Parallel Changes in Mood and Melatonin Rhythm Following an Adjunctive Multimodal Chronobiological Intervention With Agomelatine in People With Depression: A Proof of Concept Open Label Study.

Background: Agomelatine is a melatonin agonist and 5HT antagonist developed for the treatment of major depressive disorder which also has some effects on the circadian system. Since circadian dysfunctions are thought to play a role in the pathophysiology of depression, some of the mechanism of action of this drug may relate to improvements in circadian rhythms. Objective: This proof of concept open-label study sought to determine if improvements in depressive symptoms following an adjunctive multimodal intervention including agomelatine intake are associated with the magnitude of circadian realignment. This was investigated in young people with depression, a subgroup known to have high rates of delayed circadian rhythms. Methods: Young people with depression received a psychoeducation session about sleep and circadian rhythms, were asked to progressively phase advance their wake up time, and completed an 8 weeks course of agomelatine (25-50 mg). Participants underwent semi-structured psychological assessments, ambulatory sleep-wake monitoring and measurement of melatonin circadian phase before and after the intervention. Results: Twenty-four young adults with depression (17-28 years old; 58% females) completed the study. After the intervention, depressive symptoms were significantly reduced [t (23) = 6.9, p < 0.001] and, on average, the timing of dim light melatonin onset (DLMO) shifted 3.6 h earlier [t (18) = 4.4, p < 0.001]. On average, sleep onset was phase shifted 28 min earlier [t (19) = 2.1, p = 0.047] and total sleep time increased by 24 min [t (19) = -2.6, p = 0.018]. There was no significant change in wake-up times. A strong correlation (r = 0.69, p = 0.001) was found between the relative improvements in depression severity and the degree of phase shift in DLMO. Conclusion: Although this needs to be replicated in larger randomized controlled trials, these findings suggest that the degree of antidepressant response to a multimodal intervention including psychoeducation and agomelatine intake may be associated with the degree of change in evening melatonin release in young people with depression. This offers promising avenues for targeted treatment based on the prior identification of objective individual characteristics.

The relative contributions of psychiatric symptoms and psychotropic medications on the sleep-wake profile of young persons with anxiety, depression and bipolar disorders.

This study investigated the relative contribution of psychiatric symptoms and psychotropic medications on the sleep-wake cycle. Actigraphy and clinical assessments (Brief Psychiatric Rating Scale) were conducted in 146 youths with anxiety, depression or bipolar disorders. Independently of medications, mania symptoms were predictive of lower circadian amplitude and rhythmicity. Independently of diagnosis and symptoms severity: i) antipsychotics were related to longer sleep period and duration, ii) serotonin-norepinephrine reuptake inhibitors to longer sleep period, and iii) agomelatine to earlier sleep onset. Manic symptoms and different subclasses of medications may have independent influences on the sleep-wake cycle of young people with mental disorders.

Sleep-wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders.

Mood disorders are characterized by disabling symptoms and cognitive difficulties which may vary in intensity throughout the course of the illness. Sleep-wake cycles and circadian rhythms influence emotional regulation and cognitive functions. However, the relationships between the sleep-wake disturbances experienced commonly by people with mood disorders and the longitudinal changes in their clinical and cognitive profile are not well characterized. This study investigated associations between initial sleep-wake patterns and longitudinal changes in mood symptoms and cognitive functions in 50 young people (aged 13-33 years) with depression or bipolar disorder. Data were based on actigraphy monitoring conducted over approximately 2 weeks and clinical and neuropsychological assessment. As part of a longitudinal cohort study, these assessments were repeated after a mean follow-up interval of 18.9 months. No significant differences in longitudinal clinical changes were found between the participants with depression and those with bipolar disorder. Lower sleep efficiency was predictive of longitudinal worsening in manic symptoms (P = 0.007). Shorter total sleep time (P = 0.043) and poorer circadian rhythmicity (P = 0.045) were predictive of worsening in verbal memory. These findings suggest that some sleep-wake and circadian disturbances in young people with mood disorders may be associated with less favourable longitudinal outcomes, notably for subsequent manic symptoms and memory difficulties.

Dysregulated sleep-wake cycles in young people are associated with emerging stages of major mental disorders.

