[Patient and quality characteristics in the treatment with disulfiram (Antabus) in the German "Network for Alcohol Aversive Pharmacotherapy"]. / Patienten- und Qualitätsmerkmale bei der Behandlung mit Disulfiram ("Antabus") im deutschsprachigen "Netzwerk alkoholaversive Pharmakotherapie".

BACKGROUND: More than a decade ago disulfiram lost its approval for use in Germany. Nonetheless, a considerable number of psychiatric hospital outpatient departments as well as practicing physicians continue to prescribe it. These professionals have formed the "Network for Alcohol Aversive Pharmacotherapy" (NAP) to maintain a high quality of this treatment approach. OBJECTIVE: To describe the current use of disulfiram with respect to patient numbers and characteristics, side effects, and use of concomitant multimodal treatment forms. MATERIAL AND METHODS: Since 2019 the NAP has conducted an annual retrospective survey among its members regarding the aforementioned parameters. RESULTS: From 2019 to 2023 a total of 1579 treatment cases were described by 33 centers, 152 patients reported a total of 241 drinking events, 26 of them resulting in hospitalization but none causing complications or permanent harm. The most frequent side effects, in descending order, were unpleasant body odor (2.5%), fatigue, male sexual dysfunction, mildly elevated liver enzymes, allergic skin reactions and polyneuropathy (0.8%). More than one quarter of the patients suffered from comorbid depression, and approximately 5% from ADHD, borderline or other personality disorders, trauma-related disorders and anxiety disorders, respectively. Of the patients 33% were treated with antidepressants and 12% with sedating antipsychotics. Various forms of concomitant group therapy were offered to 66% of the patients. CONCLUSION: Treatment with disulfiram is legally possible, generally well-tolerated and safe. It is offered in most treatment centers as part of a comprehensive treatment plan that includes multimodal treatment of comorbid psychiatric disorders.

Levomethadone Therapeutic Drug Monitoring to Aid Opioid Withdrawal Therapy: A Short Communication.

BACKGROUND: Therapeutic drug monitoring (TDM) is recommended for opioid maintenance therapy with levomethadone. However, TDM has not yet been applied to monitor opioid withdrawal therapy clinically, although tools to improve it are required. METHODS: In this observational cohort study, repeated TDM with levomethadone was performed according to a prospective opioid withdrawal study protocol. Objective and subjective opioid withdrawal symptoms were measured using validated rating scales and correlated to levomethadone plasma concentrations. Plasma levels were measured using high-pressure liquid chromatography with column switching and spectroscopic detection of methadone and its major metabolite. RESULTS: This study included 31 opioid-dependent patients who participated in standardized opioid withdrawal therapy. The serum levels of levomethadone were found to be highly variable and below the recommended therapeutic reference range of 250 ng/mL for maintenance therapy. These serum levels were positively correlated with dosage (r = 0.632; P < 0.001) and inversely correlated with subjective (r = -0.29; P = 0.011) and objective (r = -0.28; P = 0.014) withdrawal symptoms. CONCLUSIONS: The evidence provided sheds light on how to improve levomethadone withdrawal therapy in patients with opioid dependence. It seems likely that higher initial doses at the beginning and lower dose reductions would have been advantageous. TDM can enhance the safety of opioid withdrawal therapies, minimize withdrawal symptoms, and reduce dropout rates.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotic Drugs.

