The association between persistent cognitive difficulties and depression and functional outcomes in people with major depressive disorder.

BACKGROUND: Cognitive symptoms are common during and following episodes of depression. Little is known about the persistence of self-reported and performance-based cognition with depression and functional outcomes. METHODS: This is a secondary analysis of a prospective naturalistic observational clinical cohort study of individuals with recurrent major depressive disorder (MDD; N = 623). Participants completed app-based self-reported and performance-based cognitive function assessments alongside validated measures of depression, functional disability, and self-esteem every 3 months. Participants were followed-up for a maximum of 2-years. Multilevel hierarchically nested modelling was employed to explore between- and within-participant variation over time to identify whether persistent cognitive difficulties are related to levels of depression and functional impairment during follow-up. RESULTS: 508 individuals (81.5%) provided data (mean age: 46.6, s.d.: 15.6; 76.2% female). Increasing persistence of self-reported cognitive difficulty was associated with higher levels of depression and functional impairment throughout the follow-up. In comparison to low persistence of objective cognitive difficulty (<25% of timepoints), those with high persistence (>75% of timepoints) reported significantly higher levels of depression (B = 5.17, s.e. = 2.21, p = 0.019) and functional impairment (B = 4.82, s.e. = 1.79, p = 0.002) over time. Examination of the individual cognitive modules shows that persistently impaired executive function is associated with worse functioning, and poor processing speed is particularly important for worsened depressive symptoms. CONCLUSIONS: We replicated previous findings of greater persistence of cognitive difficulty with increasing severity of depression and further demonstrate that these cognitive difficulties are associated with pervasive functional disability. Difficulties with cognition may be an indicator and target for further treatment input.

The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Psychometric evaluation of ADAS-Cog and NTB for measuring drug response.

AIMS: To conduct a psychometric analysis to determine the adequacy of instruments that measure cognition in Alzheimer's disease trials. BACKGROUND: Both the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and the Neuropsychological Test Battery (NTB) are validated outcome measures for clinical trials in Alzheimer's disease and are approved also for regulatory purposes. However, it is not clear how comparable they are in measuring cognitive function. In fact, many recent trials in Alzheimer's disease patients have failed and it has been questioned if ADAS-Cog still is a sensitive measure. MATERIALS AND METHODS: The present paper examines the psychometric properties of ADAS-Cog and NTB, based on a post hoc analysis of data from a clinical trial (NCT01024660), which was conducted by AstraZeneca, in mild-to-moderate Alzheimer's disease (AD) patients, with a Mini Mental State Examination (MMSE) Total score 16-24. Acceptability, reliability, different types of validity and ability to detect change were assessed using relevant statistical methods. Total scores of both tests, as well as separate domains of both tests, including the Wechsler Memory Scale (WMS), Rey Auditory Verbal Learning Test (RAVLT) and Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Condition, were analyzed. RESULTS: Overall, NTB performed well, with acceptable reliability and ability to detect change, while ADAS-Cog had insufficient psychometric properties, including ceiling effects in 8 out of a total of 11 ADAS-Cog items in mild AD patients, as well as low test-retest reliability in some of the items. DISCUSSION: Based on a direct comparison on the same patient sample, we see advantages of the NTB compared with the ADAS-Cog for the evaluation of cognitive function in the population of mild-to-moderate AD patients. The results suggest that not all of ADAS-Cog items are relevant for both mild and moderate AD population. CONCLUSIONS: This validation study demonstrates satisfactory psychometric properties of the NTB, while ADAS-Cog was found to be psychometrically inadequate.

The relationship between wearable-derived sleep features and relapse in Major Depressive Disorder.

BACKGROUND: Changes in sleep and circadian function are leading candidate markers for the detection of relapse in Major Depressive Disorder (MDD). Consumer-grade wearable devices may enable remote and real-time examination of dynamic changes in sleep. Fitbit data from individuals with recurrent MDD were used to describe the longitudinal effects of sleep duration, quality, and regularity on subsequent depression relapse and severity. METHODS: Data were collected as part of a longitudinal observational mobile Health (mHealth) cohort study in people with recurrent MDD. Participants wore a Fitbit device and completed regular outcome assessments via email for a median follow-up of 541 days. We used multivariable regression models to test the effects of sleep features on depression outcomes. We considered respondents with at least one assessment of relapse (n = 218) or at least one assessment of depression severity (n = 393). RESULTS: Increased intra-individual variability in total sleep time, greater sleep fragmentation, lower sleep efficiency, and more variable sleep midpoints were associated with worse depression outcomes. Adjusted Population Attributable Fractions suggested that an intervention to increase sleep consistency in adults with MDD could reduce the population risk for depression relapse by up to 22 %. LIMITATIONS: Limitations include a potentially underpowered primary outcome due to the smaller number of relapses identified than expected. CONCLUSION: Our study demonstrates a role for consumer-grade activity trackers in estimating relapse risk and depression severity in people with recurrent MDD. Variability in sleep duration and midpoint may be useful targets for stratified interventions.

