Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

Objective: Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and dopamine D2-receptor occupancy for oral and long-acting injectable (LAI) formulations.Data Sources: Databases were systematically searched for randomized controlled trials (RCTs) and uncontrolled trials concerning blood olanzapine levels in relation to clinical outcomes or D2-receptor occupancy using MEDLINE (PubMed), Web of Science, PsycINFO, and Cochrane Library (March 2021, updated in December 2021). We excluded articles not written in English or German and non-human data. Search terms included olanzapine, blood level, drug monitoring, PET, and SPECT.Study Selection: The process of study selection followed a previously published protocol and PRISMA guidelines. A total of 2,824 articles were identified through database search and 1 article via reference list check. Thirty-four studies were suitable for qualitative synthesis, and 13 studies were included in the quantitative analysis.Data Extraction: Reviewers performed data extraction and quality assessment of the included studies independently following the review protocol.Results: Evidence for a relationship between blood olanzapine level and efficacy/side effects (constipation) is considered low (Level C). In total, 3 studies of moderate quality consistently showed therapeutic thresholds of around 20 ng/mL for olanzapine 12 hours post-dose. This threshold is in line with findings from positron emission tomography (PET) studies that suggest optimal drug efficacy (65%-80% D2-receptor occupancy) between 17 and 44 ng/mL.Conclusions: We suggest a therapeutic reference range of 20-40 ng/mL for olanzapine oral and LAI formulations. In this range, optimal treatment response is expected in patients with schizophrenia and schizophrenia spectrum disorders. Side effects, especially weight gain, may already occur at therapeutic levels. However, higher plasma concentrations are in general well tolerated and should not necessarily require a dose reduction in case of good response and tolerance.

Guía de consenso de expertos para la monitorización terapéutica de drogas en neuropsicofarmacología / Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology

OBJETIVO: La Monitorización Terapéutica de Drogas (llamada en inglés TDM: therapeutic drug monitoring) combina la cuantificación de las concentraciones de medicamentos en la sangre, la interpretación farmacológica y las directrices de tratamiento. La TDM introduce una herramienta de medicina de precisión en una ípoca de gran conciencia de la necesidad de tratamientos personalizados en neurología y psiquiatría. Las indicaciones claras de la TDM incluyen la ausencia de respuesta clínica en el rango de dosis terapéuticas, la evaluación de la adherencia farmacológica, problemas de tolerancia e interacciones medicamentosas. MÉTODOS: Basándose en la literatura existente, se describieron los rangos de referencia terapéutica recomendables, los valores críticos de laboratorio y los niveles de recomendación para usar la TDM para la optimización de dosis sin indicaciones específicas, se calcularon los factores de conversión, los factores para el cálculo de concentraciones medicamentosas relacionadas con la dosis (en inglés DRC dose-to-ratioconcentration) y el cociente entre el metabolito y el compuesto original (en inglés se llama MPR: metabolite-to-parent ratio). RESULTADOS: Este resumen de las guías actualizadas del consenso por la Task Force del TDM del Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie, ofrece el conocimiento práctico y teórico para la integración de la TDM como parte de la farmacoterapia con medicamentos neuropsiquiátricos en la práctica clínica rutinaria. CONCLUSIONES: La presente traducción en español, de la guía para la aplicación del TDM en medicamentos neuropsiquiátricos, tiene como objetivo ayudar a los clínicos a mejorar la seguridad y la eficacia de los tratamientos

OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation, and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalised treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities, and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues, and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimisation without specific indications, conversion factors, factors for calculation of dose-related drug concentrations, and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuro- psychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. / Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.

TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians.

OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Standardization of depression measurement: a common metric was developed for 11 self-report depression measures.

OBJECTIVES: To provide a standardized metric for the assessment of depression severity to enable comparability among results of established depression measures. STUDY DESIGN AND SETTING: A common metric for 11 depression questionnaires was developed applying item response theory (IRT) methods. Data of 33,844 adults were used for secondary analysis including routine assessments of 23,817 in- and outpatients with mental and/or medical conditions (46% with depressive disorders) and a general population sample of 10,027 randomly selected participants from three representative German household surveys. RESULTS: A standardized metric for depression severity was defined by 143 items, and scores were normed to a general population mean of 50 (standard deviation = 10) for easy interpretability. It covers the entire range of depression severity assessed by established instruments. The metric allows comparisons among included measures. Large differences were found in their measurement precision and range, providing a rationale for instrument selection. Published scale-specific threshold scores of depression severity showed remarkable consistencies across different questionnaires. CONCLUSION: An IRT-based instrument-independent metric for depression severity enables direct comparisons among established measures. The "common ruler" simplifies the interpretation of depression assessment by identifying key thresholds for clinical and epidemiologic decision making and facilitates integrative psychometric research across studies, including meta-analysis.