BACKGROUND: The use of therapeutic drug monitoring (TDM) to guide treatment with long-acting injectable (LAI) antipsychotics, which are increasingly prescribed, remains a matter of debate. The aim of this review was to provide a practical framework for the integration of TDM when switching from an oral formulation to the LAI counterpart, and in maintenance treatment. METHODS: The authors critically reviewed 3 types of data: (1) positron emission tomography data evaluating dopamine (D2/D3) receptor occupancy related to antipsychotic concentrations in serum or plasma; D2/D3 receptors are embraced as target sites in the brain for antipsychotic efficacy and tolerability, (2) pharmacokinetic studies evaluating the switch from oral to LAI antipsychotics, and (3) pharmacokinetic data for LAI formulations. Based on these data, indications for TDM and therapeutic reference ranges were considered for LAI antipsychotics. RESULTS: Antipsychotic concentrations in blood exhibited interindividual variability not only under oral but also under LAI formulations because these concentrations are affected by demographic characteristics such as age and sex, genetic peculiarities, and clinical variables, including comedications and comorbidities. Reported data combined with positron emission tomography evidence indicated a trend toward lower concentrations under LAI administration than under oral medications. However, the available evidence is insufficient to recommend LAI-specific therapeutic reference ranges. CONCLUSIONS: Although TDM evidence for newer LAI formulations is limited, this review suggests the use of TDM when switching an antipsychotic from oral to its LAI formulation. The application of TDM practice is more accurate for dose selection than the use of dose equivalents as it accounts more precisely for individual characteristics.

Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy.

Buprenorphine is a partial µ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.

[Medicinal cannabis and cannabis-based medication: an appeal to physicians, journalists, health insurances, and politicians for their responsible handling]. / Medizinalcannabis und cannabisbasierte Arzneimittel: ein Appell an Ärzte, Journalisten, Krankenkassen und Politiker für einen verantwortungsvollen Umgang.

Since the adoption of the law of March 6, 2017, any German physician can prescribe medical cannabis flowers and cannabis-based magistral and finished medicinal products. No specific indications for prescriptions are provided in the law. The statutory health insurance companies bear the costs once an application for cost coverage has been approved by the Medical Service of the Health Funds. The German associations of psychiatry (child, adolescents, and adults), neurology, palliative care, addictology, and pain medicine are watching these developments in the media, politics, and medical world with concern due to: the option to prescribe cannabis flowers despite the lack of sound evidence and against the recommendations of the German Medical Association; the lack of distinction between medical cannabis flowers and cannabis-based magistral and finished medical products; the indiscriminately positive reports on the efficacy of cannabis-based medicines for chronic pain and mental disorders; the attempts by the cannabis industry to influence physicians; the increase in potential indications by leaders of medical opinion paid by manufacturers of cannabis-based medicines. The medical associations make the following appeal to journalists: To report on the medical benefits and risks of cannabis-based medicines in a balanced manner. To physicians: to prescribe cannabis-based medicines with caution; to prefer magistral and finished medicinal products over cannabis flowers. To politicians: to consider data according to the standards of evidence-based medicine when making decisions and provide financial support for medical research into cannabis-based medicines.

[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.

[Opioid maintenance treatment and Cannabis use]. / Opioidsubstitutionsbehandlung und Cannabiskonsum.

OBJECTIVES: More than 30 % of patients participating in an opioid maintenance program consume cannabis. This article describes the effects of additional cannabis use during an opioid maintenance treatment program. METHODS: Narrative literature research using online publication databases (MedLine, PubMed) RESULTS: The additional use of cannabis during an opioid maintenance treatment program may have negative side effects. CONCLUSION: Cannabis use should be discussed with the patient. It is in principle not a reason for discontinuing an opioid maintenance treatment program.

Evidence-Based Guidelines for the Pharmacologic Management of Methamphetamine Dependence, Relapse Prevention, Chronic Methamphetamine-Related, and Comorbid Psychiatric Disorders in Post-Acute Settings.

The increasing abuse of the street drug crystal meth (methamphetamine) in many countries worldwide has resulted in a growing demand to treat patients who have acquired a methamphetamine-related disorder. The results of a systematic literature search which led to the consensus-based recommendations by the Working Group of the German Agency for Quality in Medicine (Ärztliches Zentrum für Qualität in der Medizin - ÄZQ) are presented. Pharmacological treatments were reviewed in 58 out of the 103 publications included. They were mainly randomized controlled trials (RCT). Despite increased research activities, none of the medications studied demonstrated a convincing and consistent effect on abstinence rates, despite some having an impact on craving and retention rates or symptom control. In addition, as yet there is no sufficient evidence available for dopamine analogue treatment ("substitution") after the initial withdrawal-period. Methamphetamine-related, post-acute persistent or comorbid syndromes such as methamphetamine-associated psychosis (MAP), depressive syndromes, anxiety, and sleep disorders are usually treated in a symptom-oriented manner. Risks of interactions with methamphetamine have to be taken in account when prescribing medications with doubtful efficacy. Further research is warranted.

