International Journal of Neuropsychopharmacology最新文献

Treatment-resistant schizophrenia affects over half of individuals with schizophrenia. Clozapine is the only approved treatment in the United States but often provides limited relief. Augmenting clozapine with cariprazine (CAR) (a D3-preferring dopamine D2-D3 partial agonist) may improve outcomes. This systematic review evaluated the efficacy and safety of this combination in patients with sub-optimal response. A search of PubMed, Embase, and Cochrane Library yielded 52 cases from 21 eligible studies to be included in the analysis. Patient and treatment characteristics and clinical outcomes were synthesized. Cariprazine replaced another antipsychotic or was added to clozapine monotherapy in 44.2% and 34.6% of cases, respectively. Before treatment, 90% of patients had positive and 81% had negative symptoms. Combination therapy improved these symptoms in 66% and 83% of cases, respectively. In 19 patients with Positive and Negative Symptom Scale scores available before and after treatment, total scores decreased by 43.4%, with positive and negative subscale reductions of 23.0% and 59.1%. The combination was generally well tolerated; some patients experienced weight loss and reduced clozapine-related side effects. New adverse events occurred in 19% (most commonly akathisia at 6%). Cariprazine was discontinued in 17% of cases due to side effects or lack of efficacy. Overall, the combination appears safe and promising, especially for persistent negative symptoms, likely due to complementary neuroreceptor effects. Larger controlled trials are needed to confirm these findings.

Background: Treatment for major depressive disorder (MDD) should be optimized as early as possible in the disease course to minimize patient suffering and maximize clinical benefits. This post hoc analysis aimed to investigate the efficacy and safety of adjunctive brexpiprazole in patients who were earlier and later in the disease course.

Methods: Data were pooled from three 6-week, randomized, double-blind, placebo-controlled trials of adjunctive brexpiprazole in adult outpatients with MDD and inadequate response to antidepressant treatment. "Earlier" and "later" disease course subgroups were defined based on the proxies of median age, age at diagnosis, number of episodes, episode duration, and number of prior antidepressants. Efficacy was assessed by changes in Montgomery-Åsberg Depression Rating Scale (MADRS) total score, and safety by treatment-emergent adverse events.

Results: Greater improvement in MADRS total score at week 6 (P < .05) was observed for antidepressant + brexpiprazole 2-3 mg/day (n = 579) versus antidepressant + placebo (n = 583) in all subgroups representing earlier and later disease course, with treatment effects (least-squares mean differences in score change) ranging from -1.79 to -2.92 points. The incidence of treatment-emergent adverse events across subgroups was 53.1%-67.2% for antidepressant + brexpiprazole 2-3 mg/day and 43.0%-51.8% for antidepressant + placebo, with no consistent differences in patients who were earlier or later in the disease course.

Conclusions: Adjunctive brexpiprazole improved depressive symptoms earlier in the disease course, when benefits to patients and healthcare systems can be maximized. Adjunctive brexpiprazole also improved depressive symptoms later in the disease course; there was no advantage of delaying brexpiprazole treatment.

Trial registration: Post hoc analysis of NCT01360645, NCT01360632, NCT02196506 (ClinicalTrials.gov).

Background: Hexahydrocannabinol (HHC) is a new psychoactive substance known for its mind-altering effects and temporary legal status. It is widely used in parts of the Europe and United Kingdom as a legal alternative to ∆9-tetrahydrocannabinol, yet little research has explored its effects and safety. This study examined how HHC is processed in the body, its toxicity, and its impact on behavior in male Wistar rats.

Methods: A 1:1 mixture of (9R)-HHC and (9S)-HHC was administered via intragastric gavage at doses of 1, 5, and 10 mg/kg. Behavioral effects were assessed using the open field test and the prepulse inhibition of acoustic startle response.

Results: Two hours after the highest dose (10 mg/kg), peak concentrations of HHC were detected in blood and brain tissue. The Organization for Economic Co-operation and Development 423 toxicity test classified HHC as a Category 4 substance, estimating a lethal dose of 1000 mg/kg. Compared to controls (administered by sunflower oil), 10 mg/kg HHC reduced movement, increased anxiety, and impaired sensory processing.

Conclusions: Overall, HHC crosses the blood-brain barrier, exhibits mild toxicity, and induces behavioral effects similar to tetrahydrocannabinol. Its dose-dependent anxiogenic properties and impact on information processing highlight the importance of the appropriate dosing in any potential therapeutic use.

