was assessed between 1 month and 3 years post MI. RESULTS A 1-year incidence of 31% of major and minor depression was found in first-MI patients. The highest incidence rate for both major and minor depression was found in the first month after MI. Compared with nondepressed patients, depressed patients were younger (P=.001), female (P=.04) and were known with a previous depressive episode (P=.002). Neither major/minor depression nor depressive symptoms significantly predicted major cardiac events, but did predict health care consumption (P=.04 and P<.001, respectively). CONCLUSIONS Incidence of major and minor depression is similar in this first-MI patients population as in recurrent MI populations. Major/minor depressive disorder nor depressive symptoms predicted neither mortality nor reinfarction.

Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine.

Objective: To examine the antidepressant efficacy of a dual-acting antidepressant (mirtazapine) in patients with post-myocardial infarction (MI) depressive disorder. Antidepressants used in post MI trials with a randomized, double-blind, placebo-controlled design have been restricted to selective serotonin reuptake inhibitors (SSRIs). Antidepressant effects have been limited. Methods: In a prospective multicenter study, 2177 patients with MI were evaluated for depressive disorder during the first year post MI. Ninety-one patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for major or minor depressive disorder were randomized to a 24-week, double-blind, placebo-controlled trial. Antidepressant efficacy was tested using last-observation-carried-forward procedure and repeated measurements analysis using the SPPS mixed models approach, with as primary outcome reduction in depressive symptomatology on the 17-item Hamilton-Depression Rating Scale (Ham-D), and secondary outcomes the Beck Depression Inventory (BDI) and depression subscale of the Symptom Check List 90 items (dSCL-90) as well as the Clinical Global Impression (CGI) scale. Results: Using the “last observation carried forward” (LOCF) method, mirtazapine did not show to be superior to placebo on the Ham-D, but did on the BDI, dSCL-90, and CGI scale over the acute treatment phase of 8 weeks (n = 91). Using mixed models analysis over the entire 24 weeks of treatment (n = 40), we did find a significant difference favoring mirtazapine to placebo on the Ham-D, BDI, and CGI, but on the dSCL-90, this difference was not significant. Conclusions: This trial shows efficacy of mirtazapine on primary and secondary depression measures. Mirtazapine seems to be safe in the treatment of post-MI depression. MI = myocardial infarction; RCT = randomized controlled trial; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders; CAD = coronary artery disease; SSRI = selective serotonin reuptake inhibitors; TCA = tricyclic antidepressant; Ham-D = Hamilton-Depression Rating Scale; BDI = Beck Depression Inventory; CGI = Clinical Global Impression; dSCL-90 = Symptom Check List 90 items, depression subscale; SES = standardized effect size.

Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls

Background: Serotonin, a key denominator of the brain-gut axis, is involved in the regulation of gastrointestinal motility, secretion, and perception as well as cognition and mood. Aim: To assess the effects of an acutely lowered serotonin synthesis, using the acute tryptophan depletion (ATD) method, on visceral perception, affective memory performance, and mood in diarrhoea predominant irritable bowel syndrome patients (d-IBS) and controls. Methods: In a randomised, double blind, crossover design, 14 d-IBS patients and fourteen matched controls were studied under ATD and placebo conditions, respectively. Perception of urge and pain was scored during rectal distensions. Affective memory performance, mood, and biochemical parameters of serotonergic metabolism were simultaneously assessed. Results: ATD significantly decreased plasma tryptophan (67.0 (2.0) v 24.9 (2.0) μmol/l) and 5-hydroxyindole acetic acid concentrations (29.9 (1.0) v 15.8 (0.6) nmol/l). ATD was associated with significantly increased urge scores specifically in the lower pressure range and overall increased pain scores. ATD significantly lowered the perceptual threshold for first perception compared with placebo (patients 10.6 (1.2) v 13.6 (0.8) mm Hg, controls 12.6 (1.3) v 15.7 (1.2) mm Hg) but not for maximal tolerable discomfort (patients 50.5 (3.6) v 51.6 (3.3) mm Hg, controls 50.9 (3.3) v 48.8 (2.9) mm Hg). ATD induced a significant shift in affective memory bias towards preferential loss of positive material but no significant changes in mood. ATD did not differentially affect the patient or control group. Conclusions: We have provided evidence that serotonergic modulation by ATD affects both visceral perception as well as cognition in d-IBS and controls. Simultaneous measurement of brain and gut function and the application of ATD contribute to the elucidation of the complex pathophysiology of IBS.

