Current ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties.

To investigate efficacy, safety, and pharmacokinetics of KET01 in TRD.

KET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline.

KET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p<0.00000000001). KET01-02 trial; no differences in CADSS score (range: 0.2 to 1.3), and heart rate and blood pressure were observed between the groups on Day 1 and beyond. 10%, 12%, and 15% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 groups, respectively had CADSS score >4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively.

Oral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD.

C. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health

The first psychiatric intensive care unit (PICU) opened in the early 1970's in New York. This ward was designed to manage patient that did not respond to treatment in open psychiatric wards. There are about 15 PICUs in Sweden but the concept has not been specified by any public organs. In many county hospitals, both acute and intensive care units exists parallel.

Therefore, the aim of this study was to describe the core characteristics of PICU in Sweden and to describe the care activities provided for patients admitted to PICU.

Critical incident technique was used. In the study, eighteen caregivers at a PICU participated by completing a semi-structured questionnaire. Additional, in-depth interviews with three nurses and two assistant nurses also constitute the data.

Four categories were identified that characterise the core of PICU: the dramatic admission, protests and refusal of treatment, escalating behaviours and temporarily coercive measure. Care activities for PICU were also analysed and identified as controlling - establishing boundaries, protecting - warding off, supporting - giving intensive assistance and structuring the environment.

PICU were interpreted as a level of care as it is composed by limited structures and closeness in care.

Evaluate the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy on sleep disturbance in patients with major depressive disorder (MDD).

Pooled data from four 6- or 8-week placebo-controlled quetiapine XR (50-300mg/day, administered in the evening) monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00004) were analysed. Primary endpoint: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Post-hoc analyses assessed changes in: MADRS item 4 (reduced sleep); Hamilton Rating Scale for Depression (HAM-D) items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) and sleep disturbance factor (items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) total and item scores. MADRS total score change was analysed for patients experiencing high (baseline HAM-D sleep disturbance factor score >=4) and low (baseline HAM-D sleep disturbance factor score < 4) sleep disturbance.

In total, 2,116 patients were randomised. At last assessment, quetiapine XR (all doses combined) significantly (p< 0.001) reduced MADRS item 4, HAM-D sleep disturbance factor and items 4, 5 and 6 and PSQI total scores from baseline versus placebo. Quetiapine XR significantly (p< 0.001) improved MADRS total score from baseline versus placebo at all time points in patients experiencing high sleep disturbance (n=865, quetiapine XR; n=514, placebo). Quetiapine XR improved MADRS total score versus placebo in patients with low sleep disturbance (n=252, quetiapine; n=121, placebo): difference significant at Weeks 2(p< 0.001), 4(p< 0.05) and 6(p< 0.05).

Quetiapine XR monotherapy improved symptoms of sleep disturbance in MDD and was effective against depressive symptoms in patients experiencing high and low sleep disturbance levels. AstraZeneca funded.

Psychiatric intensive care units (PICU) are rarely described since it is secluded from external insight. At the same time, it is highly intensive since staff and patients interact around the clock in the most acute phase of psychiatric illness. the PICUs admit patients who are considered extremely unmanageable within psychosis units or acute psychiatric wards, and who often demonstrate aggressive or other forms of severe behaviors.

This raises the question: What is going on in these units and what constitutes nursing care?

Spradley's 12-step ethnographic methodology was applied. Data was collected through more than 200 hours of field work on three PICUs including 16 hours of formal interviewing and numerous of informal interviews; data also consisted of writing memos and field notes. the field work aimed to understand the staff member's way of interact with the patients and what they did to care for these patients who was considered as unmanageable.

The findings presented here describe how and when nursing care is provided in PICUs. the findings are presented in relation to themes, as these emerged within the psychiatric intensive nursing care. Six themes emerged as frames for nursing care: providing surveillance, soothing, being present, trading information, maintaining security and reducing.

These themes are used to strike a balance between turbulence and stability and to achieve equilibrium. as the nursing care intervenes when turbulence emerges, the PICU becomes a sanctuary that offers tranquility, peace and rest.

Being breastfed in infancy has been shown to benefit neurodevelopment. However, whether the benefits persist to old age remains unclear.

We examined the associations between breastfeeding and its duration on cognitive ability in young adulthood and old age, and on aging-related cognitive change over five decades. In total, 931 men from the Helsinki Birth Cohort Study born in 1934–1944 in Finland took the Finnish Defence Forces Basic Intellectual Ability Test (total and verbal, arithmetic and visuospatial subtest scores) twice, at ages 20.2 and 67.9 years, and had data on breastfeeding (yes v. no) and its duration (‘never breastfed’, ‘up to 3’, ‘3 to 6’ and ‘6 or more months’). Linear and mixed model regressions tested the associations.

At 20.2 years, breastfed men had higher cognitive ability total and visuospatial subtest scores [mean differences (MDs) ranged between 3.0–3.9, p values < 0.013], and its longer duration predicted higher cognitive ability total and arithmetic and visuospatial subtest scores (MDs ranged between 3.0 and 4.8, p values < 0.039). At 67.9 years, breastfed men had higher total cognitive ability and all subtest scores (MDs ranged between 2.6 and 3.4, p values < 0.044) and its longer duration predicted all cognitive ability scores (MDs ranged between 3.1 and 4.7, p values < 0.050). Verbal subtest scores decreased over five decades in men who were never breastfed or were breastfed for 3 months or less, and increased in those breastfed for longer than 3 months.

Neurodevelopmental advantages of breastfeeding and its longer duration persist into old age, and longer duration of breastfeeding may benefit aging-related change, particularly in verbal reasoning ability.

Results of adulthood mental health of those born late-preterm (34 + 0–36 + 6 weeks + days of gestation) are mixed and based on national registers. We examined if late-preterm birth was associated with a higher risk for common mental disorders in young adulthood when using a diagnostic interview, and if this risk decreased as gestational age increased.

A total of 800 young adults (mean = 25.3, s.d. = 0.62 years), born 1985–1986, participated in a follow-up of the Arvo Ylppö Longitudinal Study. Common mental disorders (mood, anxiety and substance use disorders) during the past 12 months were defined using the Composite International Diagnostic Interview (Munich version). Gestational age was extracted from hospital birth records and categorized into early-preterm (<34 + 0, n = 37), late-preterm (34 + 0–36 + 6, n = 106), term (37 + 0–41 + 6, n = 617) and post-term (⩾42 + 0, n = 40).

Those born late-preterm and at term were at a similar risk for any common mental disorder [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.67–1.84], for mood (OR 1.11, 95% CI 0.54–2.25), anxiety (OR 1.00, 95% CI 0.40–2.50) and substance use (OR 1.31, 95% CI 0.74–2.32) disorders, and co-morbidity of these disorders (p = 0.38). While the mental disorder risk decreased significantly as gestational age increased, the trend was driven by a higher risk in those born early-preterm.

Using a cohort born during the advanced neonatal and early childhood care, we found that not all individuals born preterm are at risk for common mental disorders in young adulthood – those born late-preterm are not, while those born early-preterm are at a higher risk. Available resources for prevention and intervention should be targeted towards the preterm group born the earliest.

Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.

We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).

One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.

Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages.

Of 12 597 Helsinki Birth Cohort Study participants, born 1934–1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders.

Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders.

Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.

Patients with schizophrenia have excess cardiovascular morbidity and mortality. Previous studies suggest that this may be partly due to inadequate somatic treatment and care, such as non-optimal use of lipid-lowering and antihypertensive pharmacotherapy, but longitudinal studies on such aetiological pathways are scarce.

We investigated the use of lipid-lowering and antihypertensive pharmacotherapy, and the risk of hospitalization for and death from coronary heart disease and stroke among patients with schizophrenia in a birth cohort of 12 939 subjects (Helsinki Birth Cohort Study). This cohort was followed for over 30 adult years by using national databases on cardio- and cerebrovascular hospitalizations and mortality and on reimbursement entitlements and use of drugs for treatment of hypertension, dyslipidaemia, coronary heart disease and diabetes.

Individuals with schizophrenia had a higher risk of hospitalization for coronary heart disease [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.03–2.57], and mortality from this disease was markedly higher (HR 2.92, 95% CI 1.70–5.00), particularly among women (p=0.001 for women, p=0.008 for men). Women with schizophrenia had also marginally increased stroke mortality (p=0.06). However, patients with schizophrenia used less lipid-lowering (odds ratio 0.47, 95% CI 0.27–0.80) and antihypertensive drug treatment (HR 0.37, 95% CI 0.22–0.61).

In this longitudinal study, coronary heart disease morbidity was increased and coronary heart disease mortality markedly increased in patients, especially in women with schizophrenia. These patients nevertheless received less antihypertensive and lipid-lowering treatment.