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.

Psychosocial stress and cannabinoid drugs affect acetylation of α-tubulin (K40) and gene expression in the prefrontal cortex of adult mice.

The dynamics of neuronal microtubules are essential for brain plasticity. Vesicular transport and synaptic transmission, additionally, requires acetylation of α-tubulin, and aberrant tubulin acetylation and neurobiological deficits are associated. Prolonged exposure to a stressor or consumption of drugs of abuse, like marihuana, lead to neurological changes and psychotic disorders. Here, we studied the effect of psychosocial stress and the administration of cannabinoid receptor type 1 drugs on α-tubulin acetylation in different brain regions of mice. We found significantly decreased tubulin acetylation in the prefrontal cortex in stressed mice. The impact of cannabinoid drugs on stress-induced microtubule disturbance was investigated by administration of the cannabinoid receptor agonist WIN55,212-2 and/or antagonist rimonabant. In both, control and stressed mice, the administration of WIN55,212-2 slightly increased the tubulin acetylation in the prefrontal cortex whereas administration of rimonabant acted antagonistically indicating a cannabinoid receptor type 1 mediated effect. The analysis of gene expression in the prefrontal cortex showed a consistent expression of ApoE attributable to either psychosocial stress or administration of the cannabinoid agonist. Additionally, ApoE expression inversely correlated with acetylated tubulin levels when comparing controls and stressed mice treated with WIN55,212-2 whereas rimonabant treatment showed the opposite.

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis.

RATIONALE: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. OBJECTIVES: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. METHODS: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. RESULTS: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. CONCLUSIONS: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.

Introduction: A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Methods: Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Results: Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Conclusion: Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].

Therapeutic drug monitoring for drugs used in the treatment of substance-related disorders: literature review using a therapeutic drug monitoring appropriateness rating scale.

BACKGROUND: The efficacy of drugs for the treatment of substance-related disorders is moderate at best. Therapeutic drug monitoring (TDM) could be an instrument to improve outcomes. Because TDM for most of those drugs is not established, the authors reviewed the literature and built a rating scale to detect the potential added value of TDM for these pharmacologic agents. METHODS: A literature search was performed for acamprosate, bupropion, buprenorphine, clomethiazole, disulfiram, methadone, naltrexone, and varenicline. The rating scale included 22 items and was divided in five categories: efficacy, toxicity, pharmacokinetics, patient characteristics, and cost-effectiveness. Three reference substances with established TDM were similarly assessed for comparison: clozapine, lithium, and nortriptyline. The three reference substances achieved scores of 15, 12, and 14 points, respectively. RESULTS: Drugs for treatment of substance-related disorders achieved 3 to 17 points, 17 for methadone, 11 for buprenorphine, 10 for disulfiram, also 10 for naltrexone for the indication opioid-dependence and 9 for the indication alcohol dependence as well as bupropion, 7 points for acamprosate, 6 points for clomethiazole, and 3 for varenicline. CONCLUSIONS: It is concluded that systematic evaluation of drug- and patient-related variables with the new rating scale can estimate the appropriateness of TDM. Because their rating revealed similar scores as the three reference drugs, it is proposed that TDM should be established for bupropion, buprenorphine, disulfiram or a metabolite, methadone, and naltrexone. An objective rating of drug- and patient-related characteristics could help laboratories focus their method development on the most likely drugs to require TDM along with a thorough drug use evaluation.

S100B and homocysteine in the acute alcohol withdrawal syndrome.

