Journal of Psychopharmacology

Szabadi, Elemer

doi: 10.1177/02698811241261022pmid: 39041250

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson’s disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion – substantia nigra pars compacta (SNc), reinforcement/motivation – ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) – VTA; arousal – ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Ghaemi, Seyyed Nassir

doi: 10.1177/02698811241257833pmid: 38863399

By manipulating inclusion criteria, one can prove whatever point one wishes in meta-analysis. This critique examines a recent meta-analysis claiming lithium ineffectiveness for suicidality, based on three biased features: inclusion of many large studies specifically designed to exclude suicidality, producing zero suicide outcomes in all groups (n = 1856), thereby artificially decreasing statistical significance; arbitrary exclusion of all trials prior to the year 2000, thereby excluding two randomized clinical trials which demonstrated benefit for lithium; and underreporting of placebo suicide events in a recent randomized trial. It thereby created a smaller effect size (two suicides with lithium versus five with placebo = RR = 0.42), though still beneficial for lithium, and a larger denominator of no events (total n for included studies = 2578), leading to the claim of statistical non-significance (95% confidence intervals (CIs) 0.1–4.5). The same literature can be analyzed including the two excluded older studies, and including the two placebo deaths in the recent trial, producing a larger effect size (two suicides with lithium versus nine with placebo, RR = 0.25). Furthermore, uninformative studies with no events could be excluded (total n for included studies = 1203), as is standard practice in meta-analysis, producing statistically significant results (95% CIs 0.05, 0.83). This more complete, more accurate, and less biased meta-analysis is provided in this article.In short, including all studies with non-zero suicide outcomes, there is clear benefit for lithium. The recent meta-analysis is a classic example of pseudoscience, using scientific technique superficially to confirm, rather than refute, one’s own opinions.

Rosada, Catarina; Lipka, Renée; Metz, Sophie; Otte, Christian; Heekeren, Hauke; Wingenfeld, Katja

doi: 10.1177/02698811241260972pmid: 38902928

Background:The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood.Aims:To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC.Methods:We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo.Results:We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter.Discussion:The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147).

Di Nicola, M; Adair, M; Rieckmann, A; Christensen M, Cronquist

doi: 10.1177/02698811241260996pmid: 39077889

Background:Data demonstrating the real-world, long-term effectiveness of vortioxetine in elderly patients with major depressive disorder (MDD) are clinically useful to confirm findings from randomized trials.Methods:RELIEVE was a multinational, 24-week, observational, prospective study in outpatients with MDD initiating vortioxetine treatment in routine care settings (NCT03555136). Here, we report data from a subgroup of 130 patients aged ⩾ 65 years. The primary study outcome was changed from baseline in patient functioning assessed using the Sheehan Disability Scale (SDS). Other clinical outcomes included depression severity (Patient Health Questionnaire-9 [PHQ-9] and Clinical Global Impressions–Severity [CGI-S]), cognitive performance (Digit Symbol Substitution Test [DSST]) and symptoms (Perceived Deficits Questionnaire – Depression-5 item [PDQ-D-5]), and health-related quality of life (HRQoL) (EuroQoL 5 Dimensions 5 Levels [EQ-5D-5L]).Results:Clinically meaningful and statistically significant improvements in patient functioning, depressive symptoms, cognitive function, and HRQoL were observed at week 24. Least squares mean SDS, PHQ-9, CGI-S, PDQ-D-5, DSST, and EQ-5D-5L scores improved from baseline by 6.5, 5.7, 1.2, 3.2, 4.4, and 0.11 points, respectively (p < 0.01 for all). Adverse events were observed in 23.1% of patients.Conclusions:Consistent with previous clinical studies of vortioxetine, this study supports the effectiveness and safety of vortioxetine in treating elderly patients with MDD in a real-world setting over a 6-month period. Patients showed clinically relevant and sustained improvements in psychosocial functioning, depressive symptoms, and cognitive function after receiving vortioxetine, which was generally well tolerated. Main study limitations include the open-label study design and lack of a placebo or comparator group.

