Stefan Löffler

Heinrich-Heine-Universität Düsseldorf, Düsseldorf, North Rhine-Westphalia, Germany

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Publications (23)81.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Ray et al. (Reports, 29 July 2011, p. 637) assume that clozapine-N4-oxide (CNO) represents a "biologically inert synthetic ligand" that selectively activates the M4 muscarinic receptor-based DREADD (designer receptor exclusively activated by a designer drug). In contrast, due to the redox cycling of CNO with clozapine and to their cell membrane permeability, CNO is biologically active and its conversion products are capable of undermining DREADD effects.
    Science 08/2012; 337(6095):646; author reply 646. · 31.20 Impact Factor
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    ABSTRACT: Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.
    European Archives of Psychiatry and Clinical Neuroscience 03/2011; 261(8):567-73. · 3.36 Impact Factor
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    ABSTRACT: The blood of 8 European patients with schizophrenia without manifest comorbidity was studied whether the classical atypical antipsychotic drug clozapine altered the amount of circulating CD34(+) hematopoietic cells. As assessed by flow cytometry, the number of CD34(+) cells increased by 433% (from 1.49 ± 1.07 × 10(6)/L, mean ± SD pretreatment, to a peak of 6.45 ± 3.47 × 10(6)/L) following first-time therapy with clozapine for 12 weeks. The increase of CD34(+) cell, neutrophil, and leukocyte counts was statistically significant (P = 0.012). A transversal investigation of 23 long-term patients and 58 controls showed elevated neutrophil counts in the clozapine-monotreated group, whereas CD34(+) cell numbers were unaltered. A transversal investigation of 12 clozapine-monotreated long-term patients and 10 controls revealed a 1.3-fold elevation of plasma interleukin 6 levels in patients on clozapine (P = 0.017). In conclusion, clozapine treatment results in an initial mobilization of CD34(+) stem and progenitor cells into the peripheral blood and in a slight long-term elevation of interleukin 6.
    Journal of clinical psychopharmacology 10/2010; 30(5):591-5. · 5.09 Impact Factor
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    ABSTRACT: Eight schizophrenic inpatients without manifest comorbidity were longitudinally studied. The aim was to find whether clozapine, the prototype of atypical antipsychotic drugs, altered their serum concentrations of high sensitive C-reactive protein (hsCRP), an inflammatory marker of high clinical importance. Following first-time therapy with clozapine, predominantly as the sole antipsychotic for 8 weeks, hsCRP profiles increased subclinically by 600%. This rise, and the Spearman correlation between hsCRP values and corresponding leukocyte counts, was statistically significant. A one-time cross-section investigation of 25 long-term clozapine patients and 25 patient controls did not show an elevation of hsCRP under clozapine after 1 year and more. It is assumed that the clozapine-evoked increase of hsCRP is part of a transient acute-phase response. The underlying inflammatory process needs clarification.
    International clinical psychopharmacology 03/2010; 25(2):101-6. · 3.35 Impact Factor
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    ABSTRACT: This case report presents a rare, potentially life-threatening vegetative disturbance, which can occur during pharmacotherapy of schizophrenia. A retrospective descriptive transversal and longitudinal section consideration of in-patient treatments of one female was performed. A 50-years old woman suffering from oligophrenia and disorganized psychosis (ICD-10: F71, F20.1; DSM-IV: 318, 295.10) successively evolved hypothermias up to 32.0 degrees C rectal, between them fever up to 40.0 degrees C rectal, hypothermia-accompanied bradycardias up to 32/min, recurrent subclinical hypoglycaemias up to 55 mg/dl and somnolence until coma under benperidol with levomepromazine or melperone, pipamperone with and without amisulpride, promethazine as well as zuclopenthixole. Within hours the hypothermias responded to antipsychotic drug holiday. No pathbreaking finding could be ensured on levels of internal medicine, toxicology, neurology as well as neurophysiology including a transient aetiologically uncertain partial insufficiency of the adenohypophysis. During long-term treatment with antipsychotics especially in higher dosage unpredictable vegetative crises may occur. Antipsychotics having pronounced 5HT2- and D2-antagonism seem to be rather associated with hypothermia. We recommend in case of hypothermia below 35,5 degrees C immediate antipsychotic or anticholinergic drug discontinuation, usage of benzodiazepines like lorazepam for a few days and a following trial with ziprasidone, aripiprazole or clozapine. These atypical neuroleptics show receptor binding profiles potentially advantageous in hypothermia.
    Psychiatrische Praxis 04/2008; 35(2):91-3. · 1.64 Impact Factor
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    ABSTRACT: Disturbed autonomic nervous system (ANS) function in schizophrenia might contribute to increased cardiovascular mortality. We obtained heart rate variability indices from 40 unmedicated schizophrenic patients and 58 matched controls. Mainly we found that patients displaying stronger psychotic symptoms as assessed by the Brief Psychiatric Rating Scale exhibit more severe cardiac ANS disturbances compared with controls.
