<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03247270</url>
  </required_header>
  <id_info>
    <org_study_id>Dnr300-16</org_study_id>
    <nct_id>NCT03247270</nct_id>
  </id_info>
  <brief_title>Physical Fitness and Brain - Interventional Study</brief_title>
  <acronym>PHYSBI</acronym>
  <official_title>Physical Fitness and Brain - Interventional Study of the Importance of Physical Fitness on Symptoms of Anxiety, Cognitive Ability and Sick Leave, in Primary Care.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Göteborg University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Göteborg University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      According to the Global Burden of Disease report in 2015, anxiety disorders are among the top&#xD;
      10 contributors to years lived with disability worldwide. There is a need for effective&#xD;
      treatment protocols. As cardiovascular fitness has a major impact on the brain's ability to&#xD;
      change structurally and functionally, interventions involving physical exercise might prove&#xD;
      positive in the treatment of persons with anxiety. Yet there are few high quality clinical&#xD;
      studies with physical exercise as an intervention for anxiety disorders.&#xD;
&#xD;
      Aims:&#xD;
&#xD;
        1. To test a 12 week physical exercise intervention for persons treated for anxiety&#xD;
           disorders within primary care. The exposure of interest is intensity of physical&#xD;
           exercise; outcomes include anxiety symptom burden, cognitive ability and sick leave.&#xD;
&#xD;
        2. To gain knowledge regarding potential mechanisms by comparing serum levels of specific&#xD;
           hormones and cytokines (characterized and associated with brain plasticity in animal&#xD;
           models) before and after different intensities of exercise.&#xD;
&#xD;
      Implementation:&#xD;
&#xD;
      Patients will be randomized into 3 groups: 1) Intervention I: 12 week exercise program with&#xD;
      low-intensity fitness training 3 times per week. 2) Intervention II: 12 week exercise program&#xD;
      with moderate to high-intensity fitness training 3 times per week. 3) Control group, who will&#xD;
      have a physiotherapy session once and will be given general advice about physical activity.&#xD;
      At baseline, 12 weeks and 1 year data of cardiovascular fitness, anxiety symptoms, cognitive&#xD;
      and working ability and biomarkers will be collected.&#xD;
&#xD;
      Impact:&#xD;
&#xD;
      If physical exercise positively affects anxiety disorders it would have significance, for the&#xD;
      patients as well as for society. In addition to increased quality of life, it may decrease&#xD;
      future marginalization and premature death among individuals suffering from anxiety&#xD;
      disorders. Reducing medical and sick-leave costs would also liberate health care resources to&#xD;
      be used elsewhere in an economically strained health care system.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overall objective To examine whether physical exercise reduces anxiety symptoms, improves&#xD;
      cognition and decreases need of sick leave in patients with anxiety disorders in primary&#xD;
      care.&#xD;
&#xD;
      Background Mental illness is the most common reason for unemployment in people of working age&#xD;
      and this is a growing patient group in Swedish primary care today. A survey by the European&#xD;
      Commission showed that 17% of the Swedish population had sought help over the past year for&#xD;
      psychiatric problems. These figures are above average for European countries and are&#xD;
      increasing. Sweden's costs for mental illness is around MSEK 70,000 annually - an increase of&#xD;
      MSEK 20,000 over ten years - and the proportion of sick leave days due to a psychiatric&#xD;
      diagnosis is currently 40%. Mental illness reduces quality of life substantially. For&#xD;
      example, 18-year-olds with anxiety disorders have increased risk of future marginalization&#xD;
      and have a two-fold increase in mortality not only due to suicide but several different death&#xD;
      causes, emphasizing the importance of finding effective treatment strategies.&#xD;
&#xD;
      The ability of the adult brain to change both structurally and functionally is called brain&#xD;
      plasticity. Both in humans and in animal models physical exercise has a major impact on brain&#xD;
      plasticity. Physical exercise can increase neurogenesis and improve memory functions in rats,&#xD;
      and circulating insulin-like growth factor I (IGF-I) can promote this effect. Brain-derived&#xD;
      neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) are also involved.&#xD;
      In addition, there is evidence that physical activity modifies neuronal activity, increases&#xD;
      the formation of synapses, and reduces inflammation markers, which may be correlated with&#xD;
      neuroprotection.&#xD;
&#xD;
      The investigators have previously demonstrated an association between physical fitness and&#xD;
      anxiety disorders, suggesting positive preventive benefits of physical exercise. The&#xD;
      beneficial effects of exercise interventions have to date mainly been demonstrated in persons&#xD;
      with depression.&#xD;
