Use of nonprohibited hallucinogenic plants: increasing relevance for public health? A case report and literature review on the consumption of Salvia divinorum (Diviner's Sage).

INTRODUCTION: : We want to call attention to a mint plant, called diviner's sage ( Salvia divinorum), originally used in shamanic ceremonies of the Mazatec Indians of Mexico. On numerous websites of the internet, this ancient herbal drug and its extracts are offered as a legal means of widening individual awareness. Regarding its dose-response relationship, the active ingredient, salvinorin A, is one of the most potent naturally occurring hallucinogens. Laws on controlled substances, except for Finland, Denmark and Australia, do not prohibit cultivating, consuming or dealing with Salvia divinorum. Ingestion by smoking, vaporising or chewing, induces a short-lived inebriant state with intense, bizarre feelings of depersonalization. This article wants to be a signal for physicians or psychotherapists to take Salvia into consideration, when exploring young people for drug use. METHODS: We report the individual perceptions of a young man consuming Salvia divinorum. We review the scarce scientific literature and consider relevant internet websites. DISCUSSION: We define open issues for further investigations and try to discuss why Salvia divinorum may be of interest for teenagers and young adults in Europe.

The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM in psychiatry.

Therapeutic monitoring of psychotropic drugs: an outline of the AGNP-TDM expert group consensus guideline.

TDM of psychotropic drugs is widely used, but there is little consensus regarding its optimal use in the clinical context. This prompted a multidisciplinary group comprised of clinical biochemists, clinical pharmacologists, and psychiatrists of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie) to provide a consensus guideline. This will allow clinical psychiatrists, practitioners, and laboratory directors involved in psychopharmacotherapy to optimize TDM of antidepressants, antipsychotics, and opioid substituents. Recommendations are also given on the combined use of TDM and pharmacogenetic tests.

Therapeutic drug monitoring of tricyclic antidepressants: how does it work under clinical conditions?

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and the UKU side-effect scale. 84 patients with depressive disorder according to DSM-IV were recruited in three centers (TDM, n = 43; no-TDM, n = 41; mean age 49.9 +/- 13.2 years, 63.1 % female). Patients were treated with either amitriptyline (n = 69) or doxepin (n = 15); the mean dosage at endpoint was 126 +/- 35 mg and 155 +/- 47 mg, respectively. The mean study duration was 21 +/- 8 days. Both groups improved according to HAMD (from 25.2 +/- 8.4 at baseline to 12.0 +/- 7.4 at endpoint) and CGI scores (68 % responders). Moderately severe or severe side effects occurred in 16 % of patients. Adequate dose adjustment was significantly higher in the TDM group (60 % vs. 46 %, p < 0.05); this led to a significantly higher rate of therapeutic serum levels in the TDM group (58 % vs. 44 %, p < 0.05). Direct effects of TDM were not found for effectiveness. Therapeutic TCA serum levels over weeks one to three, however, were associated with significantly better outcome at endpoint (p < 0.05) as measured with changes in the HAMD or CGI response rates from baseline to endpoint. Finally, considerable side effects occurred significantly more often when serum levels were above the therapeutic range (27 % vs. 11 %; p < 0.01). We conclude that treating depression with TCA can be optimized by early TDM, which is superior to clinical judgment on its own. Since the psychiatrists in charge were less than completely "compliant" to the recommendations provided together with serum levels, the effect could be more pronounced than this study shows. The results encourage further studies in order to optimize antidepressant pharmacotherapy when using TDM appropriately.

Severity of alcohol withdrawal symptoms and the T1128C polymorphism of the neuropeptide Y gene.

Neuropeptide Y (NPY) modulates ethanol drinking in rodents. The C-allele of the T1128C polymorphism of the human NPY gene has been previously associated with elevated alcohol consumption in a Finn population study. The present study tested the hypothesis that the T1128C polymorphism is associated with the diagnosis of alcoholism or with severe forms of alcohol withdrawal and with the daily consumption of alcohol in alcoholic patients. After PCR-RFLP genotyping, two groups of alcoholics with severe withdrawal symptoms (delirium tremens, n = 83; withdrawal seizures, n = 65) were compared to alcoholics with mild withdrawal symptoms (n = 97). An elevated frequency of the C-allele in the individuals with severe withdrawal symptoms was found, however not reaching statistical significance. Further a group of healthy controls (n = 102) was compared to all included alcoholics (n = 216) revealing no significant result. Alcoholics carrying the C-allele reported a non significantly elevated daily consumption of alcohol compared to alcoholics with the TT genotype. All alcohol dependent subjects with severe withdrawal symptoms revealed a significantly elevated daily consumption of alcohol compared to alcoholics with only mild withdrawal symptoms. More studies on different ethnic groups are needed to further elucidate the influence of the NPY gene on alcoholism.

Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine?

Drug monitoring in psychiatry usually serves psychoactive drug plasma concentration measurement. Anticholinergic properties offer a faster approach to monitoring pharmacodynamic intraindividual effects of the drug by measuring their effects on heart rate variability (HRV), which is sympathetically and parasympathetically controlled via cholinergic synapses. The plasma concentrations of the atypical antipsychotics clozapine and olanzapine correlated with parameters of HRV in 59 patients suffering from schizophrenia or schizoaffective disorder. HRV during 4 minutes at rest was extracted from the ECG trace of a routine digital EEG registration in addition to blood sampling for plasma concentration measurement (HPLC method). We calculated sympathetically and parasympathetically controlled heart frequency bands (low, medium and high frequency) and other HRV parameters, coefficient of variation (CV), and root mean square of successive differences (RMSSD). All HRV parameters were significantly more impaired in clozapine patients (n = 33, mean clozapine plasma concentration 331 +/- 294 ng/ml) than in olanzapine patients (n = 26, mean olanzapine plasma concentration 42 +/- 32 ng/ml) and demonstrated 1.7 - 4.8 times the cardiac anticholinergic properties of clozapine in vivo. 14 out of 14 patients with a CV beyond 3.2 % had clozapine plasma concentrations below the proposed optimal therapeutic concentration of 350 ng/ml. All HRV parameters were inversely and significantly correlated with the clozapine plasma concentrations (such as lgCV: r = - 0.73, p < 0.001) and, to a lesser extent, with the olanzapine plasma concentrations (lgCV r = - 0.44, p < 0.05). These results underline the potential clinical value of HRV parameter extraction from routine ECGs in predicting plasma concentrations and objective individual neurocardiac effects of drugs with anticholinergic properties.

Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone.

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.

A case control study on psychopharmacotherapy before suicide committed by 61 psychiatric inpatients.

OBJECTIVE AND METHOD: The pharmacotherapy of 61 suicide victims (0.24 % of 27,078 admissions from January 1, 1980 to December 31, 1999) was compared to that of a control group matched for age, gender and diagnosis at the time of discharge. RESULTS: Both groups were also comparable regarding stay in hospital, history of psychiatric disease, and frequency of hospitalisations during the year preceding the index evaluation. Multiple but not single suicide attempts were significantly more frequent in patients who were later to complete the suicide than in controls. Schizophrenia (ICD-9, ICD-10) was the most frequent diagnosis among suicide victims (44.3 %). Affective psychosis (ICD-9, ICD-10) bore the highest relative risk (0.8 %). 50 % of the schizophrenic patients in the suicide group had been continuously treated with full-dose tricyclic antidepressants. The CPZ-equivalents in the patients treated with antipsychotics were not of discriminating value. Four of 27 schizophrenic patients in the suicide group had been off neuroleptics for ten days or more; this was never observed among the controls. Lorazepam applied in 40% of the schizophrenic and in 25 % of the affective psychosis suicide victims had more often been withdrawn or reduced during the ten days preceding suicide than among controls. No schizophrenic suicide victims but five controls had been on mood stabilisers. The use of antipsychotics (classical and atypical) and a recent change in tricyclic drug or drug dose were more frequent in suicide victims with affective psychosis. Lithium had been given to one patient, but it had also been administered to six controls; this difference is significant. CONCLUSION: Mood stabilisers, especially lithium, should be considered more often in patients with previous suicide attempt(s). When changing antidepressants in affective psychosis, benzodiazepines might be given more deliberate consideration. Patients in all diagnostic categories should be closely guided by means of intensified psychotherapeutic interventions while undergoing a benzodiazepine reduction. The treatment of patients suffering from schizophrenia with full-dose tricyclic regimens should be considered as possibly enhancing the acute suicide risk in some individuals.

Therapeutic drug monitoring of clozapine in relapse prevention: a five-year prospective study.

