Journal of Psychopharmacology最新文献

Background: This study intended to examine network homogeneity (NH) alterations in drug-naive patients with panic disorder (PD) before and after treatment and whether NH could serve as a potential biomarker.

Methods: Fifty-eight patients and 85 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Patients were rescanned following a 4-week course of paroxetine monotherapy. NH was computed to evaluate intra-network functional integration across the Yeo 7-Network. Machine learning (ML) was employed to assess the diagnostic and prognostic potential of NH metrics. Transcriptome-neuroimaging association analyses were conducted to explore the molecular correlates of NH alterations.

Results: Compared with HCs, patients showed disrupted intra-network integration in the frontoparietal, default mode, sensorimotor, limbic, and ventral attention networks, with prominent NH alterations in the superior frontal gyrus (SFG), middle temporal gyrus (MTG), superior temporal gyrus (STG), somatosensory cortex, insular, and anterior cingulate cortex. Importantly, the SFG, MTG, and STG demonstrated cross-network abnormalities. After treatment, clinical improvement correlated with normalized NH in the SFG and additional changes in the inferior occipital gyrus and calcarine sulcus within the visual network. ML demonstrated the utility of NH for PD classification and treatment outcome prediction. Transcriptome-neuroimaging analysis identified specific gene profiles related to NH alterations.

Conclusions: NH reflects both pathological features and treatment-related changes in PD, providing a measure of network dysfunction and therapeutic response. Cross-network NH disruptions in hub regions and visual processing may reflect core neuropharmacological mechanisms underlying PD. ML findings support the potential of NH as a neuroimaging biomarker for diagnosis and treatment monitoring in PD.

Background: A brief inhalation of 35% CO₂ triggers subjective fear and physiological responses occurring during naturally occurring panic attacks (PAs). This CO₂ model enables to study effects of pharmacological interventions on experimental panic provocation and examine the biological mechanisms involved in PAs.

Aims: To provide a quantification of the effects of pharmacological interventions on the response to CO₂ inhalation, which was still lacking despite decades of research and numerous studies having addressed these effects.

Methods: A systematic search was performed to identify peer-reviewed papers reporting effects of pharmacological interventions to the 35% CO₂ inhalation. Multilevel meta-analyses were performed to quantify the effects of such interventions on self-reported anxiety and PA symptoms.

Results: Thirty-six studies, containing data of 980 participants (both panic disorder patients and healthy individuals), were included. Several studies reported effects of multiple pharmacological interventions, resulting in 48 effect sizes for the meta-analysis of the effects on anxiety and 34 for the effects on PA symptoms. Significant decreases in induced anxiety (-.55 (95% confidence interval (CI): -.81 to -.29), p < 0.0001) and PA symptoms (-0.31 (95%CI: -.51 to -.11), p = 0.0026) were seen after pharmacological interventions aimed at symptom reduction. Induced anxiety was significantly decreased (-.81 (95%CI: -1.13 to -.48), p < 0.0001) after pharmacological interventions that enhanced the serotonergic system.

Conclusions: This meta-analysis supports the notion that specific drugs can reduce the sensitivity to 35% CO₂ challenge, supporting a role for this procedure as experimental model to investigate panic pharmacology.

Background: Citalopram is widely used for treating major depressive disorder, but exhibits substantial inter-individual variation in clinical response. CYP3A4 is one of the cytochrome P450 enzymes (CYP450) involved in the demethylation metabolism of citalopram. Genetic polymorphisms in CYP3A4 may alter the metabolism of citalopram by affecting the enzymatic activity of CYP3A4.

Aim: This study aims to evaluate the metabolic differences of citalopram between wild-type and 21 CYP3A4 variants identified in the Chinese Han population.

Methods: An optimized in vitro incubation system was established, consisting of recombinant human CYP3A4 expressed in Spodoptera frugiperda 21 insect cells and citalopram at various concentrations. The incubation was maintained at 37°C for 30 minutes. Citalopram and demethylcitalopram were quantified using high-performance liquid chromatography with fluorescence detection. Michaelis-Menten curves were plotted, and enzyme kinetic parameters were calculated for each CYP3A4 variant.

