Treatment guesses in the Treatment for Adolescents with Depression Study: Accuracy, unblinding and influence on outcomes.

OBJECTIVE: We evaluated the presence and impact of unblinding during the influential Treatment for Adolescents with Depression Study (ClinicalTrials.gov Identifier: NCT00006286). METHOD: Our analysis was part of a Restoring Invisible and Abandoned Trials reanalysis. Treatment for Adolescents with Depression Study trialled fluoxetine, placebo, cognitive behaviour therapy or their combination, in treating adolescents with major depressive disorder. We analysed the accuracy of guesses of fluoxetine or placebo allocation, and their effects on change in Children's Depression Rating Scale-Revised at 12 weeks. RESULTS: Of 221 participants allocated to fluoxetine or placebo, 151 adolescents (68%) had their guess about pill-treatment-arm allocation recorded at week 6, and guesses were recorded for 154 independent evaluators, 159 parents and 164 pharmacotherapists. All of these groups guessed treatment allocation more accurately than would be expected by chance (60-66% accuracy; all p-values ⩽ 0.004). Guesses did not become more accurate between 6 and 12 weeks and were not predicted by adverse events, though event documentation was poor. Treatment guess had a substantial and statistically significant effect on outcome (Children's Depression Rating Scale-Revised change mean difference 9.12 [4.69; 13.55], ß = 0.334, p < 0.001), but actual treatment arm did not (1.53 [-2.83; 5.89], ß = 0.056, p = 0.489). Removing guess from the analysis increased the apparent effect of treatment arm, making it almost statistically significant at the conventional alpha-level of 0.05 (p = 0.06). CONCLUSIONS: For Treatment for Adolescents with Depression Study, treatment guesses strongly predicted outcomes and may have led to the exaggeration of drug effectiveness in the absence of actual effects. The integrity of double-blinding in trials should be routinely assessed and reported.

Dispensing of psychotropic medications to Australian children and adolescents before and during the COVID-19 pandemic, 2013-2021: a retrospective cohort study.

OBJECTIVE: To determine longitudinal patterns of dispensing of antidepressant, anxiolytic, antipsychotic, psychostimulant, and hypnotic/sedative medications to children and adolescents in Australia during 2013-2021. DESIGN: Retrospective cohort study; analysis of 10% random sample of Pharmaceutical Benefits Scheme (PBS) dispensing data. PARTICIPANTS, SETTING: People aged 18 years or younger dispensed PBS-subsidised psychotropic medications in Australia, 2013-2021. MAIN OUTCOME MEASURES: Population prevalence of dispensing of psychotropic medications to children and adolescents, by psychotropic class, gender, and age group (0-6, 7-12, 13-18 years). RESULTS: The overall prevalence of psychotropic dispensing to children and adolescents was 33.8 per 1000 boys and 25.2 per 1000 girls in 2013, and 60.0 per 1000 boys and 48.3 per 1000 girls in 2021. The prevalence of psychotropic polypharmacy was 5.4 per 1000 boys and 3.7 per 1000 girls in 2013, and 10.4 per 1000 boys and 8.3 per 1000 girls in 2021. Prevalent dispensing during 2021 was highest for psychostimulants (boys, 44.0 per 1000; girls, 17.4 per 1000) and antidepressants (boys, 20.4 per 1000; girls, 33.8 per 1000). During 2021, the prevalence of dispensing was higher than predicted by extrapolation of 2013-2019 data for many classes, including antidepressants (boys: +6.1%; 95% CI, 1.1-11.1%; girls: +22.2%; 95% CI, 17.4-26.9%), and psychostimulants (boys: +14.5%; 95% CI, 8.0-21.1%; girls: +27.7%; 95% CI, 18.9-36.6%). The increases were greatest for girls aged 13-18 years (antidepressants: +20.3%; 95% CI, 16.9-23.7%; psychostimulants: +39.0%; 95% CI, 27.9-50.0%). CONCLUSIONS: The prevalence of both psychotropic dispensing and psychotropic polypharmacy for children and adolescents were twice as high in 2021 as in 2013. The reasons and appropriateness of the marked increases in psychotropic dispensing during the COVID-19 pandemic, particularly to adolescent girls, should be investigated.