    Psychiatry Research 02/2008; 157(1-3):255-7. · 2.68 Impact Factor
  • Psychiatrische Praxis - PSYCHIAT PRAX. 01/2008; 35(2):91-93.
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    ABSTRACT: The present study examined cellular effects of the atypical antipsychotic drug clozapine on blood cells of treated patients with and without clozapine-induced agranulocytosis (CA). Blood from one patient who commenced clozapine treatment was examined at weekly intervals for 128 days. Olanzapine-treated (n = 5) and polymedicated (n = 14) schizophrenic patients, as well as healthy subjects (n = 19) and septic shock patients (n = 8), were studied for comparison. We observed dramatically increased numbers of native neutrophils stained for superoxide anion production (P < or = 0.005, n = 10) and significantly elevated expression levels of the proapoptotic genes p53 (P < or = 0.020), bax alpha (P < or = 0.001), and bik (P < or = 0.002) in all tested non-CA patients (n = 19) and CA patients (n = 4). In non-CA patients, the expression of these genes did not correlate to the percentage of apoptotic neutrophils (2.0% +/- 1.3%), but in CA patients about 37% of the neutrophils show morphologic signs of apoptosis (P < or = 0.001). Under G-CSF therapy of CA, the number of apoptotic neutrophils and the expression of the proapoptotic genes decreased significantly. In conclusion, high production of reactive oxygen species in neutrophils of clozapine-treated patients, together with increased expression of proapoptotic genes, suggests that neutrophils are predisposed to apoptosis in schizophrenic patients under clozapine therapy. The correlation between drug and proapoptotic markers was highest for clozapine and bax alpha as well as superoxide anion radicals. This indicates oxidative mitochondrial stress in neutrophils of clozapine-treated patients which probably contributes to the induction of apoptosis and sudden loss of neutrophils and their precursors in CA patients.
    Journal of Clinical Psychopharmacology 11/2005; 25(5):419-26. · 3.51 Impact Factor
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    ABSTRACT: The stress response is mediated by a negative feedback effect of glucocorticoids on corticosteroid receptors. Here, we examine the potential contribution of these receptors and their response to a glucocorticoid challenge to dysfunctions of the hypothalamic-pituitary-adrenal axis reported for patients with affective disorders. In a pilot-study, we established B-lymphoblastoid cell lines from patients suffering from affective disorders and healthy subjects and measured the quantity of glucocorticoid receptors at steady state conditions after 12-weeks cell culture. After short-term incubation with 0.1 microM hydrocortisone for 48 h, the decrease of glucocorticoid receptors was also investigated. After 12-weeks cell culture, we found a significantly higher number of cytosolic glucocorticoid receptors in B-lymphoblastoids from patients (B(max)=804.9+/-342.5 fmol/mg protein) compared to those from healthy subjects (B(max)=576.9+/-190.3 fmol/mg protein: p=0.045; t-test). The increase of the glucocorticoid receptor level in the group of patients could be attributed largely to the higher number of these receptors measured in B-lymphoblastoids of patients suffering from major depressive disorder. The in vitro regulation of glucocorticoid receptors in response to 0.1 microM hydrocortisone for 48 h resulted in a significantly larger decrease in cultures of B-lymphoblastoids derived from patients (to 32.9+/-7.5%) than in those from healthy subjects (to 45.8+/-8.2%). The stronger decrease of glucocorticoid receptors in the group of patients (p=0.0001; t-test) was independent of the duration of illness and medication, suggesting a trait-like characteristic of the response.
    Psychoneuroendocrinology 06/2005; 30(4):325-32. · 5.59 Impact Factor
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    ABSTRACT: Olanzapine is an atypical antipsychotic with a low incidence of extrapyramidal-motoric side effects. Its chemical structure is related to clozapine, which is known to induce neutropenia in up to 3% and agranulocytosis in approximately 1% of patients. It has been discussed controversially whether olanzapine also has a potential to induce neutropenia and agranulocytosis. Up to now, seven case reports of haematopoetic disturbances during olanzapine treatment have been published, including one case of olanzapine-induced agranulocytosis (Naumann et al. 1999), two cases of neutropenia (Steinwachs et al. 1999) and one leucopenia (Meissner et al. 1999). We report three subjects with reversible neutropenia under olanzapine, with rapid normalisation of neutrophil cell counts after discontinuation of olanzapine. In one case neutropenia occurred after administration of a single dose of olanzapine, in another case after 6 weeks of treatment. In both cases, patients had no clinical complications. In the third case, neutropenia appeared after 1.5 years of treatment followed by development of pneumonia. Two cases were recorded within the German drug surveillance project (AMSP); the third case was observed in a randomised, double-blind, multicentre study comparing olanzapine with clozapine.
    The World Journal of Biological Psychiatry 11/2004; 5(4):230-4. · 3.57 Impact Factor
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    The World Journal of Biological Psychiatry 02/2004; 5(1):54-5. · 3.57 Impact Factor