Predictors of engagement with remote sensing technologies for symptom measurement in Major Depressive Disorder.

BACKGROUND: Remote sensing for the measurement and management of long-term conditions such as Major Depressive Disorder (MDD) is becoming more prevalent. User-engagement is essential to yield any benefits. We tested three hypotheses examining associations between clinical characteristics, perceptions of remote sensing, and objective user engagement metrics. METHODS: The Remote Assessment of Disease and Relapse - Major Depressive Disorder (RADAR-MDD) study is a multicentre longitudinal observational cohort study in people with recurrent MDD. Participants wore a FitBit and completed app-based assessments every two weeks for a median of 18 months. Multivariable random effects regression models pooling data across timepoints were used to examine associations between variables. RESULTS: A total of 547 participants (87.8% of the total sample) were included in the current analysis. Higher levels of anxiety were associated with lower levels of perceived technology ease of use; increased functional disability was associated with small differences in perceptions of technology usefulness and usability. Participants who reported higher system ease of use, usefulness, and acceptability subsequently completed more app-based questionnaires and tended to wear their FitBit activity tracker for longer. All effect sizes were small and unlikely to be of practical significance. LIMITATIONS: Symptoms of depression, anxiety, functional disability, and perceptions of system usability are measured at the same time. These therefore represent cross-sectional associations rather than predictions of future perceptions. CONCLUSIONS: These findings suggest that perceived usability and actual use of remote measurement technologies in people with MDD are robust across differences in severity of depression, anxiety, and functional impairment.

The stability of AQT processing speed, ADAS-Cog and MMSE during acetylcholinesterase inhibitor treatment in Alzheimer's disease.

OBJECTIVES: To explore the longitudinal stability of measures of cognition during treatment with acetylcholinesterase inhibitors (AchEI) in patients with Alzheimer's disease (AD). MATERIALS AND METHODS: Cognitive status was measured in a cohort of 60 patients at 6 months after initiation of treatment with AchEI (baseline) and after an additional 6 months of treatment (endpoint). A Quick Test of Cognitive Speed (AQT), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and MMSE were administered concurrently. RESULTS: Correlations (rho) between age and AQT processing speed were non-significant, but were significant for ADAS-Cog and Mini Mental State Examination (MMSE). AQT and ADAS-Cog means did not differ significantly between baseline and endpoint. There was a small, significant reduction in MMSE point scores. Measures of stability (Spearman's rho) were moderate-to-high for all tests. Means for subgroups did not differ as a function of medication type. CONCLUSIONS: AQT processing speed, ADAS-Cog, and MMSE measures proved stable during the second 6 months of treatment with AChEI.

Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer's disease.

OBJECTIVES: Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog) has become a standard clinical trials outcome for cognition, but has been recognized as deficient in areas including coverage of cognitive domains, sensitivity and standardization. Computerized test batteries may address some of these issues. The cognitive drug research computerized assessment (CDR) system is validated in Alzheimer's disease (AD). This study was designed to further evaluate validity in relation to ADAS-Cog, mini mental state examination (MMSE) and cerebrospinal fluid (CSF) biomarkers and psychometric properties, in a population of Alzheimer's patients on stable anticholinesterase treatment. MATERIALS AND METHODS: Patients completed cognition assessments, CSF and blood sampling at baseline and 6 months later. Data for 65 patients were evaluated. RESULTS: The CDR system demonstrated good psychometric properties in this population. Measures of psychomotor speed showed possible sensitivity to decline over 6 months. CONCLUSIONS: There are a number of methodological problems with current cognition assessment methodology for clinical trials. Computerized measures and in particular millisecond reaction time measures, may address many of these issues.

Human fear conditioning is related to dopaminergic and serotonergic biological markers.

