Forecasting admissions in psychiatric hospitals before and during Covid-19: a retrospective study with routine data.

The COVID-19 pandemic has strong effects on most health care systems. Forecasting of admissions can help for the efficient organisation of hospital care. We aimed to forecast the number of admissions to psychiatric hospitals before and during the COVID-19 pandemic and we compared the performance of machine learning models and time series models. This would eventually allow to support timely resource allocation for optimal treatment of patients. We used admission data from 9 psychiatric hospitals in Germany between 2017 and 2020. We compared machine learning models with time series models in weekly, monthly and yearly forecasting before and during the COVID-19 pandemic. A total of 90,686 admissions were analysed. The models explained up to 90% of variance in hospital admissions in 2019 and 75% in 2020 with the effects of the COVID-19 pandemic. The best models substantially outperformed a one-step seasonal naïve forecast (seasonal mean absolute scaled error (sMASE) 2019: 0.59, 2020: 0.76). The best model in 2019 was a machine learning model (elastic net, mean absolute error (MAE): 7.25). The best model in 2020 was a time series model (exponential smoothing state space model with Box-Cox transformation, ARMA errors and trend and seasonal components, MAE: 10.44). Models forecasting admissions one week in advance did not perform better than monthly and yearly models in 2019 but they did in 2020. The most important features for the machine learning models were calendrical variables. Model performance did not vary much between different modelling approaches before the COVID-19 pandemic and established forecasts were substantially better than one-step seasonal naïve forecasts. However, weekly time series models adjusted quicker to the COVID-19 related shock effects. In practice, multiple individual forecast horizons could be used simultaneously, such as a yearly model to achieve early forecasts for a long planning period and weekly models to adjust quicker to sudden changes.

Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection.

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

Predicting patient outcomes in psychiatric hospitals with routine data: a machine learning approach.

BACKGROUND: A common problem in machine learning applications is availability of data at the point of decision making. The aim of the present study was to use routine data readily available at admission to predict aspects relevant to the organization of psychiatric hospital care. A further aim was to compare the results of a machine learning approach with those obtained through a traditional method and those obtained through a naive baseline classifier. METHODS: The study included consecutively discharged patients between 1st of January 2017 and 31st of December 2018 from nine psychiatric hospitals in Hesse, Germany. We compared the predictive performance achieved by stochastic gradient boosting (GBM) with multiple logistic regression and a naive baseline classifier. We tested the performance of our final models on unseen patients from another calendar year and from different hospitals. RESULTS: The study included 45,388 inpatient episodes. The models' performance, as measured by the area under the Receiver Operating Characteristic curve, varied strongly between the predicted outcomes, with relatively high performance in the prediction of coercive treatment (area under the curve: 0.83) and 1:1 observations (0.80) and relatively poor performance in the prediction of short length of stay (0.69) and non-response to treatment (0.65). The GBM performed slightly better than logistic regression. Both approaches were substantially better than a naive prediction based solely on basic diagnostic grouping. CONCLUSION: The present study has shown that administrative routine data can be used to predict aspects relevant to the organisation of psychiatric hospital care. Future research should investigate the predictive performance that is necessary to provide effective assistance in clinical practice for the benefit of both staff and patients.

Dreaming during REM sleep: autobiographically meaningful or a simple reflection of a Hebbian-based memory consolidation process?

REM sleep is a state of desynchronized electrophysiological activity of the brain. It is usually accompanied by mental activity characterized by a succession of complex visual experiences commonly referred to as dreaming. Although REM sleep and dreaming are not implicitly conjoined, when they co-occur, they have a very distinct phenomenology, as, typically, the dream plot is bizarre and incohesive which is mirrored in heightened brain activation coupled with strongly attenuated coherence levels. At the same time, owing to increased limbic system activity, REM sleep dreams are highly emotional. Moreover, concrete emotions are often unrelated to dream events. Nevertheless, REM sleep dreams are often subjectively perceived as story-like and autobiographically meaningful. Indeed, elements of salient life events, attachment figures, and personally relevant emotions, especially trauma, seem to have a higher probability of re-appearing in dreams, albeit the dream plot itself remains highly distorted. This has prompted several theories on the interpretability of dreams, some authors leaning towards dreams reflecting waking mentation, others suggesting complete dissociation between waking and dreaming, both sides not fully accounting for empirical findings. In this review, we provide an overview of recent findings on the factors mediating REM sleep neurophysiology and dream content. As a first step towards integration of conflicting research results, we introduce a testable model (Trace-Spur-model) based on Hebbian theory of neural networks, proposing that dream bizarreness is a function of state-related modulations in synaptic strength allowing for hyper-associative mental activity, possibly enabling either a restructuring and integrative consolidation or extinction of learning experiences acquired in waking. In this model, dreams are viewed as phenomenological expressions of this neurophysiologic activity where dream recall allows a fragmentary witnessing of such processes, similar to peeking into an enduring and complex networking system. However, the content of the recollected dream is probably strongly deterred by autobiographical memory bias, favoring those images we can form some sort of association with.

[Guideline-adherent psychiatric-psychotherapeutic hospital care: Normative definition of staff required using the example of depression]. / Leitliniengerechte psychiatrisch-psychotherapeutische Krankenhausbehandlung : Normative Personalermittlung am Beispiel Depression.

BACKGROUND: Unipolar depression is of high relevance in German inpatient treatment. An effective psychiatric psychotherapeutic hospital treatment also requires sufficient staff for carrying out psychotherapeutic treatment. AIMS AND OBJECTIVES: The aim of this study was to define the staff requirements for guideline-adherent psychiatric-psychotherapeutic inpatient treatment of depression on the basis of a weekly treatment schedule for a 5-week admission period. A further aim was to compare the staff required with the resources defined by the German psychiatric staffing regulations (Psych-PV). MATERIAL AND METHODS: The weekly schedule was normatively defined on the basis of the current evidence for treatment efficacy and effectiveness. The staff required was calculated on the basis of the weekly schedule. The time for psychotherapy defined by the Psych-PV was calculated using the treatment classification provided by a large nationwide database. RESULTS: Regarding psychotherapy, 280 min per week is regarded as necessary and usually sufficient according to the current evidence. The results showed clearly higher requirements of working time of psychiatrists and psychologists than those defined by the Psych-PV. In particular, the Psych-PV allows only 72 min for psychotherapy per patient and week and only a limited amount of direct patient contact with psychiatrists. CONCLUSION: The figures provided impressively show that the Psych-PV does not allow effective guideline-adherent hospital treatment within a reasonable length of hospital stay. Despite its evidential effectiveness, psychotherapeutic treatment cannot be sufficiently provided under the current financing circumstances.

[Structural quality in psychiatric and psychotherapeutic hospitals]. / Strukturqualität in psychiatrischen und psychotherapeutischen Kliniken.

BACKGROUND: The new German flat rate reimbursement system for psychiatry and psychosomatics (PEPP) is primarily based on the diagnostic classification and the costs of therapeutic processes. In 2019 the current normative standard for calculating the therapeutic staff in psychiatric clinics (Psych-PV) will be substituted by a stepwise adaptation process over 5 years. Using regionally calculated remuneration factors, all clinic budgets should eventually converge to comparable values. AIM: Major factors influencing the structural quality of therapy in psychiatric clinics are identified and recommendations are given to support the work of the Federal Joint Committee (G-BA) which has been appointed to develop new recommendations for the minimum setting of personnel requirements. RESULTS: The full reimbursement of the necessary staff and of the costs resulting from outsourcing of day clinics and outpatient departments in the community, including the obligation to treat psychiatric emergency patients is mandatory and currently not sufficiently guaranteed in the new PEPP system. A workflow which opens the possibility to finance therapeutic innovations (e.g. psychotherapy) and helps to overcome the financial sectorial boundaries between inpatient and outpatient treatment is also missing. DISCUSSION: A mandatory recommendation for minimum staff settings needs a guaranteed full financing from the political side. Additionally, important would be an option for financing of therapeutic innovations and increased costs because of changed patient structures with respect to diagnosis and severity. Moreover, a sufficient remuneration for regional treatment responsibilities and for additional financial outlay resulting from structural costs for regionally outsourced departments is needed to avoid supplementary financing by reducing the budget for the therapeutic staff.