Recognizing Increased Risk of Depressive Comorbidity after Myocardial Infarction: Looking for 4 Symptoms of Anxiety-Depression

Background: Screening for depression in myocardial infarction (MI) patients must be improved: (1) depression often goes unrecognized and (2) anxiety has been largely overlooked as an essential feature of depression in these patients. We therefore examined the co-occurrence of anxiety and depression after MI, and the validity of a brief mixed anxiety-depression index as a simple way to identify post-MI patients at increased risk of comorbid depression. Methods: One month after MI, 176 patients underwent a psychiatric interview and completed the Beck Depression Inventory (BDI) and the Symptoms of Anxiety-Depression index (SAD4) containing four symptoms of anxiety (tension, restlessness) and depression (feeling blue, hopelessness). Results: Thirty-one MI patients (18%) had comorbid depression and 37 (21%) depressive or anxiety disorder. High factor loadings and item-total correlations (SAD4, α = 0.86) confirmed that symptoms of anxiety and depression co-occurred after MI. Mixed anxiety-depression (SAD4≧3) was present in 90% of depressed MI patients and in 100% of severely depressed patients. After adjustment for standard depression symptoms (BDI; OR = 4.4, 95% CI 1.6–12.1, p = 0.004), left ventricular ejection fraction, age and sex, mixed anxiety-depression symptomatology was associated with an increased risk of depressive comorbidity (OR = 11.2, 95% CI 3.0–42.5, p < 0.0001). Mixed anxiety-depression was also independently associated with depressive or anxiety disorder (OR = 9.2, 95% CI 3.0–27.6, p < 0.0001). Conclusions: Anxiety is underrecognized in post-MI patients; however, the present findings suggest that anxiety symptomatology should not be overlooked in these patients. Depressive comorbidity after MI is characterized by symptoms of mixed anxiety-depression, after controlling for standard depression symptoms. The SAD4 represents an easy way to recognize the increased risk of post-MI depression.

Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link?

Objective Major depressive disorder and depressive symptoms have been identified as independent risk factors for cardiac mobidity and mortality in patients with ischemic heart disease. Increased susceptibility to platelet activation has been proposed as one of the mechanisms by which depression acts as a significant risk factor for thrombotic events. In this review, data on platelet activation and platelet aggregation measures in depressed patients with or without concomitant cardiovascular disease are given. Data on the influence of antidepressants on parameters of platelet activation are summarized. Methods A literature search was done by checking MEDLINE Advanced and PsycInfo from 1990 to 2003 and through checking the bibliographies of these sources. The following key words were used for this search: platelet activation, platelet aggregation, depression, depressive disorder, ischemic heart disease, calcium, and serotonin. Results There is an indication of enhanced platelet activation and aggregation in depressed patients. Next, patients with a depressive disorder show signs of a hyperactive platelet 5-HT2A receptor signal transduction system as measured by increased platelet calcium mobilization after stimulation of platelets with serotonin. Conclusions Depression appears to be associated with an increased susceptibility for serotonin-mediated platelet activation. Upregulation and/or increased sensitivity of 5-HT2A/1B receptors and downregulated 5-HT transporter receptors in the periphery may contribute to increased risk of thromboembolic events in patients with depression and cardiovascular disease. Increased platelet reactivity based on a hyperreactive 5-HT2A receptor signaling system might be influenced by antidepressive medication that antagonizes platelet 5-HT2A receptors.

Research into the specificity of depression after stroke: a review on an unresolved issue

Iwo decades of research have failed to generate consistent insight into the specificity of poststroke depression (PSD). This is, at least in part, caused by methodological difficulties. Differences in symptom profile between PSD and depression with no or another medical cause were described, but no specific and unequivocal clinical picture has been established so far. Prevalence rates of PSD varied largely between studies. In community based studies using standardised diagnostic instruments for depression, relatively low prevalence rates were reported compared to inpatient or rehabilitation studies. PSD occurs most frequently in the first few months after stroke, while a new incidence peak may occur 2-3 years after stroke. Two systematic reviews on the relation between lesion location and depression did not support the claim that left hemisphere lesions are a risk factor for PSD. A new concept of vascular depression has been proposed, which relates depression in the elderly to acute or chronic damage to the cerebral vascular system. Future efforts should aim at increasing the uniformity of study designs, assessment tools should be further improved for use in cognitively impaired patients and appropriate control groups should be defined to study the characteristic features of PSD.

Effects of Acute Tryptophan Depletion on Mood and Cortisol Release in First-degree Relatives of Type I and Type II Bipolar Patients and Healthy Matched Controls

Biological vulnerability for bipolar disorders (BD) in relatives of BD patients has not as yet been established. Serotonergic vulnerability was studied, using acute tryptophan depletion (ATD), in healthy first-degree relatives of BD patients and healthy controls. The effects of ATD on mood and cortisol release in 30 healthy adult, lifetime symptom free, unaffected first-degree relatives of BD patients (Family History; FH) were compared with effects in 15 healthy matched controls in a placebo-controlled, double-blind, crossover design. During ATD and placebo, salivary cortisol response was also assessed during a stress-inducing speech task (SIST). First-degree relatives of type II BD patients (FH II) showed an elevation of mood, whereas control subjects and relatives of type I BD patients (FH I) showed a lowering of mood after ATD. ATD was followed by a decrease in cortisol level in both FH subgroups, but not in the controls. The results suggest serotonergic vulnerability that affected mood in FH II subjects and cortisol release in both FH I and FH II subjects.