&#xD;
      The specific aims of this project are:&#xD;
&#xD;
        1. To test a 12 week physical exercise intervention for persons treated for anxiety&#xD;
           disorders within primary care. The exposure of interest is intensity of physical&#xD;
           exercise; outcomes include anxiety symptom burden, cognitive ability and sickness leave.&#xD;
&#xD;
        2. To gain knowledge regarding potential mechanisms by comparing serum levels of specific&#xD;
           hormones (characterized and associated with brain plasticity in animal models) before&#xD;
           and after different intensities of exercise.&#xD;
&#xD;
      Relationship to the research frontline In contrast to the literature on depression there are&#xD;
      very few clinical studies on physical exercise as an intervention for anxiety. All six trials&#xD;
      performed hitherto were identified as being at a high risk of bias. Higher quality trials are&#xD;
      thus required. There is a need to investigate the role of intensity, volume, frequency and&#xD;
      type of exercise on anxiety symptoms, cognitive function and working ability in people with&#xD;
      anxiety disorders. Also, the putative mechanisms behind the potential effects on anxiety&#xD;
      symptoms are not elucidated and deserve attention.&#xD;
&#xD;
      A novel feature of this study is the examination of different intensities of physical&#xD;
      fitness-improving exercise in patients with anxiety disorders. This has not previously been&#xD;
      performed and would yield valuable insight into dose-response associations between physical&#xD;
      fitness and effects on the brain. Objective measurements of physical fitness and cognition&#xD;
      are a great strength of the proposed study. Analyzing specific hormones and cytokines before&#xD;
      and after the intervention, in relation to symptoms and functional data, may provide&#xD;
      additional information about mechanistic aspects, treatment effect and prognosis. The&#xD;
      proposed research also offers opportunities to develop effective treatment protocols to&#xD;
      reduce the costs of sick-leave, an area of increasing interest world-wide.&#xD;
&#xD;
      In summary, the proposed study has the potential to provide novel and important contributions&#xD;
      to existing scientific knowledge regarding how physical exercise influences anxiety,&#xD;
      cognitive function and working ability in patients with anxiety disorders in primary care.&#xD;
&#xD;
      Work plan The study cohort will be patients diagnosed with anxiety disorders at six primary&#xD;
      care centres in Gothenburg, Southern Bohuslän and Halland including patients with panic&#xD;
      syndrome (F41.0), generalized anxiety (F41.1), mixed anxiety- and depression conditions&#xD;
      (F41.2 and F41.3), as well as anxiety UNS (F41.9). Diagnoses and comorbidities will be&#xD;
      determined by the study psychiatrist using the M.I.N.I (the Mini International&#xD;
      Neuropsychiatric Interview, Swedish version 6.0.0d DSM-IV). Intervention and follow-ups will&#xD;
      take place at Primary Care Rehab.&#xD;
&#xD;
      The investigators will exclude patients from the baseline who have physical difficulties in&#xD;
      performing a physical exercise program, pathological ECG, previous psychiatric illnesses,&#xD;
      ongoing abuse, increased risk of suicide as determined by the GP, those under 18, pregnant&#xD;
      women and those over 65 years of age. An additional exclusion criterion will be physical&#xD;
      activity level at baseline exceeding one exercise occasion per week. Both people with and&#xD;
      without ongoing treatment with psychoactive medication will be included. Supportive contact&#xD;
      for example with a health center nurse is not an exclusion criterion but persons with ongoing&#xD;
      psychotherapy will not be included unless the participants, as well as the GP, are willing to&#xD;
      take a break in therapy for the duration of the 12 week study.&#xD;
&#xD;
      Recruitment takes place at primary care centres and thus represents the individuals who seek&#xD;
      help in primary care for anxiety. Potential participants are contacted by a study&#xD;
      psychiatrist who has no healthcare provider relationship to the patient. Intervention and&#xD;
      follow-ups will take place at Primary Care Rehab. Each individual must sign a statement of&#xD;
      informed consent.&#xD;
&#xD;
      At baseline, 12 weeks and 1 year, the following data will be collected by the study&#xD;
      physician:&#xD;
&#xD;
        -  MINI International Neuropsychiatric Interview (Swedish version 6.0.0d DSM-IV)&#xD;
&#xD;
        -  Use of psychoactive prescription drugs including dosage and duration&#xD;
&#xD;
        -  Sick leave&#xD;
&#xD;
        -  Blood pressure&#xD;
&#xD;
        -  BMI&#xD;
&#xD;
        -  Self-report questions about alcohol (AUDIT self-assessment scale), smoking and diet&#xD;
&#xD;
        -  Established psychiatric self-assessment scales: Beck Anxiety Inventory (BAI), Montgomery&#xD;
           Åsberg Depression Rating Scale (MADRAS) and the quality of life instrument EQ-5D.&#xD;
&#xD;
        -  Test Design Fluency, which is part of the D-Kefs battery of tests and is well known and&#xD;
