Glutamate receptors in the mammalian central nervous system

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

/pdf/consensus-guidelines-for-therapeutic-drug-monitoring-in-18b8y5mu39.pdf

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

/pdf/agnp-consensus-guidelines-for-therapeutic-drug-monitoring-in-18q2ciintb.pdf

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens. Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1, CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking, CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone. In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with beta-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine. The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.

Drug interactions with tobacco smoking. An update.

Association of depression with medical illness: does cortisol play a role?

Background
Gabapentinoid (pregabalin and gabapentin) abuse is increasingly being reported.

Abuse and Misuse of Pregabalin and Gabapentin.

Plasma concentrations of haloperidol and its reduced metabolite (reduced haloperidol) were investigated in cigarette smokers (N=23) and nonsmokers (N=27). Steady-state plasma concentrations were obtained 12 h post bedtime dose. Haloperidol and reduced haloperidol concentrations were determined by RIA. Reduced haloperidol was separated by selective succinylation and liquid chromatography. Patients were clinically assessed with the Clinical Global Impression Scale (CGIS). Smokers had significantly lower haloperidol and reduced haloperidol plasma concentrations than nonsmokers (P<0.01, P<0.05). Clearance of haloperidol was significantly greater in smokers compared to nonsmokers (P=0.0052). CGIS assessments did not show significant differences between smokers and non-smokers. Plasma concentrations should be carefully monitored when patients either start or stop smoking.

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Effects of smoking on fluphenazine clearance in psychiatric inpatients

Plasma haloperidol levels were monitored in three schizophrenic patients when carbamazepine was either added or discontinued. The percent decrease in plasma haloperidol levels due to concomitant carbamazepine therapy was between 59% and 61%. The effects of carbamazepine on plasma haloperidol levels

Effects of carbamazepine on plasma haloperidol levels

The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixal decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed. The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit ‘flip-flop’ kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate. Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life rangingfrom 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit ‘lumps’ due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from < 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug. Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day. The apparent elimination half-life after multiple injections is approximately 3 weeks and the time to reach steady-state is approximately 3 months. The reduced metabolite of haloperidol is present in significant quantities in humans following oral therapy; however, this has not been reported in pharmacokinetic studies with the depot preparation. The therapeutic range for haloperidol has been reported to be 3 to 40 ng/ml in several studies, but these studies did not measure the reduced metabolite. It has been suggested that the presence of high concentrations of the reduced metabolite may affect the response to haloperidol. Clopenthixol is only active as the cis (Z) isomer, which is the form of the drug present in the decanoate preparation. Peak plasma concentrations are usually reached between 4 and 7 days after injection. Following multiple injections, the apparent elimination half-life is 19 days. No correlation between plasma concentrations and clinical response has been reported, but concentrations have been observed to range from 10 to 100 ng/ml following a wide range of dosages and injection intervals. Flupenthixol is available as either the palmitate or decanoate ester, although most pharmacokinetic studies have used the decanoate formulation. Like clopenthixol, flupenthixol is only active as the cis (Z) isomer which is the form present in the decanoate preparation. Peak plasma concentrations occur on approximately the seventh day following injection, and no pharmacokinetic differences have been observed between the 2% and 10% concentrations of the drug. Following a single injection, an apparent elimination half-life of 8 days was reported, whereas after multiple injections, the apparent half-life was 17 days. Following withdrawal, no statistically significant differences were noted between relapsing and non-relapsing patients, but there was a trend towards lower trough concentrations in the relapsing group. There was also a shorter apparent half-life in the relapsing group when compared with the non-relapsing patients. No correlations between plasma concentrations and clinical response were found. Most methods for converting oral preparations to depot injections have been empirically developed. One study that did examine plasma concentrations and clinical effects during conversion of oral fluphenazine to the decanoate found that 1.2 to 2.5 times the oral dose (mg/day) given weekly resulted in a smooth transition between dosage forms. Fluphenazine plasma concentrations on the decanoate were lower during the first 3 weeks in comparison with oral fluphenazine therapy. It is recommended that the initially effective dose be reduced or the injection interval increased after 4 to 6 weeks to prevent possible accumulation of drugs as plasma concentrations approach steady-state. The recommended dose of haloperidol decanoate is 20 times that of the daily oral dose (mg/day) given monthly, but this should be reduced to a factor of 15 in geriatric patients. Flupenthixol 10mg given orally daily is proposed to be equivalent to 25mg of the decanoate given weekly. The use of the mean conversion ratios as a starting point for an individual patient’s conversion is appropriate, but wide interindividual variations in pharmacokinetics require plasma level monitoring and careful clinical observation of the patient. Adverse effects from depot antipsychotics are relatively rare, except for extrapyramidal system reactions. The most serious (albeit very rare) problem that can occur with a long acting antipsychotic is the neuroleptic malignant syndrome. Due to their long apparent half-lives after injection, effective treatment of this syndrome following administration of depot antipsychotics can be difficult.

Stephen R. Saklad

Papers

Abuse and Misuse of Pregabalin and Gabapentin.

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Effects of smoking on fluphenazine clearance in psychiatric inpatients

Effects of carbamazepine on plasma haloperidol levels

Clinical pharmacokinetics of the depot antipsychotics.