The Maternal Looking Guide: a perinatal clinical tool to support the emerging mother-infant relationship'.

BACKGROUND: This study explores maternal looking - the unidirectional looking by a mother at her newborn - as a precursor to mother-infant gaze. METHODS: Phase 1 used video as a means of detailed and disciplined observation to examine how mothers look at their newborns (n = 13). Using an iterative design, intensive analysis identified and categorised patterns of looking and looking-related behaviours. This resulted in a typology of looking. Phase 2 subjected the typology to inter-rater reliability testing, with midwives as multiple raters (n = 24), using the typology to rate standardised tapes of mothers and newborns (n = 10). RESULTS: Phase 1 generated a one-page clinical tool (Maternal Looking Guide). This tool enables the assessment of mothers' looking behaviour over six constructs and allocation to one of three overall categories of looking: those women who are doing well (comfortable), those who need a referral to an expert perinatal service (worrisome) and those to whom something extra could be offered (uncomfortable). In Phase 2 the Maternal Looking Guide achieved moderate reliability. CONCLUSIONS: The Maternal Looking Guide is a practical, moderately reliable, clinical tool that can assist midwives and other perinatal workers identify those mothers who may need extra support at this critical perinatal window of opportunity. .

Trends in prescription of psychotropic medications to children and adolescents in Australian primary care from 2011 to 2018.

OBJECTIVE: To examine trends in prescribing psychotropic medications to children and adolescents in Australian primary care from 2011 to 2018. METHOD: A retrospective cohort study examined prescriptions written by general practitioners using MedicineInsight, a large Australian primary care database, covering approximately 9% of all general practitioner practices. Numbers of patients receiving prescriptions for five main classes of psychotropics (antipsychotics, antidepressants, attention deficit hyperactivity disorder medications, anxiolytics, and hypnotics/sedatives [including benzodiazepines and Z-drugs, but excluding melatonin]) were examined annually by age-group (0-4, 5-9, 10-14, 15-18 years). Melatonin was analysed separately. RESULTS: The number of patients prescribed any psychotropic increased from 25.6 to 36.2 per 1000 individuals from 2011 to 2018 (average annual increase +4.5%, 95% confidence interval [4.1%, 4.9%]; overall +41.4%). Among the five main classes, the largest annual increase was for attention deficit hyperactivity disorder medications (+9.6%, 95% confidence interval [8.8%, 10.5%]; overall +95.8%), followed by antipsychotics (+6.2%, 95% confidence interval [5.0%, 7.3%]; overall +62.8%) and antidepressants (+4.5%, 95% confidence interval [4.0%, 5.0%]; overall +42.8%). Hypnotic/sedative prescribing decreased on average 6.5% per year (95% confidence interval [-8.0%, -5.0%]; overall -40.2%). Anxiolytic prescribing remained steady. Melatonin prescriptions showed the highest increase of all (+24.7%, 95% confidence interval [23.7%, 25.8%]; overall +606.7%). The largest annual increase in antipsychotic, antidepressant or attention deficit hyperactivity disorder medication prescribing occurred in 10- to 14-year-olds (+7.5%, +6.5% and +10.4%, respectively). The largest point prevalence occurred in 2018 among 15- to 18-year-olds, with 98.5 per 1000 prescribed antidepressants. Antidepressants were more frequently prescribed to females; antipsychotics, attention deficit hyperactivity disorder medications and melatonin more often to males. The most prescribed antipsychotics were risperidone (<15 years) and quetiapine (15- to 18-year-olds). Fluoxetine was the most prescribed antidepressant in those aged 5+ years and amitriptyline in 0- to 4-year-olds. CONCLUSION: General practitioner prescribing of melatonin, antipsychotics, antidepressants and attention deficit hyperactivity disorder medications to under-19-year-olds increased markedly from 2011 to 2018. Although benzodiazepine and Z-drug prescriptions declined, this was offset by a substantial increase in melatonin prescribing.