           used by many psychologists within education and psychiatry. This is a standardized test,&#xD;
           carried out within a few minutes that measures executive abilities such as creativity,&#xD;
           response inhibition and cognitive flexibility.&#xD;
&#xD;
        -  Objective measurements of physical fitness in the form of estimated maximal oxygen&#xD;
           uptake capacity (VO2max) using Åstrand's submaximal bicycle test.&#xD;
&#xD;
        -  Blood samples will be taken, by a nurse at the health center, to analyze the potential&#xD;
           correlation of the following hormones/cytokines with symptoms and function data:&#xD;
           S-IGF-I, S-BDNF, S-VEGF and high sensitivity CRP. The blood samples are stored in a&#xD;
           separate, locked -70 freezer at c-lab Sahlgrenska. IVO has been notified of the&#xD;
           establishment of a biobank (No 946).&#xD;
&#xD;
      Patients will be randomized into three groups: 1) Intervention I: 12 week exercise program&#xD;
      with low-intensity fitness training 3 times per week. 2) Intervention II: 12 week exercise&#xD;
      program with moderate to high-intensity fitness training 3 times per week. 3) Control group.&#xD;
      The physiotherapists at Primary Care Rehab will perform the submaximal bicycle test and&#xD;
      personally design the exercise program in the gym. The patients will have a one-to-one&#xD;
      session with the physiotherapists on 2 occasions and afterwards several people will exercise&#xD;
      at the same time in the gym.&#xD;
&#xD;
      A statistical power analysis has been performed by statistician Linus Schiöler. Based on&#xD;
      other studies, an effect size of 0.5 difference between the groups is clinically relevant,&#xD;
      which equates to a 5 point difference between the groups using the BAI scale. Standard&#xD;
      deviations from a previous study using BAI as the outcome measurement were in the interval of&#xD;
      5-10. SD 9 was used in the calculations. Based on these assumptions, at least 60 patients in&#xD;
      each of the treatment arms should be included to reach 80% power at the 5% significance&#xD;
      level. Health-economic analyses will be performed using primary data generated within the&#xD;
      project concerning health-related quality of life effects caused by the intervention and&#xD;
      information about healthcare resources utilized. A health-economic model that depicts the&#xD;
      clinical trial will be constructed and used for computing cost-utility measures. Moreover,&#xD;
      the model will be constructed for performing extensive probabilistic sensitivity analyses.&#xD;
&#xD;
      Ethical considerations The Ethics Committee of the University of Gothenburg approved the&#xD;
      study: PHYSBI intervention study: EPN Göteborg Dnr: 300-16. The control group will have a&#xD;
      physiotherapy session once and will be given general advice about physical activity. There&#xD;
      will be a possibility to individualize treatments i.e. the same intensity but different&#xD;
      exercises to better fit the needs and preferences of different individuals. Coding and&#xD;
      anonymization of data occur after data collection is complete.&#xD;
&#xD;
      Collaborations The principal investigator for this project Ass Prof Maria Åberg is the chair&#xD;
      of the steering committee for Physical Fitness and Brain Epidemiological studies (PHYSBE)&#xD;
      which is a multidisciplinary umbrella organization for several projects. Prof Kjell Torén&#xD;
      from Occupational and Environmental Medicine provides epidemiological competence. Prof Margda&#xD;
      Waern provides psychiatric expertise. Physiotherapist Louise Danielsson and Prof Kristian&#xD;
      Bolin at the Department of Economics and Statistics have experience of clinical intervention&#xD;
      studies.&#xD;
&#xD;
      The results will be published in international renowned peer-reviewed research journals.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 21, 2017</start_date>
  <completion_date type="Actual">June 30, 2021</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>RCT</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: BAI</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: BAI</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: MADRS-S</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: MADRS-S</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: EQ-5D</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anxiety symptom burden</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Established psychiatric self-assessment scales: EQ-5D</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive ability</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Test Design Fluency, which is part of the D-Kefs battery of tests</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive ability</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Test Design Fluency, which is part of the D-Kefs battery of tests</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive ability</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Digit test included in WAIS test battery</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive ability</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Digit test included in WAIS test