International Journal of Neuropsychopharmacology最新文献

Background: A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome.

Methods: Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items.

Results: In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome.

Conclusions: Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics.

Background: We recently showed sex differences in the antidepressant-like potential of electroconvulsive seizures (ECS) in adolescent rats; whereas it worked for male rats, it was inefficacious in females. Because sex steroids might be important modulators of these sex disparities, we evaluated the role of estrogens in the differential response induced by adolescent ECS. Moreover, given the literature suggesting certain cognitive sequelae from ECS exposure, we aimed at evaluating its long-term safety profile in adulthood.

Methods: Adolescent Sprague-Dawley rats were pretreated with letrozole (1 mg/kg/day) or vehicle (1 mL/kg/day) for 8 days (i.p.) and treated during the last 5 days (3 hours later) with ECS (95 mA, 0.6 s, 100 Hz) or SHAM. Antidepressant-like responses were measured in the forced swim test, and long-term cognitive performance was assessed in the Barnes maze.

Results: During adolescence, whereas ECS alone exerted an antidepressant-like response in male rats, its combination with letrozole permitted ECS to also induce efficacy in females. Moreover, adolescent ECS treatment improved cognitive performance in adulthood although exclusively in male rats.

Conclusions: Adolescent ECS demonstrated an antidepressant-like potential together with certain long-term beneficial cognitive effects but exclusively in male rats. For females, efficacy was restricted to a situation in which the biosynthesis of estrogens was reduced. Therefore, estrogens and/or testosterone levels play a crucial role in the sex disparities induced by ECS in Sprague-Dawley rats. Based on this study and on the literature supporting its safety, ECS should be encouraged for use in cases of treatment-resistant depression during adolescence, while adhering to sex-specific considerations.

Background: The role of neurofilament light chain (NFL) in treatment-resistant depression (TRD) is unclear. Whether baseline NFL concentrations are associated with the antidepressant effects of low-dose ketamine infusion has not been determined.

Methods: The NFL concentrations of 71 patients with TRD and 17 healthy controls were assessed. Patients with TRD were randomly administered a single infusion of 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were assessed before infusion and sequentially at postinfusion timepoints (after 240 minutes and after 2-7 and 14 days) using the Hamilton Depression Rating Scale (HDRS).

Results: After adjustment for age, sex, and body mass index, patients with TRD were more likely to have higher concentrations of NFL than healthy controls (P < .001). A generalized estimating equation model with adjustments for infusion group, age, sex, body mass index, and baseline HDRS scores showed that baseline NFL concentrations were positively associated with subsequent HDRS scores following low-dose ketamine infusion (P = .038).

Discussion: Higher concentrations of NFL were observed among patients with TRD compared with healthy controls. Baseline NFL concentrations may predict the antidepressant effects of low-dose ketamine infusion.

Background: Racemic ketamine consists of two enantiomers, namely (R)-ketamine and (S)-ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)-enantiomer has been approved for the treatment of major depression, whereas (R)-ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of non-REM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects.

Methods: Here, we compared acute effects of the two ketamine enantiomers (15 mg/kg i.p.) on different sleep-wake stages in freely moving, EEG-equipped rats. We also evaluated the antidepressant-like activity of the enantiomers in a chronic restraint stress model of depression.

Results: (S)-ketamine but not (R)-ketamine increased REM sleep latency and decreased REM sleep time at 2 and 3 hours, and increased electroencephalogram delta power during NREM sleep. In addition, only (S)-ketamine increased wakefulness and decreased NREM sleep in the first 2 hours. In the forced swimming test, only (S)-ketamine decreased the immobility time of chronically stressed rats.

Conclusion: Effects of the two ketamine enantiomers on rat sleep-wake architecture and behavior are markedly different when administered in the same dose. (S)-ketamine remarkably affects the sleep-wake cycle and very likely sleep-related neuroplasticity, which may be relevant for its antidepressant efficacy. Our results regarding (R)-ketamine's lack of effect on vigilance and behavior are in line with recent clinical studies.

Background: Previous studies have focused on both ventral striatum (VS) and dorsal striatum (DS) in characterizing dopaminergic deficits in addiction. Animal studies suggest VS and DS dysfunction each in association with impulsive and compulsive cocaine use during early and later stages of addiction. However, few human studies have aimed to distinguish the roles of VS and DS dysfunction in cocaine misuse.

Methods: We examined VS and DS resting-state functional connectivity (rsFC) of 122 recently abstinent cocaine-dependent individuals (CDs) and 122 healthy controls (HCs) in 2 separate cohorts. We followed published routines in imaging data analyses and evaluated the results at a corrected threshold with age, sex, years of drinking, and smoking accounted for.

Results: CDs relative to HCs showed higher VS rsFC with the left inferior frontal cortex (IFC), lower VS rsFC with the hippocampus, and higher DS rsFC with the left orbitofrontal cortex. Region-of-interest analyses confirmed the findings in the 2 cohorts examined separately. In CDs, VS-left IFC and VS-hippocampus connectivity was positively and negatively correlated with average monthly cocaine use in the prior year, respectively. In the second cohort where participants were assessed with the Barratt Impulsivity Scale (BIS-11), VS-left IFC and VS-hippocampus connectivity was also positively and negatively correlated with BIS-11 scores in CDs. In contrast, DS-orbitofrontal cortex connectivity did not relate significantly to cocaine use metrics or BIS-11 scores.