Attention deficit hyperactivity disorder late birthdate effect common in both high and low prescribing international jurisdictions: a systematic review.

BACKGROUND: Multiple studies have found that the youngest children in a classroom are at elevated risk of being diagnosed with, or medicated for, ADHD. This systematic review was conducted to investigate whether this late birthdate effect is the norm and whether the strength of effect is related to the absolute risk of being diagnosed/medicated. METHODS: A literature search of the PubMed and ERIC databases and snowball and grey literature searching were conducted. RESULTS: A total of 19 studies in 13 countries covering over 15.4 million children investigating this relationship were identified. Three other studies exploring related topics were identified. The diversity of methodologies prevented a meta-analysis. Instead a systematic review of the 22 studies was conducted. A total of 17 of the 19 studies found that the youngest children in a school year were considerably more likely to be diagnosed and/or medicated than their older classmates. Two Danish studies found either a weak or no late birth date effect. There was no consistent relationship between per-capita diagnosis or medication rates and the strength of the relative age effect, with strong effects reported in most jurisdictions with comparatively low rates. CONCLUSIONS: It is the norm internationally for the youngest children in a classroom to be at increased risk of being medicated for ADHD, even in jurisdictions with relatively low prescribing rates. A lack of a strong effect in Denmark may be accounted for by the common practice of academic 'redshirting', where children judged by parents as immature have a delayed school start. Redshirting may prevent and/or disguise late birthdate effects and further research is warranted. The evidence of strong late birthdate effects in jurisdictions with comparatively low diagnosis/medication rates challenges the notion that low rates indicate sound diagnostic practices.

Doubling: a model for international clinical partnerships.

OBJECTIVES:: This article draws attention to an initiative aimed at benefiting colleagues in developing countries, through financial and/or moral support. It describes an attempt to engage The Royal College of Australian and New Zealand Psychiatrists ('the College') in supporting this philanthropic activity. It further aims to attract interest from the College and fellows in contributing to international philanthropy. CONCLUSIONS:: Doubling provides a credible model for facilitating better mental health care in situations where there are trained staff but inadequate resources. The College's resistance to engagement with this project may represent a missed opportunity for philanthropic support.

Mental Health Messages in Prominent Mental Health Apps.

PURPOSE: Many who seek primary health care advice about mental health may be using mobile applications (apps) claiming to improve well-being or relieve symptoms. We aimed to identify how prominent mental health apps frame mental health, including who has problems and how they should be managed. METHODS: We conducted a qualitative content analysis of advertising material for mental health apps found online in the United States, the United Kingdom, Canada, and Australia during late 2016. Apps were included if they explicitly referenced mental health diagnoses or symptoms and offered diagnosis and guidance, or made health claims. Two independent coders analyzed app store descriptions and linked websites using a structured, open-ended instrument. We conducted interpretive analysis to identify key themes and the range of messages. RESULTS: We identified 61 mental health apps: 34 addressed predominantly anxiety, panic, and stress (56%), 16 addressed mood disorders (26%), and 11 addressed well-being or other mental health issues (18%). Apps described mental health problems as being psychological symptoms, a risk state, or lack of life achievements. Mental health problems were framed as present in everyone, but everyone was represented as employed, white, and in a family. Explanations about mental health focused on abnormal responses to mild triggers, with minimal acknowledgment of external stressors. Therapeutic strategies included relaxation, cognitive guidance, and self-monitoring. Apps encouraged frequent use and promoted personal responsibility for improvement. CONCLUSIONS: Mental health apps may promote medicalization of normal mental states and imply individual responsibility for mental well-being. Within the health care clinician-patient relationship, such messages should be challenged, where appropriate, to prevent overdiagnosis and ensure supportive health care where needed.

