Jürgen-Christian Krieg

Cytokine Production and Treatment Response in Major Depressive Disorder

In a controlled study, such immunological parameters as whole blood production of the cytokines interleukin-6 (IL-6) and tumor-necrosis factor-α (TNF-α) were assessed in 24 inpatients with a major depressive disorder (MDD) both before and again under treatment. After a 6-week treatment period with amitriptyline, patients were classified as responders or nonresponders according to their psychopathological outcome as evaluated by the Hamilton and the Montgomery–Asberg Depression Rating Scales. Pre-treatment levels of c-reactive protein (CRP) were significantly higher in both patient subgroups than in the control subjects. In comparison to the controls, unstimulated pretreatment production of IL-6 was significantly decreased in the responders; whereas it was significantly increased in the nonresponder subgroup. Post-treatment values did not differ significantly among the patient and control groups. Pretreatment levels of TNF-α were increased in both patient subgroups, with a significant decrease during treatment only in the responder subgroup. Pretreatment levels of IL-6/105 mononuclear cells and the ratio between lymphocytes and monocytes acted as independent variables with regard to the clinical response. Our data indicate that unstimulated secretion of TNF-α is related to the psychopathological improvement; whereas, IL-6 levels might dichotomize the patients into subsequent responders and nonresponders already at admission.

Lifetime and six-month prevalence of mental disorders in the Munich Follow-up Study

SummaryThe Lifetime and 6 month DSM-III prevalence rates of mental disorders from an adult general population sample of former West Germany are reported. The most frequent mental disorders (lifetime) from the Munich Follow-up Study were anxiety disorders (13.87%), followed by substance (13.51%) and affective (12.90%) disorders. Within anxiety disorders, simple and social phobia (8.01%) were the most common, followed by agoraphobia (5.47%) and panic disorder (2.39%). Females had about twice the rates of males for affective (18.68% versus 6.42%), anxiety (18.13% versus 9.07%), and somatization disorders (1.60% versus 0.00%); males had about three times the rates of substance disorders (21.23% versus 6.11%) of females. Being widowed and separated/divorced was associated with high rates of major depression. Most disordered subjects had at least two diagnoses (69%). The most frequent comorbidity pattern was anxietyand affective disorders. Simple and social phobia began mostly in childhood or early adolescence, whereas agoraphobia and panic disorder had a later average age of onset. The majority of the cases with both anxiety and depression had depression clearly after the occurrence of anxiety. The DIS-DSM-III findings of our study have been compared with both ICD-9 diagnoses assigned by clinicians independently as well as other epidemiological studies conducted with a comparable methodology.

Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders.

Altered negative feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system is a frequent laboratory sign of major depression. It coincides with depressive episodes and partially reverses after recovery from psychopathology. Such an HPA disturbance in feedback control can be acquired as a result of stressful life experiences and be compounded by age or it can be genetically predetermined at all levels involved in fine-tuned neuroendocrine regulation. Major psychiatric disorders run in families and a high familial load for an affective illness therefore increases an individuals risk of becoming affected. We investigated whether the HPA feedback disturbance observed among patients with depression is present in otherwise healthy individuals who are at high risk for psychiatric disorders because they have a first-degree relative with an affective illness. Using rigid psychodiagnostic techniques, we screened 431 consecutively admitted patients with depression and identified 35 families with one or more high-risk probands (HRPs). The results of a combined dexamethasone/human corticotropin-releasing hormone (DEX-CRH) test showed that the group of dexamethasone-pretreated (1.5 mg; 23.00 h) HRPs released more cortisol after stimulation with human CRH (100 micrograms; 15.00 h the next day) than a control group (CPs), but less than a group of patients with an acute major depressive episode (DPs). The peak cortisol values were 146.1 +/- 147.7 nmol/l (mean +/- SD) (HRPs), 75.3 +/- 47.9 nmol/l (CPs) and 278.2 +/- 199.2 nmol/l (DPs), yielding significant (F = 9.66, p < 0.001) group differences, with values for HRPs vs. CPs and HRPs vs. DPs being significant at the 1% level (t test).(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal response pattern in the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders

One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. This is reflected by a pathological increase in the adrenocorticotropin (ACTH) and cortisol release after pretreatment with 1.5 mg dexamethasone (DEX) the previous night and a challenge with 100 μg corticotropin-releasing hormone (CRH) the next day. The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients. It is still unclear, however, whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression. In a previous study we have examined the HPA function of healthy probands with a high genetic load for affective disorders. We found that this group of high-risk probands (HRPs) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression. In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant DEX-CRH test results, so that one of the requirements for a vulnerability marker is fulfilled.

PAIN PERCEPTION IN PSYCHIATRIC DISORDERS: A REVIEW OF THE LITERATURE

Aberrations of pain experience occur frequently in psychiatric disorders and hence pathological alterations in the basic mechanisms underlying pain experience can be expected. Nevertheless, pain perception, as one of the most important basic mechanisms of pain experience, has rarely been assessed experimentally in psychiatric disorders. The authors review the relevant experimental studies on pain perception in patients with anxiety disorders, schizophrenia, depression, eating disorders and personality disorders and suggest lines for future research. Finally, they point out that the experimental study of pain perception is useful not only in understanding aberrant pain experiences in psychiatric disorders but also in elucidating pathophysiological mechanisms because pain perception is controlled by neurochemical and neurohormonal functions known to be affected by psychiatric disease processes.