Results: Our results showed that most CYP3A4 variants significantly altered citalopram metabolism. Specifically, 12 variants (*3, *4, *5, *9, *10, *16, *19, *23, *28, *31, *33, and *34) showed a 30.83% to 96.06% decrease in intrinsic clearance (CL_int) compared to wild-type, while five variants (*2, *11, *14, *17, and *18) exhibited a 13.52% to 448.56% increase (p < 0.05). Four mutants (*15, *24, *29, and *32) demonstrated CL_int similar to wild-type.

Conclusion: This study provides the first systematic data on the impact of CYP3A4 variants on citalopram metabolism, suggesting that CYP3A4 genetic polymorphism plays a significant role in citalopram metabolism, and highlighting its potential value in individualized therapy.

The last decade represented a period of unprecedented interest in, and development of, traditional psychedelic substances for the treatment of a variety of neuropsychiatric disorders. While early clinical trials of classical psychedelics, several of the major ones being tryptamines, have demonstrated robust efficacy in patients with minimal adverse effects, many of these molecules have properties that may limit their broad utility in clinical practice or require more complex methods of delivery. The functional role and importance of a "psychedelic experience" for therapeutic efficacy remain enigmatic. If the mechanism of action is reduced to mere 5-HT_2A receptor activation, this raises the question if whether therapeutic efficacy is achievable without the psychedelic effects. Furthermore, as this class of molecules typically interacts with many other members of the serotonin receptor family, including the 5-HT_1A and 5-HT_2C receptor subtypes (receptors proven to be relevant to a multitude of neuropsychiatric disorders), as well as non-serotonergic receptors, the polypharmacological aspect of psychedelic tryptamines needs further scrutiny and understanding. In this perspective, the authors will review the limitations of the current classical non-conjugated tryptamines (excludes lysergic acid diethylamide, ibogaine, and similar molecules), highlighting approaches that have been explored to improve the molecules, as well as approaches to develop new generation psychedelic and "non-psychedelic" compounds. Further, the authors will review the latest thoughts within the field on the pharmacology that could be underlying these potentially field changing therapies.

Background: Neuropeptide Y1 receptor (NPY1R) heteroreceptor complexes with galanin receptor 2 (GALR2) and Tropomyosin receptor kinase B (TrkB) contribute to neuroplasticity and mood regulation.

Aims: To determine whether transient intracerebroventricular (ICV) knockdown of NPY1R is sufficient to alter hippocampal neurogenesis and depressive-like behaviour.

Methods: Adult Sprague-Dawley rats received a single ICV injection of Accell Smart-Pool small interfering RNA (siRNA) targeting NPY1R or a scrambled control. NPY1R protein levels, NPY1R-GALR2 and NPY1R-TrkB complexes (in situ proximity ligation), proliferating cell nuclear antigen (PCNA) counts, brain-derived neurotrophic factor (BDNF) expression and forced-swim behaviour were assessed 6, 8 and 10 days post-injection in the ventral hippocampus.

Results: ICV siRNA significantly reduced NPY1R immunoreactivity (peak at day 8; p<0.05) and lowered NPY1R-GALR2 and NPY1R-TrkB heteroreceptor complexes (p<0.01 and p<0.001, respectively). PCNA-positive cell numbers and BDNF optical density were unchanged at all time points. Forced-swim immobility, climbing and swimming times likewise remained unaltered.

Conclusions: Transient ICV knockdown effectively disrupts NPY1R heteroreceptor complexes but fails to impact neurogenesis or depressive-like behaviour, indicating compensatory mechanisms that preserve hippocampal plasticity. Within the time window and conditions tested, transient NPY1R knockdown disrupted GALR2/TrkB heteroreceptor complexes without altering neurogenesis or depressive-like behaviour, delineating receptor-complex-level target engagement and motivating studies using sustained and circuit-specific manipulations to assess therapeutic potential.

