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Recent years have seen the increasing availability of large, population-based, longitudinal neuroimaging datasets, providing unprecedented capacity to examine brain-behavior relationships in the neurodevelopmental context. However, the ability of these datasets to deliver causal insights into brain-behavior relationships relies on the application of purpose-built analysis methods to counter the biases that otherwise preclude causal inference from observational data. Here we introduce these approaches (i.e., propensity score-based methods, the 'G-methods', targeted maximum likelihood estimation, and causal mediation analysis) and conduct a review to determine the extent to which they have been applied thus far in the field of developmental cognitive neuroscience. We identify just eight relevant studies, most of which employ propensity score-based methods. Many approaches are entirely absent from the literature, particularly those that promote causal inference in settings with complex, multi-wave data and repeated neuroimaging assessments. Causality is central to an etiological understanding of the relationship between the brain and behavior, as well as for identifying targets for prevention and intervention. Careful application of methods for causal inference may help the field of developmental cognitive neuroscience approach these goals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: Research is inconclusive with respect to the possible risk-increasing effect of anxiety symptoms on heavy drinking behavior among adolescents and young adults. Adult role transitions and changes in the social context from early adolescence into young adulthood may impact the association between anxiety symptoms and alcohol use., Methods: The TRacking Adolescents' Individual Lives Survey, including 2,229 individuals at baseline, was used to evaluate the bi-directional and longitudinal associations between anxiety symptoms and alcohol use, using data at 14, 16, 19, 22, and 25 years of age., Results: Cross-lagged models revealed a relatively stable negative association at 14, 16, and 19 years, showing that relatively higher anxiety symptoms were associated with relatively lower drinking levels three years later. This effect was absent in young adulthood. There was no evidence for significant associations between alcohol use and subsequent anxiety symptoms, with the exception of alcohol use at age 19, which predicted relatively lower levels of anxiety symptoms at age 22., Discussion: Overall, the results indicated that anxiety symptoms may withhold adolescents from (heavy) drinking, although this protective effect disappeared in young adulthood. Transitions in social contexts as well as autonomy and adult responsibilities could underlie the changing association between alcohol use and anxiety symptoms throughout adolescence and young adulthood., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Promoting adolescent sports participation and physical activity may be effective low-barrier prevention strategies for co-occurring adolescent substance use (SU) and mental health symptoms (MH). The objectives of this study were to: 1) explore associations between profiles of SU/MH and sports participation; and 2) determine whether physical activity and belongingness account for these associations., Methods: Data came from a representative sample of 11,994 grade 9-12 Ontarian students (ages ~14-18) previously grouped into five SU/MH profiles based on patterns of use and symptoms. A series of multinomial logistic regressions, adjusted for socio-demographics and school clustering, were used to predict the risks of students belonging to SU/MH profiles based on: 1) school sports participation (>=weekly), 2) sports and physical activity (>=60minutes; 0-7 days), and 3) sports, physical activity, and school belongingness., Results: Greater school sports participation, physical activity, and belongingness were each associated with reduced risks of belonging to most profiles with elevations in SU and/or MH symptoms relative to the low SU/MH profile (Relative Risk Ratios: sports=0.62-0.87, physical activity=0.78-0.98, belonging=0.75-0.83). Frequency of physical activity accounted for ~32-60% of the associations between sports and SU/MH profiles, while school belongingness accounted for the remaining associations. Physical activity and belongingness remained independently associated with SU/MH profiles., Conclusions: Findings suggest possible indirect associations between school sports participation and SU/MH profiles through physical activity and school belongingness, which may be promising prevention targets that have independent associations over and above sports. School sports participation may be one of a number of ways to achieve these goals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jillian Halladay reports financial support was provided by Canadian Institutes of Health Research, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Opioid-related deaths continue to increase to unprecedented rates in many regions of the world. While long-term stable treatment has been shown to reduce associated morbidity and mortality, discontinuation and numerous treatment episodes are common, limiting our understanding of the common course of treatment and associated characteristics. Therefore, using an 18-20-year follow-up of people with heroin dependence, we aimed to identify i) distinct trajectories of treatment use, ii) whether baseline characteristics predict treatment trajectory group membership, and ii) if group membership is associated with characteristics at 18-20-years post-baseline., Methods: A total of 615 people with heroin dependence were recruited from maintenance therapy, detoxification, residential rehabilitation, or needle and syringe programs as part of the Australian Treatment Outcome Study (ATOS), a