Gerald Zernig

TDM involves measuring and interpreting drug concentrations in blood plasma or serum to optimize pharmacotherapy. In psychiatry and neurology, TDM is a well-established tool for personalized drug treatments. The AGNP-TDM task force initially published guidelines for best practice TDM in 2004, 2011, and 2017. A fundamental methodological revision has now been carried out on how to determine therapeutic reference ranges and dose-related reference ranges transparently and systematically. In the current edition, 50 experts in neuropsychopharmacology offer a complete update of both ranges for each substance following an evidence-based approach. Various types of data were considered for reference range determination, ranging from meta-analyses to drug concentrations expected under recommended doses. Therapeutic reference ranges are now listed for 160 neuropsychiatric drugs, newly included for 30 drugs and revised for 88 drugs. Expected drug concentrations can be calculated based on a revised formula for 162 drugs. Obligatory TDM (i.e. for dose titration) is strongly recommended for 15 neuropsychiatric drugs and recommended for 39 drugs. TDM is classified as useful for 49 drugs and potentially useful for 62 drugs, indicating that it is recommended in specific clinical situations, such as suspected non-adherence, insufficient clinical response despite recommended doses, relapse during maintenance treatment, and many more. The 2026 update includes practical pharmacogenetic recommendations that are directly relevant to TDM. This work integrates a combination of strategies to guide drug treatments in clinical practice using all available tools. A consistent implementation of TDM and pharmacogenetic recommendations will enhance neuropsychopharmacotherapy, improve patient outcomes, and reduce healthcare costs.

Mu opioid analgesics like the full mu opioid receptor agonists morphine, methadone and fentanyl or the partial agonist buprenorphine have remained the mainstay in the treatment of moderate to severe pain. During chronic treatment, the development of tolerance to their antinociceptive effects presents a considerable therapeutic challenge, especially in opioid maintenance patients who, to complicate matters, may or may not abuse opioids on the side. In opioid-based maintenance patients, it is desirable to assess the actual degree of tolerance to effectively treat withdrawal symptoms while avoiding illegal diversion of surplus quantities of the prescribed mu opioid agonist. As a further complication, the degree of tolerance may vary considerably among different opioid effects. We are currently conducting a systematic review (PROSPERO CRD42023408416) of the quantitative evidence for these varying degrees of tolerance in either patient population (patients with primary opioid dependence, PODs vs ‘regular’ patients, REGs) for the various desired effects of and adverse drug reactions to morphine, methadone, fentanyl, and buprenorphine. A preliminary analysis indicates that tolerance to antinociceptive opioid effects in PODs is more than 6-fold (buprenorphine maintenance) to more than 7-fold (methadone maintenance). Of special consideration, no tolerance to the respiratory depressant effect in PODs seems to occur under these controlled conditions. Article published online: 12 March 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.

Rats, including those of the Sprague Dawley strain, may kill mice. Because of this muricidal behavior, it is standard practice in many research animal housing facilities to separate mice from rats (i.e., the predators) to minimize stress for the mice. We tested the effect of cohousing on the stress levels of mice from either the C57BL/6J (BL6) or the CD1 strain and Sprague Dawley rats (SD rat) by quantifying their fecal corticosterone and metabolites (FCM) concentration. We also investigated cohousing impacts a behavioral assay, i.e., conditioned place preference for intragenus (i.e., mouse–mouse or rat–rat) dyadic social interaction (DSI CPP) that was shown be sensitive to social factors, especially to handling by humans. We found that the two delivery batches of BL6 mice or SD rats, respectively, had different stress levels at delivery that were statistically significant for the BL6 mice. Even so, the BL6 mice cohoused with rats had significantly increased FCM concentrations, indicative of higher stress levels, as compared to (1) BL6 mice housed alone or (2) BL6 mice at delivery. In contrast to their elevated stress levels, the attractiveness of contextual cues associated with mouse–mouse social interaction (DSI CPP) even increased in rat-cohoused BL6 mice, albeit non-significantly. Thus, cohousing BL6 mice and rats did not impair a behavioral assay in BL6 mice that was proven to be sensitive to handling stress by humans in our laboratory. SD rats cohoused with BL6- or CD1 mice, and CD1 mice cohoused with SD rats, showed DSI CPP that was not different from our previously published data on SD rats and BL6 mice of the Jackson- or NIH substrain obtained in the absence of cohousing. CD1 mice cohoused with rats did not show an increased FCM concentration compared to delivery. Our findings suggest that the effect of cohousing rats and mice under the conditions described above on their stress levels as opposed to their behavior might be less clearcut than generally assumed and might be overriden by conditions that cannot be controlled, i.e., different deliveries. Our findings can help to use research animal housing resources, which are usually limited, more efficiently.

Rats, including those of the Sprague Dawley strain, may kill mice. Because of this muridical behavior, it is standard practice in many research animal housing facilities to separate mice from rats (i.e., the predators) to minimize stress for the mice. We therefore tested the effect of cohousing on the stress levels of mice from either the C57BL/6J (BL6) or the CD1 strain and Sprague Dawley (SD rat) by determining their fecal corticosterone or cortisol metabolites (FCM) concentration and investigated how cohousing impacts a behavioral assay, i.e., conditioned place preference for intragenus (i.e., mouse-mouse or rat-rat) dyadic social interaction (DSI CPP) that had been shown be sensitive to social factors, especially to handling by humans. We found that the two delivery batches of BL6 mice or SD rats, respectively, had different stress levels at delivery that were statistically significant for the BL6 mice. Even so, the BL6 mice cohoused with rats had significantly increased FCM concentrations, indicative of higher stress levels, as compared to (1) BL6 mice housed alone or (2) BL6 mice at delivery. In contrast to their elevated stress levels, the attractiveness for contextual cues associated with mouse-mouse social interaction (DSI CPP) even increased in rat-cohoused BL6 mice, albeit nonsignificantly. Thus, cohousing BL6 mice and rats did not impair a behavioral assay in BL6 mice that had proved to be sensitive to handling stress by humans in our laboratory. SD rats cohoused with BL6- or CD1 mice and CD1 mice cohoused with SD rats showed DSI CPP that was not different from our previously published data on SD rats and BL6 mice of the Jackson- or NIH substrain obtained in the absence of cohousing. Our findings suggest that the effect of cohousing rats and mice under the conditions described above on their stress levels as opposed to their behavior might be less clearcut than generally assumed and might be overriden by conditions that cannot be controlled, i.e., different deliveries. Our findings can help to use research animal housing resources, which usually are limited, more efficiently.

The metabotropic glutamate receptor type 5 (mGluR5) has been proposed to play a crucial role in the selection and regulation of cognitive, affective, and emotional behaviors. However, the mechanisms by which these receptors mediate these effects remain largely unexplored. Here, we studied the role of mGluR5 located in D1 receptor-expressing (D1) neurons in the manifestation of different behavioral expressions. Mice with conditional knockout (cKO) of mGluR5 in D1 neurons (mGluR5^D1 cKO) and littermate controls displayed similar phenotypical profiles in relation to memory expression, anxiety, and social behaviors. However, mGluR5^D1 cKO mice presented different coping mechanisms in response to acute escapable or inescapable stress. mGluR5^D1 cKO mice adopted an enhanced active stress coping strategy upon exposure to escapable stress in the two-way active avoidance (TWA) task and a greater passive strategy upon exposure to inescapable stress in the forced swim test (FST). In summary, this work provides evidence for a functional integration of the dopaminergic and glutamatergic system to mediate control over internal states upon stress exposure and directly implicates D1 neurons and mGluR5 as crucial mediators of behavioral stress responses.

Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationshi...