The effect of intranasal oxytocin on neurocognition in people with schizophrenia: A randomized controlled trial.

Schizophrenia is characterized by persistent cognitive deficits that significantly impact functional outcomes. Despite the current available treatments, these deficits remain inadequately addressed, highlighting the need to explore the effect of more novel treatments on cognition. The current study examined the effect of intranasal oxytocin on cognitive functioning in people with schizophrenia by utilizing data from a 12-week, randomized controlled trial. Sixty-seven participants with schizophrenia or schizoaffective disorder were randomized to receive placebo or intranasal oxytocin. Participants completed a comprehensive neuropsychological battery at baseline and 12 weeks. The results demonstrated that intranasal oxytocin did not significantly improve cognition in people with schizophrenia compared to placebo. These findings suggest that oxytocin does not worsen or enhance cognition in people with schizophrenia. Yet, the current intervention did not standardize the timing of cognitive assessments relative to the timing of oxytocin administration, which may explain our findings. Future studies attempting to clarify this relationship would benefit from employing a more controlled approach to the timing of treatment and assessments.

Racial disparities and predictors of functioning in schizophrenia.

Black Americans are diagnosed with schizophrenia spectrum disorders at more than twice the rate of White individuals and experience significantly worse outcomes following diagnosis. Little research has examined specific factors that may contribute to worse functional outcomes among Black Americans diagnosed with schizophrenia. One approach to understanding why racial disparities emerge is to examine established predictors of functioning in this population: neurocognition, social cognition, and symptom severity. The present study aims to broaden existing literature on racial differences within these domains by (a) examining racial differences in functioning and these established predictors of functioning (i.e., neurocognition, social, and symptom severity) and (b) investigating whether cognition and symptom domains similarly predict functioning between Black and White Americans with schizophrenia. Sixty-six participants' baseline neurocognition, social cognition, symptom severity, and functioning were assessed. Black participants demonstrated lower neurocognition scores and higher levels of disorganized symptoms relative to White participants. No racial differences in functioning or social cognition were observed. Further, race did not moderate the relationship between any of these established predictors and functioning outcomes. The largely nonsignificant differences in known predictors of functioning highlight the need to explore further domains that may be more relevant for understanding racial disparities in schizophrenia. Considering that psychosocial treatments for schizophrenia spectrum disorders often focus on cognition, these results underscore the importance of identifying whether these domains or other treatment targets may be better in addressing racial disparities in functioning. Possible areas of exploration for future work (e.g., structural factors, racism-related stress) are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations between Self-Rated Health and Perinatal Depressive and Anxiety Symptoms among Latina Women.

PURPOSE: The objective of this study was to determine whether decreases in or consistently low preconception to pregnancy self-rated health (SRH) were associated with perinatal depressive and anxiety symptoms among Latinas. METHODS: This is a secondary data analysis of 153 perinatal Latinas. Three groups were created to capture SRH from preconception to pregnancy: a decline in ratings, consistently low, and good+ (i.e., good, very good, or excellent). SRH was measured using two questions about their perceived physical health before and during pregnancy. Depressive symptoms and anxiety symptoms were assessed in the third trimester and six weeks postpartum using the Edinburgh Postnatal Depression Scale and State-Trait Anxiety Inventory, respectively. Life stressors were assessed in pregnancy using a modified version of the Life Experiences Survey. Linear regressions tested the associations. RESULTS: Women with consistently low (i.e., fair or poor) SRH reported significantly more prenatal depressive symptoms than women who reported consistently good+ SRH. Women who reported a decline in SRH to fair or poor reported more prenatal anxiety symptoms but decreased postpartum anxiety symptoms than women who reported consistently good+ ratings. Life stressors were positively associated with prenatal depressive and anxiety symptoms. CONCLUSIONS: Healthcare practitioners should assess changes in SRH ratings to identify risks for prenatal depressive and anxiety symptoms among Latinas, who have elevated rates of depressive and anxiety symptoms compared to non-Hispanic White women. Policymakers should provide healthcare providers with mental health resources to support at-risk Latinas during the prenatal period.

Exploring associations between perinatal depression, anxiety, and urinary oxytocin levels in Latinas.

Perinatal depression has been associated with lower oxytocin (OT) levels. However, few studies have explored this topic in relation to Latinas who are at high risk of perinatal depression. The objective of this study was to explore these associations in Latinas. A total of 108 Latinas in the third trimester of pregnancy participated in the study. Depression and urinary OT levels were assessed in pregnancy and 6 weeks postpartum. Nonparametric tests were implemented to test the proposed associations. Results revealed that 28% of the participants had probable depression in pregnancy, and 23% at 6 weeks postpartum. OT levels significantly decreased from prenatal to postpartum in the whole sample; however, participants with probable prenatal depression did not exhibit a significant change in OT levels. Participants who were depressed or anxious at 6 weeks postpartum exhibited persistently higher mean OT levels over time. A distinct pattern of higher levels of OT in depressed Latinas suggests that OT levels may be an important neuroendocrine factor contributing to depressive and anxious symptoms.

Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism.

Currently, there are no established pharmaceutical strategies that effectively treat social deficits in autism spectrum disorder (ASD). Oxytocin, a neurohormone that plays a role in multiple types of social behaviors, has been proposed as a possible therapeutic against social impairment and other symptoms in ASD. However, from the standpoint of pharmacotherapy, oxytocin has several liabilities as a standard clinical treatment, including rapid metabolism, low brain penetrance, and activity at the vasopressin (antidiuretic hormone) receptors. The present studies describe findings from a preclinical screening program to evaluate oxytocin receptor (OXTR) agonists and oxytocin metabolites for potential clinical use as more optimal treatments. We first investigated two synthetic oxytocin analogs, TC-OT-39 and carbetocin, using in vitro cell-based assays for pharmacological characterization and behavioral tests in the BALB/cByJ mouse model of ASD-like social deficits. Although both TC-OT-39 and carbetocin selectively activate the OXTR, neither synthetic agonist had prosocial efficacy in the BALB/cByJ model. We next evaluated two oxytocin metabolites: OT(4-9) and OT(5-9). While OT(5-9) failed to affect social deficits, the metabolite OT(4-9) led to significant social preference in the BALB/cByJ model, in a dose-dependent manner. The increased sociability was observed at both 24 h and 12 days following the end of a subchronic regimen with OT(4-9) (2.0 mg/kg). Overall, these results suggest that the prosocial effects of oxytocin could be mediated by downstream activity of oxytocin metabolites, raising the possibility of new pathways to target for drug discovery relevant to ASD.

Early Life Abuse Moderates the Effects of Intranasal Oxytocin on Symptoms of Premenstrual Dysphoric Disorder: Preliminary Evidence From a Placebo-Controlled Trial.

Background: Although intranasal oxytocin (OXT) has been proposed to be a promising treatment for some psychiatric disorders, little research has addressed individual difference factors that may predict response to OXT. One such factor is early life abuse (ELA), which has widespread influences on social-emotional processing and behavior. This single-blind, placebo-controlled crossover trial examined the role of ELA in shaping the effects of intranasal OXT (vs. placebo) on daily behavioral symptoms in women with three or more prospectively-diagnosed cycling symptoms of premenstrual dysphoric disorder (PMDD). Methods: Participants were ten women with PMDD (n = 8) or subthreshold PMDD (n = 2), who had experienced ELA prior to age 13 (n = 5) or no ELA (n = 5). They completed two study visits during the late luteal (premenstrual) phase: once following administration of intranasal OXT and once following intranasal placebo (counterbalanced). Participants then self-administered OXT or placebo at home three times per day for 5 days or until menstrual onset, and prospectively rated daily emotional symptoms of PMDD. Power was adequate to detect medium main and interactive effects. Results: Among women with ELA, intranasal OXT (vs. placebo) increased the premenstrual emotional symptoms of PMDD, whereas among women without ELA, OXT decreased symptoms. Conclusion: This study adds to a growing literature highlighting the importance of considering historical social contexts and traits (such as ELA) as moderators of therapeutic response to OXT.

Oxytocin, Tolerance, and the Dark Side of Addiction.

