A main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male Sprague Dawley rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training and (2) prevented the reinstatement of cocaine CPP. In the present study, we investigated which of the sensory modalities of the composite stimulus “social interaction” contributes most to the rats' preference for it. If touch was limited by steel bars spaced at a distance of 2 cm and running across the whole length of a partitioning, CPP was still acquired, albeit to a lesser degree. If both rats were placed on the same side of a partitioning, rats did not develop CPP for social interaction. Thus, decreasing the available area for social interaction from 750 to 375 cm2 prevented the acquisition of CPP to social interaction despite the fact that animals could touch each other more intensely than through the bars of the partitioning. When touch was fully restricted by a glass screen dividing the conditioning chambers, and the only sensory modalities left were visual and olfactory cues, place preference shifted to place aversion. Overall, our findings indicate that the major rewarding sensory component of the composite stimulus “social interaction” is touch (taction).

BackgroundA main challenge in the therapy of drug dependent individuals is to help them reactivate interest in non-drug-associated activities. Among these activities, social interaction is doubly important because treatment adherence itself depends on it. We previously developed a rat experimental model based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of social interaction with a gender- and weight-matched male conspecific (i) reversed CPP from cocaine to social interaction despite continuing cocaine training and (ii) prevented the reinstatement of cocaine CPP. In the present study, we investigated if the two subregions of the nucleus accumbens (Acb), i.e., the core (AcbC) and the shell (AcbSh), would differentially affect CPP for cocaine vs social interaction.Methodology/Principal FindingsAnimals were concurrently trained for CPP pairing cocaine with one compartment and social interaction with the other (i.e., mutually exclusive stimulus presentation during training). Excitotoxic lesioning of the AcbC or the BLA shifted CPP toward social interaction, whereas AcbSh inactivation shifted CPP toward cocaine.ConclusionsOverall, our findings suggest that inactivation of the AcbC or the BLA is sufficient to shift CPP away from a drug of abuse toward social interaction. Lesioning the AcbSh produced the opposite effect.

The main argument against therapeutic drug monitoring (TDM) in psychiatry, which aims at helping the prescribing physician to optimize her/his pharmacotherapy (Baumann et al. 2004), is that "there is no dose-response relationship in psychiatry". This claim of a lack of any dose-response relationship is voiced, e.g., in a recent meta-analysis (Adli et al. 2005) which suggests that increasing the dose of an antidepressant after an insufficient response to a mid-range dose only led to a clinical improvement in the case of tricyclic antidepressants but not selective serotonin reuptake inhibitors (SSRIs). Consequently, these authors recommend that SSRI dosage may be reduced without loss of efficacy. Internally inconsistent, they also suggest using TDM to monitor the dose-which would be completely unnecessary if no dose response relationship existed. In the same vein, Rasmussen and Brosen (2000) summarize their review of the literature as follows: "In several studies there has not been found a clear relationship between clinical efficacy and plasma concentration, nor any threshold that defines toxic concentrations. The available data do not suggest that any benefit be obtained from routine monitoring of SSRI plasma levels."In contrast, TDM is based on the implicit assumption that all pharmacotherapies are based on ligand-receptor interaction, i.e., show a range of concentrations in which the therapeutic effect is a linear function of the concentration of the ligand (i.e., the medication). As we will show in the following, both positions are correct and only very little additional information is necessary to reconcile both positions in a unifying hypothesis that, if implemented in future clinical trials, may lead to a considerable saving both in costs and patient risk.An impressive amount of data from randomized controlled clinical trials indeed shows that clinical effect is most often not linearly correlated with dose. This lack of a dose-response relationship can be plausibly explained if one considers that for all psychopharmacologic medications so far investigated, the plasma level-after the extracellular space in the brain the second-best pharmacokinetic compartment to correlate concentration with effect-varies up to 20-fold among subjects/patients at each administered daily dose. Figure 1 gives the respective data (Tanum et al. 2010) for the selective serotonin reuptake inhibitor (SSRI) citalopram, arguably one of the most prescribed antidepressants worldwide; Fig. 2 the data for the partial D2 receptor agonist aripiprazol (Gründer et al. 2008); and Fig. 3 our own (C.H.) data on the SSRI paroxetine. To emphasize again, this is not an effect restricted to the compounds shown in this Commentary. The up to 20-fold interindividual variation of plasma levels at each single dose is a phenomenon that has been observed for all psychopharmacological medications so far.With a 20-fold interindividual variation in plasma levels after a single dose, it is not surprising that data based on dose and not on plasma level yield dos...

Non-suicidal self-injury (NSSI) in children and adolescents is a frequent phenomenon. NSSI at any time is a significant predictor of future NSSI but also, and more importantly, for suicide attempts. Less evidence is available for the impact, or more specifically, the therapeutic effect of psychotropic drugs on the emergence of NSSI in this population. The phenomenon is clinically highly relevant since adolescent psychiatric inpatients are often affected by NSSI and most of them are treated with psychotropic drugs. While previous reviews on NSSI comprised suicidal self-injury (SSI), this review aims at elucidating the potential impact of psychotropic drugs on the emergence of specifically NSSI in children and adolescents. Systematic searches of articles indexed electronically in PubMed, Embase and PsycInfo were conducted (PROSPERO CRD42020209505). Studies included in the quantitative synthesis were evaluated using the SIGN level of evidence rating. Meta-analyses were performed using RevMan (Version 5.4). 2227 records were identified through database searches. Two additional records were identified manually. In total, seven studies were included in qualitative and four studies in quantitative analyses. In a meta-analysis, selective serotonin reuptake inhibitors (SSRIs) were compared vs. control medication (placebo or serotonin-norepinephrine reuptake inhibitor) and here, no statistically significant difference between the groups could be observed regarding the frequency of NSSI events (Risk Ratio (RR) = 1.07, 95% confidence interval (CI) 0.60-1.91, p = 0.82, I 2 = 12%). Evidence regarding the association of SSRI use and NSSI among children and adolescents is sparse and the impact of psychotropic drugs in general on NSSI rates in this population should be addressed in future clinical and observational studies.

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