battery</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sick leave</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>Questionnaire</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sick leave</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>Questionnaire</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>S-IGF-I</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>S-IGF-I</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>S-BDNF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>S-BDNF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>S-VEGF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>S-VEGF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>S-high sensitivity CRP</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>S-high sensitivity CRP</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>12 weeks after baseline</time_frame>
    <description>S-irisin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Biomarkers in serum</measure>
    <time_frame>1 year after baseline</time_frame>
    <description>S-irisin</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">168</enrollment>
  <condition>Anxiety Disorders</condition>
  <arm_group>
    <arm_group_label>Intervention I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Physical exercise intervention: 12 week exercise program with low-intensity fitness training 3 times per week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intervention II</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Physical exercise intervention:12 week exercise program with moderate to high-intensity fitness training 3 times per week</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Control group, who will have a physiotherapy session once and will be given general advice about physical activity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Intervention I</intervention_name>
    <description>Low intensive physical exercise</description>
    <arm_group_label>Intervention I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Intervention II</intervention_name>
    <description>High intensive physical exercise</description>
    <arm_group_label>Intervention II</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Panic syndrome (F41.0)&#xD;
&#xD;
          -  Generalized anxiety (F41.1)&#xD;
&#xD;
          -  Mixed anxiety- and depression conditions (F41.2 and F41.3)&#xD;
&#xD;
          -  Anxiety UNS (F41.9)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Physical difficulties in performing a physical exercise program&#xD;
&#xD;
          -  Pathological ECG&#xD;
&#xD;
          -  Previous psychiatric illnesses&#xD;
&#xD;
          -  Ongoing abuse&#xD;
&#xD;
          -  Increased risk of suicide as determined by the GP&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Physical activity level at baseline exceeding one exercise occasion per week.&#xD;
&#xD;
          -  Ongoing psychotherapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ulf Nilsson, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Göteborg University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Public Health and Community Medicine</name>
      <address>
        <city>Gothenburg</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <reference>
    <citation>Love J, Hensing G, Soderberg M, Toren K, Waern M, Aberg M. Future marginalisation and mortality in young Swedish men with non-psychotic psychiatric disorders and the resilience effect of cognitive ability: a prospective, population-based study. BMJ Open. 2016 Aug 10;6(8):e010769. doi: 10.1136/bmjopen-2015-010769.</citation>
    <PMID>27515748</PMID>
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  </reference>
  <reference>
    <citation>Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.</citation>
    <PMID>444788</PMID>
  </reference>
  <reference>
    <citation>Homack S, Lee D, Riccio CA. Test review: Delis-Kaplan executive function system. J Clin Exp Neuropsychol. 2005 Jul;27(5):599-609. doi: 10.1080/13803390490918444.</citation>
    <PMID>16019636</PMID>
  </reference>
  <reference>
    <citation>Åstrand P-O et al., (2003). Textbook of work physiology: physiological bases of exercise. Champaign:Human Kinetics.</citation>
  </reference>
  <reference>
    <citation>Drummond M et al., (2015). Methods for the economic evaluation of health care programmes. Oxford, United Kingdom, Oxford University Press.</citation>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2017</study_first_posted>
  <last_update_submitted>August 2, 2021</last_update_submitted>
  <last_update_submitted_qc>August 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anxiety Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03247270
org study id: Dnr300-16
nct id: NCT03247270
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
According to the Global Burden of Disease report in 2015, anxiety disorders are among the top
      10 contributors to years lived with disability worldwide. There is a need for effective
      treatment protocols. As cardiovascular fitness has a major impact on the brain's ability to
      change structurally and functionally, interventions involving physical exercise might prove
      positive in the treatment of persons with anxiety. Yet there are few high quality clinical
      studies with physical exercise as an intervention for anxiety disorders.