Elevations of serum homocysteine levels are a consistent finding in alcohol addiction. Serum S100B levels are altered in different neuropsychiatric disorders but not well investigated in alcohol withdrawal syndromes. Because of the close connection of S100B to ACTH and glutamate secretion that both are involved in neurodegeneration and symptoms of alcoholism the relationship of S100B and homocysteine to acute withdrawal variables has been examined. A total of 22 male and 9 female inpatients (mean age 46.9 ± 9.7 years) with an ICD-10 diagnosis of alcohol addiction without relevant affective comorbidity were examined on admission and after 24, 48, and 120 h during withdrawal. S100B and homocysteine levels in serum were collected, and severity of withdrawal symptoms (AWS-scale), applied withdrawal medication, initial serum ethanol levels and duration of addiction were recorded. Serum S100B and homocysteine levels declined significantly (P < .05) over time. Both levels declined with withdrawal syndrome severity. Females showed a trend to a more intense decline in serum S100B levels compared to males at day 5 (P = .06). Homocysteine levels displayed a negative relationship to applied amount of clomethiazole (P < .05) and correlated with age of onset of addiction. No withdrawal seizures were recorded during the trial. As it is known for homocysteine, S100B revealed to decline rapidly over withdrawal treatment in alcoholism. This effect is more pronounced in female patients. S100B could be of relevance in the neurobiology of alcohol withdrawal syndromes. It may be indirectly related to the level of stress level or glutamatergic activity during alcohol withdrawal.

[Pregnant opioid addicted patients and additional drug intake. Part I. Toxic effects and therapeutic consequences]. / Therapie von schwangeren Patientinnen mit Abhängigkeit von Opioiden und begleitenden Suchtstoffen. Teil I: Toxische Folgen und therapeutische Konsequenzen.

Opioid dependent patients often are dependent from the illegal consumption of heroin and, in addition, perform a polytoxicomanic way of consuming drugs. They suffer of various somatic and psychiatric diseases. Moreover, pregnancies of drug addicted women are classified as high-risk pregnancies. With respect to the particular consumed drug substances other than opioids during pregnancy variable forms of teratogenic and toxic effects can be assigned to the baby. Critical values of maternal substance abuse referring to fetal impairment do not exist. With regard to the possible teratogenic and toxic fetal effects of maternal consume of alcohol, tobacco, sedativa, cannabis, cocaine and amphetamines, withdrawal treatment of polytoxicomanic pregnant patients under inpatient medical supervision including medication if necessary represent the first-line-treatment. With respect to smoking, it is possible to detoxicate the patients also by an outpatient treatment. However, referring to heroin addiction, a maintenance therapy with L-methadone, D/L-methadone or buprenorphine should be preferred since fetal withdrawal symptoms of opioids otherwise can cause severe complications which even can lead to the loss of the fetus and also increase the risks for the mother. Increasing the dose of the opioid substitute may be necessary, for example, to avoid premature uterus contractions. It is to be pointed out that substitution treatment with methadone or buprenorphine also improve the medicinal compliance and psychosocial circumstances of the pregnant patients. Subsequent to delivery, the maintenance treatment should initially be pursued over a further period of time. In the follow up, the question of continuing with maintenance treatment or starting a withdrawal treatment of opioids should be discussed on an individual basis. To sum up, proceeded interdisciplinary care during pregnancy and afterwards by all the professions involved like general practioners as well as social workers, gynaecologists, paediatrists, pharmacists, psychologists and psychiatrists should be ensured. Futhermore, diagnosis and therapy of the comorbid psychiatric and infectious diseases like hepatitis A, B, C and HIV are necessary and described (see Part II. Comorbidity and their treatment).

[Pregnant opioid addicted patients and additional drug intake. Part II: Comorbidity and their therapy]. / Therapie von schwangeren Patientinnen mit Abhängigkeit von Opioiden und begleitenden Suchtstoffen. Teil II: Therapie der Komorbiditäten.