Relationship between clinical pain complaints and pain sensitivity in patients with depression and panic disorder.

OBJECTIVE There is evidence that depression and panic disorder are both associated with an increased frequency of clinical pain complaints. A change in pain sensitivity is alleged to be involved in this phenomenon. However, few studies have assessed clinical pain complaints and pain sensitivity in the same group of patients. METHODS Thirteen patients with a major depressive disorder, 13 patients with a panic disorder (diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition), and 13 healthy control subjects were investigated. None of the subjects were taking medications. Body maps were used to measure the number of painful sites as well as the intensity and unpleasantness of pain complaints in the previous 6 months. Furthermore, pain thresholds for pressure, cold, and heat were assessed at the forearm or hand. RESULTS Patients with depression and panic disorder had significantly more frequent, more intense, and more unpleasant pain complaints than healthy control subjects. Despite this similarity, patients with depression had significantly higher pain thresholds than patients with panic disorder in two (pressure and cold) of three stimulus modalities and significantly higher pressure pain thresholds than the healthy control subjects. There were no differences between the pain thresholds of patients with panic disorder and healthy control subjects. The correlations between clinical pain measures and pain thresholds were generally weak. CONCLUSIONS These findings suggest that the clinical pain complaints of patients with depression and panic disorder cannot simply be explained by changes in pain sensitivity.

Serum leptin levels increase rapidly after initiation of clozapine therapy

Weight gain is a major side-effect of treatment with clozapine. In order to investigate the influence of the atypical neuroleptic clozapine on leptin secretion, serum leptin levels were measured in 12 patients at baseline and for a 10-week period after initiation of treatment. Serum clozapine levels and levels of its metabolites were simultaneously assessed. Alterations of body weight and body composition were determined. During the 10-week observation period leptin levels differed significantly from the levels determined at baseline (P < 0.0001). during the first 2 weeks of treatment serum leptin levels at least doubled in eight of the 12 patients. the maximal relative increase over baseline was 536%. low doses of clozapine were sufficient to induce this effect. within a 10-week period mean body weight, mean body mass index, mean fat mass and mean lean body mass all increased. based on the results we suggest that in predisposed individuals clozapine induces an increased appetite; overeating and weight gain can ensue, which in turn underlie elevated leptin secretion.

Sleep deprivation affects thermal pain thresholds but not somatosensory thresholds in healthy volunteers.

Objective: Sleep disturbances have been thought to augment pain. Sleep deprivation has been proven to produce hyperalgesic effects. It is still unclear whether these changes are truly specific to pain and not related to general changes in somatosensory functions. The aim of the present study was to evaluate the effect of total sleep deprivation on thermal pain thresholds (heat, cold) and pain complaints. Thermal detection thresholds (warmth, cold) were included as covariates to determine the contribution of somatosensory functions to changes in pain processing. Methods: Twenty healthy volunteers were randomly assigned either to two nights of total sleep deprivation or to two nights of undisturbed night sleep. Sleep deprivation nights were separated by two days with normal night sleep. Heat and cold pain thresholds as well as warmth and cold detection thresholds were measured by use of a peltier thermode in the evening before and the morning after each deprivation or control night. Pain complaints were examined by use of a questionnaire in parallel. Results: During treatment nights, sleep deprivation produced a significant overnight decrease in heat pain thresholds. Cold pain thresholds tended to decrease also during sleep deprivation, whereas the warmth and cold detection thresholds remained unaffected. Accordingly, no substantial contributions of the changes in thermal detection thresholds to the changes in thermal pain thresholds were determined by regression analyses. Pain complaints were not induced by sleep deprivation. Conclusions: The present findings suggest that sleep deprivation produces hyperalgesic changes that cannot be explained by nonspecific alterations in somatosensory functions. REM = rapid eye movement; SEM = standard error of the mean.

Nocturnal sleep in huntington's disease

SummaryNocturnal sleep was studied in 16 inpatients with Huntingtons disease. In comparison with healthy controls, patients exhibited a disturbed sleep pattern with increased sleep onset latency, reduced sleep efficiency, frequent nocturnal awakenings, more time spent awake and less slow wave sleep. These abnormalities correlated in part with duration of illness, severity of clinical symptoms, and degree of atrophy of the caudate nucleus. Patients showed an increased density of sleep spindles.

The effect of sleep deprivation on pain.

Chronic pain syndromes are associated with alterations in sleep continuity and sleep architecture. One perspective of this relationship, which has not received much attention to date, is that disturbances of sleep affect pain. To fathom this direction of cause, experimental human and animal studies on the effects of sleep deprivation on pain processing were reviewed. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can counteract analgesic effects of pharmacological treatments involving opioidergic and serotoninergic mechanisms of action. The heterogeneity of the human data and the exclusive interest in rapid eye movement sleep deprivation in animals so far do not allow us to draw firm conclusions as to whether the hyperalgesic effects are due to the deprivation of specific sleep stages or whether they result from a generalized disruption of sleep continuity. The significance of opioidergic and serotoninergic processes as mediating mechanisms of the hyperalgesic changes produced by sleep deprivation are discussed.