longitudinal cohort followed up on seven occasions over 18-20-years between 2001 and 2021. Of those who had complete data (n = 393), group-based trajectory modelling and a series of multinomial logistical regressions were conducted., Results: Five trajectories of treatment use were identified: i) 'long-term low treatment' (17.2%), ii) 'rapid increase with gradual decrease' (13.9%), iii) 'late increase' (17.8%), (iv) 'long-term treatment' (27.7%), and (v) 'reduced treatment' (23.5%). Entering maintenance treatment at baseline predicted trajectory group membership, while trajectory group membership was associated with demographics and the use of heroin, methamphetamine, alcohol, and benzodiazepines at 18-20-years., Conclusions: In one of the longest cohort studies of its kind, we characterised distinct trajectories of treatment use in people with heroin dependence over 18-20-years. Clinicians should be aware of the potential impact of demographics and substance use on long-term treatment use. Despite the well-documented benefits of long-term treatment, some patients may be able to achieve abstinence from opioids without engaging in treatment over the life-course., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Moderate alcohol consumption appears to be associated with reduced inflammation. Determining whether this association is robust to common variations in research parameters has wide-reaching implications for our understanding of disease aetiology and public health policy. We aimed to conduct comprehensive multiverse and vibration of effects analyses evaluating the associations between alcohol consumption and a measure of inflammation., Methods: A secondary analysis of the 1970 British Birth Cohort Study was performed, using data from 1970 through 2016. Measurements of alcohol consumption were taken in early/mid-adulthood (ages 34 and 42), and level of inflammation marker high-sensitivity C-reactive protein (hsCRP) at age 46. Multiverse analyses were applied to comparisons of low-to-moderate consumption and consumption above various international drinking guidelines with an 'abstinent' reference. Research parameters of interest related to: definitions of drinking and reference groups; alcohol consumption measurement year; outcome variable transformation; and breadth of covariate adjustment. After identifying various analytic options within these parameters and running the analysis over each unique option combination, specification curve plots, volcano plots, effect ranges, and variance decomposition metrics were used to assess consistency of results., Results: A total of 3101 individuals were included in the final analyses, with primary analyses limited to those where occasional consumers served as reference. All combinations of research specifications resulted in lower levels of inflammation amongst low-to-moderate consumers compared to occasional consumers (1st percentile effect: -0.21; 99th percentile effect: -0.04). Estimates comparing above-guidelines drinking with occasional consumers were less definitive (1st percentile effect: -0.26; 99th percentile effect: 0.43)., Conclusions: The association between low-to-moderate drinking and lower hsCRP levels is largely robust to common variations in researcher-defined parameters, warranting further research to establish whether this relationship is causal. The association between above-guidelines drinking and hsCRP levels is less definitive., Competing Interests: Declaration of Competing Interest No conflict declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Alcohol use is a leading cause of burden of disease among young people. Prevention strategies can be effective in the short-term; however little is known about their longer-term effectiveness. The aim of this study was to examine the sustainability of universal, selective, and combined alcohol use prevention across the critical transition period from adolescence into early adulthood., Method: In 2012, a total of 2190 students (mean age, 13.3 years) from 26 Australian high schools participated in a cluster randomized controlled trial and were followed up for 3 years post baseline. Schools were randomly assigned to deliver the following: (1) universal Web-based prevention for all students (Climate Schools); (2) selective prevention for high-risk students (Preventure); (3) combined universal and selective prevention (Climate Schools and Preventure [CAP]); or (4) health education as usual (control). This study extends the follow-up period to 7-years post baseline. Primary outcomes were self-reported frequency of alcohol consumption and binge drinking, alcohol-related harms, and hazardous alcohol use, at the 7-year follow-up., Results: At 7-year follow-up, students in all 3 intervention groups reported reduced odds of alcohol-related harms compared to the control group (odds ratios [ORs] = 0.13-0.33), and the Climate (OR = 0.04) and Preventure (OR = 0.17) groups reported lower odds of hazardous alcohol use. The Preventure group also reported lower odds of weekly alcohol use compared to the control group (OR = 0.17), and the Climate group reported lower odds of binge drinking (OR = 0.12), holding mean baseline levels constant., Conclusion: This study demonstrated that both universal and selective preventive interventions delivered in schools can have long-lasting effects and reduce risky drinking and related harms into adulthood. No added benefit was observed by delivering the combined interventions., Clinical Trial Registration Information: The CAP Study: Evaluating a Comprehensive Universal and Targeted Intervention Designed to Prevent Substance Use and Related Harms in Australian Adolescents; https://www.anzctr.org.au/; ACTRN12612000026820., (Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach.

