Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders.

INTRODUCTION: The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM). METHODS: Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019. RESULTS: The study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%-25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%-22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41-1.70, severe depression 1.33, 95% CI 1.18-1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27-1.38, PIM 1.18, 95% CI: 1.14-1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11-1.46, PIM 1.27, 95% CI: 1.11-1.44), respectively. CONCLUSION: This study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.

Polypharmacy and the risk of drug-drug interactions and potentially inappropriate medications in hospital psychiatry.

PURPOSE: The aim of this study was to analyze the epidemiology of polypharmacy in hospital psychiatry. Another aim was to investigate predictors of the number of drugs taken and the associated risks of drug-drug interactions and potentially inappropriate medications in the elderly. METHODS: Daily prescription data were obtained from a pharmacovigilance project sponsored by the Innovations Funds of the German Federal Joint Committee. RESULTS: The study included 47 071 inpatient hospital cases from eight different study centers. The mean number of different drugs during the entire stay was 6.1 (psychotropic drugs = 2.7; others = 3.4). The mean number of drugs per day was 3.8 (psychotropic drugs = 1.6; others = 2.2). One third of cases received at least five different drugs per day on average during their hospital stay (polypharmacy). Fifty-one percent of patients received more than one psychotropic drug simultaneously. Hospital cases with polypharmacy were 18 years older (p < 0.001), more likely to be female (52% vs. 40%, p < 0.001) and had more comorbidities (5 vs. 2, p < 0.001) than hospital cases without polypharmacy. The risks of drug-drug interactions (OR = 3.7; 95% CI = 3.5-3.9) and potentially inappropriate medication use in the elderly (OR = 2.2; CI = 1.9-2.5) substantially increased in patients that received polypharmacy. CONCLUSION: Polypharmacy is frequent in clinical care. The number of used drugs is a proven risk factor of adverse drug reactions due to drug-drug interactions and potentially inappropriate medication use in the elderly. The potential interactions and the specific pharmacokinetics and -dynamics of older patients should always be considered when multiple drugs are used.

Predicting the risk of drug-drug interactions in psychiatric hospitals: a retrospective longitudinal pharmacovigilance study.

OBJECTIVES: The aim was to use routine data available at a patient's admission to the hospital to predict polypharmacy and drug-drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions. DESIGN: Retrospective, longitudinal study. SETTING: We used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany. PARTICIPANTS: Inpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2). OUTCOME MEASURES: The proportion of rightly classified hospital episodes. METHODS: We used gradient boosting to predict respective outcomes. We tested the performance of our final models in unseen patients from another calendar year and separated the study sites used for training from the study sites used for performance testing. RESULTS: A total of 53 909 episodes were included in the study. The models' performance, as measured by the area under the receiver operating characteristic, was 'excellent' (0.83) and 'acceptable' (0.72) compared with common benchmarks for the prediction of polypharmacy and DDI, respectively. Both models were substantially better than a naive prediction based solely on basic diagnostic grouping. CONCLUSION: This study has shown that polypharmacy and DDI can be predicted from routine data at patient admission. These predictions could support an efficient management of benefits and risks of hospital prescriptions, for instance by including pharmaceutical supervision early after admission for patients at risk before pharmacological treatment is established.

Hormone replacement therapy with L-thyroxine promotes working memory and concentration in thyroidectomized female patients after differentiated thyroid carcinoma.

Objective: It is well established that long-term hypothyroidism is associated with cognitive deficits. Based on recent literature, we hypothesized that pharmacologically induced euthyroidism would lead to improved cognitive performance compared to a hypothyroid state. Methods: We analyzed data from 14 nondepressed thyroidectomized female patients after differentiated thyroid carcinoma during hypothyroidism (due to a four-week withdrawal of thyroid hormone, T1) and euthyroidism brought about by substitution with L-thyroxine (T2). At both measurement points, patients completed a cognitive test battery as our dependent measure and Beck's Depression Inventory to control depressive states. Results: A Wilcoxon signed-rank tests revealed a significant improvement in the Rey­Osterrieth complex figure test (cognitive reproduction), Z = −3.183, p = 0.001, and the D2 concentration score, Z = −1.992, p = 0.046 in euthyroidism compared to hypothyroidism. Conclusions: Our results confirm that hormone replacement therapy with L-thyroxine promotes cognitive reproduction and concentration in thyroidectomized female patients after differentiated thyroid carcinoma.