Biological markers for acquisition and extinction of fear conditioning were studied in 40 individuals selected for displaying either good or poor acquisition of fear conditioning. as estimated by the skin conductance response. Participants with a short serotonin transporter (5-HTT) promoter allele or low monoamine oxidase activity in platelets (trbc-MAO) displayed better acquisition than those with only long alleles or high trbc-MAO, whereas participants with a long dopamine D4 receptor (D4DR) exon III allele showed delayed extinction compared with those with only short alleles. The findings, that D4DR exon III and 5-HTT promoter genotypes and trbc-MAO activity are related to human fear conditioning, a basic form of associative learning, are consistent with animal studies suggesting a genetic contribution to fear conditioning. The authors suggest that in humans these genetic mechanisms are partly dopaminergic and serotonergic in origin.

Internal consistency and temporal stability of classically conditioned skin conductance responses.

The reliability of classically conditioned skin conductance responses was investigated. Temporal stability was determined in 28 subjects studied three weeks apart (study 1), and internal consistency in 223 subjects studied once (study 2). A discriminative classical conditioning paradigm using slides with a duration of 8 s served as conditioned stimuli (CS) for an aversive unconditioned noise stimulus (study 1) or a mild unconditioned electric shock stimulus (UCS) (study 2). Electrodermal responses were recorded during a habituation phase (4 trials), an acquisition phase, where CS+ was paired repeatedly with the UCS, while CS- never was (8 trials), and an extinction phase during which shocks were withheld (8 trials each). First interval responses were measured 1-4 s after CS- onset during all phases of the experiment. During the acquisition and extinction phases, second interval responses were scored 5-9 s after CS- onset while third interval responses were determined 1-4 s after CS- termination. Internal consistency was significant for the first (rxy range 0.96-0.90), second (rxy range 0.84-0.54) and third (rxy range 0.96-0.86) skin conductance interval response. Temporal stability was highest for the first interval response (rxy range 0.72-0.37) and lowest for the second interval response (rxy range 0.51-0.05). It is concluded that the first interval skin conductance response shows adequate internal consistency and temporal stability to assess individual differences in classical conditioning.

Parental history, aversive exposure and the development of snake and spider phobia in women.

Parental history and experiential factors in the development of snake and spider phobia were studied. Phobic women (DSM-IV, n = 158) reported on family history of animal phobia and whether direct (being frightened by the phobic object) or indirect (seeing someone else being frightened by and/or being warned of the phobic object) fear exposure predated phobia development. Fifty-nine mothers (37%) and 11 fathers (7%) had snake or spider phobia, which is higher than the upper 95% confidence interval in the populations (Fredrikson, Annas, Fischer & Wik, Behavior Research and Therapy, 34, 33-39). Lifetime Relative Risk, RR, of animal phobia in probands' mother and fathers as a function of at least one phobic grandparent was 3.3 and 13.7 respectively. Indirect fear exposures were more common in snake (45%) than spider (27%) phobics (RR = 1.4). Indirect fear exposures were more common among probands with a positive parental history, the RRs being 3.6 and 2.1 as a function of maternal and paternal family history. Direct exposures were unrelated to parental history. The familial resemblance and transmission of specific phobia could be experiential in origin mediated by indirect exposures or of hereditary origin mediated by genetic factors. It may represent genetically facilitated learning and exemplify imprinting in humans.

Gender and age differences in the prevalence of specific fears and phobias.

Point prevalence of specific fears and phobias was determined in 704 respondents of 1000 randomly selected adults aged 18-70 yr. A phobia for lightning, enclosed spaces, darkness, flying, heights, spiders, snakes, injections, dentists and/or injuries was defined if subjects reported a fear that was out of conscious control, interfered with life and lead to the avoidance of the feared object [American Psychiatric Association, 1994. Diagnostic and statistical manual of mental disorders (4th edn). Washington, DC: American Psychiatric Press.] Fear intensity was assessed using visual analogue scales. A factor analysis generally supported the classification of fears and phobias into: (1) situational phobias (lightning, enclosed spaces, darkness, flying and heights); (2) animal phobias (spiders and snakes); and (3) mutilation phobias (injections, dentists, injuries). Total point prevalence of any specific phobia was 19.9% (26.5% for females and 12.4% for males). In total, 21.2% women and 10.9% men met criterias for any single specific phobia. Multiple phobias was reported by 5.4% of the females and 1.5% of the males. Animal phobia had a prevalence of 12.1% in women and 3.3% in men. Point prevalence of situational phobia was 17.4% in women and 8.5% in men. For mutilation phobia no gender difference was observed, being presented in 3.2% of the women and 2.7% of the men. Women as compared to men gave higher fear ratings for all objects and situations. Inanimate object fears and phobias were more common in older than younger individuals. Animal fears were more intense in younger than in older individuals. Fear of flying increased and fear of injections decreased as a function of age in women but not in men. Thus, specific fears and phobias are heterogeneous with respect to sex and age distribution.

Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers.

This was a double-blind, randomised, placebo-controlled, crossover study of the acute cognitive and subjective effects of nabilone 1-3 mg in healthy male volunteers. The Cognitive Drug Research computerised system (CDR system) was used to assess changes in attention, working and episodic memory. In addition, a number of self-ratings were conducted including those of mood, alertness and perceived drug effects. Impairments to attention, working and episodic memory and self-ratings of alertness were evident. Volunteers also experienced a number of subjective drug effects. These data demonstrate that acute doses of nabilone in the range 1-3 mg produce clear cognitive and subjective effects in healthy volunteers, and therefore they may be used as reference data in the future study of peripherally acting cannabinoids believed to be free from such effects.

The development of fears from early adolesence to young adulthood: a multivariate study.

BACKGROUND: Common fears change over development. Genetic and environmental risk factors for fears are partly shared across fears and partly fear-specific. The nature of the changes in common and fear-specific genetic and environmental risk factors over time is unknown. METHOD: Self-reported fears were obtained at ages 13-14, 16-17 and 19-20 from 2404 twins in the Swedish Twin Study of Child and Adolescent Development. A multivariate longitudinal twin analysis was conducted with Mx. RESULTS: Eighteen individual items formed four fear factors: animal, blood-injury, situational, and social. The best-fit model had no quantitative or qualitative sex effects or shared environmental effects, but included a strong common factor with a stable cross-time structure with highest loadings on situational and lowest loadings on social fears. New common and fear-specific genetic risk factors emerged over development. With increasing age, genetic effects declined in overall importance and became more fear-specific. Cross-time continuity in specific genetic effects was highest for animal and lowest for social fears. Social fears had a 'burst' of specific genetic effects in late adolescence. Individual-specific environmental factors impacted both on the general fear factor and on specific fears. Compared to genetic effects, the impact of the unique environment was more time-specific. CONCLUSIONS: Genetic and environmental risk factors for individual fears are partly mediated through a common fear factor and are partly fear-specific in their effect. The developmental pattern of these risk factors is complex and dynamic with new common and specific genetic effects arising in late adolescence and early adulthood.

Heritability and prevalence of specific fears and phobias in childhood.

Fears and phobias are relatively common in childhood. Both environmental and genetic theories have tried to explain the etiology behind these conditions. However, data supporting the different theories are sparse. To investigate the relative importance of genetic and environmental influences on specific phobias and fears, parental reports of animal, situational, and mutilation fears and phobias were completed for 1106 pairs of 8- to 9-year-old Swedish twins. The prevalence of specific phobias was 7.3% for boys and 10.0% for girls. Genetic. shared environmental, and nonshared environmental effects contributed to individual differences in fears and phobias in young children, but the magnitude of the effects differed between sexes. Shared environmental effects contributed to a general susceptibility for fearfulness. Genetic and nonshared environmental effects, on the other hand, contributed both to the general susceptibility and specific fearfulness, even though these effects primarily were fear specific. These results indicate that both heritable factors as well as environmental factors such as trauma, vicarious learning, and/or negative information are important for differences in fearfulness and phobias--at least in children.

Functional neuroanatomy of visually elicited simple phobic fear: additional data and theoretical analysis.

We investigated central nervous system correlates of simple phobic fear. Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) in eight volunteers with symptomatic spider phobia that were exposed to visual phobogenic and neutral stimuli. Diazepam (0.1 mg/kg body weight i.v.) or placebo was administered under double-blind conditions after initial PET scans. The PET scans were then repeated. The presence of fear was confirmed by rating procedures and increased number of nonspecific electrodermal fluctuations and by higher heart rate during phobic than during neutral stimulation. Phobic as compared to neutral stimulation elevated the regional to whole brain (relative) CBF in the secondary visual cortex but reduced relative rCBF in the hippocampus, prefrontal, orbitofrontal, temporopolar, and posterior cingulate cortex. Diazepam treatment did not affect the relative rCBF or the subjective or physiological fear indices. The observed rCBF pattern replicates our previous findings in snake phobics (M. Fredrikson et al. [1993] Psychophysiology, 30, 127-131; G. Wik et al. [1993] Psychiatry Research (Neuroimaging), 50, 15-24) and indicates that fear and anxiety affect cortical areas outside the classic limbic system areas.