Andrzej Pilc

Although therapeutic drug monitoring (TDM) is recommended for personalized clozapine (CLO) dose titration, there are no widely accepted international guidelines regarding routine TDM during long-term outpatient CLO treatment and many clinicians have limited access to TDM. This retrospective, naturalistic study aimed to examine whether CLO and norclozapine (NCLO) concentrations measured only at the time of inpatient care could predict the risk of psychiatric rehospitalization after discharge, irrespective of the potential influence of confounding factors on long-term outcomes. A total of 141 blood samples from psychiatric inpatients (71 females and 70 males, aged from 18 to 74 years) were analyzed. Serum CLO and NCLO levels were determined with high-performance liquid chromatography coupled with a UV detector. We assessed the rates of rehospitalization over 360 days after discharge. There was no correlation between either CLO or NCLO concentrations and psychiatric rehospitalization rates at any follow-up time points (day 90, 180, or 360). However, patients receiving CLO as a single psychotropic drug had significantly fewer rehospitalizations (assessed at 180 and 360 days of follow-up, p < 0.001) occurred among patients receiving CLO as a single psychotropic drug compared to combination therapy. The risk of rehospitalization was also higher in patients with a greater number of previous hospitalizations (OR = 1.15, p = 0.002) and in those taking additional psychotropic drugs (OR = 1.51, p = 0.010). Our naturalistic retrospective study (based on an in-hospital TDM database) showed no association between the baseline steady-state CLO and NCLO levels established during hospitalization and the risk of psychiatric rehospitalization. However, the use of CLO in combination with other psychotropic drugs and the number of previous hospitalizations correlated with the risk of rehospitalization. Not applicable.

Rationale Scopolamine, whose rapid and sustained antidepressant effects were first described nearly two decades ago, is associated with significant adverse effects that limit its clinical use. A safer alternative may involve coadministration of scopolamine at lower doses with other compounds that exhibit antidepressant properties. Growing evidence highlights the potential of group II metabotropic glutamate (mGlu) receptors as targets for depression treatment. Objectives This study aimed to evaluate whether the mGlu2 receptor NAM, VU6001966, can enhance the antidepressant-like effects of a subeffective dose of scopolamine in a mouse model of depression and to explore the underlying mechanism. Methods Unpredictable chronic mild stress (UCMS) was employed as an animal model of depression. Behavioral tests assessing anhedonia-, apathy-, and helplessness-like states were used to evaluate the effects of a four-day coadministration of scopolamine and VU6001966. The impact of the drug combination on spatial and non-spatial learning was assessed in both naïve and stressed mice. Protein expression levels in the prefrontal cortex (PFC) and hippocampus were measured via Western blotting. Electrophysiological recordings in the medial PFC (mPFC) were conducted to assess excitatory synaptic transmission and long-term potentiation (LTP). Results Subchronic VU6001966 treatment dose-dependently alleviated stress-induced depressive-like behaviors in mice. Moreover, a subeffective dose of VU6001966 potentiated the effects of a subeffective dose of scopolamine, significantly reducing UCMS-induced apathy- and anhedonia-like behaviors. Behavioral effects of the AMPA receptor antagonist NBQX and the TrkB receptor antagonist ANA-12 suggest that both AMPA and TrkB receptors contribute to the antidepressant-like actions of scopolamine combined with VU6001966. Consistent with these findings, Western blot analysis revealed accompanying changes in the pTrkB/TrkB ratio in the PFC. The combination of scopolamine and VU6001966 did not impair cognitive function or locomotor activity. However, electrophysiological recordings did not reveal any improvement in UCMS-induced impairments in excitatory synaptic transmission or LTP in the mPFC. Conclusions Coadministration of scopolamine with the mGlu2 NAM VU6001966 may offer a promising therapeutic strategy for the treatment of depression. Further studies are needed to clarify the underlying mechanisms and confirm its efficacy.