Substance use disorders blight the lives of millions of people and inflict a heavy financial burden on society. There is a compelling need for new pharmacological treatments as current drugs have limited efficacy and other major drawbacks. A substantial number of animal and recent clinical studies indicate that the neuropeptide, oxytocin, is a particularly promising therapeutic agent for human addictions, especially alcohol use disorders. In preliminary trials, we found that oxytocin administered by the intranasal route, which produces some neuropeptide penetration into the CNS, potently blocked withdrawal and reduced alcohol consumption in heavy drinkers. A considerable body of earlier animal studies demonstrated that oxytocin inhibits tolerance to alcohol, opioids, and stimulants as well as withdrawal from alcohol and opioids. Based on these preclinical findings and our clinical results, we hypothesize that oxytocin may exert therapeutic effects in substance dependence by the novel mechanism of diminishing established tolerance. A newer wave of studies has almost unanimously found that oxytocin decreases self-administration of a number of addictive substances in several animal models of addiction. Reduction of established tolerance should be included among the potential explanations of oxytocin effects in these studies and changes in tolerance should be examined in future studies in relationship to oxytocin influences on acquisition and reinstatement of self-administration as well as extinction of drug seeking. Oxytocin efficacy in reducing anxiety and stress responses as well as established tolerance suggests it may be uniquely effective in reducing negative reinforcement (Koob's "dark side" of addiction) that maintains chronic substance use.

A 12-week randomized controlled trial of twice-daily intranasal oxytocin for social cognitive deficits in people with schizophrenia.

Social cognition is impaired in people with schizophrenia and these deficits are strongly correlated with social functioning. Oxytocin is a hypothalamic peptide that contributes to maternal infant bonding and has diverse pro-social effects in adults. This study tested the hypothesis that 12weeks of intranasal oxytocin will improve social cognitive function in outpatients with schizophrenia and schizoaffective disorder. Sixty-eight eligible participants were randomized to oxytocin (24IU twice daily) or placebo. Social cognitive function was assessed using the Emotion Recognition-40, Brüne Theory of Mind, Reading the Mind in the Eyes test, Trustworthiness task and Ambiguous Intentions Hostility Questionnaire at baseline, 6weeks and 12weeks. In addition, social function was assessed using the Specific Levels of Functioning Scale and a role-play test, and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Fifty-five participants completed the 12-week trial. The study found no evidence for a differential advantage of oxytocin over placebo on social cognition. Among secondary outcomes, there was a modest advantage for oxytocin over placebo on a component of social functioning, although there was also evidence that the placebo group outperformed the oxytocin group on the role-play task. No between-group differences emerged on measures of psychopathology in pre-specified comparisons, but oxytocin showed significant within-group reduction in PANSS negative symptoms and significant between-group improvement in negative symptoms in the schizophrenia subgroup. Further testing is needed to clarify whether oxytocin has therapeutic potential for social cognitive deficits and/or negative symptoms in people with schizophrenia.

Reversal of social deficits by subchronic oxytocin in two autism mouse models.

Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-d-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

The influence of early life sexual abuse on oxytocin concentrations and premenstrual symptomatology in women with a menstrually related mood disorder.

Oxytocin (OT), associated with affiliation and social bonding, social salience, and stress/pain regulation, may play a role in the pathophysiology of stress-related disorders, including menstrually-related mood disorders (MRMD's). Adverse impacts of early life sexual abuse (ESA) on adult attachment, affective regulation, and pain sensitivity suggest ESA-related OT dysregulation in MRMD pathophysiology. We investigated the influence of ESA on plasma OT, and the relationship of OT to the clinical phenomenology of MRMD's. Compared to MRMD women without ESA (n=40), those with ESA (n=20) displayed significantly greater OT [5.39pg/mL (SD, 2.4) vs. 4.36pg/mL (SD, 1.1); t (58)=-2.26, p=0.03]. In women with ESA, OT was significantly, inversely correlated with premenstrual psychological and somatic symptoms (r's=-0.45 to -0.64, p's<0.05). The relationship between OT and premenstrual symptomatology was uniformly low and non-significant in women without ESA. In women with ESA, OT may positively modulate MRMD symptomatology.

A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia.

The current study explored whether oxytocin can improve social cognition and social skills in individuals with schizophrenia using a six-week, double-blind design. Fourteen participants with schizophrenia were randomized to receive either intranasal oxytocin or a placebo solution and completed a battery of social cognitive, social skills and clinical psychiatric symptom measures. Results showed within group improvements in fear recognition, perspective taking, and a reduction in negative symptoms in the oxytocin group. These preliminary findings indicate oxytocin treatment may help improve certain components of functioning in schizophrenia. Implications for the treatment of social functioning in schizophrenia are discussed.

Schizophrenia and alcohol dependence: diverse clinical effects of oxytocin and their evolutionary origins.

Beginning in 1979 with the first report that central administration of oxytocin stimulates maternal behavior in virgin rats, decades of animal research and more recent human studies have demonstrated that oxytocin has many pro-social effects. These many findings suggest that oxytocin may be an effective treatment for social deficits that are hallmark features of disorders such as autism and schizophrenia. Effects in preclinical animal models also imply that oxytocin may be an efficacious pharmacotherapy in a wide range of psychiatric disorders including psychoses and addictions. To date, 3 small clinical trials found that daily intranasal oxytocin treatment for 2-8 weeks significantly reduced psychotic symptoms in schizophrenia. Two of these trials also found improvement in social cognition or neurocognition, areas in which patients have significant deficiencies that do not respond to conventional antipsychotic treatment and contribute to disability. In another small trial, intranasal oxytocin potently blocked alcohol withdrawal. After reviewing the rationale for these trials, they are described in more detail. Questions are then asked followed by discussions of the large gaps in our knowledge about brain oxytocin systems in humans. The hope is to highlight important directions for future investigations of the role of oxytocin in the pathophysiology of psychotic disorders and addictions and to extend clinical research in these areas. Heretofore unrecognized roles for which oxytocin may have been selected during the evolution of placental mammalian maternal-infant and other social attachments are considered as possible origins of oxytocin antipsychotic and antiaddiction effects.This article is part of a Special Issue entitled Oxytocin and Social Behav.

Prosocial effects of oxytocin in two mouse models of autism spectrum disorders.

Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin.

Intranasal oxytocin blocks alcohol withdrawal in human subjects.

BACKGROUND: The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. METHODS: In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. RESULTS: All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). CONCLUSIONS: This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients.

Failed lactation and perinatal depression: common problems with shared neuroendocrine mechanisms?

In the early postpartum period, mother and infant navigate a critical neuroendocrine transition from pregnancy to lactation. Two major clinical problems that occur during this transition are failed lactation and perinatal mood disorders. These disorders often overlap in clinical settings. Failed lactation is common. Although all major medical organizations recommend 6 months of exclusive breastfeeding, only 13% of women in the United States achieve this recommendation. Perinatal mood disorders affect 10% of mothers, with substantial morbidity for mother and child. We hypothesize that shared neuroendocrine mechanisms contribute to both failed lactation and perinatal mood disorders. In this hypothesis article, we discuss data from both animal models and clinical studies that suggest neuroendocrine mechanisms that may underlie these two disorders. Research to elucidate the role of these underlying mechanisms may identify treatment strategies both to relieve perinatal depression and to enable women to achieve their infant feeding goals.

Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia.

Oxytocin has numerous prosocial and antipsychotic-like effects in animals. Prosocial effects of acute intranasal oxytocin administration have also been reported in human subjects. We conducted a randomized, placebo-controlled trial testing the effects of twice daily intranasal oxytocin treatment for 14 days on psychotic symptoms and social cognition in patients with schizophrenia. PANSS scores declined significantly and several social cognition measures improved significantly or nearly significantly in oxytocin (N=11) but not placebo (N=9) recipients. Our results suggest that, in addition to reducing classic psychotic symptoms, oxytocin may diminish certain social cognition deficits that are not improved by current antipsychotic medications.

Variations in Maternal Behavior in C57BL/6J Mice: Behavioral Comparisons between Adult Offspring of High and Low Pup-Licking Mothers.