[Where is convergence of psychiatry budgets leading to? A comparison of staffing regulations and actual personnel resources]. / Wohin führt die Konvergenz der Psychiatriebudgets? Ein Vergleich von Psych-PV-Vorgaben und tatsächlichen Personalressourcen.

BACKGROUND: Staffing regulations have determined the number of qualified staff required for sufficient, appropriate and economical inpatient mental health care in Germany since 1991. This minimum level of structural quality will probably be abolished in the context of the convergence of hospital budgets starting in 2019. AIMS AND OBJECTIVES: The aim of this study was to analyze the current fulfilment of staffing regulations in terms of time per patient in a large nationwide sample. MATERIAL AND METHODS: The required minutes of staff time as defined by staffing regulations were calculated for each patient using the treatment classifications provided by a large nationwide database. The actual use of staff time was calculated on the basis of average costs published by the German Institute for Hospital Reimbursement. Both figures were compared to calculate the fulfilment of staffing regulations. RESULTS: The study included approximately 95,000 inpatient episodes from 46 psychiatric hospitals and departments with a total length of stay of almost 2.5 million days. On average, the weekly use of staff resources per patient was 190 min (10 %) below the requirements of the staffing regulations. The largest gap in absolute terms was found in nursing staff where the weekly time per patient was 189 min (14 %) below the requirements of the staffing regulations. CONCLUSION: The convergence of psychiatric hospital budgets starts in 2019 below a level of funding required to fulfil staffing regulations. This would perpetuate inadequately funded structures and should initially be opposed with a demand for complete fulfilment of staffing regulations. Thereafter, a normative consent should be reached to define the resources required for current inpatient mental health care.

[Reimbursement in psychiatry and psychosomatics: proof of concept for a system based on daily costs]. / Vergütungssystem für Psychiatrie und Psychosomatik: Studie zur Machbarkeit eines tageskostenbasierten Entgeltsystems.

BACKGROUND: In Germany a new reimbursement system for psychiatry and psychosomatics is under development. Based on total costs of each case from selected hospitals and day clinics, in 2013 the Institute for the Hospital Remuneration System (InEK) proposed to reimburse the hospital costs daily with step-wise decreasing remuneration, mainly depending on the ICD-10 diagnosis, duration of stay and some complicating factors (PEPP grouper). It is controversial whether this degressive system will result in an inadequate remuneration of patients with longer duration of severe symptoms, such as suicidality in depression or autoaggressive behavior in borderline personality disorder and will eventually lead to advantages for acutely ill patients with short duration of stay compared to chronically ill patients. OBJECTIVES: This study formulated and tested an alternative remuneration system (proof of concept) mainly based on an analysis of daily cost data instead of the total costs of each case. MATERIAL AND METHODS: The study is based on 147,749 treatment days from 4,633 cases of patients with psychotic disorders (PEPP-PA03) in 6 hospitals. As possible cost separating factors the study analyzed days with and without intensive psychiatric care, 1 to 1 care, psychological diagnostics, magnetic resonance imaging (MRI), acute crisis intervention, age at admission, the first days of treatment and day of discharge. RESULTS AND DISCUSSION: Nearly all factors tested were shown to be statistically significant in separating daily hospital costs. Based on these findings an alternative calculation algorithm (TEPPconcret), which grouped the cases with respect to age, intensive care, 1 to 1 care, treatment days 1-4 and day of discharge, was formulated and tested. For psychotic disorders TEPPconcret with a basic rate complemented by daily add-on payments depending on the effort involved, is a serious alternative to the PEPP system and awaits further evaluation.

[Therapeutic options for weight management in schizophrenic patients treated with atypical antipsychotics]. / Möglichkeiten des Gewichtsmanagements in der Behandlung schizophrener Psychosen mit atypischen Antipsychotika.

Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.

Potential clinical targets of repetitive transcranial magnetic stimulation treatment in schizophrenia.

