Digital phenotypes of real-time suicidal ideation: Correlates and consequences.

INTRODUCTION: Suicidal ideation variability refers to within-day fluctuations in suicidal ideation, and has recently been proposed as an indicator of suicide risk. However, not much is known yet about its correlates and clinical relevance. METHODS: We examined characteristics of real-time suicidal ideation using Ecological Momentary Assessment in 82 individuals with current active suicidal ideation. Data were collected four times daily over 21 days. Latent profile analysis was used to identify subtypes of suicidal ideation. We further examined sociodemographic and clinical correlates of the profiles, and their association with the occurrence of suicide attempts during a 1-year follow-up. RESULTS: We identified three "digital" phenotypes of suicidal ideation that differed on the frequency, intensity and variability of ideation. The profiles were: high frequency, high intensity, moderate variability (Phenotype 1), moderate/high frequency, moderate intensity, high variability (Phenotype 2), and moderate frequency, low intensity, low variability (Phenotype 3). Phenotypes 1 and 2 were associated with a worse clinical profile at baseline (higher suicidal ideation and depressive symptom severity), and increased odds of suicide attempt during follow-up, compared to Phenotype 3. Phenotype 1 was further characterized by repeated suicidal behavior. CONCLUSIONS: Two phenotypes of real-time suicidal ideation were identified that appear to confer a higher risk of suicidal behavior in the near future (12 months). These phenotypes were characterized by higher variability of suicidal ideation-and also higher intensity and frequency of ideation. Considering the small sample size, the clinical usefulness of the profiles remains to be demonstrated.

Hormonal status effects on the electrophysiological correlates of performance monitoring in women.

Fluctuations in ovarian hormones are thought to play a role in the increased prevalence of mood and anxiety disorders in women. Error-related negativity (ERN) and error positivity (Pe) are two putative electrophysiological biomarkers for these internalizing disorders. We investigated whether female hormonal status, specifically menstrual cycle phase and oral contraceptive (OC) use, impact ERN and Pe. Additionally, we examined whether the relationship between the ERN and negative affect (NA) was moderated by hormonal status and tested whether the ERN mediated the relation between ovarian hormones and NA. Participants were healthy, pre-menopausal women who were naturally cycling (NC) or using OCs. Using a counterbalanced within-subject design, all participants performed a speeded-choice reaction-time task twice while undergoing electroencephalography measurements. NC women (N = 42) performed this task during the early follicular and midluteal phase (when estrogen and progesterone are both low and both high, respectively), while OC users (N = 42) performed the task during active OC use and during their pill-free week. Estradiol and progesterone levels were assessed in saliva. Comparing the two cycle phases within NC women revealed no differences in the (Δ)ERN, (Δ)Pe or NA. We did observe a negative relation between phase-related changes in the ΔERN and changes in NA. Mediation analysis additionally showed that phase-related changes in estradiol were indirectly and negatively related to NA through a reduction of ΔERN amplitudes. When comparing active OC users with NC women, we observed increased ΔPe- but not (Δ)ERN amplitudes in the former group. No evidence was found for moderating effects of menstrual cycle phase or OC use on the relation between the ERN and NA. These findings suggest that hormonal status may impact the neural correlates of performance monitoring and error sensitivity, and that this could be a potential mechanism through which ovarian hormones influence mood.

Associations of plasma androgens with suicidality among men and women: A 9-year longitudinal cohort study.

BACKGROUND: Testosterone has been implicated in suicidality in cross-sectional studies. Stress that coincides with a suicide attempt may alter androgen levels, so prospective studies are needed to exclude reverse causation. We aimed to examine the associations of plasma androgens with concurrent and future suicidality, and if present, whether these associations were mediated by a behavioral trait like reactive aggression. METHODS: Baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate with a radioimmunoassay. Suicidality was assessed using the Suicidal Ideation Scale at baseline and after 2-, 4-, 6-, and 9-year follow-up. Men and women were analyzed separately, and potential confounders were considered. RESULTS: Participants (N = 2861; 66.3% women) had a mean age of 42.0 years (range 18-65) and almost half (46.9%) fulfilled criteria for a major depressive or anxiety disorder. At baseline 13.2% of men and 11.2% of women reported current suicidal ideation. In participants who were non-suicidal at baseline, slightly more men than women reported suicidal ideation during follow-up (14.7% vs. 12.5%), whereas the reverse pattern was observed for suicide attempts (3.6% vs. 4.2%). None of the associations between androgens and current and future suicidality were significant. LIMITATIONS: Androgens were determined once, which may have been insufficient to predict suicidality over longer periods. DISCUSSION: The lack of associations between plasma levels of androgens determined by 'gold-standard' laboratory methods with suicidality do not support previous cross-sectional and smaller studies in adult men and women with values within the physiological range.

Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing.

BACKGROUND: Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. AIM: To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. METHODS: Cross-sectional study in 85 healthy premenopausal women of West-European descent. RESULTS: We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. LIMITATIONS: Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. CONCLUSIONS: Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs.

General, Specific and Unique Cognitive Factors Involved in Anxiety and Depressive Disorders.

Comorbidity among anxiety and depressive disorders is the rule rather than the exception. The Integrative Hierarchical Model proposes that each of these disorders contains general (common to all), specific (common to some) and unique components. However, research into this model is limited and hampered by small (clinical) sample sizes. The aim of the present study is to investigate the incremental validity of the cognitive constructs Anxiety Sensitivity, Pathological Worry and Cognitive Reactivity to sad mood over and above the personality traits neuroticism and extraversion. Symptomatic (N = 1,111) and remitted (N = 834) patients were selected from the 2,981 participants of the Netherlands Study of Depression and Anxiety (NESDA). Results revealed both specific and unique cognitive components of anxiety and depression. Across symptomatic and remitted groups, Anxiety Sensitivity was specific to social anxiety disorder and panic disorder, Aggression Reactivity was a unique component of dysthymia, and Rumination on Sadness was unique to major depressive disorder. We conclude that cognitive constructs have additional value in understanding anxiety and depressive disorders. Moreover, they prove to be more than mere epiphenomena of current disorders.

Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions.

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders.

A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females.

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity.

Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsivity consists of two dissociable components that previous studies have failed to separate: functional and dysfunctional impulsivity. We compared participants with a genetic predisposition to have relatively high striatal DA levels (DAT1 9-repeat carriers, DRD2 C957T T/T homozygotes, and DRD4 7-repeat carriers) with participants with other genetic predispositions. We predicted that the first group would show high scores of dysfunctional, but not functional, self-reported impulsivity and greater difficulty in inhibiting a behavioral response to a stop-signal, a behavioral measure of impulsivity. In a sample of 130 healthy adults, we studied the relation between DAT1, DRD4, and C957T polymorphism at the DRD2 gene (polymorphisms related to striatal DA) and catechol-Omethyltransferase (COMT) Val158Met (a polymorphism related to frontal DA) on self-reported dysfunctional and functional impulsivity, assessed by the Dickman impulsivity inventory (DII), and the efficiency of inhibitory control, assessed by the stop-signal paradigm. DRD2 C957T T/T homozygotes and DRD4 7-repeat carriers indeed had significantly higher scores on self-reported dysfunctional, but not functional, impulsivity. T/T homozygotes were also less efficient in inhibiting prepotent responses. Our findings support the claim that dopaminergic variation affects dysfunctional impulsivity. This is in line with the notion that the over-supply of striatal DA might weaken inhibitory pathways, thereby enhancing the activation of, and the competition between responses.

Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression.

Meta-analyses evaluating the association between the serotonin transporter polymorphism (5-HTTLPR) with neuroticism and depression diagnosis as phenotypes have been inconclusive. We examined a gene-environment interaction on a cognitive vulnerability marker of depression, cognitive reactivity (CR) to sad mood. A total of 250 university students of European ancestry were genotyped for the 5-HTTLPR, including SNP rs25531, a polymorphism of the long allele. Association analysis was performed for neuroticism, CR and depression diagnosis (using a self-report measure). As an environmental pathogen, self-reported history of childhood emotional abuse was measured because of its strong relationship with depression. Participants with the homozygous low expressing genotype had high CR if they had experienced childhood emotional maltreatment but low CR if they did not have such experience. This interaction was strongest on the Rumination subscale of the CR measure. The interaction was not significant with neuroticism or depression diagnosis as outcome measures. Our results show that 5-HTTLPR is related to cognitive vulnerability to depression. Our findings provide evidence for a differential susceptibility genotype rather than a vulnerability genotype, possibly because of the relatively low levels of abuse in our sample. The selection of phenotype and environmental contributor is pivotal in investigating gene-environment interactions in psychiatric disorders.

The educational patterning of health-related adversities in individuals with major depression.