The amount of maternal licking received by newborn rats affects their adult stress reactivity and maternal behavior. Mouse studies in which litters were cross-fostered between strains that exhibit high vs. low amounts of maternal behavior also suggest that rearing conditions affect adult outcomes. The current study is the first to compare within a single mouse strain (C57BL/6J) behavioral responses between adult animals reared by mothers that exhibited frequencies of pup-licking (PL) at the high end and the low end of the normal distribution within the strain. Maternal behaviors were coded during 10-s intervals every 3 min during five 1-h periods (two light, three dark cycle) on postpartum days 2, 4, 6, and 8 in 36 unrelated C57BL/6J mothers. The distribution of mean frequencies/h for PL, still crouched nursing, hovering over pups, self-grooming, and no contact with pups were determined. Offspring (6-12 weeks of age) from the eight mothers who exhibited the highest mean frequencies of PL and the seven mothers who exhibited the lowest PL frequencies underwent the following tests over three consecutive weeks: (1) elevated plus-maze (EPM) and 1-h open field on three successive days, (2) 3-h open field with an acute stressor (IP saline injection) at the 1-h time point, and (3) acoustic startle and prepulse inhibition. Females reared by low PL mothers exhibited significantly more time in the closed arms of the EPM, less locomotion, center time, and rearing during the first test in the open field, greater reactivity to an acute stressor, and reduced prepulse inhibition, an index of sensorimotor gating. Male offspring from low PL dams had reduced reactivity to an acute stressor, but no other altered performance in the behavioral tests. PL frequencies of C57BL/6J mothers appear to selectively alter behavior outcomes, primarily in female offspring.

Depressive disorder and thyroid axis functioning during pregnancy.

BACKGROUND: Depression and thyroid dysfunction are prevalent in women, including pregnant women. The aim of this study was to assess the relationship between depression and thyroid function during pregnancy. METHODS: One hundred and ninety-nine pregnant women three times during pregnancy were assessed for depressive disorder and for thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) concentrations. RESULTS: Prevalence of depressive disorder was 6.5% in early pregnancy, 3.0% in middle pregnancy and 3.5% in late pregnancy. There were no women with overt thyroid dysfunction. Subclinical hyperthyroidism was found in 23% of women in early pregnancy, in 5% of women in middle pregnancy and in 6% of women in late of pregnancy. In late pregnancy depressed women compared to non-depressed women had significantly higher FT(4) concentrations and a strong trend towards lower TSH concentrations as well as higher prevalence of subclinical hyperthyroidism. CONCLUSIONS: These findings show an association between thyroid dysfunction and depression in late pregnancy. Because gestational depression might interfere with pregnancy outcome, evaluation of thyroid function during gestation is warranted.

Screening for antenatal depression with the Edinburgh Depression Scale.

This study aimed to evaluate how precise the Edinburgh Depression Scale (EDS) is in screening for major depressive disorder (MDD) during different periods of pregnancy. A random sample of 230 pregnant women was interviewed in the first, second, and third trimesters of pregnancy using the EDS and not-patient version of the Structured Clinical Interview for DSM-III-R (SCID-NP). We evaluated test-retest reliability of the EDS; area under the ROC curve (AUC), sensitivity, specificity, and positive predictive value (PPV) of the EDS against the SCID-NP diagnoses in the first, second, and third trimesters of pregnancy. Test-retest reliability of the EDS was 0.81 (p < 0.001). An optimal cutoff score of the EDS for screening current SCID-NP diagnosis of MDD was 12 and higher in the first trimester of pregnancy (AUC 0.94, sensitivity 92%, specificity 95%, and PPV 52%) and 11 and higher in the second and third trimesters of pregnancy (AUC 0.96 and 0.90, respectively; sensitivity 100% and 88%, respectively; specificity 92% and 92%, respectively; PPV 25% and 29%, respectively). The EPDS is a reliable instrument for repeated evaluations of depressive symptoms during pregnancy. It has a good sensitivity and specificity for detecting antenatal MDD with optimal cutoff of 11/12 or higher.