      Aims:

        1. To test a 12 week physical exercise intervention for persons treated for anxiety
           disorders within primary care. The exposure of interest is intensity of physical
           exercise; outcomes include anxiety symptom burden, cognitive ability and sick leave.

        2. To gain knowledge regarding potential mechanisms by comparing serum levels of specific
           hormones and cytokines (characterized and associated with brain plasticity in animal
           models) before and after different intensities of exercise.

      Implementation:

      Patients will be randomized into 3 groups: 1) Intervention I: 12 week exercise program with
      low-intensity fitness training 3 times per week. 2) Intervention II: 12 week exercise program
      with moderate to high-intensity fitness training 3 times per week. 3) Control group, who will
      have a physiotherapy session once and will be given general advice about physical activity.
      At baseline, 12 weeks and 1 year data of cardiovascular fitness, anxiety symptoms, cognitive
      and working ability and biomarkers will be collected.

      Impact:

      If physical exercise positively affects anxiety disorders it would have significance, for the
      patients as well as for society. In addition to increased quality of life, it may decrease
      future marginalization and premature death among individuals suffering from anxiety
      disorders. Reducing medical and sick-leave costs would also liberate health care resources to
      be used elsewhere in an economically strained health care system.
Overall objective To examine whether physical exercise reduces anxiety symptoms, improves
      cognition and decreases need of sick leave in patients with anxiety disorders in primary
      care.

      Background Mental illness is the most common reason for unemployment in people of working age
      and this is a growing patient group in Swedish primary care today. A survey by the European
      Commission showed that 17% of the Swedish population had sought help over the past year for
      psychiatric problems. These figures are above average for European countries and are
      increasing. Sweden's costs for mental illness is around MSEK 70,000 annually - an increase of
      MSEK 20,000 over ten years - and the proportion of sick leave days due to a psychiatric
      diagnosis is currently 40%. Mental illness reduces quality of life substantially. For
      example, 18-year-olds with anxiety disorders have increased risk of future marginalization
      and have a two-fold increase in mortality not only due to suicide but several different death
      causes, emphasizing the importance of finding effective treatment strategies.

      The ability of the adult brain to change both structurally and functionally is called brain
      plasticity. Both in humans and in animal models physical exercise has a major impact on brain
      plasticity. Physical exercise can increase neurogenesis and improve memory functions in rats,
      and circulating insulin-like growth factor I (IGF-I) can promote this effect. Brain-derived
      neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) are also involved.
      In addition, there is evidence that physical activity modifies neuronal activity, increases
      the formation of synapses, and reduces inflammation markers, which may be correlated with
      neuroprotection.

      The investigators have previously demonstrated an association between physical fitness and
      anxiety disorders, suggesting positive preventive benefits of physical exercise. The
      beneficial effects of exercise interventions have to date mainly been demonstrated in persons
      with depression.

      The specific aims of this project are:

        1. To test a 12 week physical exercise intervention for persons treated for anxiety
           disorders within primary care. The exposure of interest is intensity of physical
           exercise; outcomes include anxiety symptom burden, cognitive ability and sickness leave.

        2. To gain knowledge regarding potential mechanisms by comparing serum levels of specific
           hormones (characterized and associated with brain plasticity in animal models) before
           and after different intensities of exercise.

      Relationship to the research frontline In contrast to the literature on depression there are
      very few clinical studies on physical exercise as an intervention for anxiety. All six trials
      performed hitherto were identified as being at a high risk of bias. Higher quality trials are
      thus required. There is a need to investigate the role of intensity, volume, frequency and
      type of exercise on anxiety symptoms, cognitive function and working ability in people with
      anxiety disorders. Also, the putative mechanisms behind the potential effects on anxiety
      symptoms are not elucidated and deserve attention.

      A novel feature of this study is the examination of different intensities of physical
      fitness-improving exercise in patients with anxiety disorders. This has not previously been
      performed and would yield valuable insight into dose-response associations between physical
      fitness and effects on the brain. Objective measurements of physical fitness and cognition
      are a great strength of the proposed study. Analyzing specific hormones and cytokines before
      and after the intervention, in relation to symptoms and functional data, may provide
      additional information about mechanistic aspects, treatment effect and prognosis. The
      proposed research also offers opportunities to develop effective treatment protocols to
      reduce the costs of sick-leave, an area of increasing interest world-wide.