Despite the introduction of atypical antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. Currently, there is evidence from clinical studies suggesting that treatment with repetitive transcranial magnetic stimulation (rTMS) may improve schizophrenia symptoms. Our review provides an overview of clinical rTMS studies in schizophrenic patients. A systematic search of the literature (Cochrane and Medline databases up to December 2005) was conducted. Most studies showed methodological problems due to their explorative character and small sample sizes. In some studies, a treatment effect of high-frequency rTMS applied over the prefrontal cortex was seen with respect to negative symptoms. On the other hand, low-frequency rTMS in the temporal lobe area might lead to a suppression of auditory hallucinations. It is concluded that larger sham-controlled studies are required to allow an adequate assessment of the clinical and neurobiological effects of rTMS in schizophrenic patients. The currently available data provide insufficient evidence to support the use of rTMS as an adjuvant treatment for schizophrenic psychopathology, but encourage further investigation of rTMS as a novel treatment approach.

[A new method for the treatment of depression: repetitive transcranial magnetic stimulation]. / Ein neues Behandlungsverfahren der Depression: Die repetitive transkranielle Magnetstimulation (rTMS).

Recent data suggest that repetitive transcranial magnetic stimulation (rTMS) is effective in treating depressive symptoms to a lesser extent compared with classical electroconvulsive therapy. However, rTMS represents an economical and well tolerable procedure in relation to the expenditure of electroconvulsive therapy with anaesthesia. Usually, rTMS is applicated as an add-on-therapy accompanying psychopharmacological treatment. So far, it has predominantly been used for patients with long-standing and so called treatment-refractory symptoms. However, even in the early phase of a depressive episode rTMS would be possibly more effective. In many cases, the standard procedure-application of up to 10 rTMS-sessions will not be enough to produce therapeutic benefit. Therefore rTMS series including up to 20 sessions are recommended. Long-term studies are needed to clarify the role of rTMS for relapse prevention and to determine the optimal frequency and duration of rTMS in such an indication. Although numerous results of newer studies suggest a moderate antidepressive effect of rTMS, its application in daily clinical routine practice cannot be recommended yet. Larger, accurate designed and controlled studies, especially involving patients of old age, are needed to evaluate the true tolerability and effectiveness of rTMS as a new treatment option for depressive symptoms.

Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia.

OBJECTIVE: This randomized double-blind multicenter trial evaluated the effects of olanzapine vs. clozapine on subjective well-being, quality of life (QOL) and clinical outcome. METHOD: The primary objective was to demonstrate non-inferiority of olanzapine, mean dosage 16.2 +/- 4.8 (5-25 mg/day) vs. clozapine, mean dosage 209 +/- 91 (100-400 mg/day) regarding improvement on the 'Subjective Well-Being under Neuroleptic Treatment' (SWN) Scale after 26 treatment weeks in 114 patients with schizophrenia. Secondary outcome parameters included: Munich QOL Dimension List (MLDL), Positive and Negative Symptom Scale (PANSS), Clinical Global Impression (CGI). RESULTS: SWN scores improved significantly in both groups, olanzapine was non-inferior to clozapine (group difference 3.2 points in favor of olanzapine; 95% CI: 4.2;10.5). MLDL-satisfaction, PANSS and CGI-S improved similarly, olanzapine yielded a higher CGI Therapeutic Index. Individual SWN and PANSS changes correlated only moderately (r = -0.45). CONCLUSION: Olanzapine was non-inferior to clozapine. The lack of a marked correlation between PANSS and SWN improvements indicates that patients and psychiatrists perceive treatment differently.

A functional-structural model to understand cardiac autonomic nervous system (ANS) dysregulation in affective illness and to elucidate the ANS effects of antidepressive treatment.

Numerous studies provide evidence that major depression (MD) is associated with certain disorders of cardiac autonomic nervous system (ANS) function, in particular, with an autonomic neurocardiac imbalance characterized by a low cardiovagal modulation, a raised sympathetic nerve activity and a high resting heart rate. We assume that such MD-associated cardiac ANS disorders are mainly caused by functional-structural abnormalities within the central autonomic network (CAN), in particular, by well-defined abnormalities of hypothalamic structures in MD. In view of the well-known association between an autonomic neurocardiac imbalance and the risk for cardiac arrhythmias, we assume that MD-associated cardiac ANS disorders are at least partly responsible for the high cardiovascular mortality risk in MD. It is, however, still unclear whether antidepressive treatment will lower the risk for cardiovascular complications in MD. There is convincing evidence that a successful antidepressive treatment with electroconvulsive therapy, cognitive behavioral therapy, or pharmacotherapy with primarily non-antimuscarinergic antidepressants can improve an initially disturbed cardiac ANS function in MD. These studies correspond well to our findings that treatment with both, nefazodone or reboxetine, can induce a reduction of central sympathetic nerve activity and an increase of the initially lowered cardiovagal modulation depending on the improvement of depressive symptoms after treatment. Since both effects occured obviously independent from the primarily serotonergic or noradrenergic action of the antidepressants, our findings suggest the existence of a generally supraordinate and uniform mechanism underlying the ANS effects of antidepressive treatment with drugs inhibiting serotonin- or noradrenaline reuptake.

