Anxiety DisordersPhase 2NCT00018057
Study of Neuro-Cognitive Correlates of Pediatric Anxiety Disorders
A Phase 2 study testing Attention Bias Modification Training, Fluoxetine and Cognitive Behavioral Therapy in people with Anxiety Disorders and Major Depressive Disorder, run by National Institute of Mental Health (NIMH) at 2 sites in United States.
Trial summary
Study Description: This study examines relations between neurocognitive and clinical features of pediatric anxiety disorders. The study uses neuro-cognitive tasks, functional magnetic resonance imaging (fMRI), as well as magneto- and electro-encephalography (M/EEG). Read more about this study
- Who is it for?
- Ages 8 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Anxiety Disorders, Major Depressive Disorder
- What is being tested?
- Attention Bias Modification Training, Fluoxetine and Cognitive Behavioral Therapy
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 3,500 participants
- Where
- 2 sitesUnited States
- Study dates
- 2 Oct 2001to 1 Jan 2029
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 65 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- ALL JUVENILE SUBJECTS
- Age: 8-17 (subjects who consent as 17-year-olds but turn 18 during the course of the study will be eligible to complete all procedures completed by other subjects who consent as 17-year-olds but do not turn 18).
- Consent: can give consent/assent (Parents will provide consent; minors will provide assent)
- IQ: all subjects will have IQ>70 (Assessment relies on either a WASI or assessment by trained clinical staff during the subject s screening visit. Completion of required activities during the screening visit requires an IQ above 70.)
- Language: all subjects will speak English (Tasks in this protocol have not been validated in languages other than English)
- ALL ADULT SUBJECTS
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- Age: 18-65
- Consent: can give consent
- IQ: all subjects will have IQ>70 (Assessment relies on either a WASI or assessment by trained clinical staff during the subject s screening visit. Completion of required activities during the screening visit requires an IQ above 70.)
- Language: all subjects will speak English (Tasks in this protocol have not been validated in languages other than English)
- ALL SUBJECTS WITH AN ANXIETY DISORDER
- Diagnosis: Current Diagnosis of OCD, Social Phobia, Separation Anxiety, Generalized Anxiety Disorder, or Panic Disorder (Based on K-SADS (juveniles) or SCID (adults))
- Symptom Severity: Clinically significant, ongoing anxiety symptoms (This will be documented by clinician review with patients and their families during at least two visits with families.)
- Clinical Impairment: Clinically significant, ongoing distress or impairment from anxiety (This will be documented by clinician review with patients and their families during at least two visits with families.)
- ALL PREVIOUSLY ENROLLED ADOLESCENT PATIENTS, CHILD AND ADULT HEALTHY VOLUNTEERS, AND ALL HEALTHY VOLUNTEERS TURNED PATIENTS
- Diagnosis: Current Diagnosis of OCD, Social Phobia, Separation Anxiety, Generalized Anxiety Disorder, or Panic Disorder; No current diagnosis (Based on K-SADS (juveniles) or SCID (adults))
- Clinical Impairment (as applicable): Clinically significant, ongoing symptoms (This will be documented by clinician review with patients and their families during at least two visits with families.)
- Symptom Severity (as applicable): Clinically significant, ongoing symptoms (This will be documented by clinician review with patients and their families during at least two visits with families.)
Who cannot join
- ALL SUBJECTS
- Any serious medical condition or condition that interferes with fMRI or M/EEG scanning, and for patients electing medication, any condition that increases risk of SSRI treatment. (All patients will complete a medical history. Healthy volunteer participants will be medication- free and have no current serious medical conditions, based on a review of their medical history. Subjects only will be excluded from the MRI portions of the study based on this exclusion criterion.)
- Pregnancy (Subjects only will be excluded from the MRI portions of the study based on this exclusion criterion.)
- Current use of any psychoactive substance; current suicidal ideation as indicated by the presence of intent for engaging in suicidal behaviors; current diagnosis of attention deficit hyperactivity disorder (ADHD) of sufficient severity to require pharmacotherapy. (These factors could complicate treatment with an SSRI. No subject on medication will be accepted into the trial. Subjects will not be taken off of medications to enter the trial.)
- Current diagnoses, major depressive disorder (MDD), post-traumatic distress disorder, conduct disorder. (These factors may be affected by SSRI treatment, influencing ability to detect effects on anxiety/symptoms of depression. Of note, subjects who present with a diagnosis of MDD will not be eligible for inclusion at the outset of the study. However, youth with anxiety disorders frequently develop MDD when followed over time. Subjects will be allowed to remain in the study if they develop these diagnoses after enrollment.)