Antipsychotic prescribing patterns in children and adolescents attending Australian general practice in 2011 and 2017.

Background: Antipsychotics are increasingly prescribed to children and adolescents worldwide, but little is known about reasons for prescribing. We aimed to examine patterns of paediatric antipsychotic prescribing in Australian primary care services in 2011 and 2017, including diagnoses, sociodemographic characteristics, off-label prescribing, and psychotropic co-prescribing. Methods: Retrospective analysis of electronic health records (EHRs) using a large Australian general practice database (MedicineInsight). Diagnoses of mental disorders were extracted from EHRs and associated with antipsychotic prescriptions within the same calendar year for three age-groups: 0-9, 10-14, and 15-18-year-olds. Results: In 2017, children/adolescents with mental health diagnoses were more likely to be prescribed antipsychotics (2.9% of 27,412 patients) than in 2011 (2.0% of 8418 patients; absolute difference +0.9, 95% CI + 0.5, +1.4). The likelihood was greater for patients with bipolar disorders (21.6% vs. 41.5%), eating disorders (1.1% vs. 7.2%), and autism without behavioural problems (3.7% vs. 6.1%). Depression/anxiety (adjusted 26.8% of patients 2011; 30.8% 2017) was the most common diagnosis associated with antipsychotics in both years. Most antipsychotics were prescribed off-label (69.8% 2011; 79.7% 2017; absolute difference +9.8, 95% CI + 1.54, +18.4). Off-label prescribing increased most among those aged 15-18-years, females, and patients living in outer regional/remote/very remote communities and the most disadvantaged areas. The three most frequently prescribed antipsychotics in both years were risperidone, quetiapine, and olanzapine. Psychotropic co-prescribing among patients receiving antipsychotic prescriptions was approximately 69% in both years. Conclusions: Prescribing antipsychotics for mental health diagnoses to children/adolescents attending Australian general practices was more frequent in 2017 than 2011, and most commonly associated with depression/anxiety diagnoses. In both years, most prescribing was off-label. The majority of patients were co-prescribed other classes of psychotropics along with antipsychotics.

Emerging psychosis in adolescents--a practical guide.

BACKGROUND: Emerging psychosis is a challenging presentation for the general practitioner as there is disagreement in the literature about classification and appropriate treatment protocols. OBJECTIVE: This paper highlights three main issues in primary care: recognising early signs of emerging psychosis, and how and when to refer patients; complexities associated with comorbid substance use; and management when the patient is referred back to primary care in the post-acute phase. DISCUSSION: Emerging psychosis is a complex presentation that warrants a considered approach right from the initial assessment. This paper emphasises the rationale for 'watchful waiting' in the interest of diagnostic certainty before potentially harmful treatments are commenced. There are also guidelines for a balanced approach to management, where engagement with the patient, monitoring medication effects and preventing relapse are the main aims.

Barriers to access to clinical trial data: Obstruction of a RIAT reanalysis of the treatment for adolescents with depression study.

BACKGROUND: Public access to data has been a major step in attempting to reduce bias in scientific literature. Data to verify efficacy outcomes are now more accessible; however, little has been done to ensure public access to harms data from RCTs, which are equally important in ascertaining possible misreporting and protecting safety. OBJECTIVE: The treatment for adolescents with depression study (TADS) has influenced most international practice guidelines for treating children and adolescents with depression, supporting first-line prescription of fluoxetine in combination with cognitive behavioural therapy (CBT). However, after over 30 publications by the TADS team, reporting on harms remains highly deficient and we aimed to redress this lack. METHODS: In undertaking a restoring invisible and abandoned trials (RIAT) reanalysis of TADS' effectiveness and safety outcomes, we sought access to de-identified serious adverse events (SAE) data. RESULTS: This paper describes our unsuccessful efforts to obtain more detailed SAE data from TADS' data custodians, highlighting several problematic blocks to comprehensive safety reporting. CONCLUSION: Comprehensive access to clinical trial data is necessary to ensure safe and fully informed guidelines for treating children and adolescents with depression.