Background: Recent studies suggest that young adult participation in, and volume of, alcohol consumption has decreased. However, the evidence on trends in harmful alcohol consumption in this age group is limited. The current paper aims to examine changes over time in harmful alcohol consumption using a robust, widely employed measure., Methods: The literature was systematically searched for articles reporting on Alcohol Use Disorders Identification Test (AUDIT) scores in young adults aged 18-24 years. The key data extracted were year of measurement and mean AUDIT score (proportion above clinical cut-off was not relevant for these analyses). Cross-temporal meta-analysis was applied to the extracted data., Results: A decrease was found in young adults' AUDIT scores measured between 1989 and 2015 (b=-0.13, β=-0.38, p = 0.015, 95 % CI=-0.24, -0.03), representing a 0.63 standard deviation change over this period. Variance did not change over this time, suggesting scores decreased equally over the distribution., Conclusions: Results indicate that harmful alcohol consumption in young adults may have declined between 1989 and 2015. Despite the continued problems posed by dependence and short and long-term harms, these promising findings offer hope that the considerable alcohol-related disease burden in this age group may be reduced. Ongoing data collection is required to evaluate whether these declines in young adulthood persist into later life, and future research should explore the reasons for declining harmful alcohol consumption in young adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: There is substantial evidence that psychosocial programs delivered online can be effective in treating and preventing mental health problems. However, use of evidence-based programs in the community is currently suboptimal, and there is a lack of evidence around how to increase engagement with existing evidence-based programs. Novel approaches to increasing the acceptability of online programs such as the use of brief engagement-facilitation interventions (EFI) require evaluation., Aims: The aims of this study are to 1) examine the effectiveness of a brief online engagement-facilitation intervention (EFI) presented prior to an online self-help mental health program (myCompass) in improving uptake of and adherence to that program, and 2) assess if greater uptake and/or adherence are associated with improved efficacy (greater reduction in symptoms of depression and anxiety) relative to a control condition)., Methods: A three-arm randomized controlled trial will be conducted (target sample: N = 693 participants recruited via social media). An active online cognitive behavioral therapy (iCBT) intervention will be delivered either with (arm 1) or without (arm 2) the EFI. An attention control group (arm 3) will enable testing of the relative efficacy of the iCBT intervention. Primary outcomes are uptake of the intervention (initiation) and adherence (module completion)., Results: Findings will inform the more efficient dissemination of a range of psychosocial programs into the community, with potential for significant efficiency gains in treating common mental health problems., Conclusions: Greater engagement with online psychosocial programs may lead to significant reductions in the burden of common mental health problems in the community., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001565235., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Relatively little is known about factors that may lead to the development of a substance use disorder (SUD), across a range of drug classes. This study aimed to identify factors that predict the likelihood of transition from use to SUD and the speed with which this may occur at the population level, with a focus on the impact of pre-existing mental disorders., Methods: Data were collected as part of the 2007 Australian National Survey of Mental Health and Wellbeing, a nationally representative survey of 8841 Australian adults. A series of discrete time survival analyses were undertaken on data pertaining to the age of onset of use and symptoms of use disorder, for alcohol, cannabis, sedatives, stimulants, and opioids, as well as the impact of pre-existing mood and anxiety disorders on the likelihood of developing a SUD., Results: Lifetime cumulative probability estimates indicated that 50.4% of stimulant, 46.6% of opioid, 39% of sedative, 37.5% of alcohol, and 34.1% of cannabis users would develop a SUD on those substances, within an estimated 14, 12, 8, 30, and 23 years after onset respectively. Pre-existing mental disorders were significantly associated with increased risk of developing a SUD for alcohol, cannabis and stimulant use disorder., Conclusion: The relative speed associated with the transition from use to SUD emphasizes the narrow window of time available to intervene, underscoring the urgency of early identification of mental health conditions and the timely provision of appropriate evidence-based interventions, which could potentially prevent the development of secondary SUDs., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: There is no standardized approach to the measurement of social anxiety. Researchers and clinicians are faced with numerous self-report scales with varying strengths, weaknesses, and psychometric properties. The lack of standardization makes it difficult to compare scores across populations that use different scales. Item response theory offers one solution to this problem via equating different scales using an anchor scale to set a standardized metric. This study is the first to equate several scales for social anxiety disorder., Study Design and Setting: Data from two samples (n = 3,175 and n = 1,052), recruited from the Australian community using online advertisements, were used to equate a network of 11 self-report social anxiety scales via a fixed parameter item calibration method., Results: Comparisons between actual and equated scores for most of the scales indicted a high level of