BACKGROUND: Major depressive disorder and depression severity are socially patterned, disfavouring individuals from lower socioeconomic groups. Depressive disorders are associated with several adverse health-related outcomes. We examined the educational patterning of somatic health, lifestyles, psychological function and treatment modalities in individuals suffering from major depressive disorder. METHODS: We used cross-sectional medical and psychiatric data from 992 participants of The Netherlands Study of Depression and Anxiety (NESDA) with a diagnosed current major depressive disorder. Associations of education with somatic, lifestyle-related, and psychological outcomes, and with treatment modalities, adjusted for depression severity, were examined by means of (multinomial and binary) logistic and linear regression analyses. RESULTS: In addition to and independent of major depressions being more severe in the less educated patients, metabolic syndrome, current smoking, low alcohol consumption, hopelessness and low control were more prevalent in a group of less educated individuals suffering from major depression, compared with their more highly educated peers. The less educated persons were more likely to be treated with antidepressant medication and less likely to receive psychotherapy treatment. None of these observations were explained by a higher depression severity in the less educated group. LIMITATIONS: The cross-sectional design does not allow us to make direct causal inferences regarding the mutual influences of the different health-related outcomes. CONCLUSIONS: Further research should explore the necessity and feasibility of routine screening for additional health risk, particularly among less educated depressed individuals.

Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers.

Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer risk-averse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness.

Memory of childhood trauma before and after long-term psychological treatment of borderline personality disorder.

The present study investigated the consistency of self-reports of childhood traumatic events in a sample of 50 patients with a borderline personality disorder (BPD) before and after 27 months of intensive treatment with schema focused therapy or transference focused psychotherapy. The mean number of reported sexual, physical and emotional traumatic events did not change following treatment. Test-retest correlations of the trauma-interview also indicated high stability of the total number of sexual, physical and emotional events reported. The majority of the patients, however, did no longer report at least one of the 33 listed events after psychotherapy, and the majority reported at least one event that they had not mentioned before the start of treatment. These findings were not related to type of treatment or changes in suppression, intrusions, avoidance of intrusions, dissociative symptoms, depressive symptoms, and borderline symptoms.

Recurrence of suicidal ideation across depressive episodes.

BACKGROUND: In recent years it has become clear that depression is a recurrent disorder, with the risk of recurrence in those with two or more episodes being as high as 90%. This has prompted interest in the consistency of individual depressive symptoms across consecutive episodes, an issue that is important for symptoms such as suicidal ideation, where a past history may give important indicators of future behaviour. METHODS: We prospectively examined 69 individuals with a history of Major Depression, over 12 months, 38 of whom experienced a recurrence of major depression during the follow-up period. RESULTS: Spearman's rank order correlations between severity ratings of each symptom of major depression during a previous episode and severity ratings at recurrence showed significant associations for suicidality, guilt or worthlessness and thinking difficulties only. Weighted kappa coefficients indicated relatively low levels of agreement across episodes for most diagnostic symptoms, with suicidality showing the strongest relationship. Using a broad definition of suicidality-- any reporting of thoughts of death or suicide during episode-- a much higher level of agreement (kappa = .64) was found, with 83% of individuals falling into the same category (suicidal/non-suicidal) at both episodes. LIMITATIONS: This study was based on a relatively small sample and examines re-emergence of suicidal ideation in the absence of suicidal behaviour. CONCLUSIONS: This study provides preliminary evidence of cross-episode consistency in the recurrence of suicidal ideation, in line with the differential activation theory of suicidality in depression.

Autobiographical memory in depressed and non-depressed patients with borderline personality disorder.

OBJECTIVES: The present study investigated the specificity of autobiographical memories among depressed and non-depressed borderline patients, compared with depressed patients and controls. The influence of childhood trauma, intrusions of traumatic events, avoidance of intrusions, dissociation and depression on memory specificity was also studied. METHOD: The Autobiographical Memory Test (AMT), a trauma interview and self-report measures of intrusions, avoidance, depression and dissociation were administered to 83 borderline outpatients, 26 depressed outpatients and 30 controls. RESULTS: Depressed borderline patients and depressed patients reported fewer specific memories than controls. Depressed patients generated fewer specific memories than non-depressed borderline patients. Neither trauma nor traumatic intrusions, avoidance of intrusions or dissociation were related to the specificity of memories. Level of depressive symptoms (BDI) was also not related, but the presence of a depression was. CONCLUSION: In this large sample of outpatients with borderline personality disorder, only the subgroup with a co-morbid diagnosis of depression had trouble remembering specific events from the past. Trauma, intrusions, avoidance of intrusions and dissociation seem to be unrelated to the specificity of autobiographical memories in borderline personality disorder.

Monoamine depletion in psychiatric and healthy populations: review.

A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine depletion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications. The evidence also suggests that ATD and APTD affect different cognitive functions, in particular different memory systems. Few studies investigated cognitive effects of the procedures in patients. Patients who are in remission for longer may also be vulnerable to ATD and AMPT, but the relationship with prior treatment is much weaker. For these patients, individual vulnerability markers are the more important determinants of depressive response, making these techniques potentially useful models of vulnerability to depression.