      In summary, the proposed study has the potential to provide novel and important contributions
      to existing scientific knowledge regarding how physical exercise influences anxiety,
      cognitive function and working ability in patients with anxiety disorders in primary care.

      Work plan The study cohort will be patients diagnosed with anxiety disorders at six primary
      care centres in Gothenburg, Southern Bohuslän and Halland including patients with panic
      syndrome (F41.0), generalized anxiety (F41.1), mixed anxiety- and depression conditions
      (F41.2 and F41.3), as well as anxiety UNS (F41.9). Diagnoses and comorbidities will be
      determined by the study psychiatrist using the M.I.N.I (the Mini International
      Neuropsychiatric Interview, Swedish version 6.0.0d DSM-IV). Intervention and follow-ups will
      take place at Primary Care Rehab.

      The investigators will exclude patients from the baseline who have physical difficulties in
      performing a physical exercise program, pathological ECG, previous psychiatric illnesses,
      ongoing abuse, increased risk of suicide as determined by the GP, those under 18, pregnant
      women and those over 65 years of age. An additional exclusion criterion will be physical
      activity level at baseline exceeding one exercise occasion per week. Both people with and
      without ongoing treatment with psychoactive medication will be included. Supportive contact
      for example with a health center nurse is not an exclusion criterion but persons with ongoing
      psychotherapy will not be included unless the participants, as well as the GP, are willing to
      take a break in therapy for the duration of the 12 week study.

      Recruitment takes place at primary care centres and thus represents the individuals who seek
      help in primary care for anxiety. Potential participants are contacted by a study
      psychiatrist who has no healthcare provider relationship to the patient. Intervention and
      follow-ups will take place at Primary Care Rehab. Each individual must sign a statement of
      informed consent.

      At baseline, 12 weeks and 1 year, the following data will be collected by the study
      physician:

        -  MINI International Neuropsychiatric Interview (Swedish version 6.0.0d DSM-IV)

        -  Use of psychoactive prescription drugs including dosage and duration

        -  Sick leave

        -  Blood pressure

        -  BMI

        -  Self-report questions about alcohol (AUDIT self-assessment scale), smoking and diet

        -  Established psychiatric self-assessment scales: Beck Anxiety Inventory (BAI), Montgomery
           Åsberg Depression Rating Scale (MADRAS) and the quality of life instrument EQ-5D.

        -  Test Design Fluency, which is part of the D-Kefs battery of tests and is well known and
           used by many psychologists within education and psychiatry. This is a standardized test,
           carried out within a few minutes that measures executive abilities such as creativity,
           response inhibition and cognitive flexibility.

        -  Objective measurements of physical fitness in the form of estimated maximal oxygen
           uptake capacity (VO2max) using Åstrand's submaximal bicycle test.

        -  Blood samples will be taken, by a nurse at the health center, to analyze the potential
           correlation of the following hormones/cytokines with symptoms and function data:
           S-IGF-I, S-BDNF, S-VEGF and high sensitivity CRP. The blood samples are stored in a
           separate, locked -70 freezer at c-lab Sahlgrenska. IVO has been notified of the
           establishment of a biobank (No 946).

      Patients will be randomized into three groups: 1) Intervention I: 12 week exercise program
      with low-intensity fitness training 3 times per week. 2) Intervention II: 12 week exercise
      program with moderate to high-intensity fitness training 3 times per week. 3) Control group.
      The physiotherapists at Primary Care Rehab will perform the submaximal bicycle test and
      personally design the exercise program in the gym. The patients will have a one-to-one
      session with the physiotherapists on 2 occasions and afterwards several people will exercise
      at the same time in the gym.

      A statistical power analysis has been performed by statistician Linus Schiöler. Based on
      other studies, an effect size of 0.5 difference between the groups is clinically relevant,
      which equates to a 5 point difference between the groups using the BAI scale. Standard
      deviations from a previous study using BAI as the outcome measurement were in the interval of
      5-10. SD 9 was used in the calculations. Based on these assumptions, at least 60 patients in
      each of the treatment arms should be included to reach 80% power at the 5% significance
      level. Health-economic analyses will be performed using primary data generated within the
      project concerning health-related quality of life effects caused by the intervention and
      information about healthcare resources utilized. A health-economic model that depicts the
      clinical trial will be constructed and used for computing cost-utility measures. Moreover,
      the model will be constructed for performing extensive probabilistic sensitivity analyses.