The majority of opioid dependent patients suffer from various psychiatric and somatic comorbid diseases like mood and anxiety disorders, psychotic diseases, personality disorders, HIV infection, Hepatitis B and C. If medical treatment is needed, grouping active substances to FDA Pregnancy Categories (A, B, C, D or X) may be helpful. The majority of substances reported here only fulfill the FDA-categories C or D, which means that they could have teratogenic effects, but with probably different rank order. First of all, referring to mood, personality and anxiety disorders, the focus should be laid on non-pharmacological treatment by offering psychotherapeutic and supporting psychosocial interventions to the patients. However, opioid dependent pregnant patients who suffer from severe diseases such as psychosis, bipolar affective disorder or severe depression, may need psychoactive medication like antipsychotics, antidepressants or mood stabilizers to prevent them from harm caused by psychotic ideas and actions and/or suicidality. However these medications may comprise fetal risks, especially when taken together, and therefore should only be used when benefit and risks are considered together with patients and their relatives. It is important to avoid acute or renewed psychiatric decompensation. We present the current differentiated knowledge for therapy of opioid dependent patients with antipsychotics, antidepressants (e.g. higher fetal risk in case of treatment with fluoxetine and paroxetine) or mood stabilizers. All of them should only be used after considering benefit and risks. During pregnancy, there should not be switched between different antidepressant drugs. Referring mood stabilizers, the intake of valproic acid should be avoided in pregnancy or at least, dosage should be kept as low as possible since severe teratogenetic effects are known. In addition the specific drug treatment of HIV and hepatitis B during pregnancy is described. During childbirth HIV-infected patients should receive zidovudine intravenously to prevent vertical transmission. Co-infection with hepatitis C cannot be treated during pregnancy, since interferons are associated with a severe risk of fetal malformations and ribavirin has teratogenic effects; for this reason interferon therapy should be started after delivery.

The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients.

BACKGROUND: Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia. METHODS: For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected. RESULTS: The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail. CONCLUSIONS: The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.

Chronic Psychosocial Stress Causes Increased Anxiety-Like Behavior and Alters Endocannabinoid Levels in the Brain of C57Bl/6J Mice.

Introduction: Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice (n=12), mice exposed to social defeat stress (n=11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion: The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.

Differential relationships of PTSD and childhood trauma with the course of substance use disorders.

A large body of research documents the link between Posttraumatic Stress Disorder (PTSD) and the course of Substance Use Disorders (SUD). Similar relationships have been reported between Childhood Trauma (CT) and the course of illness in patients with SUD even in the absence of PTSD, but few studies have examined differential effects of PTSD and CT (independent of PTSD) in this population. We used the International Diagnostic Checklist (IDCL) and the Posttraumatic Diagnostic Scale (PDS) to diagnose PTSD in a sample of patients with SUD (N = 459). The Childhood Trauma Questionnaire (CTQ) and the European Addiction Severity Index (EuropASI) were administered to assess childhood trauma and addiction related problems including comorbid psychopathological symptoms. The sample was divided into three groups: patients with experiences of CT and PTSD (CT-PTSD), experiences of CT without PTSD (CT-only), and neither experiences of CT nor PTSD (No trauma) to examine their differential associations with the course and severity of SUD. Patients of both the CT-PTSD (n = 95) and the CT-only group (n = 134) reported significantly higher levels of anxiety and depression as well as more suicidal thoughts and suicide attempts during their lifetime than the No trauma group (n = 209). Regarding most variables a graded association became apparent, with the highest level of symptoms in the CT-PTSD group, an intermediate level in the CT-only group and the lowest level in the No trauma group. The CT-PTSD group also differed in almost all substance use variables significantly from the No trauma group, including a younger age at first use of alcohol and cannabis, more cannabis use in the last month, and more lifetime drug overdoses. Our results confirm the relationships of both CT and PTSD with psychiatric symptoms in patients with SUD. Thus, it seems important to include both domains into the routine assessment of SUD patients. Specific treatments for comorbid PTSD but also for other consequences of childhood trauma should be integrated into SUD treatment programs.