Twenty-three outpatients with schizophrenia (ICD-10 F20.xx) treated with clozapine (CZ) as monotherapy entered a prospective study on relapse prevention. Every 4 weeks, psychopathology was assessed by the Brief Psychiatric Rating Scale (BPRS), and plasma CZ and norclozapine levels were measured. Patients were enrolled after complete remission of positive symptoms for at least 4 months according to the psychosis cluster of the BPRS and at a mean of 3.3 years after their last hospitalization. At the time of enrollment, the median BPRS total score was 29 points (range, 19-48). Within 4 months, the baseline CZ plasma level was established as the mean of CZ levels from at least four subsequent measurements. These baseline plasma levels were considered as the optimal relapse-preventing plasma CZ levels in the individual patients. When the patients were enrolled, they were considered to be prone to relapse. Relapse was defined as clinical deterioration, hospitalization, or both. Plasma levels were considered a prognostic factor, and patients were defined as at increased risk if plasma levels decreased by more than 40% from baseline CZ plasma level. The effect of plasma CZ levels on clinical outcome was evaluated by a Cox regression with plasma level as a time-dependent covariate. Within 46 months of enrollment, 32 episodes of relapse events in 10 patients were available for evaluation. Seventeen patients had a plasma level decrease of more than 40% at some point. In 12 of these, the decrease was present for more than 12% of the observation period. Eight patients of this group relapsed, and three of these had to be rehospitalized. Two patients relapsed, although their plasma levels decreased by more than 40% for less than 12% of the observation period. Within the first 2 years, relapse-free survival curves illustrate that both groups (episodes under elevated risk and episodes not under elevated risk) had identical relapse patterns, but from then on the relapse risk increased rapidly in the group with longer exposure to elevated risk. In a Cox model with a 40% decrease of plasma CZ levels as a dichotomous time-varying explanatory covariate, the risk ratio is 6 (95% confidence interval = 2-19, p = 0.003). The 10 patients who relapsed exhibited safe plasma levels (less than a 40% decrease from their baseline levels) for only 210 months, and 13 nonrelapsing patients had plasma levels defined as safe for 426 months.

Isolation and identification of clozapine metabolites in patient urine.

Biotransformation products of the atypical neuroleptic clozapine were isolated from urine samples of three schizophrenic patients by solid-phase extraction, liquid-liquid extraction for the separation of unpolar and polar metabolites, and thin-layer chromatography followed by final purification by high-performance liquid chromatography. Their structures were elucidated by mass spectrometry and (1)H NMR spectroscopy and in some cases by enzymatic deconjugation. Besides the known metabolites desmethylclozapine, clozapine N-oxide, 8-deschloro-8-hydroxyclozapine, and 8-deschloro-8-hydroxydesmethylclozapine, the unpolar fraction contained 7-hydroxyclozapine and a compound in which the piperazine ring of clozapine was partially degraded to an ethylenediamine derivative. Novel metabolites identified in the polar fraction were the sulfate and glucuronide conjugates of 7-hydroxyclozapine N-oxide, 8-deschloro-8-hydroxyclozapine-O-glucuronide, and the O-glucuronide of N-hydroxydesmethylclozapine; further conjugates were tentatively identified as 9-hydroxydesmethylclozapine-O-sulfate and 6-hydroxyclozapine-O-sulfate. In addition, the previously described conjugates 7-hydroxydesmethylclozapine-O-sulfate, 7-hydroxyclozapine-O-glucuronide and -O-sulfate, 8-deschloro-8-hydroxydesmethylclozapine-O-glucuronide, and the quaternary ammonium glucuronide of clozapine were detected.

Relevance of liver enzyme elevations with four different neuroleptics: a retrospective review of 7,263 treatment courses.

Data on liver enzyme elevations were collected in a retrospective study of 7,263 treatment courses with haloperidol, clozapine, perphenazine, and perazine. Charts of 233 patients hospitalized between 1980 and 1992 at Tübingen University Psychiatric Clinic were selected because clinically relevant increases of liver enzymes had been detected during monotherapy with one of the four examined neuroleptics. At least one hepatic enzyme (mostly alanine aminotransferase [ALAT]) exceeded the established reference range of 3-fold elevations of ALAT, aspartate aminotransferase, gamma-glutamyl transpeptidase, and glutamate dehydrogenase and 2-fold elevations of alkaline phosphatase (AP) during monotherapy with clozapine in 15%, perazine in 7.6%, perphenazine in 4%, and haloperidol in 2.4% of the cases. If all liver enzyme abnormalities with any elevation greater than the conventional upper limits are considered, incidences were as follows: clozapine, 78%; perphenazine, 62%; perazine, 59%; and haloperidol, 50%. Testing for overall differences within the four neuroleptics resulted in significantly different incidences of liver enzyme elevations (chi2 test,p < 0.0001). Threefold increases of AP (>540 U/L) were seen in three patients receiving haloperidol (0.3%) only. Twofold increases of AP (>360 U/L) were distributed as follows: clozapine, 1%; haloperidol, 0.8%; perazine, 0.3%; and perphenazine, 0.1%. Only in the group with 1-fold elevations of AP (>180 U/L) were the differences within the drug regimens significant (clozapine, 40.3%; haloperidol, 33.2%; perphenazine, 23.4%; and perazine, 23.1%; chi2 test, p < 0.0001). In the period under study, no instance of icterus occurred.