Conclusion: These findings associate VS rsFC with impulsivity and the severity of recent cocaine use. How DS connectivity partakes in cocaine misuse remains to be investigated.

Background: Clinician adherence to guideline recommendations in the pharmacological therapy of schizophrenia is important for favorable patient outcomes. To evaluate whether prescriptions followed the guidelines for pharmacological therapy of schizophrenia, we recently developed a summary indicator of multiple quality indicators: the individual fitness score (IFS). It is unclear whether adherence to the guidelines is related to patient outcomes. Here, we investigated correlations between the IFS values and psychotic symptoms in patients with schizophrenia.

Methods: We assessed whether patients' current prescriptions adhered to the guideline recommendations using the IFS in 47 patients with treatment-resistant schizophrenia (TRS) and 353 patients with non-TRS (total n = 400), respectively. We investigated correlations between the IFS and total scores and scores on the 5 subscales of the Positive and Negative Syndrome Scale (PANSS). Furthermore, we explored correlations between over 2-year longitudinal changes in IFS values and changes in psychotic symptoms in some patients (n = 77).

Results: We found significant negative correlation between the IFS and PANSS total score in all patients with schizophrenia (β = -0.18, P = 9.80 × 10-5). The IFS was significantly and nominally negatively correlated with the PANSS total score in patients with non-TRS (Spearman's rho = -0.15, P = 4.40 × 10-3) and patients with TRS (rho = -0.37, P = .011), respectively. The IFS was also significantly and nominally negatively correlated with several factors, such as the negative and depressed factors, in patients with non-TRS and patients with TRS, respectively (P < .05). Furthermore, the change in IFS values was marginally negatively correlated with the changes in PANSS total scores and scores on the positive and depressed factors (P < .05).

Conclusions: These findings suggest that efforts to improve clinician adherence to guideline recommendations for pharmacological therapy of schizophrenia, as assessed by the IFS, may lead to better outcomes in patients with schizophrenia.

Background: Paliperidone palmitate 6-month (PP6M) demonstrated noninferiority to paliperidone palmitate 3-month in preventing relapse in patients with schizophrenia in a phase 3 double-blind (DB) study (NCT03345342). Here, we report long-term efficacy and safety results from a 2-year single-arm, open-label extension (OLE; NCT04072575) of this DB study.

Methods: Participants who completed the DB study without relapse were enrolled and followed-up every 3 months up to 2 years. Participants received 4 PP6M gluteal injections (700/1000 mg eq.) at baseline, 6-month, 12-month, and 18-month visits. Efficacy endpoints included assessment of relapse, Positive and Negative Syndrome Scale total score, Personal and Social Performance score, and Clinical Global Impression-Severity scale change from baseline. Safety was assessed by treatment-emergent adverse events (TEAEs), physical examinations, and laboratory tests.

Results: Of 178 participants enrolled, 154 (86.5%) completed the OLE (mean age: 40.4 years, men: 70.8%; mean duration of PP6M exposure during OLE: 682.1 days). Overall, 7/178 (3.9%) participants relapsed between 20 and 703 days after enrolment. Mean (SD) changes from baseline to endpoint were as follows: Positive and Negative Syndrome Scale total score, 0.7 (8.22); Clinical Global Impression-Severity, 0.0 (0.51); and Personal and Social Performance Scale, 0.5 (7.47). Overall, 111/178 participants (62.4%) reported ≥1 TEAE; most common (>5%) TEAEs were headache (13.5%) and increased blood prolactin/hyperprolactinemia (18.0%); 8/178 (4.5%) participants experienced serious TEAEs, and 6/178 (3.4%) participants withdrew due to TEAEs. No deaths were reported.

Conclusions: The relapse rate observed with PP6M during the 2-year OLE was low (3.9%). Clinical and functional improvements demonstrated in the DB study were maintained during OLE, and no new safety concerns were identified.

Trial registration: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

Results from a pilot, 6-week, randomized, open-label, rater-blinded study, with 46-week extension, indicate very good tolerability with exceptional, clinically important, increasing efficacy of evenamide (7.5, 15, and 30 mg bid), a glutamate modulator, as add-on treatment to antipsychotics in 161 treatment-resistant, schizophrenia patients. Ninety-five percent of patients completed 6 weeks (1 discontinued for adverse event), and 89% continued in the extension. Results from the first 100 patients enrolled showed very low attrition over 1 year (77 completers); data pooled from all dose groups showed the Positive and Negative Syndrome Scale total score improved significantly (P < .001; paired t test; last observation carried forward [LOCF]) from baseline at 6 weeks (-9.4), 6 months (-12.7), and 1 year (-14.7); similarly, the proportion of responders (≥20% improvement) increased over time from 6 weeks (16.5%) to 6 months (39%) to 1 year (47.4%). Noteworthy improvement was also observed at each timepoint on the Clinical Global Impression - Severity scale and Clinical Global Impression of Change, indicating progressively increasing efficacy of evenamide up to 1 year.