Hubertus Himmerich

Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients

Body weight gain frequently occurs during drug treatment of psychiatric disorders and is often accompanied by increased appetite or food craving. While occurrence and time course of this side effect are difficult to predict, it ultimately results in obesity and the morbidity associated therewith in a substantial part of patients, often causing them to discontinue treatment even if it is effective. This paper reviews the available epidemiological data on the frequency and extent of weight gain associated with antidepressant, mood-stabilizing, and antipsychotic treatment. Possible underlying pathomechanisms are discussed with special attention to central nervous control of appetite including the role of leptin and the tumor necrosis factor system. Metabolic alterations induced by drug treatment such as type 2 diabetes mellitus and the metabolic syndrome are also considered. Weight gain appears to be most prominent in patients treated with some of the second generation antipsychotic drugs and with some mood stabilizers. Marked weight gain also frequently occurs during treatment with most tricyclic antidepressants, while conventional antipsychotics typically induce only slight to moderate weight gain. Serotonin reuptake inhibitors may induce weight loss during the first few weeks, but some of them induce weight gain during long-term treatment. Several antidepressant and antipsychotic drugs are identified which reliably do not cause weight gain or even reduce weight. Based on these insights, countermeasures to manage drug-induced weight gain are suggested.

Differentiating moderate and severe depression using the Montgomery–Åsberg depression rating scale (MADRS)

BACKGROUND MADRS cut-off scores for moderate and severe depression were estimated in relation to the Hamilton Depression Rating Scale (HAMD(17)) and the Clinical Global Impressions Scale (CGI). METHOD HAMD(17), MADRS, and CGI ratings from patients with major depression (DSM-IV) were analyzed (N=85). Receiver operating characteristics (ROC) curves were applied. RESULTS Mean age was 51.4+/-14.5 years, 69% were female. Mean MADRS scores were 23.4+/-13.2, HAMD(17), MADRS, and CGI scores were highly correlated (r>0.85; P<0.0001). Best separation between moderate and severe depression according to CGI criteria was achieved with a MADRS score of 31 (sensitivity 93.5%, specificity 83.3%). LIMITATIONS Studies to validate severity gradations including DSM-IV or ICD-10 diagnostic severity categories are recommended. CONCLUSIONS Empirically based MADRS cut-off scores to separate moderate from severe depression on the basis of HAMD(17) and CGI severity ratings in patients with major depression were yielded.

Depression, comorbidities and the TNF-α system

Depression has frequently been reported to be associated with other physical diseases and changes in the cytokine system. We aimed to investigate associations between a medical history of depression, its comorbidities and cytokine plasma levels in the Bavarian Nutrition Survey II (BVS II) study sample and in patients suffering from an acute depressive episode. The BVS II is a representative study of the Bavarian population aged 13-80years. The disease history of its 1050 participants was assessed through face-to-face interviews. A sub-sample of 568 subjects and 62 additional acutely depressed inpatients of the Max Planck Institute of Psychiatry participated in anthropometric measurements and blood sampling. Tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R) p55 and sTNF-R p75 plasma levels were measured using enzyme-linked immunosorbent assays. A history of depression was associated with a higher incidence of high blood pressure, peptic ulcer, dyslipoproteinemia, osteoporosis, allergic skin rash, atopic eczema and thyroid disease. Within the BVS II sample, participants with a history of depression differed from subjects who had never had depression with regard to sTNF-R p55 and sTNF-R p75 levels even when controlling for age, BMI and smoking status. Acutely depressed inpatients showed even higher levels of sTNF-R p55 and sTNF-R p75 than subjects in the normal population. TNF-alpha levels were also significantly elevated in acutely depressed patients. These results confirm earlier studies regarding the comorbidities of depression and support the hypothesis that activation of the TNF-alpha system may contribute to the development of a depressive disorder.

Clozapine and olanzapine are associated with food craving and binge eating: results from a randomized double-blind study.