Background: Anhedonia is a key symptom and part of the diagnostic criterion of major depressive disorder (MDD). However, the relationship between anhedonia severity and the clinical, humanistic, and economic burden among patients with MDD is poorly understood.

Methods: Adults diagnosed with depression were identified from the 2022 US National Health and Wellness Survey (NHWS). Participants with depression were recontacted to participate in an online cross-sectional survey to collect data on anhedonia, using the Snaith-Hamilton Pleasure Scale (SHAPS). Multivariable analyses assessed the association of SHAPS score with health-related outcomes, while controlling for age, sex, race, comorbidity burden, and insurance status. The SHAPS (score range: 14 to 56) assesses the ability to experience pleasure, with higher scores indicating greater levels of anhedonia.

Results: Of the 8270 NHWS respondents with depression who met inclusion criteria, 665 completed the recontact survey (mean age, 58.4 years; female, 78.3%). Mean SHAPS score was 25.4 (range, 14-47). After adjustments for covariates, higher SHAPS scores were significantly (all P <.05) associated with higher levels of depression (β = 0.211) and anxiety (β = 0.126), poorer mental (β = -0.339) and physical health-related quality of life (β = -0.178), greater impairment while working [rate ratio (RR) = 1.02], and higher direct medical costs (RR = 1.02).

Conclusions: In adults with depression, higher levels of anhedonia were associated with greater clinical, humanistic, and economic burden. These results highlight the need for targeted treatments to help patients with MDD with prominent anhedonia attain improved clinical, humanistic, and work productivity outcomes.

Background: To investigate the association between prenatal illicit substance exposure and infant mortality, addressing the unclear links between specific and multiple substances and increased mortality.

Methods: This 16-year retrospective cohort study used Taiwan's National Health Insurance Research Database, the Taiwan Maternal and Child Health dataset, and the Integrated Illegal Drug Database, including 1 937 301 pregnant women who delivered from 2004 to 2019. Among them, 11 477 used illicit drugs during pregnancy, with a matched control group of 45 908 non-users based on maternal age, income, and childbirth year. Of the drug users, 26.9% used multiple substances, primarily methamphetamine and opioids. The primary outcome was all-cause mortality within the first year of life, with analyses stratified by substance type and timing of exposure. Cox regression models were employed to assess mortality, with results presented as adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). A P-value below .05 was considered statistically significant.

Results: Infant from illicit drug-exposed mothers had a higher all-cause mortality rate (0.7%) compared to the control group (0.4%). Polysubstance use, which in most cases involved methamphetamine or opioids, was significantly associated with increased mortality risk (aHR 1.53, 95% CI 1.00-2.34), whereas no single substance alone-including methamphetamine (aHR 1.38, 95% CI 0.87-2.19) or opioids (aHR 1.63, 95% CI 0.98-2.72)-showed a statistically significant association. 3,4-Methylenedioxymethamphetamine, ketamine, and cannabis were likewise not linked to increased mortality. Mortality risk increased with drug exposure during pregnancy, with borderline significant associations in the first (aHR 1.82, 95% CI 0.98-3.37) and second trimesters (aHR 1.96, 95% CI 0.99-3.86), suggesting heightened vulnerability during early to mid-gestation.

Conclusion: One-year infant mortality is elevated among women with illicit substance use, with a higher proportion of deaths attributed to preterm birth and hypoxic events. The highest mortality risk was observed among those with polysubstance use. The findings underscore a dire public health issue, associating prenatal illicit substance exposure, notably multiple substances use, opioids, and methamphetamine, with heightened infant mortality rates, calling for targeted interventions and further research.

Background: The lack of a rodent model for both motor and phonic tics hinders research on deep brain stimulation (DBS) for refractory Tourette syndrome (TS). Striatal disinhibition with a gamma-aminobutyric acid A antagonist (bicuculline) was previously shown to induce hyperkinesia and vocalizations in monkeys, indicating its potential as a TS model. In rats, however, only hyperkinesia was validated, prompting us to investigate whether they can also develop abnormal vocalizations and whether both conditions respond to thalamic DBS.

Methods: Rats underwent surgical implantation of a unilateral guide cannula targeting the caudate putamen (CPu) or nucleus accumbens (NAc). Additionally, they were implanted with an ipsilateral stimulation electrode targeting the border between the central medial (CM) and ventrolateral (VL) thalamic nuclei. Motor changes and ultrasound vocalizations were recorded and characterized offline.