- Past or current history of mania, psychosis, or severe pervasive developmental disorder. (These factors may be affected by SSRI treatment, influencing ability to detect effects on anxiety/symptoms of depression. Of note, subjects who present with a diagnosis of MDD will not be eligible for inclusion at the outset of the study. However, youth with anxiety disorders frequently develop MDD when followed over time. Subjects will be allowed to remain in the study if they develop these diagnoses after enrollment.)
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- Recent use of an SSRI with failure to respond or tolerate SSRI treatment at an adequate dose and duration. (This is designed to exclude subjects who have failed a trial of an SSRI for their current problem with anxiety. For previously enrolled participants, including patients and healthy volunteers, current use of an SSRI does not exclude participation from follow-up research tasks.)
- History of any (excepting nicotine-related and cannabis-related) DSM5-defined moderate to severe substance use disorder (or DSM-IV-defined substance dependence).
- HEALTHY ADULT SUBJECTS
- -Any current psychiatric diagnosis (Assessment relies on SCID)
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
NIH Clinical Center Office of Patient Recruitment (OPR), 800-411-1222 ext. TTY dial 711, ccopr@nih.gov
- Recruiting
University of Maryland, College Park
College Park, Maryland, 20742
Nathan Fox, Ph.D., Not Listed, fox@umd.edu
About this study
Study Description:
This study examines relations between neurocognitive and clinical features of pediatric anxiety disorders. The study uses neuro-cognitive tasks, functional magnetic resonance imaging (fMRI), as well as magneto- and electro-encephalography (M/EEG). Patients will be studied over one year, before and after receiving either one of two standard-of-care treatments: cognitive behavioral therapy (CBT) or fluoxetine, a serotonin reuptake inhibitor (SSRI). Healthy comparisons will be studied at comparable time points.
Read more
Primary Objectives:
To compare healthy youth and symptomatic, medication-free pediatric patients studied prior to receipt of treatment. The study seeks to detect relations between clinical features of anxiety disorders at baseline and a wide range of neurocognitive features associated with attention, memory, and response to motivational stimuli.
Secondary Objectives:
- To document relations between baseline neurocognitive features and response to Cognitive Behavioral Therapy (CBT) or fluoxetine, as defined by the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Improvement (CGI) Scale.
- To document relations between post-treatment changes in neurocognitive features and anxiety symptoms on the PARS following treatment with Cognitive Behavioral Therapy (CBT) or fluoxetine.
- To document relations among broad arrays of clinical, cognitive, and neural measures
Primary Endpoints:
Indices of percent-signal change in hypothesized brain regions, comprising amygdala, striatum, and prefrontal cortex (PFC) for each fMRI and MEG paradigm.
Secondary Endpoints:
- Treatment-response as defined by a continuous measure, the Pediatric Anxiety Rating Scale score (PARS), and a categorial measure, the Clinical Global Improvement (CGI) score.
- Levels of symptoms and behaviors evoked by tasks that engage attention, memory, and elicit responses to motivational stimuli. ...
Read the detailed description
Study Description:
This study examines relations between neurocognitive and clinical features of pediatric anxiety disorders. The study uses neurocognitive tasks, functional magnetic resonance imaging (fMRI), as well as magneto- and electro-encephalography (M/EEG). Patients will be studied over one year, before and after receiving either one of two standard-of-care treatments: cognitive behavioral therapy (CBT) or fluoxetine, a serotonin reuptake inhibitor (SSRI). Healthy comparisons will be studied at comparable time points.
Primary Objectives:
-To compare healthy youth and symptomatic, medication-free pediatric patients studied prior to receipt of treatment. The study seeks to detect relations between clinical features of anxiety disorders at baseline and a wide range of neurocognitive features associated with attention, memory, and response to motivational stimuli.
Secondary Objectives:
- To document relations between baseline neurocognitive features and response to Cognitive Behavioral Therapy (CBT) or fluoxetine, as defined by the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Improvement (CGI) Scale.
- To document relations between post-treatment changes in neurocognitive features and anxiety symptoms on the PARS following treatment with Cognitive Behavioral Therapy (CBT) or fluoxetine.
- To document relations among broad arrays of clinical, cognitive, and neural measures
Primary Endpoints:
-Indices of percent-signal change in hypothesized brain regions, comprising amygdala, striatum, and prefrontal cortex (PFC) for each fMRI and MEG paradigm.
Secondary Endpoints:
- Treatment-response as defined by a continuous measure, the Pediatric Anxiety Rating Scale score (PARS), and a categorial measure, the Clinical Global Improvement (CGI) score.
- Levels of symptoms and behaviors evoked by tasks that engage attention, memory, and elicit responses to motivational stimuli.