Increased apoptosis of neutrophils in a case of clozapine-induced agranulocytosis - a case report.

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.

Uptake of clozapine into HL-60 promyelocytic leukaemia cells.

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.

Disturbance of serotonin 5HT2 receptors in remitted patients suffering from hereditary depressive disorder.

AIM: The characteristics of 5HT2 receptor binding were investigated in major depression in vivo using positron emission tomography and the radioligand F-18-altanserin. METHODS: Twelve patients from families with high loading of depression living in a geographically restricted region were examined and compared with normal control subjects. At the time of the PET measurement all patients were remitted; in some of them remission was sustained by antidepressive medication. Binding potential was assessed by Logan's graphical analysis method. RESULTS: The binding of F-18-altanserin was about 38% lower in patients than in healthy controls (p < 0.001). A multiple regression analysis revealed that this difference was mainly induced by depression rather than by medication. CONCLUSIONS: The data suggest that 5HT2 receptors are altered in depression. We present evidence for a reduction of the receptor density, which might be usable as trait marker of subjects susceptible for depressive illness.

Dopamine D2 receptor binding before and after treatment of major depression measured by [123I]IBZM SPECT.

Fifteen patients fulfilling DSM-IV criteria for major depression were investigated with the specific dopamine D2 receptor antagonist [123I]iodobenzamide (IBZM). Two single photon emission computed tomography (SPECT) examinations were performed before and after 6 weeks of treatment with a selective serotonin re-uptake inhibitor (SSRI). Striatal D2 receptor binding was calculated and normalized to the cerebellum. In a non-psychiatric control group (n = 17), which was investigated once with [123I]IBZM and SPECT, striatal IBZM binding decreased significantly with age (0.092 per decade). The age-dependent correlation was lower in subjects with major depression and did not reach statistical significance. There was no significant difference in mean IBZM binding between depressives and control subjects. Age-corrected baseline IBZM binding in the striatum was significantly lower in treatment responders than in depressed non-responders and control subjects. Furthermore, in the depressive group there was a significant linear correlation between treatment response and change of D2 receptor binding during treatment in the basal ganglia. IBZM binding increased in treatment responders and decreased in non-responders. In accordance with animal studies, the results suggest an association between changes in the dopaminergic system and treatment response in major depression.

Specific binding of 3H-spiperone to peripheral blood cells: relevance for the interpretation of binding studies in psychiatric disorders.

1. There is an ongoing discussion regarding the elevated binding of 3H-spiperone to lymphocytes of schizophrenic patients. Several authors described an atypical binding pattern with a saturable high-affinity and a nonsaturable binding site both displaceable by (+)-butaclamol. Recent findings are still controversial (Fartacek et al., 1997; Wodarz et al., 1996), possibly due to methodological differences. The authors investigated 3H-spiperone binding to different peripheral blood cells including B- and T-lymphoblastoids. 2. B-lymphocytes (KD = 0.081 nM; Bmax = 0.46 x 10(-15) mol/10(6) cells) and macrophages (KD = 0.1-1 nM, Bmax = 2.44 x 10(-15) mol/10(6) cells) are characterized by a minor but saturable binding of 3H-spiperone in a concentration range between 0.5 and 1 nM. Above 1 nM, only non-saturable binding was measurable. Interestingly, Epstein-Barr virus (EBV) transformed lymphoblastoids (KD = 0.13 nM) have nearly the same affinity for 3H-spiperone as native B-cells, but an increased number of binding sites (Bmax = 1.76 x 10(-15) mol/10(6) cells). 3. Membranes from B-lymphoblastoids displayed a saturable binding in a concentration between 0 and 1.8 nM of 3H-spiperone (KD = 0.5 nM and Bmax = 1.72 x 10(-15) mol/mg protein). Extraction with 1% digitonin resulted in a similar binding characteristic (KD = 0.17 nM and Bmax = 1.97 x 10(-15) mol/mg protein). 4. T-cells, granulocytes and MOLT-3-cells did not show is a saturable binding even not at high concentrations of 3H-spiperone. 5. The pharmacological profile of the high-affinity 3H-spiperone binding site is clearly different from the dopamine D2 and D4, serotonin 5-HT2 histamine H1 and noradrenergic alpha1 and alpha2 receptor, respectively. 6. In summary, the results suggest that spiperone binding studies to enriched lymphocytes of psychiatric patients should be interpreted cautiously. Variable amounts of leucocytes might result in a higher proportion of nonsaturable, butaclamol displaceable spiperone binding with relevance for the calculation of KD and Bmax of the saturable high-affinity site. Interestingly, homogenous B-lymphoblastoid cell lines have the same binding characteristics as native B-lymphocytes and therefore should be recommended for characterization of 3H-spiperone binding sites.