AIM: To determine if disturbed sleep-wake cycle patterns in young people with evolving mental disorder are associated with stages of illness. METHODS: The sleep-wake cycle was monitored using actigraphy across 4 to 22 days. Participants (21 healthy controls and 154 persons seeking help for mental health problems) were aged between 12 and 30 years. Those persons seeking mental health care were categorized as having mild symptoms (stage 1a), an 'attenuated syndrome' (stage 1b) or an 'established mental disorder' (stage 2+). RESULTS: The proportions of individuals with a delayed weekdays sleep schedule increased progressively across illness stages: 9.5% of controls, 11.1% of stage 1a, 25.6% of stage 1b, and 50.0% of stage 2+ (χ(2) (3 d.f.) = 18.4, P < 0.001). A similar pattern was found for weekends (χ(2) (3 d.f.) = 7.6, P = 0.048). Compared with controls, stage 1b participants had later sleep onset on weekends (P = 0.015), and participants at stages 1b and 2+ had later sleep offset on both weekdays and weekends (P < 0.020). Compared with controls, all participants with mental disorders had more wake after sleep onset (P < 0.029) and those at stages 1a and 2+ had lower sleep efficiency (P < 0.040). Older age, medicated status and later weekdays sleep offset were found to be the three strongest correlates of later versus earlier clinical stages. CONCLUSIONS: In relation to clinical staging of common mental disorders in young people, the extent of delayed sleep phase is associated with more severe or persistent phases of illness.

The relationship between sleep-wake cycle and cognitive functioning in young people with affective disorders.

Although early-stage affective disorders are associated with both cognitive dysfunction and sleep-wake disruptions, relationships between these factors have not been specifically examined in young adults. Sleep and circadian rhythm disturbances in those with affective disorders are considerably heterogeneous, and may not relate to cognitive dysfunction in a simple linear fashion. This study aimed to characterise profiles of sleep and circadian disturbance in young people with affective disorders and examine associations between these profiles and cognitive performance. Actigraphy monitoring was completed in 152 young people (16-30 years; 66% female) with primary diagnoses of affective disorders, and 69 healthy controls (18-30 years; 57% female). Patients also underwent detailed neuropsychological assessment. Actigraphy data were processed to estimate both sleep and circadian parameters. Overall neuropsychological performance in patients was poor on tasks relating to mental flexibility and visual memory. Two hierarchical cluster analyses identified three distinct patient groups based on sleep variables and three based on circadian variables. Sleep clusters included a 'long sleep' cluster, a 'disrupted sleep' cluster, and a 'delayed and disrupted sleep' cluster. Circadian clusters included a 'strong circadian' cluster, a 'weak circadian' cluster, and a 'delayed circadian' cluster. Medication use differed between clusters. The 'long sleep' cluster displayed significantly worse visual memory performance compared to the 'disrupted sleep' cluster. No other cognitive functions differed between clusters. These results highlight the heterogeneity of sleep and circadian profiles in young people with affective disorders, and provide preliminary evidence in support of a relationship between sleep and visual memory, which may be mediated by use of antipsychotic medication. These findings have implications for the personalisation of treatments and improvement of functioning in young adults early in the course of affective illness.

Body mass, cardiovascular risk and metabolic characteristics of young persons presenting for mental healthcare in Sydney, Australia.

OBJECTIVES: To determine the body mass, cardiovascular and metabolic characteristics of young people presenting for mental healthcare. DESIGN: Cross-sectional assessments of body mass, cardiovascular and metabolic risk factors. SETTING: Two primary-care based sites in Sydney, Australia for young people in the early stages of mental disorders. PARTICIPANTS: A clinical sample of young people (12-30 years) with mental health problems. OUTCOME MEASURES: Daily smoking rates, body mass index (BMI), blood glucose and lipids, blood pressure (BP) and pulse rate. RESULTS: Of 1005 young people who had their BMI determined (62% female; 19.0±3.5 years), three quarters (739/1005) also had BP recordings and one-third (298/1005) had blood sampling. Clinically, 775 were assigned to one of three diagnostic categories (anxious-depression: n=541; mania-fatigue, n=104; developmental-psychotic n=130). The profile of BMI categories approximated that of the comparable segments of the Australian population. Older age, lower levels of social functioning and higher systolic BP were all associated with high BMI. In a subset (n=129), current use of any psychotropic medication was associated (p<0.05) with increased BMI. Almost one-third of cases were current daily smokers (compared to population rate of 11%). Males had a higher proportion of raised glucose and high-density lipoprotein (HDL) compared to females (9.3% and 34.1% vs 2.1% and 5.9%, respectively). Overall, there was no relationship between BMI and fasting glucose but significant relationships with triglycerides and HDL were noted. Furthermore, there were no significant relationships between diagnostic subgroup and metabolic profiles. CONCLUSIONS: Daily smoking rates are increased among young people presenting for mental healthcare. However, these young people do not demonstrate adverse cardiometabolic profiles. The high levels of smoking, and association of BMI with adverse social circumstances, suggest that risk factors for chronic disease are already present and likely to be compounded by medication and social disadvantage.