      Ethical considerations The Ethics Committee of the University of Gothenburg approved the
      study: PHYSBI intervention study: EPN Göteborg Dnr: 300-16. The control group will have a
      physiotherapy session once and will be given general advice about physical activity. There
      will be a possibility to individualize treatments i.e. the same intensity but different
      exercises to better fit the needs and preferences of different individuals. Coding and
      anonymization of data occur after data collection is complete.

      Collaborations The principal investigator for this project Ass Prof Maria Åberg is the chair
      of the steering committee for Physical Fitness and Brain Epidemiological studies (PHYSBE)
      which is a multidisciplinary umbrella organization for several projects. Prof Kjell Torén
      from Occupational and Environmental Medicine provides epidemiological competence. Prof Margda
      Waern provides psychiatric expertise. Physiotherapist Louise Danielsson and Prof Kristian
      Bolin at the Department of Economics and Statistics have experience of clinical intervention
      studies.

      The results will be published in international renowned peer-reviewed research journals.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: RCT
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Anxiety symptom burden
time frame: 12 weeks after baseline
description: Established psychiatric self-assessment scales: BAI
measure: Anxiety symptom burden
time frame: 1 year after baseline
description: Established psychiatric self-assessment scales: BAI
measure: Anxiety symptom burden
time frame: 12 weeks after baseline
description: Established psychiatric self-assessment scales: MADRS-S
measure: Anxiety symptom burden
time frame: 1 year after baseline
description: Established psychiatric self-assessment scales: MADRS-S
measure: Anxiety symptom burden
time frame: 12 weeks after baseline
description: Established psychiatric self-assessment scales: EQ-5D
measure: Anxiety symptom burden
time frame: 1 year after baseline
description: Established psychiatric self-assessment scales: EQ-5D
measure: Cognitive ability
time frame: 12 weeks after baseline
description: Test Design Fluency, which is part of the D-Kefs battery of tests
measure: Cognitive ability
time frame: 1 year after baseline
description: Test Design Fluency, which is part of the D-Kefs battery of tests
measure: Cognitive ability
time frame: 12 weeks after baseline
description: Digit test included in WAIS test battery
measure: Cognitive ability
time frame: 1 year after baseline
description: Digit test included in WAIS test battery
measure: Sick leave
time frame: 12 weeks after baseline
description: Questionnaire
measure: Sick leave
time frame: 1 year after baseline
description: Questionnaire
measure: Biomarkers in serum
time frame: 12 weeks after baseline
description: S-IGF-I
measure: Biomarkers in serum
time frame: 1 year after baseline
description: S-IGF-I
measure: Biomarkers in serum
time frame: 12 weeks after baseline
description: S-BDNF
measure: Biomarkers in serum
time frame: 1 year after baseline
description: S-BDNF
measure: Biomarkers in serum
time frame: 12 weeks after baseline
description: S-VEGF
measure: Biomarkers in serum
time frame: 1 year after baseline
description: S-VEGF
measure: Biomarkers in serum
time frame: 12 weeks after baseline
description: S-high sensitivity CRP
measure: Biomarkers in serum
time frame: 1 year after baseline
description: S-high sensitivity CRP
measure: Biomarkers in serum
time frame: 12 weeks after baseline
description: S-irisin
measure: Biomarkers in serum
time frame: 1 year after baseline
description: S-irisin
arm group label: Intervention I
arm group type: Experimental
description: Physical exercise intervention: 12 week exercise program with low-intensity fitness training 3 times per week.
arm group label: Intervention II
arm group type: Experimental
description: Physical exercise intervention:12 week exercise program with moderate to high-intensity fitness training 3 times per week
arm group label: Control group
arm group type: No Intervention
description: Control group, who will have a physiotherapy session once and will be given general advice about physical activity.
