Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic vs non-autistic women.

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala-the brain's 'salience detector'-while processing emotional faces vs shapes was tested in 16 autistic and 21 non-autistic women by functional magnetic resonance imaging in a placebo-controlled, within-subject, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35-voxel cluster, Montreal Neurological Institute (MNI) coordinates of peak voxel = -22 -10 -28; mean change = +0.079%, t = 3.159, PTukey = 0.0166) but not among non-autistic women (mean change = +0.003%, t = 0.153, PTukey = 0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not in non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin's effects on the amygdala to specifically include autistic women and specify the subregion of the effect.

The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

BACKGROUND: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. METHODS: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. RESULTS: Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. CONCLUSIONS: The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.

The early impact of COVID-19 on mental health and community physical health services and their patients' mortality in Cambridgeshire and Peterborough, UK.

BACKGROUND: COVID-19 has affected social interaction and healthcare worldwide. METHODS: We examined changes in presentations and referrals to the primary provider of mental health and community health services in Cambridgeshire and Peterborough, UK (population ~0·86 million), plus service activity and deaths. We conducted interrupted time series analyses with respect to the time of UK "lockdown", which was shortly before the peak of COVID-19 infections in this area. We examined changes in standardized mortality ratio for those with and without severe mental illness (SMI). RESULTS: Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking). This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for eating disorders, for which there was no evidence of change. Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality was primarily in the over-70s. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity. CONCLUSIONS: COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. "Supply" changes may have reduced access to mental health services for some. "Demand" changes may reflect a genuine reduction of need or a lack of help-seeking with pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.

Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans.

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive-compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

Modafinil Improves Episodic Memory and Working Memory Cognition in Patients With Remitted Depression: A Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Cognitive dysfunction is a core feature of depression and tends to persist even after mood symptoms recover, leading to detrimental effects on clinical and functional outcomes. However, most currently available treatments have not typically addressed cognition. Modafinil has been shown to have beneficial effects on cognitive function and therefore has the potential to improve cognition in depression. The objective of this double-blind, placebo-controlled study was to investigate the effects of modafinil on cognitive functions in patients with remitted depression. METHODS: In total, 60 patients with remitted depression participated in the study. Cognitive functions were evaluated with tests of working memory, planning, attention, and episodic memory from the Cambridge Neuropsychological Test Automated Battery at the baseline session and after treatment. A double-blind, randomized, placebo-controlled, parallel groups design was used to assess the effects of single-dose (200 mg) modafinil (n = 30) or placebo (n = 30) on cognition and fatigue. The main outcome measures were neurocognitive test scores from the Cambridge Neuropsychological Test Automated Battery. Visual analogue scales for subjective feelings and fatigue were used as secondary measures. RESULTS: The modafinil group had significantly better performance on tests of episodic memory (p = .01, ηp2 = .10) and working memory (p = .04, ηp2 = .06). Modafinil did not improve planning or sustained attention. CONCLUSIONS: This study suggested that modafinil (200 mg) could improve episodic memory and working memory performance in patients with remitted depression. Modafinil may have potential as a therapeutic agent to help remitted depressed patients with persistent cognitive difficulties.

Lack of deleterious effects of buspirone on cognition in healthy male volunteers.

Buspirone is a serotonin 5-HT(1A) receptor agonist licensed for the treatment of anxiety. Other anxiolytic drugs such as benzodiazepines show significant sedative and other unwanted effects on cognition. Studies to date have yet to investigate cognitive effects of buspirone using well-validated computerized tests. The aim of this study was to assess acute subjective and cognitive effects of buspirone in healthy volunteers. Sixty healthy male volunteers received 20 mg buspirone, 30 mg buspirone, or placebo per os in a double-blind parallel groups design (N=20 per group). Subjective ratings (visual analogue scales) were completed at baseline, and at 1.5 and 3.5 hours post-capsule. Cognitive assessment was undertaken between 1.5 and 3.5 hours post-capsule, including tests of memory, executive planning, impulse control, decision making and cognitive flexibility. The 30 mg buspirone group showed significantly higher subjective ratings of contentedness 3.5 hours after capsule relative to placebo. Treatment and placebo groups did not differ significantly on cognitive measures. In contrast to benzodiazepines, the anxiolytic buspirone appears to lack detectable deleterious effects on cognition when administered acutely at clinically meaningful doses. Future research directions are discussed in relation to acute and chronic studies in neuropsychiatric populations.