Ambulatory sleep-wake patterns and variability in young people with emerging mental disorders.

BACKGROUND: The nature of sleep-wake abnormalities in individuals with mental disorders remains unclear. The present study aimed to examine the differences in objective ambulatory measures of the sleep-wake and activity cycles across young people with anxiety, mood or psychotic disorders. METHODS: Participants underwent several days of actigraphy monitoring. We divided participants into 5 groups (control, anxiety disorder, unipolar depression, bipolar disorder, psychotic disorder) according to primary diagnosis. RESULTS: We enrolled 342 participants aged 12-35 years in our study: 41 healthy controls, 56 with anxiety disorder, 135 with unipolar depression, 80 with bipolar disorder and 30 with psychotic disorders. Compared with the control group, sleep onset tended to occur later in the anxiety, depression and bipolar groups; sleep offset occurred later in all primary diagnosis groups; the sleep period was longer in the anxiety, bipolar and psychosis groups; total sleep time was longer in the psychosis group; and sleep efficiency was lower in the depression group, with a similar tendency for the anxiety and bipolar groups. Sleep parameters were significantly more variable in patient subgroups than in controls. Cosinor analysis revealed delayed circadian activity profiles in the anxiety and bipolar groups and abnormal circadian curve in the psychosis group. LIMITATIONS: Although statistical analyses controlled for age, the sample included individuals from preadolescence to adulthood. Most participants from the primary diagnosis subgroups were taking psychotropic medications, and a large proportion had other comorbid mental disorders. CONCLUSION: Our findings suggest that delayed and disorganized sleep offset times are common in young patients with various mental disorders. However, other sleep-wake cycle disturbances appear to be more prominent in broad diagnostic categories.

Functional impairment in adolescents and young adults with emerging mood disorders.

BACKGROUND: Between 30 and 60% of adults with unipolar or bipolar disorders exhibit impairments across multiple domains. However, little is known about impaired functioning in youth with mood disorders. AIMS: To examine the prevalence of objective, subjective and observer-rated disability in a large, representative sample of young people with a primary mood disorder. METHOD: Individuals aged 16-25 years presenting to youth mental health services for the first time with a primary mood disorder participated in a systematic diagnostic and clinical assessment. Impairment was assessed using objective (unemployment or disability payments), observer- (Social and Occupational Functioning Assessment Scale; SOFAS) and self-rated measures (role functioning according to the Brief Disability Questionnaire). RESULTS: Of 1241 participants (83% unipolar; 56% female), at least 30% were functionally impaired on the objective, self-rated and/or observer-rated measures, with 16% impaired according to all three criteria. Even when current distress levels were taken into account, daily use of cannabis and/or nicotine were significantly associated with impairment, with odds ratios (OR) ranging from about 1.5 to 3.0. Comorbid anxiety disorders were related to lower SOFAS scores (OR = 2-5). CONCLUSIONS: Levels of disability were significant, even in those presenting for mental healthcare for the first time. Functional impairment did not differ between unipolar and bipolar cases, but some evidence suggested that females with bipolar disorder were particularly disabled. The prevalence of comorbid disorders (50%) and polysubstance use (28%) and their association with disability indicate that more meaningful indicators of mood episode outcomes should focus on functional rather than symptom-specific measures. The association between functioning and nicotine use requires further exploration.

Sleep-wake cycle in young and older persons with a lifetime history of mood disorders.

Considering the marked changes in sleep and circadian rhythms across the lifespan, age may contribute to the heterogeneity in sleep-wake profiles linked to mood disorders. This study aimed to investigate the contributions of age and depression severity to sleep-wake disturbances. The Hamilton Depression Rating Scale (HDRS) was administered to assess current symptoms severity in 238 persons with a history of a mood disorder between 12 and 90 years of age (y.o.). Actigraphy was recorded over five to 22 days. Regression analyses and analyses of variance [age (12-19 y.o., 20-39 y.o., 40-59 y.o., and ≥ 60 y.o.) by depression severity (HDRS< and ≥ 8)] were conducted. The 12-19 y.o. and 20-39 y.o. groups had a delayed sleep schedule and acrophase compared to all other groups. The ≥ 60 y.o. group had a lower rhythmicity and amplitude (p ≤ .006) than the 12-19 y.o. group (p ≤ .046). Participants with a HDRS ≥ 8 spent longer time in bed, had later sleep offset times and had lower circadian rhythmicity than those with a HDRS<8 (p ≤ .036). Younger age and higher HDRS score correlated with later sleep onset and offset times, longer time in bed, higher WASO, lower sleep efficiency and later acrophase (p ≤ .023). Age was a significant predictor of delayed sleep and activity schedules (p ≤ .001). The profile of sleep-wake cycle disturbances associated with mood disorders changes with age, with prominent sleep phase delay during youth and reduced circadian strength in older persons. Conversely, disruptions in sleep consolidation seem more stable across age.