agreement with mean differences <0.10 (equivalent to a mean difference of less than one point on the standardized metric)., Conclusion: This study demonstrates that scores from multiple scales that measure social anxiety can be converted to a common scale. Rescoring observed scores to a common scale provides opportunities to combine research from multiple studies and ultimately better assess social anxiety in treatment and research settings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The K6 and K10 are well-validated screening measures for psychological distress and are widely used. However, the accuracy of these scales in identifying common mental disorders may be suboptimal. This study aimed to develop a brief scale of psychological distress--the Distress Questionnaire-5 (DQ5)--and validate its diagnostic accuracy in identifying common mental disorders, relative to the K6 and K10., Study Design and Setting: The DQ5 was developed from a pool of 347 items reflecting a range of mental health symptoms. Validation of the DQ5 was conducted concurrently, on the basis of DSM-5 criteria for seven common mental disorders. A population-based sample of Australian adults (n = 3,175) was recruited online, with data weighted to reflect population estimates of disorder prevalence, age, and gender., Results: At specified cut points, the DQ5 was significantly more accurate in identifying individuals who met criteria for each of the disorders examined relative to the K6, with the exception of major depression where there was no significant difference in sensitivity or specificity., Conclusion: The DQ5 is a promising tool for identifying psychological distress in the community, with potential for use in a range of clinical settings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The experience of traumatic events has been linked to the development of psychopathology. Changing perspectives on psychopathology have resulted in the hypothesis that broad dimensional constructs account for the majority of variance across putatively distinct disorders. As such, traumatic events may be associated with several disorders due to their relationship with these broad dimensions rather than any direct disorder-specific relationship. The current study used data from 8871 Australians to test this hypothesis. Two broad dimensions accounted for the majority of relationships between traumatic events and mental and substance use disorders. Direct relationships remained between post-traumatic stress disorder and six categories of traumatic events in the total population and between drug dependence and accidents/disasters for males only. These results have strong implications for how psychopathology is conceptualized and offer some evidence that traumatic events are associated with an increased likelihood of experiencing psychopathology in general., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To investigate factors that may bias the reporting of major depression symptoms among older adults, specifically the presence of physical conditions, bereavement, episode onset, and episode length., Methods: A secondary data analysis of a nationally representative cross-sectional survey of community-dwelling older Australian adults aged 50-85 years who completed the depression module in the 2007 Australian National Survey of Mental Health and Wellbeing (N=629) was conducted. Depression symptomatology was assessed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria using the World Mental Health Composite International Diagnostic Interview., Results: Multiple indicators multiple causes modeling indicated a unidimensional factor structure of depression. Two depressive symptoms displayed measurement noninvariance (i.e., nonequivalency): worthlessness/guilt and suicidality/thoughts of death. Specifically, older adults who were bereaved were significantly less likely to report worthlessness/guilt (OR: 0.29; 95% CI: 0.16-0.50) and more likely to report suicidality/thoughts of death (OR: 4.67; 95% CI: 2.84-7.68), compared with older adults who were not bereaved. Examination of latent mean differences revealed that older adults with physical conditions displayed significantly greater depression severity compared with older adults without physical conditions., Conclusion: The presence of physical conditions and episode onset and length do not appear to differentially influence reporting of depression symptoms among older Australian adults, suggesting these factors do not bias prevalence estimates of depression. Reporting of worthlessness/guilt and suicidality/thoughts of death may be biased toward older adults who are bereaved; however, these did not influence overall depression severity., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Given high rates of comorbidity among mental disorders, better methods to rapidly screen across multiple mental disorders are needed. Building on existing Patient Reported Outcomes Measurement Information System (PROMIS) item banks, the present study aimed to select items to assess panic disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, adult attention-deficit hyperactivity disorder, substance use disorder, suicidal thoughts and behaviors, and psychosis., Study Design and Setting: A four-stage process to select items involved systematic literature searches, item refinement and standardization, obtaining feedback from consumers and experts, and reduction of item pools in preparation for calibration in a population-based sample., Results: From 6,900 items collected across the eight mental health conditions, 2,002 were standardized and rated by small groups of consumers and experts. Expert ratings of item relevance tended to correlate moderately with consumer ratings, with variation across conditions. An algorithm was used to generate final item pools ranging from 45 to 75 items., Conclusion: The study successfully applied a systematic