Aripiprazole in the maintenance treatment of bipolar disorder: a critical review of the evidence and its dissemination into the scientific literature.

BACKGROUND: Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature. METHODS AND FINDINGS: We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations. CONCLUSIONS: A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature. Please see later in the article for the Editors' Summary.

The increased use of antidepressants has contributed to the worldwide reduction in suicide rates.

Numerous ecological studies have shown an inverse association between antidepressant use and suicide rates and a smaller number of individual-based studies have shown an association between current antidepressant use and reduced suicide risk. Such evidence is often cited in support of the notion that antidepressants prevent suicide. However, more recently, the premises underlying this proposition, namely that suicide is caused by depression and that antidepressants relieve depression, have been challenged and the potential harm caused by antidepressants has been highlighted. In this article, Goran Isacsson and Charles Rich debate with Jon Jureidini and Melissa Raven the motion that the increased use of antidepressants has contributed to the worldwide reduction in suicide rates.

Antidepressant Prescribing and Suicide/Self-Harm by Young Australians: Regulatory Warnings, Contradictory Advice, and Long-Term Trends.

In 2004, the US Food and Drug Administration (FDA) controversially issued a black box warning that antidepressants were associated with an increased risk of suicidal thoughts and behaviours in people aged under 18 years. In 2007, the warning was expanded to include young adults aged under 25 years. In 2005, the Australian Therapeutic Goods Administration responded to the FDA warning by requiring Product and Consumer Information leaflets to be updated to reflect the risk. However, there was considerable debate, and at times emotive backlash, in academic journals and the international media. Prominent US and Australian mental health organisations and psychiatrists challenged the FDA warning. They argued that, on balance, antidepressant use was likely to reduce the risk of suicide. Several ecological studies were cited misleadingly as evidence that decreasing antidepressant use increases suicide risk. From 2008 to 2018, Australian per-capita child, adolescent and young adult antidepressant dispensing (0-27 years of age) and suicide (0-24 years) rates have increased approximately 66% and 49%, respectively. In addition, there was a 98% increase in intentional poisonings among 5 to 19 year-olds in New South Wales and Victoria between 2006 and 2016, with substantial overlap between the most commonly dispensed psychotropics and the drugs most commonly used in self-poisoning. These results do not support claims that increased antidepressant use reduces youth suicide risk. They are more consistent with the FDA warning and the hypothesis that antidepressant use increases the risk of suicide and self-harm by young people. Causal relationships cannot be established with certainty until there is a vast improvement in post-marketing surveillance. However, there is clear evidence that more young Australians are taking antidepressants, and more young Australians are killing themselves and self-harming, often by intentionally overdosing on the very substances that are supposed to help them.

How do we safely treat depression in children, adolescents and young adults?

Increasing concerns about the safety and efficacy of antidepressant drugs for children, adolescents and young adults have been countered by claims that reduced prescribing of antidepressants may have dangerous consequences. This leaves clinicians unsure as to how to weigh up the evidence and apply it to their patients. This paper promotes an approach of evaluating the evidence in each study according to the importance of the outcomes being measured in that study. It finds that on important measures such as mortality, hospitalization and quality of life, the evidence is unfavourable for antidepressants in this population. Here, an approach is suggested that primary care physicians might adopt with their depressed young patients. Through a combination of 'watchful waiting' and physical and emotional rehabilitation, physicians can actively intervene without reliance on medication or psychotherapy.

Paediatric antidepressants: Benefits and risks.

The data supporting the use of "antidepressants" in children and adolescents is largely unavailable. Academic publications give a different picture as regards benefits and harms to publications from regulatory other sources. Despite disagreements about the data driving use of these medicines, in practice "antidepressants" may now be the most commonly used drugs by adolescent girls, and children's mental health services are attracting increasing attention.This paper reviews the difficulties surrounding the data. It outlines a case for benefits (as well as risks) that would require physicians to exert a greater degree of professional autonomy than service managers might wish.