Frequent alcohol, nicotine or cannabis use is common in young persons presenting for mental healthcare: a cross-sectional study.

OBJECTIVES: To determine the prevalence of recent alcohol, nicotine or cannabis use in young persons presenting for mental healthcare. DESIGN: A cross-sectional study of young people seeking mental healthcare completed self-report questionnaires regarding their use of alcohol, nicotine or cannabis. SETTING: Data were collected from two sites as part of the national headspace services programme. PARTICIPANTS: 2122 young people aged 12-30 years provided information as part of a patient register; a subset of N=522 participants also provided more detailed information about their patterns of alcohol use. OUTCOME MEASURES: Prevalence levels of recent alcohol, nicotine or cannabis use within relevant age bands (12-17, 18-19 and 20-30) or primary diagnostic categories. RESULTS: The rates for use at least weekly of alcohol for the three age bands were 12%, 39% and 45%, and for cannabis 7%, 14% and 18%, respectively. The rates of daily nicotine use for the three age bands were 23%, 36% and 41%. The pattern of alcohol use was characterised by few abstainers as well as many risky drinkers. Age of onset across all three substances was approximately 15 years. Individuals who used any of the three substances more frequently were likely to be older, male or have psychotic or bipolar disorders. CONCLUSIONS: Frequent use of alcohol, nicotine or cannabis in young people seeking mental healthcare is common. Given the restricted legal access, the patterns of use in those aged 12-17 years are particularly notable. Reductions in substance use needs to be prioritised within services for at-risk young people.

Applying clinical staging to young people who present for mental health care.

AIM: The study aims to apply clinical staging to young people who present for mental health care; to describe the demographic features, patterns of psychological symptoms, disability correlates and clinical stages of those young people; and to report longitudinal estimates of progression from less to more severe stages. METHODS: The study uses cross-sectional and longitudinal assessments of young people managed in specialized youth clinics. On the basis of clinical records, subjects were assigned to a specific clinical 'stage' (i.e. 'help-seeking', 'attenuated syndrome', 'discrete disorder' or 'persistent or recurrent illness'). RESULTS: Young people (n = 209, mean age = 19.9 years (range = 12-30 years), 48% female) were selected from a broader cohort of n = 1483 subjects. Ten percent were assigned to the earliest 'help-seeking' stage, 54% to the 'attenuated syndrome' stage, 25% to the 'discrete disorder' stage and 11% to the later 'persistent or recurrent illness' stage. The interrater reliability of independent ratings at baseline was acceptable (κ = 0.71). Subjects assigned to the 'attenuated syndrome' stage reported symptom and disability scores that were similar to those assigned to later stages. Longitudinally (median = 48 weeks), transition to later clinical stages were 11% of the 'help-seeking', 19% of the 'attenuated syndrome' and 33% of the 'discrete disorder' groups. CONCLUSION: Among young people presenting for mental health care, most are clinically staged as having 'attenuated syndromes'. Despite access to specialized treatment, a significant number progress to more severe or persistent disorders.

Distress and disability in young adults presenting to clinical services with mood disorders.