Results: CPu bicuculline elicited arrhythmic shoulder jerks that tend to appear in fading bursts and sporadically alternate with sustained generalized hyperextension. Nucleus accumbens bicuculline elicited similar hyperkinesia, but at a much lower dose to prevent convulsions. DBS of CM/VL, but not adjacent regions, attenuated hyperkinesia with lower intensity showing stronger effects. In addition, bicuculline in NAc, but not CPu, elicited nonsensical vocalizations. However, the effect of CM/VL DBS on vocalizations remained inconclusive.

Conclusions: Hyperkinesia temporal features, co-development with vocalizations, and responsiveness to CM/VL DBS suggest striatal disinhibition may serve as a TS rat model. However, other movement disorders with vocal complications cannot be excluded, given the challenge of validating key tic indicators in animals, such as premonitory urge and suppressibility.

Background: Motor impulsivity is a symptom shared by several psychiatric disorders. Stress exacerbates impulsivity, but the neurocircuits involved are unknown. We have shown that the orbitofrontal cortex (OFC) is activated during a rodent motor impulsivity task and that chronic unpredictable stress (CUS) increases premature responding. In this study, we examine the role of the OFC projection to dorsal medial striatum (DMS) in motor control, and test whether this pathway mediates the effects of stress on impulsive action.

Methods: Motor impulsivity was measured with the 1-choice serial reaction time test (1-CSRTT). To determine if OFC-DMS projections are involved in controlling impulsivity, we used pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated chemogenetic manipulation during 1-CSRTT. We examined stress effects on OFC-DMS neuronal activation using Fos immunohistochemistry. To assess if stress increases impulsivity through OFC-DMS projections, we chemogenetically manipulated the pathway in stressed rats during behavior.

Results: We found OFC-DMS projections inhibit premature responding in a well-mastered task. Stress attenuated OFC neuronal activation, including the OFC-DMS projection neurons, during behavior. However, selectively activating the projection in stressed rats was not sufficient to abolish the stress effects. Finally, the response to stress depended on baseline trait impulsivity. Rats with low trait impulsivity were more vulnerable to stress and showed attenuated activation of OFC-DMS neurons but increased activation of other OFC cell populations.

Conclusions: These results suggest the OFC-DMS pathway modulates impulsivity in concert with other OFC neuronal populations. Furthermore, stress effects are baseline-dependent and affect only low-impulsivity rats, possibly by altering the balance of activation in functionally opposing neuronal populations.

Background: Heterogeneous pathophysiological characteristics in patients with major depressive disorder (MDD) lead to individually differentiated sensitivities to antidepressants. Based on the hypothesis that gamma-band dynamic fluctuations in cortical functional connectivity (FC) in response to salient stimuli are linked to pathophysiological characteristics, we conducted a classification analysis for antidepressant responsiveness prediction.

Methods: Biosignals and psychological measures were acquired from 47 patients with MDD prior to treatment. After 8 weeks of antidepressant therapy, patients were divided into non-remitted MDD (nrMDD; aged 42.55 ± 11.52 years; n = 20) and remitted MDD (rMDD; aged 47.22 ± 11.59 years; n = 27) groups based on their depressive symptom reduction. Electroencephalography (EEG) signals were acquired during the duration-variant auditory mismatch negativity paradigm. From the deviant condition, gamma-band weighted phase-lag index-based dynamic fluctuations were evaluated using a template generated from 21 demography-matched healthy control (aged 43.81 ± 14.10 years) data.

Results: Using these dynamic functional connectivity (dFC) features, a machine learning-based classification analysis was performed for nrMDD and rMDD. Using leave-one-out cross-validation, the linear discriminant analysis classifier achieved the best accuracy (82.98%) for classifying nrMDD and rMDD. Further simple effect analyses identified three core dFC features for nrMDD: (i) relatively intact time-dependent FC between the left frontal and right temporal regions; (ii) disrupted right frontoparietal FC; and (iii) disrupted left fronto-temporal FC. These dFC features commonly exhibit transient hyperconnections in patients with nrMDD.

Conclusions: We demonstrated that gamma-band dFC responses to salient stimuli could serve as potential biomarkers for antidepressant responsiveness prediction in patients with MDD.