Depression is a prevalent and debilitating mental disorder, and the underlying mechanisms of depression remain unclear. Emerging evidence highlights the importance of chemokines, particularly CX₃CL1/CX₃CR1 signaling, in the pathophysiology of depression. CX₃CL1 (Fractalkine, CX₃C chemokine ligand 1) is an essential chemokine and exerts its biological effects by binding to its receptor, CX₃CR1. This interaction plays a pivotal role in mediating communication between microglia and neurons within the central nervous system. Numerous studies have suggested that CX₃CL1/CX₃CR1 signaling is a critical regulator of neuroinflammation and synaptic plasticity. Therefore, this narrative review provides a comprehensive overview of the role of CX₃CL1/CX₃CR1 signaling in neuroinflammation, synaptic plasticity, and cognition. In addition, we discuss the critical role of this signaling pathway in the pathophysiology of depression and antidepressant treatments and highlight its significance in the field of neuropsychopharmacology.

Background: Risky decision-making is a cardinal feature of bipolar disorder (BD), yet no targeted pharmacotherapies exist for this behavioral deficit. Dopamine transporter knockdown (DAT KD) mice reproduce the DAT hypoexpression profile of BD and demonstrate pharmacologically sensitive, BD-relevant patterns of risky decision-making and hyperexploration in the cross-species translatable Iowa Gambling Task (IGT) and Behavioral Pattern Monitor (BPM), respectively. Agonists of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor that presynaptically modulates dopamine transmission, may normalize these deficits and thereby represent a novel therapeutic avenue for the management of BD.

Aims: Assessment of the impact of TAAR1 activation on BD-relevant behaviors in a mouse model of mania.

Methods: The effects of the TAAR1 agonist R05256390 (0, 0.3, and 1.0 mg/kg, i.p.; within-subjects) were first determined on unconditioned exploration in male and female DAT KD and wildtype (WT) littermate mice in the BPM and then on risky decision-making in the IGT (1.0 mg/kg).

Results: Consistent with people with BD, DAT KD mice exhibited hyperlocomotion, elevated specific exploration, and more linear movement in the BPM, plus elevated risk preference in the IGT. R05256390 (0.3 and 1 mg/kg) reduced locomotion in DAT KD males and WT females, respectively, as well as specific and diversive exploration across genotypes. TAAR1 activation also reduced risky choice in DAT KD mice while elevating this behavior in WTs.

Conclusions: These findings support the potential for TAAR1 agonists as novel treatments for hyperactivity and risky decision-making in BD, and suggest an inverted U-shaped relationship between dopamine tone and decision-making optimization.

Background: Major depressive disorder (MDD) is a globally prevalent condition associated with significant morbidity and cognitive dysfunction. Vortioxetine, a novel antidepressant with multimodal serotonergic activity, has shown potential advantages over conventional antidepressants in both efficacy and tolerability. This meta-analysis evaluates the efficacy, cognitive improvement, and safety profile of vortioxetine in MDD.

Methods: A comprehensive search of multiple search engines yielded 16 randomized controlled trials that studied the efficacy of vortioxetine and other antidepressants. About 3127 MDD patients in the vortioxetine group and 3102 in the control group were analyzed. Primary efficacy outcomes were changes in Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression-Improvement, and Clinical Global Impression-Severity scores, and the secondary outcome measure was cognition using the digit symbol substitution test scores. Safety was assessed via reported adverse effects (AEs), including the treatment-induced sexual dysfunction. The sensitivity analysis was done excluding the study with a high impact.

Results: Vortioxetine demonstrated a small but significant reduction in depressive symptoms compared to placebo, but showed similar efficacy to duloxetine and venlafaxine. Excluding the high-impact study did not cause much variation in the findings. There was a small but statistically insignificant improvement in cognition with vortioxetine compared to the control group. Vortioxetine had a favorable safety profile with only mild symptoms reported. The most commonly reported symptom was nausea. Vortioxetine also showed a non-significant trend toward fewer sexual AEs.

Conclusion: Vortioxetine is an effective and well-tolerated antidepressant for the management of MDD. Though the tolerability was comparable to other antidepressants, there was a potentially lower incidence of sexual side effects. A further elaborate exploration in terms of dose-specific efficacy and cognitive improvement will be promising for optimizing individualized treatment strategies.

This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.