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale0-6: clozapine, 36.6 ± 8.8 to 15.9 ± 13.7; olanzapine, 36.7 ± 9.9 to 19.1 ± 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 ± 0.6 to 2.5 ± 1.5; olanzapine, 4.5 ± 0.6 to 2.3 ± 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Successful antidepressant therapy restores the disturbed interplay between TNF-α system and HPA axis

BACKGROUND In depressed patients, alterations in the hypothalamo-pituitary-adrenocortical (HPA) system are the most consistent neurobiological finding. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines. METHODS We examined alterations in plasma levels of tumor necrosis factor-alpha (TNF-alpha), levels of its soluble receptors p55 (sTNF-R p55) and p75 (sTNF-R p75) as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 70 depressed inpatients without inflammation. RESULTS On admission, TNF-alpha levels were inversely associated with the ACTH response to the combined dex/CRH test. Changes in TNF-alpha, sTNF-R p55, and sTNF-R p75 plasma levels from admission to discharge were positively correlated with the dex/CRH test outcome at discharge. Subgroup analysis revealed that this association was restricted to those patients achieving remission. In this subgroup, TNF-alpha levels at discharge were also positively correlated with dex/CRH test response at discharge. CONCLUSIONS Our results suggest that elevated HPA axis activity in acute depression suppresses TNF-alpha system activity, while after remission, when HPA axis activity has normalized, the TNF-alpha system seems to gain influence on the HPA system.

Inflammatory cytokines in general and central obesity and modulating effects of physical activity.

Context Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date. Objective To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects. Design, Setting, and Participants A cross-sectional study comprising 117 obese patients (body mass index (BMI) ≥ 30) and 83 non-obese community-based volunteers. Main Outcomes Measures Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR). Results General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants. Conclusions Results confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.

Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapines and olanzapines similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapines differential effects on interleukin-6.

Regulatory T cells increased while IL-1β decreased during antidepressant therapy

BACKGROUND Regulatory T cells (Tregs, CD4(+)CD25(hi)) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1β, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4(+)CD25(hi) Tregs in these immunological processes during antidepressant therapy. METHODS 16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctors choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1β, and measured IL-1β, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4(+)CD25(hi) Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21). RESULTS HAMD-21 score, IL-1β serum levels as well as LPS-stimulated IL-1β and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4(+)CD25(hi) cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed. CONCLUSIONS The increase in CD4(+)CD25(hi) Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.

Mania and attention-deficit/hyperactivity disorder: common symptomatology, common pathophysiology and common treatment?

Purpose of review Attention-deficit/hyperactivity disorder (ADHD) and mania show broad symptom overlap, and high comorbidity exists between ADHD and bipolar disorder. This raises the question concerning common neurobiological pathomechanisms and concerning common treatments. Recent findings On genetic, biochemical, electrophysiological, brain morphological and neuropsychological levels, the commonalities of ADHD and mania and the commonalities between ADHD and bipolar disorder (independent of manic state) are outlined. An intriguing finding is that both ADHD and mania are characterized by an unstable wakefulness regulation assessed by EEG measures of vigilance, by ratings of sleepiness and by deficits in sustained attention tasks. In both mania and ADHD, this unstable wakefulness regulation is supposed to be a central pathogenetic factor leading to attention deficits and inducing the hyperactive, impulsive and sensation-seeking behavior as an autoregulatory attempt to stabilize wakefulness by increasing external stimulation. Evidence is accumulating to suggest that psychostimulants do not have a high risk of triggering or aggravating mania, but might even be a treatment option in acute mania. Summary ADHD and mania share many symptoms and several pathogenetic aspects. The common belief that stimulants are contraindicated in mania has been challenged, and controlled trials to study the possible antimanic effects of vigilance-stabilizing drugs such as stimulants are justified and necessary.

Impact of antipsychotics on cytokine production in-vitro

OBJECTIVE A growing body of data from genetic, immunological and clinical studies indicates an involvement of the immune system in the pathophysiology of schizophrenia and suggests that the modulation of the cytokine system by antipsychotics may be one cause for the improvement of psychotic symptoms. However, the influence of the typical antipsychotics chlorpromazine and haloperidol, and the effect of typical and atypical antipsychotics on the TSST-1-stimulated blood cell secretion of cytokines, and specifically the interleukin (IL)-17 production have not been studied so far, although IL-17 is a leading pro-inflammatory cytokine. METHOD We measured levels of IL-1β, IL-2, IL-4, IL-6, IL-17 and tumor necrosis factor-α (TNF-α) in stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antipsychotics (chlorpromazine, haloperidol, clozapine, N-desmethylclozapine and quetiapine with four different concentrations each) or not. RESULTS Under TSST-1 stimulation, antipsychotics as a group had no influence on IL-1β or IL-6 concentrations but increased IL-4 levels. The most consistent findings were seen regarding IL-17. Mean IL-17 concentrations differed significantly between blood with and without antipsychotic supplements and were increased over all antipsychotics and almost all of the applied antipsychotic concentrations. TNF-α levels were increased by chlorpromazine; N-desmethylclozapine and quetiapine reduced IL-2 production. CONCLUSIONS Antipsychotics might, among other mechanisms, act as such by increasing the production of IL-17.