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    ABSTRACT: A 45-year-old female suffering from severe chronic schizophrenia of the paranoid type did not respond to typical antipsychotics. Five weeks after starting therapy with clozapine, she developed a clozapine-induced agranulocytosis (CA). Discontinuation of clozapine and treatment with granulocyte colony-stimulating factor (G-CSF) led to normalization of blood neutrophil counts within three weeks. This report suggests enhanced apoptosis of blood neutrophils during the acute phase of CA resulting from enhanced expression of the pro-apoptotic proteins Bax and Bik and from a decrease of the anti-apoptotic BCl-X(L) mRNA. The time course of decline and recovery of neutrophilic cells, as well as the release pattern of endogenous G-CSF, resembles those of chemotherapy-induced neutropenia. The kinetics of CD 34-positive cells mimics that of cytotoxic progenitor cell mobilization, e. g., after cytostatic drug administration. Our findings argue against the hypothesis that clozapine-mediated inhibition of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) release is involved in CA development. Because clozapine-induced cell death mainly affects the neutrophil lineage, the elucidation of the exact mechanism of CA may open new perspectives for the treatment of psychiatric and possibly hematological disorders.
    Pharmacopsychiatry 02/2003; 36(1):37-41. · 2.11 Impact Factor
  • U Henning, S Löffler, K Krieger, A Klimke
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    ABSTRACT: The atypical antipsychotic, clozapine, exerts superior efficacy in therapy-resistant schizophrenia, but unfortunately induces agranulocytosis with an incidence of 0.8 - 1 %. In this study, we investigated the cellular uptake of clozapine into human promyelocytic leukaemia HL-60 cells using HPLC with electrochemical detection. On incubation with 1.25 to 40 microM clozapine for 30 min, a saturable, energy- and temperature-dependent uptake process takes place (K m = 18.8 microM, k cat = 1.36 nmol/5 min/mg protein at 37 degrees C). This suggests membrane passage of clozapine by a carrier mechanism. 10 microM Indatraline, an inhibitor of dopamine, noradrenaline and serotonin (5-HT) reuptake, but not the selective 5-HT reuptake inhibitor fluvoxamine, markedly reduced the transport of clozapine by 62 %, whereas addition of 10 mM glucose to the incubation medium increased intracellular clozapine concentrations by 28 %. Since cyclosporine A, vinblastine or verapamil up to a final concentration of 10 microM did not alter the intracellular accumulation of clozapine, an involvement of P-glycoprotein seems to be unlikely. In summary, clozapine uptake into HL-60 cells meets criteria of an active unidirectional transport. Its molecular correlates remain to be established.
    Pharmacopsychiatry 06/2002; 35(3):90-5. · 2.11 Impact Factor
  • Schizophrenia Research - SCHIZOPHR RES. 01/2000; 41(1):240-241.
  • S. Löffler, K. Fehsel, U. Henning, A. Klimke
    European Psychiatry 01/1998; 13. · 3.29 Impact Factor
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    ABSTRACT: The dopaminergic system is a candidate neurotransmitter system thought to be involved in the pathogenesis of depression. This study addresses the issue whether the antidepressant efficacy of serotonin reuptake inhibition is related to changes in the cerebral dopaminergic system. Cerebral dopamine-D2 receptors were characterized in 13 patients with major depression using the dopamine-D2 receptor antagonist iodobenzamide and single photon emission tomography. Dopamine receptor binding was assessed twice, before and during serotonin reuptake inhibition. An increase in dopamine-D2 receptor binding during serotonin reuptake inhibition was found in striatum and anterior cingulate gyrus in treatment responders, but not in nonresponders. The increase in dopamine-D2 receptor binding correlated significantly with clinical recovery from depression as assessed with the Hamilton depression scale (r = 0.59 for right and left striatum respectively, P < 0.05; r = 0.79 for the anterior cingulate gyrus, P < 0.05 after Bonferroni correction). Qualitatively similar correlations were observed in the precentral gyrus, the medial frontal gyrus, the inferior frontal gyrus, and the frontal part of the opercular gyrus, but these correlations failed to reach statistical significance after correction for the effects of multiple testing. No such correlations were found in the superior frontal gyrus, the orbitofrontal gyrus, the gyrus rectus, the superior parietal gyrus, or the superior temporal gyrus. The data strengthen the concept that the striatum and the anterior cingulate gyrus are involved in mood regulation. Dopamine-D2 receptors may constitute a central role in this domain.
    NeuroImage 05/1997; 5(4 Pt 1):251-60. · 6.25 Impact Factor
  • Biological Psychiatry - BIOL PSYCHIAT. 01/1997; 42(1).
  • S. Löffler, U. Henning, A. Klimke
    Biological Psychiatry - BIOL PSYCHIAT. 01/1997; 42(1).
  • S. Löffler, U. Henning, A. Klimke
    Biological Psychiatry - BIOL PSYCHIAT. 01/1997; 42(1).
  • European Psychiatry - EUR PSYCHIAT. 01/1996; 11.

Publication Stats

170 Citations
81.91 Total Impact Points

Institutions

  • 1997–2011
    • Heinrich-Heine-Universität Düsseldorf
      • • Medizinische Fakultät
      • • Klinik und Poliklinik für Psychiatrie und Psychotherapie der HHU, Rheinische Kliniken Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2008–2010
    • Klinikum Offenbach GmbH
      Frankfurt, Hesse, Germany