- Conditions
- Anxiety Disorders, Major Depressive Disorder
- Being tested
- Attention Bias Modification Training, Fluoxetine, Cognitive Behavioral Therapy
- Keywords
- fMRI, Emotion, Normal Volunteers, Magnetic Resonance Imaging, CBT
- Medical subject headings
- Anxiety Disorders, Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Attention Bias Modification TrainingBehavioural
The intervention is computer-based. The active and control treatments have two components. In one component of the active intervention, subjects are asked to indicate the identity of a letter that appears behind a neutral face, opposite from an angry face. In another component of the active intervention, subjects are asked to identify numbers that are hidden within a puzzle, in locations distal from angry faces. In both components of the active intervention, subjects implicitly learn to shift their attention away from angry faces. This is because the faces are systematically arranged to be far removed from letters and numbers that need to be identified. The control arm of the intervention involves similar components. However, unlike in the intervention arm, angry faces appear in various locations near letters and numbers. Therefore, attention is not shaped in the control arm. This intervention requires five minutes per session and is administered before weekly psychotherapy sessions.
FluoxetineDrug
Randomized assignment.
Cognitive Behavioral TherapyBehavioural
| Study group | Role | What they receive |
|---|---|---|
| Active | Experimental | Subjects in both treatment arms receive cognitive behavioral therapy (CBT) for a 12-week period. In the final eight weeks of the trial, the subjects complete either the active-intervention arm or the control invention arm. In these arms, either the active or control treatment is administered immediately before a CBT session. Receives: Behavioral: Attention Bias Modification Training; Drug: Fluoxetine; Behavioral: Cognitive Behavioral Therapy |
| Control | Placebo comparator | Subjects in both treatment arms receive cognitive behavioral therapy (CBT) for a 12-week period. In the final eight weeks of the trial, the subjects complete either the active-intervention arm or the control invention arm. In these arms, either the active or control treatment is administered immediately before a CBT session. Receives: Behavioral: Attention Bias Modification Training |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pediatric Anxiety Rating Scale (PARS)
Clinician-rated report
Measured: Weekly
Clinical Global Improvement (CGI) Scale
Clinician-rated report
Measured: Weekly
Secondary outcomes (1)
Another secondary objective is to document relations between post-treatment changes in neurocognitive features and anxiety symptoms on the PARS following treatment with Cognitive Behavioral Therapy (CBT) or fluoxetine.
Prior research in adults finds changes in symptoms to relate to changes in brain function. If confirmed in youth, this would provide insights on mechanisms of therapeutic change and targets for novel therapies
Measured: Changes in symptoms on PARS and changes after 8-12 weeks of treatment in patients
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2001 (estimated)
- Study start2 Oct 2001
- Primary completion1 Jan 2029 (estimated)
- Study completion1 Jan 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Anxiety DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 3,500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Daniel S Pine, M.D., Principal investigator, National Institute of Mental Health (NIMH)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00018057
- Sponsor's protocol ID
- 010192
- Other IDs
- 01-M-0192
- Status last verified
- 9 Jul 2026
- First submitted
- 29 Jun 2001
- Last updated
- 16 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Meigs JM, Kiderman M, Kircanski K, Cardinale EM, Pine DS, Leibenluft E, Brotman MA, Naim R. Sleepless nights, sour moods: daily sleep-irritability links in a pediatric clinical sample. J Child Psychol Psychiatry. 2024 Sep;65(9):1175-1183. doi: 10.1111/jcpp.13959. Epub 2024 Feb 14.
PubMed 38355141Byrne ME, Bernstein RA, Pine DS, Kircanski K. Ecological Momentary Assessment of Youth Anxiety: Evaluation of Psychometrics for Use in Clinical Trials. J Child Adolesc Psychopharmacol. 2023 Dec;33(10):409-417. doi: 10.1089/cap.2023.0025. Epub 2023 Dec 5.
PubMed 38052059Tseng WL, Naim R, Chue A, Shaughnessy S, Meigs J, Pine DS, Leibenluft E, Kircanski K, Brotman MA. Network analysis of ecological momentary assessment identifies frustration as a central node in irritability. J Child Psychol Psychiatry. 2023 Aug;64(8):1212-1221. doi: 10.1111/jcpp.13794. Epub 2023 Mar 28.
PubMed 36977629Linke JO, Haller SP, Xu EP, Nguyen LT, Chue AE, Botz-Zapp C, Revzina O, Perlstein S, Ross AJ, Tseng WL, Shaw P, Brotman MA, Pine DS, Gotts SJ, Leibenluft E, Kircanski K. Persistent Frustration-Induced Reconfigurations of Brain Networks Predict Individual Differences in Irritability. J Am Acad Child Adolesc Psychiatry. 2023 Jun;62(6):684-695. doi: 10.1016/j.jaac.2022.11.009. Epub 2022 Dec 21.
PubMed 36563874Newsome P, Ruiz SG, Gold AL, Pine DS, Abend R. Fear-potentiated startle reveals diminished threat extinction in pathological anxiety. Int J Psychophysiol. 2023 Jan;183:81-91. doi: 10.1016/j.ijpsycho.2022.11.011. Epub 2022 Nov 25.
PubMed 36442665Naim R, Shaughnessy S, Smith A, Karalunas SL, Kircanski K, Brotman MA. Real-time assessment of positive and negative affective fluctuations and mood lability in a transdiagnostic sample of youth. Depress Anxiety. 2022 Dec;39(12):870-880. doi: 10.1002/da.23293. Epub 2022 Nov 3.
PubMed 36325887Haller SP, Archer C, Jeong A, Jaffe A, Jones EL, Harrewijn A, Naim R, Linke JO, Stoddard J, Brotman MA. Changes in Internalizing Symptoms During the COVID-19 Pandemic in a Transdiagnostic Sample of Youth: Exploring Mediators and Predictors. Child Psychiatry Hum Dev. 2024 Feb;55(1):206-218. doi: 10.1007/s10578-022-01382-z. Epub 2022 Jul 6.
PubMed 35794298Scheinost D, Dadashkarimi J, Finn ES, Wambach CG, MacGillivray C, Roule AL, Niendam TA, Pine DS, Brotman MA, Leibenluft E, Tseng WL. Functional connectivity during frustration: a preliminary study of predictive modeling of irritability in youth. Neuropsychopharmacology. 2021 Jun;46(7):1300-1306. doi: 10.1038/s41386-020-00954-8. Epub 2021 Jan 21.
PubMed 33479511Cardinale EM, Freitag GF, Brotman MA, Pine DS, Leibenluft E, Kircanski K. Phasic Versus Tonic Irritability: Differential Associations With Attention-Deficit/Hyperactivity Disorder Symptoms. J Am Acad Child Adolesc Psychiatry. 2021 Dec;60(12):1513-1523. doi: 10.1016/j.jaac.2020.11.022. Epub 2021 Jan 10.
PubMed 33440203Linke JO, Abend R, Kircanski K, Clayton M, Stavish C, Benson BE, Brotman MA, Renaud O, Smith SM, Nichols TE, Leibenluft E, Winkler AM, Pine DS. Shared and Anxiety-Specific Pediatric Psychopathology Dimensions Manifest Distributed Neural Correlates. Biol Psychiatry. 2021 Mar 15;89(6):579-587. doi: 10.1016/j.biopsych.2020.10.018. Epub 2020 Nov 9.
PubMed 33386133Smith AR, Haller SP, Haas SA, Pagliaccio D, Behrens B, Swetlitz C, Bezek JL, Brotman MA, Leibenluft E, Fox NA, Pine DS. Emotional distractors and attentional control in anxious youth: eye tracking and fMRI data. Cogn Emot. 2021 Feb;35(1):110-128. doi: 10.1080/02699931.2020.1816911. Epub 2020 Sep 21.
PubMed 32954946Filippi CA, Sachs JF, Phillips D, Winkler A, Gold AL, Leibenluft E, Pine DS, Fox NA. Infant behavioral reactivity predicts change in amygdala volume 12 years later. Dev Cogn Neurosci. 2020 Apr;42:100776. doi: 10.1016/j.dcn.2020.100776. Epub 2020 Mar 21.
PubMed 32452462Haller SP, Kircanski K, Stringaris A, Clayton M, Bui H, Agorsor C, Cardenas SI, Towbin KE, Pine DS, Leibenluft E, Brotman MA. The Clinician Affective Reactivity Index: Validity and Reliability of a Clinician-Rated Assessment of Irritability. Behav Ther. 2020 Mar;51(2):283-293. doi: 10.1016/j.beth.2019.10.005. Epub 2019 Nov 27.
PubMed 32138938Smith AR, Nelson EE, Kircanski K, Rappaport BI, Do QB, Leibenluft E, Pine DS, Jarcho JM. Social anxiety and age are associated with neural response to social evaluation during adolescence. Dev Cogn Neurosci. 2020 Apr;42:100768. doi: 10.1016/j.dcn.2020.100768. Epub 2020 Feb 10.
PubMed 32077442Abend R, Gold AL, Britton JC, Michalska KJ, Shechner T, Sachs JF, Winkler AM, Leibenluft E, Averbeck BB, Pine DS. Anticipatory Threat Responding: Associations With Anxiety, Development, and Brain Structure. Biol Psychiatry. 2020 May 15;87(10):916-925. doi: 10.1016/j.biopsych.2019.11.006. Epub 2019 Nov 15.
PubMed 31955915