process to select items for assessing a range of mental disorders. This process for item selection may be applied to additional mental and physical health conditions. The calibration of the present item pools into final item banks will enable the development of flexible measures to assess risk of mental health problems, although more effectively accounting for comorbidity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To provide estimates of the prevalence and correlates of subjective memory complaints in older individuals by using population-based Australian data., Design: 2007 National Survey of Mental Health and Well-Being., Setting: Australia., Participants: 1,905 community-dwelling participants aged 65-85 years., Measurements: Subjective memory complaints were assessed by using two questions reflecting: (1) poorer memory compared with others of the same age ("worse memory"); and (2) a decline in memory performance over the previous 5 years ("declining memory"). Twelve-month and lifetime diagnoses were derived from structured diagnostic interviews. Other correlates investigated included chronic physical conditions, lifestyle factors, and service use. Analyses adjusted for scores on the Mini-Mental State Examination., Results: Subjective memory complaints were reported by one-third (33.5%) of respondents. Those who reported either complaint were more likely to report psychological distress, poor functioning, service use, and negative self-assessed mental and physical health. "Declining memory" over the past 5 years was also related to an increase in the rates of psychiatric disorders. After adjusting for other variables of interest, associations were established between subjective memory complaints and psychological distress, poor functioning, negative self-assessed mental health, and alcohol use disorders. Except for the association between "declining memory" and anxiety and depression, these associations remained significant after excluding those with scores <27 on the Mini-Mental State Examination., Conclusions: Subjective memory complaints were associated with several negative clinical characteristics that should be considered when interpreting these complaints. Subjective memory complaints may be valid indicators of psychopathology and the need for clinical assessment., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Objective: To provide population-based Kessler Psychological Distress Scale (K10) normative data for older adults and cut scores for screening., Participants: Adults age ≥65 years who participated in either the 1997 or 2007 Australian National Surveys of Mental Health and Well-being (N = 3,697)., Measurements: The proportion of respondents who reported psychological distress, and the correspondence of K10 scores with diagnosis of mental disorder, disability, and service use., Results: Scores on the K10 corresponded well with rates of mental disorder. Higher K10 scores were associated with increased levels of internalizing disorder, comorbidity, functional disability, and service use. Receiver operating characteristic curve analysis revealed an area under the curve score of 0.86, suggesting good predictive power. For screening purposes, a cut score of 15 was found to be associated with the best balance between sensitivity (0.77) and specificity (0.78). Similar levels of predictive power were observed across various subgroups of the population. Score ranges for groups who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition affective or anxiety disorder showed that for those age 65-75, a score of 20 or greater and a score of 17 or greater for those older than 75 years warrant heightened clinical interest., Conclusions: The K10 exhibits sensitivity to internalizing disorders as they occur across the lifespan and can be used with confidence when assessing psychological distress in old-age community dwellers. The significant association between higher K10 scores and disability suggests that the presence of psychological distress, regardless of diagnostic status, requires clinician attention., (Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: In an attempt to improve dose intensity and therapeutic effectiveness in breast cancer, GM-CSF was incorporated into a multi-drug every other week chemotherapy regimen that had been previously reported to have promising activity, but whose dose-limiting toxicity was neutropenia., Patients and Methods: A Phase I-II study in patients with locally advanced or metastatic breast cancer was initiated using GM-CSF and a 5-drug chemotherapy regimen employing oral cyclophosphamide daily for 7 days and doxorubicin, vincristine, methotrexate, 5-fluorouracil, and leucovorin IV every 2 weeks for 10 courses. In the first 8 patients, GM-CSF in escalating doses (1-20 micrograms/kg s.c. per day) was given on days 8-13 of each 2 week cycle. In the last 12 patients, GM-CSF was given on days 3-14 of each cycle in an attempt to improve its effectiveness by prolonging treatment duration., Results: The regimen was poorly tolerated. Only 10 patients completed all 10 courses of treatment, and most of those required dose delays and/or reductions. GM-CSF failed to reduce neutropenia when given by either schedule. Furthermore, thrombocytopenia was severe and progressive, especially with the more prolonged GM-CSF schedule in which the mean lowest nadir platelet count was 15,000/microliters. Anemia, fatigue, mucositis, and neutropenic fevers were also common, and dose escalations were not possible in any patient. Central venous catheter complications were also common. Complete or partial remissions were observed in 15 of 20 patients, but response durations were brief., Conclusions: GM-CSF in two different schedules failed to ameliorate myelosuppression when used in combination with this multiple drug, every other week regimen. Neutropenia and, especially, thrombocytopenia remained dose limiting.