intervention type: Behavioral
intervention name: Intervention I
description: Low intensive physical exercise
arm group label: Intervention I
intervention type: Behavioral
intervention name: Intervention II
description: High intensive physical exercise
arm group label: Intervention II
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ulf Nilsson, PhD
role: Study Chair
affiliation: Göteborg University
facility: 
country: Sweden
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PMID: 27515748
citation: Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008 Jan;9(1):58-65. doi: 10.1038/nrn2298.
PMID: 18094706
citation: Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, Eriksson PS. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci. 2003 Sep;24(1):23-40. doi: 10.1016/s1044-7431(03)00082-4.
PMID: 14550766
citation: Carro E, Nunez A, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci. 2000 Apr 15;20(8):2926-33. doi: 10.1523/JNEUROSCI.20-08-02926.2000.
PMID: 10751445
citation: Lee TMC, Wong ML, Lau BW, Lee JC, Yau SY, So KF. Aerobic exercise interacts with neurotrophic factors to predict cognitive functioning in adolescents. Psychoneuroendocrinology. 2014 Jan;39:214-224. doi: 10.1016/j.psyneuen.2013.09.019. Epub 2013 Sep 25.
PMID: 24149089
citation: Eliakim A, Oh Y, Cooper DM. Effect of single wrist exercise on fibroblast growth factor-2, insulin-like growth factor, and growth hormone. Am J Physiol Regul Integr Comp Physiol. 2000 Aug;279(2):R548-53. doi: 10.1152/ajpregu.2000.279.2.R548.
PMID: 10938244
citation: Kohut ML, McCann DA, Russell DW, Konopka DN, Cunnick JE, Franke WD, Castillo MC, Reighard AE, Vanderah E. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun. 2006 May;20(3):201-9. doi: 10.1016/j.bbi.2005.12.002. Epub 2006 Feb 28.
PMID: 16504463
citation: Stranahan AM, Martin B, Maudsley S. Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease. Curr Alzheimer Res. 2012 Jan;9(1):86-92. doi: 10.2174/156720512799015019.
PMID: 22329653
citation: Aberg MA, Waern M, Nyberg J, Pedersen NL, Bergh Y, Aberg ND, Nilsson M, Kuhn HG, Toren K. Cardiovascular fitness in males at age 18 and risk of serious depression in adulthood: Swedish prospective population-based study. Br J Psychiatry. 2012 Nov;201(5):352-9. doi: 10.1192/bjp.bp.111.103416. Epub 2012 Jun 14.
PMID: 22700083
citation: Aberg MA, Nyberg J, Toren K, Sorberg A, Kuhn HG, Waern M. Cardiovascular fitness in early adulthood and future suicidal behaviour in men followed for up to 42 years. Psychol Med. 2014 Mar;44(4):779-88. doi: 10.1017/S0033291713001207. Epub 2013 Jun 6.
PMID: 23739044
citation: Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE. Exercise for depression. Cochrane Database Syst Rev. 2013 Sep 12;2013(9):CD004366. doi: 10.1002/14651858.CD004366.pub6.
PMID: 24026850
citation: Danielsson L, Papoulias I, Petersson EL, Carlsson J, Waern M. Exercise or basic body awareness therapy as add-on treatment for major depression: a controlled study. J Affect Disord. 2014 Oct;168:98-106. doi: 10.1016/j.jad.2014.06.049. Epub 2014 Jul 5.
PMID: 25043321
citation: Stubbs B, Vancampfort D, Rosenbaum S, Firth J, Cosco T, Veronese N, Salum GA, Schuch FB. An examination of the anxiolytic effects of exercise for people with anxiety and stress-related disorders: A meta-analysis. Psychiatry Res. 2017 Mar;249:102-108. doi: 10.1016/j.psychres.2016.12.020. Epub 2017 Jan 6.
PMID: 28088704
citation: Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988 Dec;56(6):893-7. doi: 10.1037//0022-006x.56.6.893. No abstract available.
PMID: 3204199
citation: Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979 Apr;134:382-9. doi: 10.1192/bjp.134.4.382.
PMID: 444788
citation: Homack S, Lee D, Riccio CA. Test review: Delis-Kaplan executive function system. J Clin Exp Neuropsychol. 2005 Jul;27(5):599-609. doi: 10.1080/13803390490918444.
PMID: 16019636
citation: Åstrand P-O et al., (2003). Textbook of work physiology: physiological bases of exercise. Champaign:Human Kinetics.
citation: Drummond M et al., (2015). Methods for the economic evaluation of health care programmes. Oxford, United Kingdom, Oxford University Press.
responsible party type: Sponsor
mesh term: Anxiety Disorders
sharing ipd: Undecided