BACKGROUND: Distress and/or dysfunction are well established as key reasons for help-seeking. We explore the characteristics of groups defined by high or low distress or disability in young people with unipolar depression (UP) or bipolar disorder (BD). METHODS: Individuals aged 12 to 25 years presenting to youth mental health services for the first time with a primary diagnosis of UP or BD were assessed using the Kessler Psychological Distress Scale (Kessler-10) and the Work and Social Adjustment Scale (WSAS). Four groups with high or low distress or impairment were defined (according to scores above or below the group medians for the Kessler-10 and WSAS). Multinomial logistic regression (MNLR) was used to examine how cases with high levels of distress and disability (reference group) differed from the other three groups. RESULTS AND DISCUSSION: The sample comprised 1,746 cases (90% UP, 56% female) with a median age of 17.5 years. Median scores on the Kessler-10 and WSAS were both high (30 and 20, respectively) and were significantly inter-correlated (r = 0.62); the high impairment/distress group was the largest sub-group (39% of cases). The MNLR analysis demonstrated that younger age was associated with lower impairment groups (irrespective of distress level), whilst male gender was associated with lower distress (irrespective of impairment). Compared to the low impairment/distress cases, the high impairment/distress group was significantly more likely to use cannabis and/or alcohol. Age, substance use and possibly gender are probably better predictors of distress/impairment sub-group than mood disorder sub-type in youth.

Thoughts of death or suicidal ideation are common in young people aged 12 to 30 years presenting for mental health care.

BACKGROUND: Reducing suicidal behaviour is a major public health goal. Expanding access to care has been identified as a key strategy. In Australia, a national network of primary-care based services (headspace) has been established for young people with mental ill-health. This study determines the socio-demographic, psychopathological and illness-stage correlates of suicidal ideation in young persons attending headspace services. METHODS: Suicidal ideation was recorded using the specific suicide item of the Hamilton Depression Rating Scale (HDRS) in a cohort of subjects aged 12-30 years (N = 494) attending headspace services. RESULTS: Of the 494 young persons assessed, 32% (158/494) had a positive response to any level of the HDRS suicide item, consisting of 16% (77/494) reporting that life was not worth living and a further 16% (81/494) reported thoughts of death or suicidal ideation. Young women (19%; 94/494) were more likely to report any positive response as compared with young men (13%; 64/494) [χ²(2,494) = 13.6, p < .01]. Those with 'attenuated syndromes' reported positive responses at rates comparable to those with more established disorders (35% vs. 34%; χ²(1,347) = 0.0, p = 0.87). However, more serious levels of suicidal ideation were more common in those with depressive disorders or later stages of illness. In multivariate analyses, the major predictors of the degree of suicidal ideation were increasing levels of clinician-rated depressive symptoms (beta = 0.595, p < .001), general psychopathology (beta = 0.198, p < .01), and self-reported distress (beta = 0.172, p < .05). CONCLUSIONS: Feelings that life is not worth living, thoughts of death or suicidal ideation are common in young people seeking mental health care. These at-risk cognitions are evident before many of these individuals develop severe or persistent mental disorders. Thoughts of death or suicidal ideation may well need to be a primary intervention target in these young people.

Are cardiometabolic and endocrine abnormalities linked to sleep difficulties in schizophrenia? A hypothesis driven review.

Schizophrenia is a psychiatric disorder that includes symptoms such as hallucinations, disordered thoughts, disorganized or catatonic behaviour, cognitive dysfunction and sleep-wake disturbance. In addition to these symptoms, cardiometabolic dysfunction is common in patients with schizophrenia. While previously it has been thought that cardiometabolic symptoms in patients with schizophrenia were associated with medications used to manage this disorder, more recently it has been demonstrated that these symptoms are present in drug naive and unmedicated patients. Sleep-wake disturbance, resulting in chronic sleep loss has also been demonstrated to induce changes in cardiometabolic function. Chronic sleep loss has been associated with an increased risk for weight gain, obesity and cardiac and metabolic disorders, independent of other potentially contributing factors, such as smoking and body mass index. We hypothesise that the sleep-wake disturbance comorbid with schizophrenia may play a significant role in the high prevalence of cardiometabolic dysfunction observed in this patient population. Here we present a critical review of the evidence that supports this hypothesis.

Delivering youth-specific mental health services: the advantages of a collaborative, multi-disciplinary system.

OBJECTIVE: Evidence suggests that quality mental health care is based on well-integrated multi-disciplinary care provided by a range of mental health, substance use, and general healthcare clinicians. There is a growing focus in Australia on providing this type of mental health care to young people, particularly those in the early stages of a major disorder. The development of such services has proceeded on the basis of limited service-based data and has also been impeded by current healthcare funding structures. METHODS: This report outlines the service characteristics of three models: a traditional 'fee for service' model, a specialized youth mental health clinic, and a new headspace multi-disciplinary site in South Western Sydney. RESULTS: Naturalistic data from these three services collected during their developmental phase indicate that each model is associated with differential demographic, illness and service organization characteristics. CONCLUSIONS: Compared with 'fee-for-service' type care, specialized youth models provide greater access to a broad range of multi-disciplinary clinicians.