[Do the New German OPS codes map the relevant therapeutic activities in psychiatric clinics?]. / Abbildung des psychiatrisch-psychotherapeutischen Leistungsspektrums durch die aktuellen OPS-Komplexcodes.

OBJECTIVE: Actual codes for operations and procedures (OPS) in psychiatry and psychosomatics should map cost separating therapeutic activities so far defined in Germany by the normative specifications of the psychiatry staff enactment (PsychPV). OPS codes should also allow re-estimating underlying therapy times. METHOD: Therapeutic activities of the PsychPV fulfilling the minimal criteria of the OPS definition were classified as multiples of a therapeutic 25 minute unit. RESULTS: Therapeutic activities of the PsychPV are mapped to OPS complex codes in a variable degree (psychiatrists 35 %, psychologists 42 %, nurses 43 %, special therapists 59 %). CONCLUSION: Actual OPS codes are inappropriate for identifying relevant cost-separating factors in the therapy of psychiatric in-patients. They cannot assure in their actual form the standards given by the PsychPV and need substantial revision.

Clozapine mobilizes CD34+ hematopoietic stem and progenitor cells and increases plasma concentration of interleukin 6 in patients with schizophrenia.

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.

[Recurrent dysregulation of body temperature during antipsychotic pharmacotherapy]. / Rezidivierende Temperaturregulationsstörung unter Therapie mit Neuroleptika.

OBJECTIVE: This case report presents a rare, potentially life-threatening vegetative disturbance, which can occur during pharmacotherapy of schizophrenia. METHOD: A retrospective descriptive transversal and longitudinal section consideration of in-patient treatments of one female was performed. RESULTS: 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. CONCLUSIONS: 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.

Clozapine induces oxidative stress and proapoptotic gene expression in neutrophils of schizophrenic patients.

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.

Increased levels of glucocorticoid receptors and enhanced glucocorticoid receptor auto-regulation after hydrocortisone challenge in B-lymphoblastoids from patients with affective disorders.

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.

Increased serum interleukin-1beta and interleukin-6 in elderly, chronic schizophrenic patients on stable antipsychotic medication.

In schizophrenia, alterations of proinflammatory cytokine levels have been reported and related to the disease and psychopathology. However, only limited conclusions can be drawn in view of confounding factors such as infection, age, sex, smoking, and antipsychotic medication. Chronic schizophrenic patients with a long-term disease process and medication period have not been investigated so far. We have measured serum levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)alpha in 41 elderly, chronic schizophrenic patients and 23 age- and sex-matched controls using enzyme-linked immunosorbent assay (ELISA). We assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine, and the two main clozapine metabolites, desmethylclozapine and clozapine metabolite N-oxide, by high-pressure liquid chromatography (HPLC). IL-1beta and IL-6 levels were increased in treatment-resistant schizophrenic patients compared with healthy controls, whereas TNFalpha showed no difference. We did not find statistically significant differences of cytokine levels between medication groups and there was no correlation with serum levels of antipsychotics or psychopathological rating scores. Elevations of IL-1beta and IL-6 in elderly chronic schizophrenic patients may be related to an active disease process lasting until old age. Despite missing correlations, long-term treatment effects in treatment-resistant patients may have affected TNFalpha, leading to control levels. Post-mortem and animal studies should clarify the presence of altered immune function in the brain as well as the effect of cytokine levels in relation to neurodevelopmental disturbances and schizophrenia-associated behavior.