Background: The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns. Methods: Rapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels. Results: Scopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC). Conclusion: Subchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

The desire to find a gold-standard therapy for depression is still ongoing. Developing one universal and effective pharmacotherapy remains troublesome due to the high complexity and variety of symptoms. Over the last decades, the understanding of the mechanism of pathophysiology of depression and its key consequences for brain functioning have undergone significant changes, referring to the monoaminergic theory of the disease. After the breakthrough discovery of ketamine, research began to focus on the modulation of glutamatergic transmission as a new pharmacological target. Glutamate is a crucial player in mechanisms of a novel class of antidepressants, including hallucinogens such as ketamine. The role of glutamatergic transmission is also suggested in the antidepressant (AD) action of scopolamine and psilocybin. Despite fast, robust, and sustained AD action hallucinogens belonging to a group of rapid-acting antidepressants (RAA) exert significant undesired effects, which hamper their use in the clinic. Thus, the synergistic action of more than one substance in lower doses instead of monotherapy may alleviate the likelihood of adverse effects while improving therapeutic outcomes. In this review, we explore AD-like behavioral, synaptic, and molecular action of RAAs such as ketamine, scopolamine, and psilocybin, in combination with mGlu2/3 receptor antagonists.

Major depressive disorder is one of the most severe mental disorders. It strongly impairs daily functioning, and, in extreme cases, it can lead to suicide. Although different treatment options are available for patients with depression, there is an ongoing search for novel therapeutic agents, such as scopolamine (also known as hyoscine), that would offer higher efficacy, a more rapid onset of action, and a more favorable safety profile. The aim of our study was to review the current clinical evidence regarding the use of scopolamine, a promising therapeutic option in the treatment of depression. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases up to 5 June 2023. We included randomized placebo-controlled or head-to-head clinical trials that compared the clinical efficacy and safety of scopolamine in the treatment of major depressive disorder. Two reviewers independently conducted the search and study selection and rated the risk of bias for each study. Four randomized controlled trials were identified in the systematic review. The included studies investigated the use of scopolamine administered as an oral, intramuscular, or intravenous drug, alone or in combination with other antidepressants. The results indicated that scopolamine exerts antidepressant effects of varying intensity. We show that not all studies confirmed a statistically and clinically significant reduction of depressive symptoms vs. placebo. A broader perspective on scopolamine use in antidepressant treatment should be confirmed in subsequent large randomized controlled trials assessing both effectiveness and safety. Therefore, studies directly comparing the effectiveness of scopolamine depending on the route of administration are required.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu₇ NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu₇ activity in the T-REx 293 cell line expressing a recombinant human mGlu₇ receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu₇ IC₅₀ = 6.14 µM) was selective over other group III mGlu receptors (mGlu₄ and mGlu₈), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.

Major depressive disorder remains a prevalent world-wide health problem. Currently available antidepressant medications take weeks of dosing, do not produce antidepressant response in all patients,...

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu₄ receptor positive allosteric modulatory activity (EC₅₀ = 282–656 nM). Selectivity screening revealed that they were devoid of activity at mGlu₁, mGlu₂ and mGlu₅ receptors, but modulated mGlu₇ and mGlu₈ receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu₄ PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu₄ PAM ADX88178. Graphical Abstract

Pharmaco-electroencephalography (pharmaco-EEG) is a technique used to assess the effects of psychotropic medications on the bioelectrical activity of the brain. The purpose of this study was to assess the treatment response with the use of the Hamilton Depression Rating Scale (HDRS) and via EEG. Over an 8-week period, we analyzed electroencephalographic tracings of 91 patients hospitalized for major depression at the Medical University of Warsaw. Thirty-nine of those patients received tricyclic antidepressants (TCAs), 35 received fluoxetine, and 17 received fluoxetine augmented with magnesium (Mg) ions. All patients had their serum drug levels monitored. The highest proportion of patients (88.2%) who showed adequate responses to treatment was observed in the fluoxetine+Mg group, whereas the lowest rates of treatment response were observed in the TCA group (58.3%). This difference was statistically significant (p = 0.029, Phi = 0.30). Our study demonstrated a relationship between achieving remission (HDRS ≤ 6 at week 8 of treatment) and obtaining a positive pharmaco-EEG profile 6 h after administration of the first dose in the group receiving fluoxetine augmented with Mg ions (p = 0.035, Phi = 0.63).