Taylor, David; Vallianatou, Kalliopi; Gandhi, Shreyans; Casetta, Cecilia; Howes, Oliver; MacCabe, James

doi: 10.1177/02698811241262767pmid: 39041349

Background:Clozapine is known to cause agranulocytosis. Mandatory monitoring schemes are aimed at reducing the risk of agranulocytosis and of the consequences of agranulocytosis. All cases of agranulocytosis occurring in people prescribed clozapine are assumed to be caused by clozapine.Methods:In a previous study, we examined a cohort of patients listed on our hospital database as having had clozapine-induced agranulocytosis and applied specific criteria to identify those with confirmed clozapine-related, life-threatening agranulocytosis. In this study, we examine the cases not meeting these specific criteria.Results:In the original study, 9 of 23 cases met the criteria for clozapine-induced, life-threatening agranulocytosis. Of the 13 remaining cases for whom data were available, 5 were probably caused by clozapine but were not life-threatening. Three cases were the result of concomitant cancer chemotherapy. Three were anomalous results probably related to measurement error. For the remaining two cases, the cause was not identified.Conclusion:Not all cases of agranulocytosis occurring in people taking clozapine are caused by clozapine. The widely used threshold criterion-based diagnosis overestimates the risk of agranulocytosis. True clozapine-related agranulocytosis is best identified by pattern-based criteria: rapid fall in neutrophil counts over around 2 weeks to below 0.5 × 109/L for two consecutive days (unless clozapine is stopped very early or granulocyte colony stimulating factor is given) where other possible causes (benign ethnic neutropenia, cancer chemotherapy) can be ruled out.

Hayley, Amie C; Shiferaw, Brook; Aitken, Blair; Rositano, Joanna; Downey, Luke A

doi: 10.1177/02698811241261024pmid: 39068640

Background:Methamphetamine is frequently co-consumed with alcohol, yet combined effects on visually guided behaviours have not been experimentally assessed. This study examined whether methamphetamine and alcohol-induced changes in gaze behaviour can be accurately detected and indexed during a simulated driving task to establish characteristic patterns relevant to traffic safety.Methods:In a randomised, placebo-controlled, cross-over study design, the effects of acute oral methamphetamine (0.42 mg/kg) were assessed with and without low doses of alcohol (target 0.04% blood alcohol content) on gaze behaviour during driving. Twenty healthy adults (mean age 29.5 years (SD ± 4.9), 40% female) completed four, 1-h simulated drives with simultaneous eye monitoring using the SensoMotoric Instruments cap-mounted eye tracker over a 4-week experimental paradigm. Gaze entropy measures were used to quantify visual scanning efficiency, expressed as gaze transition entropy and stationary gaze entropy. Fixations, recorded as duration (milliseconds, ms) and rate (count) per minute, were examined in 10-min bins over the duration of the drive. Driving performance was assessed by the standard deviation of lateral position, standard deviation of speed and steering variability.Results:Methamphetamine increased the rate and duration of fixations and produced a less dispersed but more disorganised pattern of gaze during highway driving while preserving performance. Alcohol alone impaired both oculomotor control and driving performance, even when consumed at levels well below the legal limit stipulated in many international jurisdictions.Conclusions:Methamphetamine-affected drivers display inefficient exploration in a limited visual range during driving. Eye-tracking metrics thus show potential for indexing intoxication due to psychoactive substance usage.

Illenberger, Jessica M; Flores-Ramirez, Francisco J; Pascasio, Glenn; Franco, Marissa; Mendonsa, Brandon; Martin-Fardon, Rémi

doi: 10.1177/02698811241260989pmid: 38888086

Background:The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats.Aims:This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress.Methods:Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress.Results:The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking.Conclusions:The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder.

Papp, Mariusz; Gruca, Piotr; Litwa, Ewa; Lason, Magdalena; Newman-Tancredi, Adrian; Depoortère, Ronan

doi: 10.1177/02698811241254832pmid: 38825869

Background:The highly selective 5-HT1A serotonin receptor “biased” agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM).Aims:Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT1A receptor activation in the RAAD activity of NLX compounds.Results/Outcomes:In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT1A antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT1A receptors.Conclusions/Interpretation:These data indicate that 5-HT1A receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine’s primary mechanism of action) but also by activating 5-HT1A receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine’s troublesome side effects.

Schroyens, Natalie; Vercammen, Laura; Özcan, Burcu; Ossorio Salazar, Victoria Aurora; Zaman, Jonas; De Bundel, Dimitri; Beckers, Tom; Luyten, Laura

doi: 10.1177/02698811241261375pmid: 39068641

Background:The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear.Aims:The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice.Methods:In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS− without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS− was assessed.Results:We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test.Conclusion:In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.