Active [3H]-dopamine uptake displayed by native lymphocyte suspensions is mainly due to contaminating platelets.

Kinetic and pharmacologic properties of specific [3H]-dopamine uptake by native human lymphocytes were investigated. Our results suggest that uptake of [3H]-dopamine measured with lymphocytes after separation over Ficoll-Paque or Percoll is mainly caused by platelets which are always part of freshly prepared lymphocyte suspensions. The investigations were extended to well-defined cell lines in order to compare the pharmacological properties of native and immortalized cells regarding the uptake of [3H]-dopamine without any influence of contaminating cells such as platelets. Using the human neuroblastoma cell line IMR32 we demonstrate a GBR-12909 and cocaine-sensitive specific uptake of dopamine, whereas dopamine uptake in platelets is performed by an imipramine-sensitive serotonin transporter. Blood-derived stable cell lines (MOLT-3 and EBV-transformed B-lymphocytes) exhibited no [3H]-dopamine uptake. The view that specific [3H]-dopamine uptake on native human lymphocytes is mainly caused by platelets and not specific for lymphocytes is supported by the finding that homogenous B- and T-lymphoblastoids (MOLT-3 and EBV-transformed B-lymphocytes) exhibited no comparable uptake.

Imaging dopamine D4 receptors in the living primate brain: a positron emission tomography study using the novel D1/D4 antagonist [11C]SDZ GLC 756.

The dopamine D4 receptor has lately attracted interest since it has been hypothesized to be involved in the pathogenesis and pharmacotherapy of neuropsychiatric diseases. The present study provides first in vivo evidence of dopamine D4 receptors in primate brain using a [11C]benzo[g]quinoline, the novel radioligand [11C]SDZ GLC 756 ([11C]GLC: in vitro dissociation constants at human receptor clones [nM]: 1.10 at D1; 0.40 at D2; 25 at D3; 0.18 at D4.2; 6.03 at D5). Dynamic positron emission tomography scans were performed on healthy baboons (Papio hamadryas, n = 3). Specific receptor binding (SB) was calculated for striatum and neocortex (frontal, temporal, parietal, and occipital) based on the differences between the regional and the cerebellar concentration of [11C]. Blockade of D1 and D5 receptors by SCH23390 (1.7 pmol/kg) diminished SB in the striatum by 55 +/- 4% (mean +/- standard deviation, P < 0.05) and in the frontal cortex by 13 +/- 8% (P < 0.05) when compared to SB in the unblocked state (SB(D1-D5)). In the presence of the dopamine antagonists SCH23390 (1.7 micromol/kg) and raclopride (5.7 pmol/kg)--which mask the D1, D2, D3, and D5 subtypes--SB of [11C]GLC to D4 receptors (SB(D4)) was demonstrated in the striatum and all cortical regions of interest. In the striatum, the ratio of SB(D4)/SB(D1-D5) was 0.13 +/- 0.07. In the neocortex, SB(D4)/SB(D1-D5) was notably higher (0.77 +/- 0.29; mean of all cortical regions of interest). The widespread distribution of dopamine D4 receptors suggests a basic functional role of this receptor subtype in the modulation of cortical and subcortical neuronal activity.