A multirisk approach to predicting chronicity of postpartum depression symptoms.

BACKGROUND: Persistence of postpartum depression (PPD) carries potential adverse implications for the emerging mother-child relationship and for child development. METHODS: This study was designed to investigate factors related to the onset and persistence of PPD; in particular, we examined the cumulative effect of a range of psychosocial risk factors in predicting chronic PPD symptoms. One hundred and five women were interviewed at three assessment periods: within the first days after childbirth, at 6 months, and at 18 months postpartum. RESULTS: Depressive symptoms at 6 months predicted 18 months depressive symptoms, even when controlling for the contribution of maternal depression at birth. Psychosocial risk had a moderating influence on the stability of depressive symptomatology. Women with two or more risk factors at birth were more likely to have stable depressive symptomatology across the infants' first 18 months of life. CONCLUSION: To prevent a chronic course of PPD it may be necessary to identify both depressive symptoms and relevant psychosocial risk factors.

Testosterone and gonadotropins but not estrogen associated with spatial ability in women suffering from schizophrenia: a double-blind, placebo-controlled study.

The aim of this study was to investigate the association between estrogen and spatial ability tasks in women suffering from schizophrenia. For this purpose, a placebo-controlled, double-blind, three-time cross-over study using 17beta-estradiol combined with norethisterone acetate for replacement therapy and as an adjunct to a naturalistic maintenance antipsychotic treatment was carried out over a period of 8 months. Nineteen women (mean age=38.0 years, SD=9.9 years) with schizophrenia hospitalized for the first time or repeatedly were included in the study. Sex hormones - 17beta-estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, testosterone, and dehydroepiandrosterone sulfate - were measured and the patients completed a neuropsychological test in the last two active drug and/or placebo phases. Three different spatial ability tasks - spatial orientation, spatial visualization, and flexibility of closure - were measured by a paper-and-pencil test. No association between estrogen and spatial ability was found; however, in an additional exploratory data analysis, high levels of testosterone, LH, and FSH correlated significantly with performance in the flexibility of closure task. This is the very first study, based on estrogen intervention instead of physiological hormone changes, to examine the association between estrogen and spatial ability in women with schizophrenia.

Estrogen and comprehension of metaphoric speech in women suffering from schizophrenia: results of a double-blind, placebo-controlled trial.

OBJECTIVE: The effects of estrogen on comprehension of metaphoric speech, word fluency, and verbal ability were investigated in women suffering from schizophrenia. The issue of estrogen-dependent neuropsychological performance could be highly relevant because women with schizophrenia frequently suffer from hypoestrogenism. METHOD: A placebo-controlled, double-blind, crossover study using 17beta-estradiol for replacement therapy and as an adjunct to a naturalistic maintenance antipsychotic treatment was carried out over a period of 8 months. Nineteen women (mean age = 38.0 years, SD = 9.9 years) with schizophrenia were included in the study. Comprehension of metaphoric speech was measured by a lexical decision paradigm, word fluency, and verbal ability by a paper-and-pencil test. RESULTS: Significant improvement was seen for the activation of metaphoric meaning during estrogen treatment (P = .013); in contrast, no difference was found for the activation of concrete meaning under this condition. Verbal ability and word fluency did not improve under estrogen replacement therapy either. CONCLUSIONS: This is the very first study based on estrogen intervention instead of the physiological hormone changes to examine the estrogen effects on neuropsychological performance in women with schizophrenia. In addition, it is the first time that the effect of estrogen on metaphoric speech comprehension was investigated in this context. While in a previous study estrogen therapy as adjunct to a naturalistic maintenance treatment with antipsychotics did not show an effect on psychopathology measured by a rating scale, a significant effect of estrogen on the comprehension of metaphoric speech and/or concretism, a main feature of schizophrenic thought and language disturbance, was found in the present study. Because the improvement of formal thought disorders and language disturbances is crucial for social integration of patients with schizophrenia, the results may have implications for the treatment of these individuals.

High clozapine concentrations in leukocytes in a patient who developed leukocytopenia.

Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.

Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia.

BACKGROUND: Estrogen has been hypothesized to have a protective and antipsychotic-like effect in women at risk for schizophrenia. The aim of the present study was to evaluate the association between menstrual cycle and/or estrogen levels and psychotic symptoms in a sample of women with schizophrenia. METHOD: One hundred and twenty-five premenopausal women with schizophrenia and regular menses were examined. The levels of 17beta-estradiol and other hormones of the gonadal axis were assessed in the follicular, peri-ovulatory, and luteal phases of the menstrual cycle. The effects of the menstrual cycle phase and/or the estradiol level on the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) scores were calculated by means of regression analyses. RESULTS: Significant improvement in psychotic, but not depressive, symptoms was observed during the luteal phase, compared with other days of the menstrual cycle. CONCLUSIONS: The present findings indicate that estradiol may have specific antipsychotic-like effects on the symptoms of schizophrenia. Thus further investigation into the therapeutic effect of estrogen may be worthwhile.

Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study.

The expected therapeutic effect of estrogen as an adjunct treatment to antipsychotics in women suffering from schizophrenia for relapse prevention was to be tested under real-life conditions. A multicenter, randomized, placebo-controlled, double-blind, cross-over study based on an A-B-A-B (and/or B-A-B-A) design was applied. Forty-six hypoestrogenic women with schizophrenia hospitalized for the first time or repeatedly were included in the study. Their average age was 37.9 and they had been suffering from schizophrenia for 8.4 years. During the drug treatment phases, they received a three-phase estrogen-gestagen combination drug (17beta-estradiol+norethisterone acetate) in addition to an antipsychotic drug. Significant effects of the adjuvant hormone replacement therapy on the estradiol levels could be observed, and high and low levels of estradiol prevailed in the active drug and placebo phases, respectively. We did not find any difference either in defined relapse events or in the psychopathology between estradiol replacement and placebo phases. Neither did the required antipsychotic doses or the tolerance data differ between the two phases. Thus, the results of our study do not confirm the hypothesis that a combined estradiol/antipsychotic therapy is superior to an antipsychotic monotherapy for relapse prevention.

Plasma concentrations of estradiol in women suffering from schizophrenia treated with conventional versus atypical antipsychotics.

BACKGROUND: Low estrogen levels leading to an elevated rate of menstrual dysfunctions such as amenorrhea and irregular menstruation have been described in women with schizophrenia and have often been attributed to antipsychotic-induced hyperprolactinemia. However, there is some evidence that "hypoestrogenism" in schizophrenic women does not occur exclusively under medication with hyperprolactinemia-inducing antipsychotics. While the precise mechanism of low estrogen levels in schizophrenic women has not been elucidated yet, "hypoestrogenism" is of clinical relevance because estrogen seems to endow an antipsychotic-like effect in schizophrenia and thus positively affect the course of illness in schizophrenic women. In addition, low levels of estrogen might have a negative effect on bone mineral density and on the cardiovascular system. METHODS: To test the "hypoestrogenism hypothesis", hormone levels in 75 women with schizophrenia diagnosed according to DSM-IV and ICD-10 were determined in the follicular, periovulatory, and luteal phases of the menstrual cycle. Levels of estradiol, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and testosterone were assessed. RESULTS: The serum levels of estradiol were generally reduced during the entire menstrual cycle compared to normal reference values. With low levels of LH over the entire cycle and of progesterone in the luteal phase, anovulatory cycles were assumed. Hypoestrogenism was found in about 60% of the patients in accordance with a strict definition (estradiol serum level below 30 pg/ml in the follicular phase and below 100 pg/ml in the periovulatory phase). To rule out a possible effect of hyperprolactinemia on the gonadal axis and a subsequent effect on estradiol levels from treatment with conventional ("typical") antipsychotics, serum estradiol levels of patients treated with certain atypical antipsychotics known to induce only a mild increase in prolactin, or no increase at all, were compared with those from patients treated with conventional antipsychotics. The data clearly indicate high prolactin levels in the latter, but low levels in the group treated with atypical antipsychotics. In both groups, however, low levels of estradiol compared to normal reference values were measured. CONCLUSIONS: The present findings provide evidence that hypoestrogenism in schizophrenia occurs in women with and without antipsychotic-induced hyperprolactinemia. Further research should be conducted to clarify the cause of hypoestrogenism in schizophrenic women and focus on possible clinical implications.